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Background Filgotinib (FIL) is an oral, selective janus kinase 1 inhibitor under development for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. Safety and efficacy of FIL was investigated in the FINCH clinical program, which includes three Phase 3, summarized, summarized studies in patients with moderate to severely active RA. FINCH1: patients with inadequate response to MTX (NCT02889796); FINCH2: patients receiving conventional disease-modifying antirheumatic drugs (csDMARDs) with inadequate response to biological DMARDs (NCT02873936); FINCH3: MTX-naïve patients initiating MTX ± FIL, or receiving FIL monotherapy (NCT02886728). We present pooled safety data up to 24 weeks (W24). Methods The FINCH studies enrolled patients with RA (2010 ACR/EULAR criteria), ≥6 swollen joints and ≥6 tender joints at screening and Day 1. Safety analyses included patients receiving ≥1 dose of study drug. Patients in FINCH 1 and 2 who did not experience at least a 20% improvement in both swollen joint count and tender joint count by W14 discontinued study drug and switched to standard of care. W24 safety data from all studies were aggregated and ummarized. Key safety endpoints were treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of interest, deaths and treatment-emergent laboratory abnormalities. Results 3,452 patients were evaluated; 2,088 received FIL. At W24, the frequency of TEAEs and TEAEs of interest were similar for those who received FIL and those in the control groups (Table 1). Most TEAEs were infections. Laboratory abnormality rates were similar between FIL and control groups, and were mild to moderate (grades 1 and 2). Overall, the frequency of major adverse cardiac events, herpes zoster virus, deep vein thrombosis and pulmonary embolism was low, and similar across groups. Conclusion Pooled data from this large database highlights the favourable safety and tolerability profile of FIL in patients with RA both as monotherapy and in combination with MTX/csDMARD. Disclosures D. Walker: Other; Received support from Lilly, Pfizer, Novartis and Roche. K. Winthrop: Grants/research support; Received grants for clinical research from Bristol-Myers Squibb Company and Insmed Incorporated. Other; Received support from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Eli Lilly & Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi, and UCB. M.C. Genovese: Other; Gilead Sciences Inc., Galapagos NV, AbbVie Inc. Eli Lilly and Company, Pfizer. B.G. Combe: Honoraria; Honoraria from AbbVie, BMS, Gilead, Janssen, Eli Lilly and Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB. Y. Tanaka: Honoraria; Received from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly and Co., Pfizer, AbbVie, YL Biologics, BMS, Takeda, Misubishi-Tanabe, Novartis, Eisai, Janssen, Teijin. Grants/research support; Received grant support from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, BMS, UCB, Daiichi-Sankyo, Eisai, and Ono. A. Kivitiz: Consultancies; Consultant for AbbVie, Celgene, Horizon, Janssen, Merck, Novartis, Pfizer, UCB, Genzyme,Sanofi, Regeneron, SUN Pharma Advanced Research, Boehringer Ingelheim and Flexion. Shareholder/stock ownership; Shareholder of Novartis. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. L. Ye: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Gilead Sciences, Inc. Shareholder/stock ownership; Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. E. Keystone: Consultancies; AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer, PuraPharm, Sandoz,, Sanofi-Aventis, Sanofi- Genzyme Samsung Bioepsis, and UCB. Other; AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer, PuraPharm, Sandoz,, Sanofi-Aventis, Sanofi-Genzyme, Samsumg Bioepsis, and UCB. R. Westhovens: Corporate appointments; An investigator and advisor for Celltrion and Galapagos/Gilead. W. Rigby: Consultancies; Consultancy for Gilead. G.R. Burmester: Consultancies; Consultancy from AbbVie, Gilead, Eli Lilly, and Pfizer. Honoraria; Honoraria from AbbVie, Gilead, Eli Lilly, and Pfizer.

Background Filgotinib (FIL) is an oral, potent, selective Janus kinase 1 inhibitor that has shown good efficacy and was well tolerated for treatment of rheumatoid arthritis (RA). The objective of this study was to evaluate efficacy and safety of FIL treatment in patients with RA who have had an inadequate response to methotrexate (MTX). Methods This Phase 3, double-blind, active- and placebo (PBO)-controlled study randomised patients with active RA (3:3:2:3) to FIL 200mg, FIL 100mg, adalimumab [ADA] 40mg every 2 weeks, or PBO daily for up to 52 weeks; results through week 24 are presented. Patients also received background MTX. Primary efficacy endpoint was proportion of patients achieving ACR20 at week 12; additional clinical assessments included ACR50 and ACR70 and DAS28-CRP score ≤3.2 and 50% of ADA response) was performed for DAS28-CRP ≤3.2 and Results Of 1,759 patients randomised, 1,755 received study drug: 475 FIL 200mg; 480 FIL 100mg; 325 ADA; and 475 PBO, of which 89.5%, 90.4%, 88.9%, and 81.3%, respectively, completed 24 weeks of study drug. 81.8% were female, mean (standard deviation [SD]) duration of RA was 7.8 (7.6) years, and mean (SD) DAS28-CRP was 5.7 (0.9). At week 12, significantly more patients in the FIL 200mg and 100mg arms achieved an ACR20 improvement vs PBO (Table 1). More patients receiving FIL achieved ACR50 and ACR70 improvements, DAS28-CRP scores ≤3.2 and Conclusion FIL 200mg and 100mg led to significant improvement in signs and symptoms of RA, prevented radiographic progression, improved physical function compared to PBO, and was well-tolerated. Efficacy of FIL 200mg was non-inferior to ADA based on DAS28-CRP ≤3.2. Disclosures D. Walker: Other; Received support from Lilly, Pfizer, Novartis and Roche. B.G. Combe: Honoraria; Received honoraria from AbbVie, BMS, Gilead, Janssen, Eli Lilly and Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB. A.J. Kivitiz: Consultancies; Consultant to AbbVie, Celgene, Horizon, Jansses, Merck, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, SUN Pharma Advanced Research, Boehringer Ingelheim, Flexion and Novartis. Shareholder/stock ownership; Shareholder of Novartis. Y. Tanaka: Honoraria; Honoraria from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly ans Co., Pfizer, AbbVie, YL Biologics, BMS, Takeda, Misubishi-Tanabe, Novartis, Eisai, Janssen, Teijin. Grants/research support; Grant support from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, BMS, UCB, Daiichi-Sankyo, Eisai, Ono, Astellas, Eli Lilly, Pfizer, Abbvi and YL. D. van der Heijde: Corporate appointments; Director of Imaging Rheumatology bv. Consultancies; Consultant for consultant for AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. L. Ye: Corporate appointments; Employee of Gilead Sciences, Inc.. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. N. Mozaffarian: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. R.B.M. Landewé: Consultancies; Consultant for AbbVie, AstraZeneca, BMS, Galapagos, Pfizer, Eli Lilly, Novartis, and UCB.. S. Bae: None. E.C. Keystone: Consultancies; Consultant for AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer,, PuraPharm, Sandoz, Sanofi-Aventis, Sanofi-Genzyme, Samsumg Bioepsis, and UCB. P. Nash: Consultancies; Consultant for AbbVie, BMS, Jansses, Pfizer, Roche, Lilly, Sanofi, MSD, Novartis, Celgene and Gilead.

Background:EULAR and ACR guidelines recommend a treat-to-target approach for rheumatoid arthritis (RA). For patients failing their first conventional synthetic disease-modifying antirheumatic drug (csDMARD), EULAR recommends switching to or adding another DMARD. Understanding treatment patterns, durability, and healthcare costs associated with treatments initiated after first csDMARD can help optimize treatment for these patients.Objectives:To describe real-world healthcare costs among patients with RA who failed their first csDMARD.Methods:The study included adults with ≥2 RA claims ≥30 days apart in a large US health claims database, who started a csDMARD regimen as the first DMARD then switched to or added another DMARD (index date [ID], 1/1/2012–3/31/2017). All patients had continuous enrollment 1-year before and ≥1 year after ID. Treatment duration was defined as number of days from initial treatment fill until loss of treatment persistence. Unadjusted mean total annualized per-patient-per-year (PPPY) healthcare costs while on treatment were compared via analysis of variance. A generalized linear model with gamma distribution and log link was used to compare total costs adjusted for pre-index costs, patient characteristics, and type of initiated treatment.Results:The study involved 7,816 patients (median age of 54 yrs, 74% female). Mean (standard deviation) duration of index therapy was 14.0 (12.6) months for patients overall (9.2 [10.1] for monotherapy vs 16.9 [13.1] for combination therapy,P< .0001).Prior to switching, the unadjusted mean PPPY healthcare costs totaled $12,923: $13,923 for monotherapy vs $12,317 (P= .0009) for combination therapy. Once switched, patients accrued unadjusted mean PPPY on-treatment healthcare costs of $30,742: $28,757 on monotherapy vs $31,943 (P= .0003) on combination therapy. Figure 1 details pre- and post-ID unadjusted costs by index therapy.Patients on non-TNFi bDMARD monotherapy had higher adjusted total healthcare cost (cost ratio [CR] = 1.58,P= .0052) than the total cost on JAKi monotherapy, whereas csDMARD monotherapy (CR = 0.28,P< .0001) and csDMARD + csDMARD(s) (CR = 0.26,P< .0001) had lower total cost than the cost on JAKi monotherapy. Other factors impacting costs included baseline Charlson Comorbidity Index (CCI) = 2 or ≥3 vs CCI = 1 (CR = 1.14 and 1.25, respectively; bothP< .0001), baseline total (medical + pharmacy) healthcare costs (CR = 1.24,P< .0001), and baseline opioid use (CR = 1.11,P< .0001, Figure 2).Conclusion:Real-world data demonstrate short durability of available treatments initiated after first csDMARD. Among the initiated treatments, lowest total healthcare costs were associated with csDMARD, followed by JAKi, then TNFi, and finally non-TNFi bDMARD.Disclosure of Interests:Robin K Dore Grant/research support from: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Consultant of: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Jenya Antonova Employee of: Gilead Sciences. Inc., Lawrence Chang Consultant of: Gilead Sciences, Inc., Magdaliz Gorritz Consultant of: Gilead Sciences, Inc., Xin Wang Consultant of: Gilead Sciences, Inc., Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background:EULAR and ACR guidelines recommend a variety of treatment options for rheumatoid arthritis (RA) patients who failed a first conventional synthetic disease-modifying antirheumatic drug (csDMARD). The recent launches of Janus kinase inhibitors (JAKi) have stimulated interest in comorbidities such as malignancy, venous thromboembolism (VTE: deep vein thrombosis [DVT] or pulmonary embolism [PE]), anemia, and infections in patients with RA. Understanding the epidemiology of these conditions can help optimize treatment decisions within the treat-to-target approach following the first csDMARD.Objectives:Estimate the real-world prevalence, incidence, and costs of these comorbidities among patients switching from a first csDMARD to another DMARD.Methods:From a large US health claims database, the study selected adults with RA (≥2 RA claims ≥30 days apart) who started a csDMARD regimen as first DMARD, then switched (index date [ID], 1/1/2012–3/31/2017) to another DMARD regimen (monotherapy or combination with csDMARD). All patients had continuous enrollment 1 year before and ≥1 year after the ID. The study estimated baseline prevalence (%) and on-treatment incidence (per 100 patient-years [P100PY]) of malignancy, VTE, anemia, and infections (any, serious, opportunistic, and herpes zoster). Generalized linear models with gamma distribution and log link function estimated the impact of baseline characteristics on mean annualized healthcare costs per-patient-per-year (PPPY) associated with incident conditions. The recycled prediction method calculated adjusted total costs differences of these conditions.Results:Among study patients (N = 7,816, median age 54 yrs, 74% female), the 38% on monotherapy index treatments had mean (standard deviation) treatment duration 9.2 (10.1) mo and the 52% on combination therapies had treatment duration 16.9 (13.0) mo.Baseline prevalence was 1.5% for VTE, 1.3% for malignancy, 15.6% for anemia, and 71.0% for infection (Figure 1). During next treatment, the incidence rates (P100PY) were: 0.7 for VTE, 2.1 for malignancy, 7.8 for anemia and 79.4 for infection (Figure 1).Modeling showed that total healthcare cost more than doubled for RA patients with vs without incident occurrence of malignancy (2.9), followed by PE (2.7) and DVT (2.1) (P< .0001) (Figure 2). Total PPPY adjusted healthcare costs were higher in patients with vs without incident conditions: DVT $60,430 vs $28,927, PE $77,942 vs $29,000, malignancy $81,779 vs $28,565, anemia $50,097 vs $26,959, and infection $32,431 vs $22,774, including serious infections $52,935 vs $26,723, opportunistic infections $39,239 vs $28,947, and herpes zoster $30,638 vs $29,515.Conclusion:In the real world, RA patients were affected by VTE, malignancy, anemia and infections prior to switching from first csDMARD to the next treatment. While on the next treatment, patients developed new cases of these comorbidities, most of which were associated with increased adjusted total healthcare costs. Clinicians should account for the burden of these comorbidities in selecting treatments for RA patients who failed their first csDMARD.Disclosure of Interests:Robin K Dore Grant/research support from: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Consultant of: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Jenya Antonova Employee of: Gilead Sciences. Inc., Lawrence Chang Consultant of: Gilead Sciences, Inc., Huan Huang Consultant of: Gilead Sciences, Inc., Hyunchung Kim Consultant of: Gilead Sciences, Inc., Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background:EULAR and ACR guidelines recommend a treat-to-target approach for patients with RA including regular assessments of disease activity. Glucocorticoids are commonly used to control inflammation associated with uncontrolled disease. However, patients using glucocorticoids may develop short- and long-term side effects.Objectives:To examine the real-world use of glucocorticoids among patients with RA who are disease-modifying antirheumatic drug (DMARD)-naïve or failing their first conventional synthetic DMARD (csDMARD) or biologic DMARD (bDMARD).Methods:From a large US health claims database, this study included adults with ≥2 RA claims ≥30 days apart who started (index date [ID], 1/1/2012–3/31/2017) a first DMARD (DMARD-naïve) or patients who newly initiated a csDMARD and then switched to or added another DMARD (csDMARD switchers), and patients who initiated a first bDMARD and then switched to another bDMARD or Janus kinase inhibitor (JAKi; bDMARD switchers). All patients had continuous enrollment 1-year before and ≥1 year after ID and were evaluated for pre- and post-ID use of glucocorticoids (oral or injectable), prednisone equivalent dose (PED), and duration of exposure ≥30 days.Results:The study included 28,201 patients in the DMARD-naïve cohort, 7,816 csDMARD switchers, and 4,656 bDMARD switchers (median age 54 years for all, 73%–78% female).Among DMARD-naïve patients, 66.5% used glucocorticoids during the pre-ID period (Figure 1) and 61.2% had >7.5 mg/day PED, 21.2% had >30 mg/day PED, and 21.2% had ≥30 days of exposure to glucocorticoids (Figure 2). Post-ID, 69.4% of patients used glucocorticoids, while 54.7% had >7.5 mg/day PED, 13.5% had >30 mg/day PED, and 44.9% had ≥30 days of exposure to glucocorticoids.Among csDMARD switchers, 84.5% of patients used glucocorticoids during the pre-ID period (Figure 1), and 73.4% had >7.5 mg/day PED, 16.0% had >30 mg/day PED, and 56.4% had ≥30 days of exposure to glucocorticoids (Figure 2). During the post-ID treatment, 74.1% of patients used glucocorticoids, 56.2% had >7.5 mg/day PED, 14.4% had >30 mg/day PED, and 45.8% had ≥30 days of exposure to glucocorticoids.Among bDMARD switchers, 85.1% of patients used glucocorticoids in the pre-ID period (Figure 1), and 70.2% had >7.5 mg/day PED, 17.4% had >30 mg/day PED, and 55.2% had ≥30 days of exposure to glucocorticoids (Figure 2). During post-ID treatment, 75.4% of patients used glucocorticoids and 59.7% of patients had >7.5 mg/day PED, 16.7% had >30 mg/day PED, and 45.6% had ≥30 days of exposure to glucocorticoids.Conclusion:Real world glucocorticoid use was high in all categories of DMARD-treated RA patients, at baseline and during their next treatment, suggesting ongoing medical needs. Glucocorticoid doses exceeded 7.5 mg/day for most patients. In addition, many patients had ≥30 days exposure to glucocorticoids, posing an additional safety risk.Disclosure of Interests:Robin K Dore Grant/research support from: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Consultant of: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Eli Lilly and Co., Gilead Sciences, Inc., GlaxoSmithKline, Myriad, Novartis, Pfizer, Radius, Regeneron, Sanofi, and UCB., Jenya Antonova Employee of: Gilead Sciences. Inc., Magdaliz Gorritz Consultant of: Gilead Sciences, Inc., Lawrence Chang Consultant of: Gilead Sciences, Inc., Handing Xie Consultant of: Gilead Sciences, Inc., Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background JIA is the most common chronic inflammatory rheumatic disease of childhood. TNF inhibitors are used for long-term control of pJIA disease. Objectives To evaluate the 7 year (y) safety of Adalimumab treatment with or without methotrexate (ADA±MTX) when used in current clinical practice for treatment of patients (pts) with active pJIA. Methods This is a 7 y interim analysis of an ongoing, multicenter, non-interventional, observational registry of pts with pJIA with up to10 y safety follow-up. Included pts were treated with ADA±MTX or MTX alone as comparison arm according to routine clinical care in PRINTO/PRCSG centres in EU, USA and Australia. MedDRA observational adverse events (AEs) were recorded from 1st day in the registry through last contact, irrespective of duration of registry treatment. Results In January 2014, enrollment was complete. As of June 1, 2016 cut-off date, 838 pts (301- MTX arm and 537 - ADA±MTX arm) were treated in the registry. There were 39 pts who rolled over from MTX to ADA±MTX arm. At registry entry mean pJIA disease duration was 1.3 y and 3.7 y and mean AJC71 was 5.8 and 5.2 for MTX and ADA±MTX arms, respectively. CHAQ disability index was 0.6 for both arms. Mean duration of study drug exposure in registry was 2.0 y (range: 0.0 – 7.1) and 2.5 y (range: 0.0 – 7.9) for MTX and ADA±MTX arms, respectively. Mean duration of observation in registry was 3.9 y (range: 0.0 – 7.2) and 3.5 y (range: 0.0 – 7.9) for MTX and ADA±MTX arms, respectively. Overall, 213 pts (70.8%) in MTX and 225 pts (41.9%) in ADA±MTX arms discontinued registry drug through 7 y. Main reasons (not exclusively) for registry drug discontinuation for MTX arm: pts required additional therapy (32.6%), other (13.3%), lack of efficacy (11.6%), AEs (9.3%), or pts achieved JIA remission (8.6%); for ADA±MTX arm: lack of efficacy (17.9%), other (7.3%), lost to follow-up (5.6%), AEs (5.4%), or pts achieved JIA remission (5.0%). Frequencies and rates of treatment-emergent AEs (from 1st dose date of registry drug in registry up to last dose + 70 days in registry, excluding AEs occurring during treatment interruption) were similar to those reported for observational AEs (from 1st day in registry up to last contact irrespective of drug treatment duration) (Table). Rate of serious infections was similar between MTX and ADA±MTX arms. One pt (0.2%) reported an event of opportunistic infection (fungal oesophagitis) in ADA±MTX arm. No reports of deaths, malignancies, active tuberculosis, oral candidiasis, demyelination, or congestive heart failure. Conclusions Overall, ADA±MTX was well-tolerated in these pts with pJIA with no new safety signals. The retention rate for registry drug was higher in ADA±MTX arm compared to MTX arm. Acknowledgements AbbVie sponsored the study & contributed with PRINTO & PRCSG to analysis, review, approval of the abstract. X. Leahy & A. Deshmukh (AbbVie) contributed to research. Medical writing: G. Patki (AbbVie). Disclosure of Interest N. Ruperto Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, H. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, Takeda, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals, K. Nanda Consultant for: Medac Pharma, Inc., M. Toth: None declared, I. Foeldvari Consultant for: AbbVie and Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech and Novartis, C. Rabinovich Grant/research support from: UCB Pharma, Janssen, D. Kingsbury: None declared, K. Marzan Grant/research support from: AbbVie, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, and Swedish Orphan Biovitrum, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, and Sanofi, K. Minden Grant/research support from: Pfizer, AbbVie and Roche/Chugai, Consultant for: Pfizer, Roche, and Pharma-Allergan, Speakers bureau: Pfizer, Roche, and Pharma-Allergan, E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, Novartis, and Roche, Speakers bureau: AbbVie, Novartis, Sobi, Pfizer, and Roche, R. Kuester Grant/research support from: AbbVie Inc. and Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac, Pfizer, Roche, and UCB, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, and MedImmune, D. Lovell Consultant for: AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, Genentech, Amgen and Forest Research, Speakers bureau: Wyeth Pharmaceuticals

Background Ph3 studies demonstrated clinical efficacy of 2 different once-daily (QD) doses of baricitinib (bari) (2mg and 4mg) in patients (pts) with active rheumatoid arthritis (RA) and an inadequate response (IR) to conventional synthetic DMARDs1 or biologic DMARDs2. In general, larger, more rapid and more consistent treatment effects were observed for the 4mg dose across measures. Objectives To investigate the effects of bari dose step-down in patients who had achieved sustained low disease activity (LDA) or remission with bari 4mg QD. Methods Pts who completed a bari Ph3 Study (RA-BEGIN, RA-BEAM, RA-BUILD, or RA-BEACON) could enter a long-term extension study, RA-BEYOND. In RA-BEYOND, pts who had received bari 4mg for at least 15 months and who had achieved sustained LDA or remission (defined by CDAI score at 2 consecutive visits at least 3 months apart) were re-randomized in a double blind manner to continue receiving bari 4mg or to step down to a 2mg QD dose. Disease activity was assessed at a 12 week (wk) landmark following re-randomization. Results Among pts who achieved satisfactory and sustained disease control with bari 4mg QD, randomized, double blind dose reduction to 2mg QD was associated with modest, statistically significant increases in disease activity across measures at a subsequent 12 wk landmark assessment (Table). However, a large majority of pts (in both the continued 4mg and reduced to 2mg groups) retained the state of LDA or remission that led to their re-randomization. Conclusions Consistent with completed studies, these data indicate that 4mg QD was the most efficacious dose of bari for pts with RA in clinical studies. Most pts who had achieved sustained disease control with bari 4mg sustained LDA or remission 12 wks after randomized, blinded dose taper to 2mg QD. References Dougados M et al.Ann Rheum Dis 2015;74(S2):79; Genovese M et al.Ann Rheum Dis 2015;74(S2):75–76. Disclosure of Interest T. Takeuchi Grant/research support from: Eli Lilly & Co., Astellas, Bristol-Myers K.K., Chugai, Ltd, Daiichi Sankyo, Eisai, AYUMI Pharmaceutical Corporation, Takeda, Teijin Pharma, AbbVie GK, Asahikasei Pharma, Taisho Toyama Pharmaceutical Co., Consultant for: Eli Lilly & Co., Astra Zeneca K.K., Novartis, Mitsubishi Tanabe, Asahi Kasei Medical, AbbVie GK, Daiichi Sankyo, Bristol-Myers K.K., Nipponkayaku, Janssen, Merck Serono, Takeda, Astellas, Speakers bureau: AbbVie GK, Bristol-Myers K.K., Chugai, Eisai, Janssen, Mitsubishi Tanabe, Pfizer, Takeda, Astellas, Daiichi Sankyo, Celtrion, Nipponkayaku, M. Genovese Grant/research support from: AbbVie, Astellas, Eli Lilly & Co., Galapagos, Pfizer, Vertex, Consultant for: AbbVie, Astellas, Crescendo Bioscience, Eli Lilly &Co., Galapagos, Pfizer, L. Xie Shareholder of: Eli Lilly and Co., Employee of: Eli Lilly and Co., M. Issa Shareholder of: Eli Lilly & Co., Employee of: Eli Lilly & Co., A. L. Pinto Correia Shareholder of: Eli Lilly & Co., Employee of: Eli Lilly & Co., T. Rooney Shareholder of: Eli Lilly & Co., Employee of: Eli Lilly & Co., K. Emoto Shareholder of: Eli Lilly & Co., Employee of: Eli Lilly & Co., J. Smolen Grant/research support from: AbbVie, Janssen, Eli Lilly & Co., MSD, Pfizer, Roche, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Eli Lilly & Co., Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB

This phase 1 study investigated the pharmacokinetics (PK) and glucodynamics of insulin lispro (Humalog; Eli Lilly and Co., Indianapolis, IN) or regular human insulin (Humulin R; Eli Lilly and Co.) administered with or without (+/-) recombinant human hyaluronidase (rHuPH20).Healthy male volunteers (n = 26), 18-55 years old with body mass index 18-28 kg/m(2), weight70 kg, and normal fasting glucose, were randomized to a crossover sequence of two subcutaneous injections, each followed by a 6-h euglycemic clamp targeting glucose 90-110 mg/dL: Cohort 1 received 20 U of Humalog +/- 300 U of rHuPH20 (11.3 microg/mL), whereas Cohort 2 received 20 U of Humulin R +/- 240 U of rHuPH20 (10 microg/mL). Pharmacokinetic parameters included peak serum insulin concentration (C(max)), time to C(max) (t(max)), and area under the curve (AUC) of serum concentration versus time. Glucodynamic parameters included time to maximal glucose infusion rate (tGIR(max)) and area under the GIR-versus-time curve (G).For Humalog and Humulin R, respectively, rHuPH20 co-administration reduced t(max) by 51% (P = 0.0006) and 58% (P = 0.0002), increased C(max) by 90% (P = 0.0003) and 142% (P0.0001), increased early exposure (AUC(0-2h)) by 85% (P0.0001) and 211% (P0.0001), and reduced late exposure (AUC(4-6h)) by 41% (P0.0001) and 48% (P0.0001). Similarly, rHuPH20 reduced tGIR(max) by 41% (P = 0.006) and 35% (P = 0.01), increased early metabolism (G(0-2h)) by 52% (P = 0.001) and 127% (P0.0001), and reduced late metabolism (G(4-6h)) by 29% (P = 0.002) and 26% (P = 0.03) for Humalog and Humulin R, respectively. Injections were well tolerated.Co-administration of rHuPH20 accelerated the PK and glucodynamics of both insulin formulations. Additional studies are necessary to evaluate the clinical relevance of these findings in patients with diabetes.

Background Juvenile idiopathic arthritis (JIA) is one of the most common childhood rheumatic diseases. Adalimumab (ADA) is approved for moderate to severe polyarticular JIA (pJIA) in patients (pts) ≥4 yrs in Australia and Japan and for pts ≥2 yrs in the US and EU. Objectives To evaluate long-term safety and effectiveness of ADA in pts with moderately to severely active pJIA who are prescribed and treated with ADA in routine clinical practice. Methods This is an ongoing, multicenter, non-interventional, observational registry of pts with moderately to severely active pJIA who are treated with either ADA ± methotrexate (MTX) or MTX alone as part of their routine clinical care. 800 pts (500 ADA/300 MTX) were to be enrolled in the US, EU, and Australia. The follow-up observational period is 10 yrs from enrollment into one of the treatment arms. Observational adverse events (AEs) were recorded from the first day in the registry through last contact, irrespective of registry treatment duration. Clinical outcomes were assessed by 27-joint juvenile arthritis disease activity score (JADAS27), based on CRP. 5 yr interim data are presented. Results As of January 2014, enrollment is complete. 842 pts (540 ADA/302 MTX) were treated as of the March 28, 2014 cutoff. Mean pJIA disease duration at enrollment was 1.3 and 3.7 yrs and mean duration of study exposure was 643 and 653 days for MTX and ADA arms, respectively. Baseline mean AJC73 was 5.8 and 5.4 for MTX and ADA, respectively, and CHAQ-DI was 0.6 for both groups. Overall, 153 pts (50.7%) in the MTX arm and 132 pts (24.4%) in the ADA arm discontinued registry drug. Of those, 22 (7.3%) and 23 (4.3%) in the MTX and ADA arm, respectively, discontinued due to an AE, and 39 of the 153 pts in the MTX arm discontinued as they switched to the ADA arm. The observational AEs are summarized (Table). No deaths, malignancies, or opportunistic infections were reported. In the ADA arm, there were 13 (2.4%) pts with serious infectious AEs (abdominal abscess, acute tonsillitis, appendicitis, cellulitis, gastroenteritis, mononucleosis, viral meningitis, pneumonia, pyelonephritis, scarlet fever, subcutaneous abscess, tonsillitis, urinary tract infection, and varicella). Frequencies and rates of treatment-emergent AEs were similar to those reported for observational AEs. Mean JADAS27 improved from 12.1 at baseline to 9.4, 6.1, 5.1, 4.4 at months 1, 3, 6, and 12 for pts in the MTX arm and from 12.1 at baseline to 7.4, 5.5, 4.4, 4.5 in the ADA arm, respectively (observed data). Conclusions Overall, ADA is well-tolerated in these pts with active pJIA. No new safety signals were observed, and based on this interim analysis, the known safety profile of ADA remains unchanged. Acknowledgements AbbVie sponsored the study (NCT00783510), contributed with PRINTO and PRCSG to the design, and participated in data collection, analysis, and interpretation, and in the writing, review, and approval of the abstract. Medical writing support was provided by Jessica L. Suboticki, PhD, of AbbVie. Disclosure of Interest N. Ruperto Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals. NR has served on speaker9s bureau for Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, H. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals, C. Wallace Grant/research support from: Pfizer, Amgen, Consultant for: Amgen, Novartis, M. Toth: None declared, I. Foeldvari Consultant for: AbbVie, Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech, Novartis, E. Rabinovich Grant/research support from: UCB Pharma, Janssen Research & Development, LLC, Hoffmann-La Roche Inc., AbbVie, P. Vavrincova: None declared, D. Kingsbury Grant/research support from: AbbVie, K. Marzan Grant/research support from: AbbVie, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum; Participates on a data management committee of a phase 3 trial by Sanofi, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, K. Minden Grant/research support from: Pfizer, Abbvie, Consultant for: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, Speakers bureau: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche and speaker9s fees from AbbVie, Novartis, Pfizer, Roche, R.-M. Kuester Grant/research support from: AbbVie, Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac GmbH, UCB Biosciences, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, MedImmune, D. Lovell Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, Genentech; served on data and safety monitoring boards for Amgen, Forest Research, Speakers bureau: Wyeth Pharmaceuticals

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a multitargeted antifolate that inhibits several folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, mucositis, and skin rash. These toxicities are more frequent in vitamin-deficient (folate and vitamin B 12 ) patients, and can be ameliorated by the co-administration of folate and vitamin B 12 . The use of prophylactic dexamethasone is also recommended to reduce the frequency of severe skin rash. Pemetrexed has significant single-agent activity in previously treated and untreated patients with non-small cell lung cancer (NSCLC). A recent phase III trial comparing pemetrexed with docetaxel in previously treated NSCLC patients showed equivalent efficacy with less bone marrow toxicity (eg, neutropenia) in the pemetrexed group. These results were pivotal in the approval of pemetrexed for the treatment of refractory NSCLC. Pemetrexed has been combined with the platinums (ie, cisplatin, carboplatin, and oxaliplatin) in NSCLC to yield clinical activity similar to that of other platinum-based doublets. A comparative phase III trial of cisplatin/pemetrexed against cisplatin/gemcitabine (Gemzar; Eli Lilly and Co) is under way. Pemetrexed has also been evaluated in combination with gemcitabine, and although the optimal dose and schedule of this combination has not been defined, clinical activity similar to other nonplatinum-based doublets has been observed. Preliminary evidence suggests that pemetrexed can be combined with thoracic radiation therapy, but more data are needed to evaluate the potential advantage(s) pemetrexed may have in this setting. Pemetrexed/platinum doublets also appear to possess activity in extensive stage small cell lung cancer. A phase II trial of single-agent pemetrexed is under way in both sensitive- and refractory-relapsed small cell lung cancer. Given the activity and excellent tolerability of pemetrexed, further studies in lung cancer are warranted.

Aim: Vascular endothelial growth factor (VEGF) and VEGF-receptor 2-mediated signaling and angiogenesis likely contribute to HCC pathogenesis. RAM is a fully human IgG1 monoclonal antibody and a VEGF-receptor 2 antagonist. Methods: Eligible pts had advanced HCC, stage BCLC C or B refractory or not amenable to locoregional therapy; Child-Pugh A; ECOG PS 0 or 1; intolerance to sorafenib despite dose reduction, or disease progression during or following sorafenib; and adequate hematologic and biochemical parameters. Pts were randomized 1:1 to receive RAM (8 mg/kg IV) plus best supportive care (BSC) or placebo (PBO) plus BSC every 2 weeks until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size of 544 pts was calculated to enable 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.75. Results: Between Nov 2010 and April 2013, 565 eligible pts were randomized (RAM 283; PBO 282). Baseline pt characteristics were balanced between arms. The OS HR was 0.866 (95% CI 0.717, 1.046; p = 0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. Median PFS with RAM and PBO was 2.8m and 2.1m, respectively (HR 0.63, 95% CI 0.52–0.75; p 5% of treated RAM pts included: hypertension (12.3% RAM arm vs 3.6% PBO arm), asthenia (5.1% vs 1.8%), aspartate aminotransferase increased (5.4% vs 8.3%), and malignant neoplasm progression (6.5% vs 4.0%). In 250 pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (pre-specified), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059) median OS was 7.8m for RAM vs 4.2m for PBO. Conclusions: No new safety signals were observed. The primary end point was not met. In a selected pt population with an elevated baseline AFP, a meaningful OS improvement in the RAM arm was observed. The relationship between AFP and RAM benefit warrants further investigation. Disclosure: J.F. Blanc: reports personal fees from Imclone systems / Lilly, during the conduct of the study; T.E. Pfiffer: reports Lilly, the sponsor of REACH trial, gave financial support to "Instituto do Cancer do Estado de Sao Paulo" ICESP to run part of the trial, during the conduct of the study; personal fees from Lilly, outside the submitted work; T. Okusaka: received grant money and personal fees from Eli Lilly. Relevant financial activities outside the submitted work include grant money and personal fees from several companies; J. Trojan: reports participation as a speaker and on the advisory board for Eli Lilly; J. Sastre: reports receiving personal fees for lectures from Eli Lilly, Roche, Merck, Bayer, Sanofi, and MSD; I. Chau: received research support from Eli Lilly & Co, honorarium from ImClone LLC and Eli Lilly & Co., has also been a consultant, received payment for lectures, educational presentations, and travel and meeting expenses from several other companies; S. Chang and P.B. Abada: is an employee of and has stock ownership in Eli Lilly & Co.; L. Yang: is an employee of ImClone Systems, a wholly owned subsidiary of Eli Lilly and Co., and has stock ownership in Eli Lilly and Co.; J. Schwartz: was an employee of Imclone Systems and has stock ownership in Eli Lilly. All other authors have declared no conflicts of interest.

Background MF, PV, and ET are neoplasms characterized by activation of JAK2 signaling, and the majority of cases are associated with the gain of function JAK2 V617F mutation. Given that wild-type JAK2 plays a pivotal role in multiple stages of hematopoiesis it is desirable to treat JAK2V617F-positive cases by selectively inhibiting JAK2 V617F while minimizing inhibition of wild-type JAK2 in order not to impede normal marrow function. LY2784544 is a selective inhibitor of JAK2 which demonstrates dose dependent selectivity for JAK2 V617F/STAT5 signaling. LY2784544 entered clinical testing in a Phase I trial in MF, PV, and ET patients (I3X-MC-JHTA, NCT01134120). We have previously reported early interim analysis from this study and provide here an update following completion of study enrollment. Methods The study’s primary objectives were to determine the safety and tolerability of LY2784544 and define a recommended oral daily dose for further study in patients with JAK2 V617F-positive MF, ET, or PV. Secondary objectives included determination of pharmacokinetics and evaluation of response using the IWG-MRT response criteria (2006), European Leukemia Net response criteria for PV and ET (EULN 2009), and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et. al. Blood 2011). Study design included a standard 3+3 dose-escalation to define the maximum tolerated dose (MTD) and was amended to allow cohort expansions at multiple doses demonstrating potential clinical merit. Results Patients Prior to closing to enrollment, 47 patients were consented; 9 did not meet eligibility screening. The 38 treated patients included 31 MF (22 pMF, 6 post-PV MF and 3 post-ET MF), 6 PVs, and 1 ET patient(s), and 86% had received prior systemic therapy for their MPN. Dosing and tolerability of LY2784544: Systemic exposures were approximately dose proportional across the tested range from 30 to 300 mg. Daily doses of 200 mg or greater were associated with CTCAE Grade 3 increases in serum creatinine. In general, increases in serum creatinine occurred within the first 2 weeks of either starting treatment or after an increase in study drug dose. With the available data, the elevations in serum creatinine appear to be fully reversible after dose reduction or drug holiday in the majority of patients. The maximum tolerated daily dose of LY2784544 when given on a continuous daily basis was determined to be 120 mg per day. Serious AEs, across all grades and doses, included increased creatinine/acute renal insufficiency (4 grade 3, 5 grade 2, 1 grade 1), hyperuricemia (2 grade 4, 1 grade 1), hyperkalemia (1 grade 1), and anemia (1 grade 3). This study allowed intrapatient dose escalation, and 34 patients received 120 mg during their study participation. There were 4 patients dosed at 120 mg with SAEs but all were unrelated to study drug treatment (anemia, influenza, enterococcal bacteremia, hematuria and pneumonia). At 120 mg, the most frequently reported drug-related AEs across all grades were diarrhea (44%), nausea (29%), increased creatinine (21%), and anemia, vomiting, fatigue (9% each). Of these related AEs at 120 mg, there was 1 Grade 3 anemia, 3 Grade 3 increased creatinine, and 2 Grade 3 fatigue. There were no Grade 4 AEs. Efficacy Among a cohort of 10 MF patients who only received 120 mg, 3 achieved a clinical improvement. Analyzing across dose levels, a palpable spleen length reduction of ≥50% was seen in 15 of 27 evaluable patients (56%) at any time. The median duration of these responses was 18.3 weeks (range from 0.7 to 148.1 weeks). At 12 weeks, 56% of patients (15/27) reported a ≥50% improvement in Total Symptom Score on the MPN-SAF. Of the 6 PV patients, 3 achieved a clinicohematologic PR. Findings from a central pathology review of serial bone marrow samples will be presented at the meeting. Conclusions A recommended phase II dose for daily dosing of LY2784544 was identified as 120 mg. This dose has been well tolerated and associated with clinical improvements, supporting ongoing Phase II testing of LY2784544 in MPNs. Disclosures: Verstovsek: Eli Lilly and Co: Research Funding. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding. Salama:Eli Lilly and Co: Research Funding. Giles:Eli Lilly and Co: Employment. Pitou:Eli Lilly and Co: Employment. Hayden Zimmermann:Eli Lilly and Co: Employment. Price:Eli Lilly and Co: Employment. Walgreen:Eli Lilly and Co: Employment. Prchal:Eli Lilly and Co: Research Funding.

Background Limited information is available on the effects of etanercept (ETN) on the juvenile idiopathic arthritis (JIA) subtypes, extended oligoarticular JIA (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA). Objectives To assess the efficacy and safety of ETN in paediatric subjects with eoJIA, ERA, and PsA. Methods CLIPPER is an ongoing, Phase 3b, open-label, multi-centre study; the primary analyses (12-week data) are reported here. Subjects with eoJIA (2–17 y old), ERA (12–17 y old), or PsA (12–17 y old) received ETN 0.8 mg/kg once weekly (max. dose 50 mg). Endpoints included the percentage of subjects achieving American College of Rheumatology (ACR) Paediatric 30 (primary endpoint) and 50/70/90/100 criteria at Week 12. Logistic regression analysis was used to compare the ACR Paediatric 30 data with historical placebo data from a meta-analysis of JIA studies [1] and a juvenile-onset spondyloarthropathy study [2]. Results 127 subjects (mean age 11.7 y) received ≥1 dose of ETN; 5 (3.9%) subjects discontinued the study. Concomitant disease-modifying anti-rheumatic drugs, corticosteroids, and non-steroidal anti-inflammatory drugs were received by 109 (85.8%), 16 (12.6%), and 74 (58.3%) subjects, respectively. ACR Paediatric 30/50/70/90/100 response rates (Tables 1 and 2) were similar across all JIA subtypes. Odds ratios for ACR Paediatric 30 showed a significant advantage of ETN over the historical placebo data. Treatment-emergent adverse events (TEAEs), treatment-emergent infections, serious TEAEs, and malignancies were reported in 45 (35.4%), 58 (45.7%), 4 (3.1%), and 0 (0.0%) subjects, respectively. Serious TEAEs were 1 (0.8%) case each of abdominal pain, bronchopneumonia, gastroenteritis, and pyelocystitis. One (0.8%) subject reported an opportunistic infection of herpes zoster. No clinically meaningful differences in safety were observed across the JIA subtypes. Conclusions Etanercept treatment for 12 weeks was effective in treating subjects with the JIA subtypes, eoJIA, ERA, or PsA, with no unexpected safety findings. References Ruperto N, et al. Arthritis Rheum 2003;48(Suppl 9):S90. Burgos-Vargas R, et al. Ann Rheum Dis 2008;67(Suppl 2):69. Disclosure of Interest G. Horneff Grant/Research support from: Abbott, Pfizer Inc., Wyeth., N. Ruperto Grant/Research support from: Abbott, AstraZeneca, Bristol-Myers Squibb, Centocor Research and Development, Eli Lilly and Co., “Francesco Angelini” s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer Inc., Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Wyeth, Xoma, Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Novartis, Roche, R. Burgos-Vargas Grant/Research support from: Abbott, Consultant for: Abbott, Bristol-Myers Squibb, Janssen, Pfizer Inc., Roche, Speakers Bureau: Abbott, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc., Roche, V. Panaviene: None Declared, D. Alvarez Employee of: Pfizer Inc., C. Zang Employee of: Pfizer Inc., J. Wajdula Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Woodworth Employee of: Pfizer Inc., B. Vlahos Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., A. Martini Grant/Research support from: Abbott, AstraZeneca, Bristol-Myers Squibb, Centocor Research and Development, Eli Lilly and Co., “Francesco Angelini” s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer Inc., Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Wyeth, Xoma, Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Novartis, Roche

Disclosure K. Mansouri: K. Mansouri is an employees of Eli Lilly and Co. L. Cirri: L. Cirri is an employees of Eli Lilly and Co. P. Shi: P. Shi is an employees of Eli Lilly and Co. O. Hamid: O. Hamid is an mployees of Eli Lilly and Co. All other authors have declared no conflicts of interest. AIs are used as first-line treatment for postmenopausal women with hormone-receptor-positive MBC. Overexpression of PKC α has been linked to AI resistance in several studies. We examined whether Enza, a serine/threonine kinase inhibitor that targets PKC, could improve the effect of Ful in pts who progressed following first-line AI treatment for MBC. Postmenopausal pts with hormone-receptor-positive, HER2-negative, locally advanced or MBC who progressed on prior AI received a loading dose of Ful 500 mg IM on Day (D) 1 and 250 mg on D 15 of Cycle (C) 1 and D 1 of each cycle thereafter. Enza 500 mg or PBO was administered orally once daily (QD) or 250 mg twice daily (BID). Primary endpoint was the clinical benefit rate (CBR). Secondary endpoints were response rate (RR), duration of CB, progression-free survival (PFS) and safety. A total of 156 pts was randomly assigned to therapy; 152 received at least 1 dose of study drug (39 BID; 55 QD; 58 PBO). Baseline disease characteristics were balanced across arms. There was no statistically significant difference in CBR between pts in Ful + Enza vs Ful + PBO. There was no statistically significant difference in CBRs, RRs and PFS between pts on QD and BID dosing schedules. Pts on BID dosing had numerically more TEAEs vs those on QD and PBO (61.5%, 43.6%, and 46.6%, respectively) and numerically more Grade 3/4 TEAEs vs QD and PBO (17.9%, 9.1%, and 5.2%, respectively). Most frequent Grade 3/4 TEAEs in the BID arm were fatigue (n [%]) (4 [10.3%]), dyspnea (2 [5.1%]) and nausea (2 [5.1%]). 8 pts died; 5 due to disease, 3 due to AEs: 1 drug-related hepatic dysfunction (Enza QD arm), 1 non-drug-related myocardial infarction and 1 non-drug-related respiratory failure (both in the Enza BID arm). Ful + Enza [QD + BID] N = 94 Ful + PBO N = 58 P-value vs PBO CBR Number of responders, n (%), (95% CI) 41 (43.6) (33.4, 54.2) 24 (44.8) (31.7, 58.5) 0.62 RR, % (95% CI) 5.3 (1.7, 12.0) 5.2 (1.1, 14.4) 0.64 PFS, months (95% CI) 5.2 (3.5, 7.4) 5.5 (3.8, 7.4) 0.59 Median duration of CB, months 9.6 9.7 0.86 CBR = complete response + partial response + stable disease Addition of Enza to Ful does not improve disease outcome in pts with locally advanced or MBC after progression on AI.

MUSTAFA, OZGUROGLU/0000-0002-8417-8628 WOS:000468121800002 PubMed ID: 30735435 Background: Treatment options for patients with advanced esophageal or esophagogastric junction (EGJ) cancer are limited. Current guidelines for first-line treatment of advanced esophageal or EGJ cancer recommend chemotherapy containing a platinum and a fluoropyrimidine agent. Pembrolizumab demonstrated antitumor activity in previously treated patients with advanced esophageal cancer and in patients with gastroesophageal junction cancer. Aim: To describe the design and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-590 study, which will be conducted to investigate pembrolizumab in combination with chemotherapy as first-line treatment in patients with advanced esophageal or EGJ cancer. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA.K Kato has received research funding from Merck Sharp & Dohme Corp., Merck Serono, ONO Pharmaceutical Co. Ltd and Shionogi, Inc.MA Shah has received research funding from Boston Biomedical, Inc., F Hoffmann-La Roche AG and Merck Sharp & Dohme Corp. P Enzinger has acted as an advisor for Astellas Pharma, Inc., BeiGene Co, Celgene Corp., Eli Lilly and Co., Five Prime Therapeutics, Inc. and Merck Sharp & Dohme Corp.J Bennouna has received honoraria from and acted as an advisor for AstraZeneca Plc, Boehringer-Ingelheim GmbH, F Hoffmann-La Roche AG, Merck Sharp & Dohme Corp. and Shire Plc.A Adenis has received honoraria from Bayer AG, Bristol-Myers Squibb and Sanofi SA; acted as an advisor for Bayer AG, Bristol-Myers Squibb and Servier Laboratories; received research funding from Bayer AG, Bristol-Myers Squibb, Merck Sharp & Dohme Corp., Pfizer, Inc. and Sanofi SA; and received travel, accommodation or expenses from Bayer AG, Bristol-Myers Squibb and Merck Sharp & Dohme Corp.JM Sun has acted as an advisor for Boehringer-Ingelheim GmbH and received research funding from AstraZeneca Plc.BC Cho has received honoraria and acted as an advisor for AstraZeneca Plc, Boehringer-Ingelheim GmbH, Bristol-Myers Squibb, F Hoffmann-La Roche AG, Merck Sharp & Dohme Corp., Novartis International AG and Yuhan Co. Ltd; served on speaker bureaus for AstraZeneca Plc, Bristol-Myers Squibb, Merck Sharp & Dohme Corp. and Novartis International AG; and received research funding from AstraZeneca Plc, Bayer AG, Novartis International AG and Yuhan Co. Ltd. M Ozguroglu has received honoraria from Janssen Pharmaceutica NV and acted as an advisor for Astellas Pharma, Inc. and Janssen Pharmaceutica NV.T Kojima has received honoraria from Oncolys Biopharma, Inc. and has intellectual property interests in Amgen, Inc., Astellas Pharma, Inc., Merck Sharp & Dohme Corp., Oncolys Biopharma, Inc., ONO Pharmaceutical Co. Ltd and Shionogi, Inc.Y Zhu, LA McLean and S Shah are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., NJ, USA. LA McLean and S Shah own stock in the company.T Doi has acted as an advisor for Amgen Inc., Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Kyowa Hakko Kirin Co. Ltd, Eli Lilly Japan KK, Merck Sharp & Dohme Corp. and Novartis International AG; and received research funding from Astellas Pharma, Inc., Bayer AG, Boehringer Ingelheim GmbH, Celgene Corp., Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Janssen Pharmaceutica NV, Kyowa Hakko Kirin Co. Ltd, Eli Lilly Japan KK, Merck Serono, Merck Sharp & Dohme Corp., Novartis International AG, Pfizer, Inc., Sumitomo Corp., Taiho Pharmaceutical Co. Ltd and Takeda Pharmaceutical Co. Ltd.C Hierro has received research funding from Bayer and lecture fees and travel grants from Lilly, Ignyta and Roche.L Shen and V Kostorov report no conflicts of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

A. Nasir, R.D. Van Horn, B. Domazet, X.S. Ye, K.M. Credille, A. Kyshtoobayeva, J.T. Brandt, E.H. Westin, A.E. McGlothlin, T.R. Holzer. Eli Lilly and Co., Diagnostic and Experimental Medicine, Indianapolis IN, USA; Eli Lilly and Co., Lilly Research Labs, Indianapolis IN, USA; Clarient, Immunopathology, Aliso Viejo CA, USA; Eli Lilly and Co., Oncology Business Unit, Indianapolis IN, USA; Eli Lilly and Co., Statistics, Indianapolis IN, USA

A. Nasir, R.D. Van Horn, B. Domazet, X.S. Ye, K.M. Credille, A. Kyshtoobayeva, J.T. Brandt, E.H. Westin, A.E. McGlothlin, T.R. Holzer. Eli Lilly and Co., Diagnostic and Experimental Medicine, Indianapolis IN, USA; Eli Lilly and Co., Lilly Research Labs, Indianapolis IN, USA; Clarient, Immunopathology, Aliso Viejo CA, USA; Eli Lilly and Co., Oncology Business Unit, Indianapolis IN, USA; Eli Lilly and Co., Statistics, Indianapolis IN, USA

7195 Background: The improved efficacy of pemetrexed (ALIMTA, Eli Lilly and Co) in combination with cisplatin versus cisplatin alone, in a phase 3 trial of patients with MPM, has led to a demand for patient access to pemetrexed prior to regulatory approval. An Eli Lilly and Co EAP was opened to allow access to all eligible patients with malignant mesothelioma. This non-randomized study was designed to gather additional efficacy and safety data on pemetrexed alone and in combination with cisplatin. The experience of those previously treated patients with MPM is reported here. Methods: Previously treated patients with malignant mesothelioma were enrolled in this study. Treatment consisted of pemetrexed 500mg/m2 alone or in combination with cisplatin 75mg/m2. Treatment was administered once every 21 days for a maximum of 6 cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilence database. R...

Background:The Janus kinase (JAK)-1 preferential inhibitor filgotinib (FIL) improved rheumatoid arthritis (RA) signs and symptoms in 3 phase (P)3 trials.1–3 Like other RA therapies, JAK inhibition is associated with increased infection rates.4Objectives:To assess long-term safety across the FIL program regarding infections, including serious infections (SI).Methods:Patients (pts) meeting 2010 ACR/EULAR RA criteria in pooled analysis of P2 DARWIN 1–2 (D1–2), P3 FINCH 1–3 (F1–3), and long-term extension studies (DARWIN 3, FINCH 4) were included. The placebo (PBO)-controlled as-randomised data set included pts receiving FIL 100 mg (FIL100), FIL 200 mg (FIL200), or PBO up to week (W)12 (D1–2, F1–2). The active-controlled as-randomised data set included pts receiving FIL100, FIL200, adalimumab (ADA), or methotrexate (MTX) up to W52 (F1, F3). The long-term as-treated data set included pts in all 7 studies receiving FIL100 or FIL200; data after rerandomisation were included and contributed to treatment received.Exposure-adjusted incidence rates (EAIRs) per 100 patient-years exposure (PYE) and differences with 95% confidence intervals (CIs) were calculated using Poisson regression; EAIRs for tuberculosis (TB) in active controlled sets were calculated using an Exact Poisson method. Kaplan-Meier (KM) event probabilities with 95% CIs were provided for SI. If pts had multiple events within the same treatment period, only the first event was counted in EAIR calculation; PYE were calculated up to the last follow-up time or day before next treatment, including after first event. For KM analysis, time to event was calculated until the first event.Results:Of 2267/1647 pts in as-treated set receiving FIL200/FIL100, 1697 had treatment-emergent infection; 118 were SI. Baseline potential risk factors for pts with SI are in Table.Table 1.Baseline characteristics of pts with/without treatment emergent SIaParameter, n (%)SIN = 92No SIN = 2491Medical history Chronic lung disease13 (14.1)125 (5.0) Chronic renal disease3 (3.3)23 (0.9) Infections and infestations29 (31.5)499 (20.0)Baseline body mass index, kg/m2 64 (69.6)1749 (70.2) ≥3028 (30.4)742 (29.8)Age, years 67 (72.8)2006 (80.5) ≥6525 (27.2)485 (19.5)Former/current smoker30 (32.6)677 (27.2)Oral corticosteroids, mg 28 (56.0)731 (66.1) ≥7.522 (44.0)375 (33.9) Missing data421385aPhase 3 (FINCH 1-4) studies, as randomised.SI, serious infection.In 12W PBO-controlled period, infection rates were 17.9%/15.6%/13.3% for FIL200/FIL100/PBO. In 52W ADA-controlled period, infection EAIRs (95% CIs)/100 PYE were 46.9 (40.9, 53.7)/43.7 (38.0, 50.4)/43.4 (36.5, 51.5), FIL200/FIL100/ADA; and 38.5 (33.8, 43.9)/39.0 (31.1, 48.8)/42.2 (36.1, 49.3), FIL200/FIL100/MTX in 52W MTX-controlled period; 24.8 (23.1, 26.5)/34.4 (30.4, 38.8), FIL200/FIL100 in long-term analysis. In 12W PBO-controlled period, there was no active TB for FIL200/FIL100/PBO. In 52W ADA-controlled period, active TB EAIRs (95% CIs)/100 PYE were: 0 (0.0, 0.8)/0 (0.0, 0.8)/0.3 (0.0, 1.9), FIL200/FIL100/ADA and 0 (0.0, 0.6)/0 (0.0, 1.9)/0 (0.0, 1.0), FIL200/FIL100/MTX in 52W MTX-controlled period; 0/0.1 (0.0, 0.5), FIL200/FIL100 in long-term analysis.SI rate or EAIRs are in Figure. Most common infections were upper respiratory tract infection and nasopharyngitis; majority were low grade. Pneumonia was most common SI (Conclusion:EAIRs of infections and SI for FIL were similar to PBO, ADA, and MTX. At 52W, incidence rates of SI were comparable for FIL100 and FIL200. Long-term SI EAIR for FIL100 was slightly higher than for FIL200.References:[1]Genovese et al. JAMA. 2019;322:315–25.[2]Westhovens et al. Ann Rheum Dis. 2021; online first.[3]Combe et al. Ann Rheum Dis. 2021; online first.[4]Strand et al. Arthritis Res Ther. 2015;17:362.Disclosure of Interests:James Galloway Speakers bureau: Pfizer, Bristol-Myers Squibb, UCB and Celgene, Maya H Buch Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi, Grant/research support from: Pfizer, Roche, and UCB, Kunihiro Yamaoka Speakers bureau: AbbVie, Actelion Pharmaceuticals Japan, Asahikasei Pharma Corp, Astellas Pharma, AYUMI Pharma Co, Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, Eisai Pharma, Eli Lilly, GlaxoSmithKline, Gilead G.K., Hisamitsu Pharma Co., Janssen Pharma, Mitsubishi-Tanabe Pharma, MSD, Nippon Kayaku, Nippon Shinyaku, Ono Pharma, Otsuka Pharma, Pfizer, Sanofi, and Takeda Industrial Pharma, Consultant of: Asahikasei Pharma Corp., AbbVie, Gilead G.K., Pfizer, Astellas Pharma Inc, Eli Lilly Japan K.K., and Japan Tobacco Inc., Grant/research support from: Takeda Industrial Pharma, Pfizer, Astellas Pharma, Daiichi Sankyo, Eli Lilly, Eisai Pharma, Teijin Pharma, MSD, Shionogi, Chugai Pharma, Nippon Kayaku, Mitsubishi-Tanabe Pharma, and AbbVie, Cianna Leatherwood Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Iyabode Tiamiyu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Deyuan Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos BV, Employee of: Galapagos BV, Daniel Aletaha Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Grant/research support from: AbbVie, Novartis, Roche, Kevin Winthrop Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly and Co., Galapagos NV, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer

I NTRODUCTION: The hallmark of sickle cell disease (SCD) is hemoglobin S (HbS) polymerization upon deoxygenation, resulting in red blood cell (RBC) sickling, oxidative damage, membrane damage, hemolysis, cell adhesion, and vaso-occlusion. Exacerbating the pathogenesis of SCD, the HbS RBC has [1] increased (↑) 2,3-DPG with decreased (↓) O2 affinity (↑ P50) and [2] ↓ RBC ATP. FT-4202, a small molecule allosteric activator of erythrocyte pyruvate kinase (PKR), increases PKR activity resulting in ↓ 2,3-DPG levels and ↑ ATP levels in RBCs. In healthy volunteer (HV) studies (Kalfa et al. Blood 2019), FT-4202 was well tolerated, demonstrating physiologic responses (↓ 2,3-DPG and ↑ ATP) with biologic effects including ↑ O2 affinity, ↓ reticulocytes (P METHODS: In the SD and 14-day MD cohorts, pts with SCD were randomized 3:1 to FT-4202 or placebo. Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, ECGs and laboratory parameters. PK/PD blood sampling was performed for up to 72h after the last dose and at the end-of-study visit; PD parameters included 2,3-DPG, ATP, P50, RBC deformability with controlled deoxygenation and reoxygenation (Lorrca® oxygenscan) and varying osmolality (Lorrca® osmoscan). To maintain study blind, pt identifiers were removed when needed. RESULTS: As of 17-July-2020, the SD (700 mg FT-4202) cohort is complete and the 1st MD cohort (MD-1, 300 mg once daily) is enrolling. Unblinded data from the SD and blinded data from the MD-1, 3 pt safety lead-in (randomized 2:1) are summarized. No serious adverse events (SAEs) or TEAEs leading to pt withdrawal were reported. In the SD cohort, 7 pts (2 males, 5 females, all HbSS) received 700 mg FT-4202 (n=5) or placebo (n=2). Six transient Grade 1 TEAEs occurred in 4 of 7 (57%) pts, including 3 TEAEs (arthralgia, headache, palpitations) in 2 of 5 (40%) pts receiving FT-4202 and 3 TEAEs (back pain, myalgia, pruritis) in 2 of 2 (100%) pts receiving placebo. RBC ATP concentrations increased by 30% and RBC 2,3-DPG concentrations decreased by 26% 24h after FT-4202. Increased O2 affinity (↓P50) with a decreased point of sickling (PoS) and improved HbS RBC deformability were observed in all FT-4202-treated pts. Improved HbS RBC membrane function was also demonstrated with a shift of the osmoscan results towards normal. Improved hematologic parameters, including ~0.9 g/dL Hb increase compared with placebo, were also observed 24h after a single dose of FT-4202. In 3 pts with SCD (3 females, all HbSS) who thus far completed MD-1, 14 days of 300 mg FT-4202 or placebo daily was well tolerated, with 1 pt reporting transient, unrelated Grade 2 TEAEs of nausea/vomiting at the end of the 14-day dosing period. Laboratory changes relative to pretreatment for each pt are shown in Table 1. In 2 of 3 SCD MD-1 pts treated with FT-4202/placebo (currently blinded), Hb increased by > 1 g/dL, % reticulocytes decreased, and markers of hemolysis were improved after 14 days of treatment (compared to pre-treatment levels). Hematologic parameters returned to pre-treatment levels 4 to 7 days post-treatment (data not shown) without clinical AEs. Functional studies in the 2 pts with increased Hb showed improved RBC deformability (↓ PoS) and improved RBC membrane function while on study treatment relative to pre-treatment and/or post-treatment. CONCLUSION: FT-4202 has a favorable safety profile in pts with SCD receiving a single dose or up to 14 days of dosing. A single dose of FT-4202 led to decreased 2,3-DPG and increased ATP, resulting in increased O2 affinity, decreased PoS, improved RBC deformability, and improved RBC membrane function. Initial blinded results of daily dosing with 300 mg FT-4202/placebo over 14 days show improvement in both hematologic and hemolytic parameters in 2 of 3 pts with SCD, along with improved RBC functional studies, suggesting the pharmacodynamic consequences of PKR activation may be of clinical benefit in SCD. Multiple-dose cohorts are ongoing to further evaluate the safety, PK/PD, and biological activity of FT-4202 following daily administration in pts with SCD; updated data will be presented. Disclosures Brown: Imara, Inc.: Consultancy, Research Funding; Forma Therapeutics, Inc,: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis, Inc.: Consultancy, Research Funding. Kalfa:Agios Pharmaceuticals, Inc: Consultancy, Research Funding; Forma Therapeutics, Inc: Research Funding. Kuypers:Forma Therapeutics, Inc.: Research Funding. Saraf:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Boards, Speakers Bureau; Novartis, Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer, Global Blood Therapeutics, Novartis: Research Funding. Estepp:Global Blood Therapeutics, Forma Therapeutics, Pfizer, Eli Lilly and Co: Research Funding; Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; ASH, NHLBI: Research Funding. Malik:Aruvant Sciences, CSL Behring: Patents & Royalties; Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy. Ribadeneira:Forma Therapeutics, Inc.: Current Employment. Forsyth:Forma Therapeutics, Inc.: Current Employment. Schroeder:Forma Therapeutics, Inc.: Current Employment. Wu:Forma Therapeutics, Inc.: Current Employment. Kelly:Forma Therapeutics, Inc.: Current Employment. Telen:Forma Therapeutics: Research Funding; GlycoMimetics Inc.: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background:Despite effective treatments, many patients (pts) with rheumatoid arthritis (RA) have inadequate responses to biologic DMARDs (bDMARD-IR), highlighting an unmet need. It is unclear whether prior bDMARD use affects efficacy of the oral, selective JAK-1 inhibitor filgotinib (FIL).Objectives:To explore clinical response to FIL in bDMARD-IR pts stratified by mode of action (MOA) and number of prior bDMARDs.Methods:The global, phase 3 FINCH-2 (NCT02873936) study treated 448 bDMARD-IR pts with active RA.1Pts were randomised 1:1:1 to once-daily FIL 200 mg, FIL 100 mg, or placebo (PBO) for 24 weeks. Efficacy was assessed by percent of pts achieving low disease activity (LDA) or remission at week (W)24 as measured by CDAI and DAS28(CRP) stratified by number and MOA of prior bDMARDs. Comparisons were not adjusted for multiplicity. Nonresponder imputation was used.Results:In total, 448 bDMARD-IR pts were included, 105 with prior experience with ≥3 bDMARDs (Table). At W24, pts receiving FIL were in LDA at a higher proportion vs PBO, irrespective of number of prior bDMARDs or MOA (Figure 1). For pts receiving FIL 200 vs PBO, DAS28(CRP) ≤3.2 was achieved at W24 by 52% vs 26%, 51% vs 22%, and 38% vs 9% of pts with 1, 2, or ≥3 prior bDMARDs, respectively, and 49% vs 21% and 50% vs 13% of pts exposed to TNF or IL-6 inhibitors; for all subgroups, rates were significantly higher vs PBO (Figure 1). Delta between FIL 200 mg and PBO was maintained irrespective of number or type of prior bDMARDs. At W24, pts receiving FIL achieved remission at numerically higher rates vs PBO (Figure 2). For pts receiving FIL 200 mg vs PBO, DAS28(CRP) Table.Number and MOA of prior bDMARDsFIL 200 mgn = 147FIL 100 mgn = 153PBOn = 148TotalN = 448Prior bDMARDs 173 (49.7)86 (56.2)77 (52.0)236 (52.7) 237 (25.2)33 (21.6)36 (24.3)106 (23.7) ≥337 (25.2)34 (22.2)34 (23.0)105 (23.4)LOE ≥1 bDMARD125 (85.0)129 (84.3)126 (85.1)380 (84.8)Intolerance ≥1 bDMARD36 (24.5)34 (22.2)32 (21.6)102 (22.8)Prior TNFi121 (82.3)134 (87.6)124 (83.8)379 (84.6) LOE ≥1 TNFi97 (66.0)113 (73.9)103 (69.6)313 (69.9) Intolerance ≥1 TNFi25 (17.0)24 (15.7)24 (16.2)73 (16.3)Prior non-TNFi73 (49.7)62 (40.5)75 (50.7)210 (46.9) LOE ≥1 non-TNFi52 (35.4)43 (28.1)56 (37.8)151 (33.7) Intolerance ≥1 non-TNFi13 (8.8)13 (8.5)11 (7.4)37 (8.3)Prior IL-6i34 (23.1)35 (22.9)32 (21.6)101 (22.5) LOE ≥1 IL-6i25 (17.0)22 (14.4)21 (14.2)68 (15.2) Intolerance ≥1 IL-6i5 (3.4)10 (6.5)5 (3.4)20 (4.5)Data presented as n (%).i, inhibitor; LOE, lack of efficacy.Conclusion:Treatment with FIL vs PBO led to higher rates of LDA and remission in pts with IR to IL-6 or TNF inhibition, or to 1, 2, or ≥3 prior bDMARDs, with a similar safety profile to the overall study population. A significantly higher proportion of pts overall receiving FIL 200 mg vs PBO were in LDA at W24. Improved efficacy of FIL vs PBO in pts who previously failed multiple bDMARDs indicates distinct benefits of selective JAK-1 inhibition with FIL.References:[1]Genovese, et al.JAMA2019;322(4):315–25.Disclosure of Interests: :Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB, Grace C. Wright Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Exagen, Eli Lilly, Myriad Autoimmune, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Exagen, Eli Lilly, Myriad Autoimmune, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, UCB, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd., Kenneth Kalunian Grant/research support from: Pfizer, Lupus Research Alliance, Sanford Consortium, Consultant of: Genentech, Nektar, BMS, Janssen, AstraZeneca, Biogen, Vielabio, Equillium, Eli Lilly, ILTOO, Abbvie, Amgen, Roche, Gilead, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ying Guo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Shangbang Rao Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., YingMeei Tan Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background:EULAR guidelines recommend a treat-to-target approach focusing on reducing inflammation to prevent joint damage, physical disability, and mortality.1However, patients consider reduction in pain and fatigue, along with maintenance of physical function, and improvement in health-related quality of life (HRQoL) important areas for improvement with RA treatment.2In the FINCH 2 study, filgotinib (FIL)—a potent, selective, oral small molecule Janus kinase 1 inhibitor—in combination with conventional synthetic (cs)DMARD therapy significantly improved the signs and symptoms of rheumatoid arthritis (RA) in patients with an inadequate response to a biologic (b)DMARD compared with placebo (PBO).3In addition, patients experienced significant improvements in HAQ-DI at week (W)12 and W24 with FIL 100 mg (p 3Objectives:To evaluate the rate and magnitude of change in patient-reported outcomes (PROs) from FINCH 2 assessing pain, HRQoL, and fatigue.Methods:Patients in this double-blind, randomised study (NCT02873936) received FIL 200 mg, FIL 100 mg, or PBO while continuing csDMARD therapy. PROs were collected prospectively on day 1 and at the W2, W4, W8, W12, W14, W16, W20, and W24 visits for assessment of pain (VAS pain scale) and on day 1 and at W4, W12, and W24 for assessment of fatigue (FACIT-Fatigue) and HRQoL (SF-36). Changes from baseline for each PRO at each time point up to W24 were analysed longitudinally using a mixed-effects model for repeated measures. P values for the difference between each FIL arm and PBO at each time point were calculated.Results:Among the 448 patients randomised and treated (FIL 200 mg, n = 147; FIL 100 mg, n = 153; PBO, n = 148) 381 (85.0%) completed the study. Baseline mean (SD) VAS pain scale was 67 (21.0), SF-36 physical component summary (PCS) was 31.1 (7.89), SF-36 mental component summary (MCS) was 44.3 (11.6), and FACIT-Fatigue score was 24.4 (11.6); baseline values did not vary between treatment groups. Significantly greater improvements in VAS pain scores began at W2 and were maintained through W24 for patients who received either dose of FIL vs PBO (Fig 1A). FIL also significantly improved patients’ fatigue at W4, W12, and W24 compared with PBO for those receiving 200 mg doses, and at W4 and W12 for those receiving 100 mg doses (Fig 1B). HRQoL related to physical functioning (SF-36 PCS) was significantly enhanced at W4, W12, and W24 with both doses of FIL as compared with PBO (Fig 2A). Improvements to mental-health-related QoL (SF-36 MCS) were reported for FIL as early as W4 and maintained through W24, with statistically significant improvements at W4 and W12 for FIL 200 mg vs PBO (Fig 2B).Conclusion:In a patient population with refractory disease that had inadequate response to prior bDMARDs and had significant disease at baseline, FIL treatment—coadministered with csDMARD therapy—was able to provide rapid and sustained improvements in key measures of pain, HRQoL, and fatigue as reported by patients.References:[1]Smolen, et al.Ann Rheum Dis. 2017;76:960–77.[2]Fautrel, et al.Rheumatol Int.2018;38:935–47.[3]Genovese, et al.JAMA. 2019;322(4):315–25.Disclosure of Interests:David Walker Grant/research support from: Gilead, Consultant of: Gilead, Lilly, Pfizer, Roche, Speakers bureau: Lilly, Pfizer, Roche, Tsutomu Takeuchi Grant/research support from: AbbVie, Asahikasei Pharma Corp., Astellas Pharma, Inc., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Nipponkayaku Co. Ltd., Shionogi & Co., Ltd., Takeda Pharmaceutical Co., Ltd., UCB Japan, Consultant of: Astellas Pharma, Inc., Chugai Pharmaceutical Co, Ltd., Eli Lilly Japan,, Speakers bureau: Abbvie, AYUMI Pharmaceutical Corp., Bristol-Myers Squibb, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan, Gilead Sciences, Inc., Mitsubishi-Tanabe Pharma Corp., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd, Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Shangbang Rao Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., I-Heng Lee Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background:Filgotinib (FIL), an oral, potent, selective JAK-1 inhibitor, provided statistically significant and clinically meaningful improvement in rheumatoid arthritis (RA) signs and symptoms, physical function, radiographic progression, and quality of life in a comprehensive clinical program of 4 phase 3 (FINCH 1–4;NCT02889796,NCT02873936,NCT02886728,NCT03025308) and 3 phase 2 (DARWIN 1–3;NCT01668641,NCT01894516,NCT02065700) trials in patients (pts) with early and biologic-refractory RA.1–3Objectives:To assess long-term safety of FIL.Methods:Treatment-emergent adverse events (TEAEs) from the FIL clinical program were integrated and presented for pts receiving FIL 200 mg or FIL 100 mg QD (including pts who transitioned to FIL from placebo [PBO], methotrexate [MTX], adalimumab [ADA], or another dose of FIL) as well as pts receiving PBO, MTX, and ADA across all 7 studies. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for adverse events (AEs) of interest per treatment. Incidence was total number of pts with events, and PY exposure was time between first and last doses. Major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) were centrally adjudicated by an independent committee.Results:Across the 7 trials, 4057 pts with RA (2227 pts FIL 200 mg; 1600 pts FIL 100 mg) received >1 dose of treatment for 5493 total PY of exposure (3079.2 PY FIL 200 mg; 1465.3 PY FIL 100 mg) (Table). EAIRs of serious AEs and TEAEs leading to death in pts receiving FIL were comparable to those for PBO, ADA, or MTX, with no dose-dependent effect (Figure 1). EAIR for herpes zoster (HZ), serious, and opportunistic infections are shown in Figure 2. EAIR for HZ were low overall, but numerically slightly higher for FIL relative to PBO, ADA, and similar to MTX. Serious infection EAIRs were comparable between pts receiving FIL 100 mg and ADA, and numerically slightly lower for FIL 200 mg and MTX. Rates of opportunistic infections (including active tuberculosis) were low overall; EAIR for FIL doses were comparable to placebo and numerically lower than ADA or MTX. Rates of MACE and VTE were numerically lower for FIL relative to PBO (Figure 1). Malignancies, including nonmelanoma skin cancer, were rare overall, and rates were low in pts receiving FIL (Figure 1).Table.Total exposure to study treatments pooled from 7 studiesNumber of patientsPatient-years of exposureFIL 200 mg22273079.2FIL 100 mg16001465.3ADA325290.1MTX416356.2PBO781302.4Patients could contribute to >1 treatment group.ADA, adalimumab; FIL, filgotinib; MTX, methotrexate; PBO, placebo.Conclusion:In this integrated analysis, FIL was well-tolerated, and no new safety concerns were identified. No clinically meaningful dose-dependent safety effects were observed. MACE and VTE were uncommon. Serious infections rates were low; HZ reactivation was infrequent. Safety results were consistent with selective JAK-1 inhibition and highlight the favourable safety and tolerability of FIL in patients with RA.References:[1]Genovese, et al.JAMA2019;322(4):315–25.[2]Westhovens, et al.Ann Rheum Dis2017;76:998–1008.[3]Kavanaugh, et al.Ann Rheum Dis2017;76:1009–19.Disclosure of Interests:Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd., Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Deyuan Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ying Guo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB

Olaratumab (Lartruvo™) is a fully human IgG1 monoclonal antibody targeted against the human platelet-derived growth factor (PDGF) receptor α (PDGFRα). It was developed by Eli Lilly and Co. (previously ImClone Systems) after PDGFRα was identified as a potential therapeutic target in a variety of cancers. Olaratumab acts by selectively binding PDGFRα, thereby blocking PDGF ligand binding and inhibiting PDGFRα activation and downstream signalling. In October 2016, olaratumab received its first global approval, in the USA, for use in combination with doxorubicin for the treatment of adult patients with soft tissue sarcoma. The approval was granted by the US FDA under its Accelerated Approval Program based on the results of the JGDG phase II trial (NCT01185964). In addition, the EMA granted conditional approval for olaratumab in this indication in November 2016 following a review under the EMA's Accelerated Assessment Program. An international, confirmatory phase III trial in patients with soft tissue sarcoma is ongoing (ANNOUNCE; NCT02451943). Olaratumab has also been investigated in phase II trials in several other cancers. This article summarizes the milestones in the development of olaratumab leading to this first approval, for use in combination with doxorubicin for the treatment of soft tissue sarcoma in adults.

Background:The once daily, oral Janus kinase (JAK)-1 preferential inhibitor filgotinib (FIL) improved signs and symptoms of rheumatoid arthritis (RA) in phase (P)3 trials.1-3 Patients (pts) with RA have increased herpes zoster (HZ) reactivation risk vs the general population. JAK inhibition is associated with increased infection incidence, including HZ.4Objectives:To assess long-term safety of FIL across the global clinical program with respect to HZ.Methods:Pts meeting 2010 ACR/EULAR RA criteria in a pooled analysis of P2 DARWIN 1–2 (D1–2), P3 FINCH 1–3 (F1–3), and long-term extension studies (D3, F4) were included. Placebo (PBO)-controlled as-randomised analysis included pts receiving FIL 100 mg (FIL100), FIL 200 mg (FIL200), or PBO up to week (W)12 (D1–2, F1–2); active-controlled as-randomised analysis included pts receiving FIL100, FIL200, adalimumab (ADA), or methotrexate (MTX) up to W52 (F1, F3). Long-term as-treated analysis included pts in all 7 studies receiving FIL100, FIL200, ADA, MTX, or PBO; data after re-randomisation were included and contributed to treatment received. Exposure-adjusted incidence rates (EAIR)/100 patient-years, calculated up to the last follow-up time or day, and differences with 95% confidence intervals (CIs) were calculated from the Poisson model. Logistic regression model was used for treatment-emergent (TE) HZ risk factor analysis and odds ratio (95% CI) and P value were provided.Results:Table 1 shows TE HZ EAIRs in a pooled analysis. Rates of HZ were lower for FIL200 vs PBO during the 12W PBO-controlled period. At 52W, HZ rates were higher for FIL200/100 vs active control. Long-term HZ rates increased for FIL200 vs FIL100.Table 1.EAIR of treatment-emergent herpes zosterNPatient-years exposureEAIR(95% CI)EAIR diff(95% CI vs PBO/active control)12W PBO-controlled FIL200777179.80.6 (0.1, 3.9)−0.56 (−2.5, 1.3) FIL100788181.61.1 (0.3, 4.4)−0.02 (−2.2, 2.2) PBO781178.41.1 (0.3, 4.5)Active-controlled, as-randomiseda FIL200475439.71.4 (0.6, 3.0)0.69 (−0.7, 2.1) FIL100480443.40.9 (0.3, 2.4)0.23 (−1.1, 1.5) ADA325297.60.7 (0.2, 2.7)Active-controlled, as-randomiseda FIL200626578.01.7 (0.9, 3.2)0.65 (−0.8, 2.2) FIL100207195.01.5 (0.5, 4.8)0.46 (−1.6, 2.5) MTX416372.21.1 (0.4, 2.9)Long-term as-treatedb FIL20022674047.71.8 (1.4, 2.3)NC FIL10016472032.91.1 (0.8, 1.7)NCaup to W52. bdata cut for LTE FINCH 4, Sept 19, 2019; DARWIN 3, April 26 2019.ADA, adalimumab; CI, confidence interval; EAIR, exposure-adjusted incidence rate; FIL, filgotinib; MTX, methotrexate; NC, not calculated; PBO, placebo; W week.Figure 1 shows multivariate logistic regression model of TE risk factors.Of 104 pts with TE HZ in long-term as-treated analysis set, 5 receiving FIL200 had history of HZ; EAIR (95% CI) was 8.7 (3.6–21.0). Of 8 pts with multiple events, 3 had events of differing severity for the same HZ episode.EAIRs (95% CI) of TE HZ in Asia were: 3.7 (1.7–8.1) FIL200, n=197; 2.8 (1.3–6.3) FIL100, n=158; 0 ADA, n=40; 2.8 (0.4–19.6) MTX, n=43; and 3.4 (0.5–23.8) PBO, n=77 in long-term as-treated population. EAIRs (95% CI) in rest of the world were: 1.6 (1.2–2.1) FIL200, n=2070; 0.9 (0.6–1.5) FIL100, n=1489; 0.8 (0.2–3.1) ADA, n=285; 0.9 (0.3–2.9) MTX, n=373; and 0.7 (0.2–2.9) PBO, n=704 for all pts as-treated.Most TE HZ infections were mild to moderate and non-serious; 6 were serious; 2 were recurrences. No visceral TE HZ occurred across the FIL RA program; there was 1 case each of genital, disseminated, and ophthalmic HZ. The disseminated HZ occurred in a pt with prior HZ history. Lymphopenia was not associated with HZ during the PBO-controlled W12 period.Conclusion:HZ was more common in both FIL groups vs ADA or MTX up to 52 weeks but comparable vs PBO during the 12-week placebo-controlled period. In multivariate analyses, prior history of HZ, Asian region, and age ≥50 years were associated with increased HZ risk.References:[1]Genovese et al. JAMA. 2019;322:315–25.[2]Westhovens et al. Ann Rheum Dis. 2021; online first.[3]Combe et al. Ann Rheum Dis. 2021; online first.[4]Higarashi and Honda. Drugs. 2020;80:1183–201.Disclosure of Interests:Kevin Winthrop Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly and Co., Galapagos NV, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Maya H Buch Speakers bureau: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Consultant of: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Grant/research support from: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Jeffrey Curtis Grant/research support from: AbbVie, Amgen, BMS, Corrona, Eli Lilly, Janssen, Myriad, Pfizer, Regeneron, Roche, and UCB, Gerd Rüdiger Burmester Speakers bureau: AbbVie; Eli Lilly; Pfizer; and Gilead Sciences, Inc., Consultant of: AbbVie; Eli Lilly; Pfizer; and Gilead Sciences, Inc., Daniel Aletaha Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Medac, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Sanofi/Genzyme, and UCB, Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, and Sanofi/Genzyme, Grant/research support from: AbbVie, Merck Sharp & Dohme, Novartis, and Roche, Koichi Amano Speakers bureau: AbbVie GK, Astellas, Chugai Pharmaceutical Co. Ltd., Eli Lilly, GlaxoSmithKline KK, Pfizer Japan, Mitsubishi-Tanabe Pharma, Grant/research support from: Asahi Kasei Pharma, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Iyabode Tiamiyu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Cianna Leatherwood Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Qi Gong Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos, BV, Employee of: Galapagos, BV, James Galloway Speakers bureau: Pfizer, Bristol-Myers Squibb, UCB and Celgene

Background:There are discordant results regarding a potential increased risk of gastro-intestinal perforation (GIP) in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ) compared to conventional synthetic disease modifying anti rheumatic drugs (csDMARDs) or TNF inhibitors (TNFis) (1–3).Objectives:The aim of our study was to compare the risk of diverticulitis and GIP in RA patients treated with TCZ compared to rituximab (RTX) and abatacept (ABA).Methods:We conducted a multicentric study of patients with RA, prospectively followed in 3 observational French registries evaluating the effectiveness and safety of RTX (Autoimmunity and Rituximab (AIR)), ABA (Orencia and Rheumatoid Arthritis (ORA)), and TCZ (REGistry–RoAcTEmra (REGATE)). Using a propensity score approach, we compared the risk of diverticulitis or GIP during treatment with TCZ vs RTX and ABA. The following covariates were included in the propensity score: age, sex, history of diabetes and neoplasia, Charlson Comorbidity Index, number of previous csDMARDs and TNFi, history of TNFi, daily dose of glucocorticoids (GCs) at baseline, co-treatment with a csDMARDs, average DAS28 during follow-up, duration of RA, and exposure time to the considered bDMARDs.Results:4501 patients (1496 treated by TCZ, 1986 by RTX and 1019 by ABA) were included. 21 and 9 GIP occurred in the TCZ treated patients, compared to 10 and 8 in the RTX treated patients and 10 and 2 in the ABA treated patients (corresponding incidence rate (IR) are shown in table 1). Two deaths occurred in patients experiencing GIP: 1 (12.5%) due to undetermined rectal perforation among a RTX treated patient, and 1 (11.1%) due to a perforated ulcer among a TCZ treated patient. Based on inverse probability weighting (IPW), there was an increased risk of diverticulitis and GIP in the TCZ treated patients compared with RTX or ABA (table 1). In a subgroup analysis, we confirmed an increased risk of GIP due to diverticulitis but not to any other etiology. Older age (p=0.05), GCs at baseline (p=0.10) and average daily dose of GCs during follow-up (p=0.08) seemed associated with GIP only in univariate analysis. Compared to RTX and ABA, diverticulitis and GIP among TCZ patients occurred earlier after the last perfusion (p=0.01), with atypical clinical presentation (slow transit in 30%, p=0.04) and lower acute phase reactants when the event occurred (C-reactive protein: 31.2±58.4 vs 88.2±89.6 mg/L, p=0.005). Perforated diverticulitis seemed to have higher dose of GCs at the time of the event compared to diverticulitis without perforation in univariate analysis (p=0.06).Table 1.Incidence (/1000 PY) and risk of diverticulitis or GIPAE (n)IRAE (n)IRAE (n)IRIPW analysisOR[95 CI]pOR[95 CI]pExposition (PY)TCZ (ref)3 990RTX6 322ABA2 389TCZ vs RTXTCZ vs ABADiverticulitis215.3101.6104.24.5[2.6-7.6]3.4[1.7-6.5]GIP92.381.320.82.8[1.5-5.1]0.0015.4[1.4-19.9]0.01*Diverticular GIP61.530.520.83.8[1.7-8.5]0,0016.9[1.9-25.4]0.004*Due to another etiology30.750.8001.4[0.5-3.9]0.5--AE=adverse events; PY=person-yearsConclusion:TCZ was associated with an increased risk of diverticulitis, and GIP due to diverticulitis, compared to RTX and ABA. Our study confirms an increased risk of GIP in RA patients treated with TCZ, which might be explained by an increased risk of diverticulitis with misleading clinical presentation.References:[1]Strangfeld A et al. Ann Rheum Dis. 2016 Jul 12[2]Xie F, Yun H et al. Arthritis Rheumatol. 2016 May 1[3]Barbulescu A et al. OP0231, Ann Rheum Dis. 2018 Jun 1;77(Suppl 2):164–5.Disclosure of Interests:Claire Rempenault: None declared, Cédric Lukas: None declared, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Thierry Schaeverbeke: None declared, Daniel Wendling: None declared, Thao Pham Speakers bureau: Novartis, Janssen, Lilly, Xavier Mariette Consultant of: BMS, Gilead, Medimmune, Novartis, Pfizer, Servier, UCB, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jacques Morel: None declared

Objectives:To assess long term efficacy of tocilizumab in treatment-naive patients with Takayasu arteritis (TAK).Methods:In this multicenter, prospective, open-labelled trial, we aim to evaluate the benefit of adding tocilizumab to steroids in treatment-naïve patients with TAK, on discontinuation of steroids after 6 months of tocilizumab treatment, and to assess relapse-free survival following tocilizumab discontinuation.Results:Thirteen patients with TAK were included, with a median age of 32 years [19-45] and 12 (92%) females. Six (54%) patients met the primary end-point. Among 11 (85%) patients which achieved remission at 6 months, 6 (54%) have reached primary endpoint.. Among the 5 remaining patients which continued steroids, 3 had a prednisone-equivalent dosage < 5mg/day. A significant decrease of disease activity was observed after 6 months of tocilizumab therapy: decrease of median NIH scale (3 [3-4] at baseline, versus 1 [0-2] after 6 months; p No severe AEs were considered related to study treatment and none required tocilizumab interruption or dose reduction. No deaths have occurred during the study period.Conclusion:Tocilizumab seems an effective steroid sparing therapy in TAK but its effect appears to be suspensive.Disclosure of Interests:Arsene Mekinian: None declared, david Saadoun: None declared, jerome.connault@chu-nantes.fr jerome.connault@chu-nantes.fr: None declared, i-quere@chu-montpellier.fr i-quere@chu-montpellier.fr: None declared, Patrick Jégo: None declared, nicolas.limal@aphp.fr nicolas.limal@aphp.fr: None declared, wxv wxv: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Mathieu Vautier: None declared, lea.savey@aphp.fr>; lea.savey@aphp.fr>;: None declared, Patrice cacoub: None declared, olivier fain: None declared

Background:Overlap between systemic sclerosis (SSc) and another auto-immune systemic disease (AISD) in the same patient seems to be more frequent than each disease’s prevalence would explain.Objectives:Our aim was to investigate for overlap syndrome from 2 French cohorts of SSc patients and to compare their characteristics with non-overlap SSc.Methods:Our study was retrospective observational and bicentric. Patients responding to the 2013 ACR-EULAR scleroderma classification criteria for SSc were screened for concomitant AISD. Patients satisfying 2010 ACR-EULAR diagnostic criteria for rheumatoid arthritis (RA) and/or 2016 ACR-EULAR classification criteria for Sjögren’s syndrome (SgS) and/or 2012 SLICC systemic lupus erythematosus (SLE) classification criteria were included in our study. Patient, disease, and treatment characteristics were retrospectively retrieved from medical records and were compared to a SSc cohort.Results:A population of 534 SSc patients was studied. Thirty-four (6.4%) patients were identified as having overlap syndrome. There was 21 (3.9%) patients with RA, 14 (2.6%) with GSS and 4 (0.7%) with SLE (5 patients had 2 AISD). Diagnosis of RA, SLE or SgS was made after diagnosis of SSc for 22 (65%) patients, concomitantly for 10 patients (29%), and before for 2 (6%) patients. Interestingly, two patients with SSc/RA overlap were tested ACPA-positive 2 and 5 years before the first arthritis, respectively. Patients with SSc/RA were severe with 81% of them having erosive disease and despite treatment, only 48% (10/21) patients achieved RA remission (DAS28-CRP < 2.6) at the time of their last visit. Disease duration was longer in patients with SSc overlap syndrome compared to non-overlap patients (15.5 ± 10.6 yearsvs.9.5 ± 8, p < 0.001). Proportion of limited cutaneous SSc was similar in overlap and non-overlap groups (70.6%vs.75.5%, respectively, p = NS), as was the positivity for anti-centromeres antibodies (50%vs.43.2%, respectively, p = NS). The disease phenotype of SSc overlap syndrome was similar to the one of non-overlap SSc in terms of prevalence of pulmonary arterial hypertension, interstitial lung disease, digital ulcer and mortality. With respect to treatments, patients with overlap were more likely to receive glucocorticoids (85.3%vs.45%, p < 0.001), immunosuppressive drugs (82.4%vs.49.2%, p < 0.001) and biologic DMARD (bDMARD, 52.9 %vs.3.8%, p < 0.001). The most prescribed bDMARDs in the overlap population was tocilizumab (40.6%), TNF-alpha inhibitor (29.4%) and rituximab (26.5%) (p < 0.001 for all comparisonvs.non-overlap SSc).Conclusion:We found a prevalence of overlap syndrome higher than 5% among SSc patients. While SSc overlap and non-overlap share common characteristics, overlap patients are more likely to receive glucocorticoids and biologics such as anti-TNF. These overlap should be searched actively (eg, screening for ACPA) since some treatment used for other autoimmune diseases such as glucocorticoids or TNF-alpha inhibitor may be harmful in SSc.Disclosure of Interests:Marc SCHERLINGER Consultant of: Amgen, Mylan, Fresenius Kabi, Johanna Lutz: None declared, Jean Sibilia: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Thierry Schaeverbeke: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Emmanuel Chatelus: None declared, Marie-Elise Truchetet: None declared

Background:Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the treatment of the signs and symptoms of osteoarthritis (OA).Objectives:To assess the improvement in physical function following treatment with subcutaneous (SC) tanezumab in three Phase 3 OA studies.Methods:All three randomized, double-blind, controlled studies enrolled patients (pts) with radiographically-confirmed OA of the hip or knee, who had inadequate response or could not tolerate standard of care analgesics. Study 1 was a dose-titration study (NCT02697773), where pts received two SC doses of: placebo at baseline/week (wk) 8; tanezumab 2.5 mg at baseline/wk 8; or tanezumab 2.5 mg at baseline/5 mg at wk 81. In Study 2 (NCT02709486), pts received three SC doses of placebo, tanezumab 2.5 mg, or 5 mg (at baseline/wk 8/wk 16). In Study 3 (NCT02528188), pts received a stable dose of nonsteroidal anti-inflammatory drugs (NSAIDs) before randomization to double-dummy tanezumab 2.5 mg or 5 mg (at baseline and every 8 wks during a 56 wk treatment period) or twice daily oral NSAIDs. Pts completed Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function subscale questionnaires in clinic. The least squares (LS) mean (standard error (SE)) change from baseline was calculated for each timepoint up to wk 16 and significance was calculated versus placebo (Studies 1 and 2) or NSAID (Study 3).Results:A total of 4541 pts were evaluated (n=696 in Study 1, n=849 in Study 2 and n=2996 in Study 3). In Studies 1 and 2, there were statistically significant improvements from baseline for all tanezumab treated groups versus placebo at wks 2, 4, 8, 12 and 16 (Table 1).In Study 3, the tanezumab 2.5 mg group showed a significant improvement from baseline at wk 2, compared with the NSAID group (Table 2).At wk 4, both tanezumab treatment groups showed a significant improvement from baseline compared with the NSAID group (Table 2). The tanezumab 5 mg group showed a significant improvement from baseline compared with the NSAID group at wks 8 and 16 (Table 2).Table 1.Change from baseline in WOMAC Physical Function: Study 1 and 2Study 1Study 2Tanezumab 2.5 mg n=231Tanezumab 2.5/5 mg n=233Placebon=232Tanezumab 2.5 mg n=283Tanezumab5 mgn=284Placebon=282Wk 2LS mean (SE)-2.89 (0.21)-3.05 (0.21)-2.14 (0.21)-1.95 (0.14)-1.69 (0.14)-1.26 (0.14)p vs placebo0.00040.0014Wk 4LS mean (SE)-3.30 (0.21)-3.38 (0.21)-2.28 (0.21)-2.52 (0.15)-2.50 (0.15)-1.71 (0.15)p vs placeboWk 8LS mean (SE)-3.17 (0.21)-3.12 (0.21)-2.55 (0.21)-2.38 (0.15)-2.52 (0.15)-1.76 (0.15)p vs placebo0.00570.0114Wk 12LS mean (SE)-3.61 (0.22)-3.80 (0.22)-2.75 (0.22)-2.83 (0.16)-2.87 (0.16)-2.04 (0.16)p vs placebo0.0004Wk 16LS mean (SE)-3.22 (0.22)-3.45 (0.22)-2.56 (0.22)-2.68 (0.16)-2.69 (0.16)-2.02 (0.17)p vs placebo0.00650.0002Table 2.Change from baseline in WOMAC Physical Function in Study 3Tanezumab 2.5 mg n=1002Tanezumab 5 mg n=998NSAID n=996Wk 2LS mean (SE)-1.76 (0.08)-1.64 (0.08)-1.55 (0.08)p vs NSAID0.01500.3286Wk 4LS mean (SE)-2.29 (0.09)-2.31 (0.09)-1.96 (0.09)p vs NSAID0.00040.0001Wk 8LS mean (SE)-2.46 (0.10)-2.69 (0.10)-2.27 (0.10)p vs NSAID0.0517Wk 16LS mean (SE)-3.27 (0.11)-3.39 (0.11)-3.08 (0.11)p vs NSAID0.06910.0030Conclusion:Consistent improvements in WOMAC Physical Function were seen across the first 16 wks for all dose groups of tanezumab-treated pts versus placebo in Study 1 and 2. The tanezumab 5 mg group in Study 3 showed a significant improvement at wks 4, 8 and 16 compared with the NSAID group. Improving physical function could help OA pts attain treatment goals beyond pain relief, improving their ability to perform important daily activities.References:[1]Schnitzer, T. J.et al. JAMA 2019Disclosure of Interests:Steven P Stanos Consultant of: Pfizer, Sanofi, Scilex, Salix, Speakers bureau: Scilex, Wilson J Chang: None declared, Cory Hultman Employee of: Eli Lilly and Co., Mojgan Sadrarhami Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., Takaharu Yamabe Shareholder of: Pfizer, Employee of: Pfizer, Peter Park Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

Summary Background To our knowledge, no controlled studies of the effects of long-term growth hormone replacement on fracture risk in adult patients with growth hormone deficiency exist. We assessed the effect of growth hormone treatment on fracture risk in patients with growth hormone deficiency from the international Hypopituitary Control and Complications Study (HypoCCS) surveillance database. Methods In this prospective cohort study, patients with growth hormone deficiency were analysed from the HypoCCS database of adults with hypopituitarism from the USA, Canada, Japan, and 14 European countries. Patients were eligible if they were aged 18 years or older and had an established diagnosis of growth hormone deficiency, either alone or with multiple pituitary hormone deficiencies, as identified by clinical history and biochemical testing. Patients were assessed over a mean follow-up period of 4·6 years (SD 3·8). The effect of growth hormone treatment on fracture risk was assessed by Cox proportional hazard modelling with adjustment for several confounders. Findings Between Jan 3, 1996, and Dec 15, 2012, we enrolled 10 673 patients to this study. Of the enrolled patients, 1032 patients were excluded from assessment because of incomplete data, leaving 9641 in the analysis cohort. Of these patients, 8374 of received growth hormone and 1267 did not. Annual fracture incidence rate was lower in patients who received growth hormone than in those who did not (fracture incidence rate 1·19% vs 1·91%, hazard ratio [HR] 0·69, 95% CI 0·54–0·88). However, no difference in fracture risk was observed between patients who did and did not receive growth hormone treatment in the subgroup of patients with pre-existing osteoporosis (n=826; 0·97, 0·48–1·95). Interpretation Our results suggest that growth hormone replacement therapy could be protective against fracture for adult patients with growth hormone deficiency without previously reported osteoporosis. Starting growth hormone therapy before the onset of osteoporosis might be optimum for bone health of adult patients with growth hormone deficiency. Funding Eli Lilly and Co.

Summary Background Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. Methods In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177. Findings Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9–91·8) vs placebo; 48·1% (41·2–55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4–85·7) vs placebo; 33·9% (27·0–40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5–80·8) vs placebo; 35·9% (28·2–43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0–82·8) vs placebo; 30·8% (23·7–37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6–86·0) vs placebo; 47·2% (39·9–54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7–79·9) vs placebo; 38·9% (31·7–46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6–76·5) vs placebo; 36·9% (29·1–44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3–75·0) vs placebo; 33·8% (26·3–41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted. Interpretation Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option. Funding Eli Lilly and Co.

INTRODUCTION: The survival of patients with chronic myeloid leukemia in chronic phase (CML-CP) is approaching that of general population after the approval of tyrosine-kinase inhibitors (TKI), particularly in younger patients who achieve remission. The optimal frontline TKI therapy in older patients in the context of comorbidity remains unknown. The aim of this study is to develop the LEukemia Artificial intelligence Program (LEAP) for treatment recommendations for patients with CML-CP. METHODS: From July 30, 2000 to November 25, 2014, 630 consecutive patients with newly diagnosed CML-CP were enrolled in frontline TKI therapy (imatinib 400 mg/day, imatinib 800 mg/day, nilotinib, dasatinib, and ponatinib). We included 101 social, demographic, clinical, chromosomal, and molecular variables such as the distance from home address to our institution, primary language, the European Treatment and Outcome Study (EUTOS) risk, the EUTOS long-term survival (ELTS) risk, and the severity of comorbidities by Adult Comorbidity Evaluation 27 (ACE-27). We developed an extreme gradient boosting decision tree model through ensemble learning after hyperparameter tuning. Hyperparameter optimization was calculated with Stampede2, a supercomputer located at Texas Advanced Computing Center, which was ranked as the 15th fastest supercomputer in June 2018. The extreme gradient boosting decision tree model was developed for the prediction of overall survival using only the training/validation cohort. We evaluated the final performance with the independent test cohort. A difference in hazard ratios of less than 0.005 between the best treatment option and alternative TKI therapy was considered as the LEAP recommendation. The test cohort was divided into the LEAP recommendation and the LEAP non-recommendation cohort by the LEAP recommendation. To confirm the association and causation of the LEAP recommendation with survival, we performed backward multivariate Cox regression, and inverse probability of treatment weighing (IPTW) to balance baseline difference of covariates. We calculated SHapley Additive exPlanations1 values to interpret the black box of the LEAP recommendation for the evaluation of the significance of variable for prediction. RESULTS: The whole cohort was randomly divided into a training/validation (N=504) cohort and a test cohort (N=126) at a 4:1 ratio (Figure 1). The training/validation cohort was used for 3-fold cross validation to develop the LEAP CML-CP model. The number of decision trees was 8417, 14659, and 14190 in the first, second, and third cross validation cohort, respectively (Figure 2). The accuracy of prediction at each iteration is shown in Supplemental Figure 1. The area under the curve (AUC) of the training in the first, second, and third cross validation cohort was 0.966, 0.978, and 0.977, respectively; the AUC of the validation in the first, second, and third cross validation cohort was 0.815, 0.832, and 0.742, respectively. The AUC in the test cohort was 0.819. We divided the test cohort (N=126) into the LEAP recommendation (N=94, 75%) and LEAP non-recommendation cohort (N=32, 25%) (Table 1). The LEAP did not recommend one particular TKI (P=0.128). Overall survival did not differ significantly by the type and dose of TKI (P=0.472) (Supplemental Figure 2). Patients in the LEAP recommendation cohort achieved higher rates of overall deep response (Table 2). In the test cohort, treatment consistent with the LEAP recommendation was associated with improved failure-free survival, transformation-free survival, event-free survival, and overall survival (P The median overall survival was 139 months (range, 3.7-216.1), and the median overall survival was 127 months and 148 months in the LEAP recommendation and LEAP non-recommendation cohorts, respectively (P=0.902). Backward multivariate Cox regression analysis and IPTW analysis confirmed the association and causation of improved OS with the LEAP recommendation, respectively (Supplemental Table 1; Supplemental Table 2). The SHAP values identified the presence and degrees of comorbidities and ELTS scores as top three importance for the prediction (Figure 4). Conclusion: The LEAP CML-CP recommendation improves overall survival in patients with CML-CP through higher tolerance, lower rates of progression, and higher rates of deep response. Disclosures Sasaki: Pfizer: Consultancy; Otsuka: Honoraria. Kantarjian:Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Takeda: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Novartis: Research Funding; Immunogen: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Ravandi:Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Selvita: Research Funding. Konopleva:Agios: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Astra Zeneca: Research Funding; Ablynx: Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding. Borthakur:AstraZeneca: Research Funding; Polaris: Research Funding; AbbVie: Research Funding; Incyte: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Merck: Research Funding; Eli Lilly and Co.: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Strategia Therapeutics: Research Funding; Arvinas: Research Funding; Janssen: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; BMS: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Wierda:Oncternal Therapeutics Inc.: Research Funding; Xencor: Research Funding; Cyclcel: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; Miragen: Research Funding; KITE pharma: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Gilead Sciences: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:celgene: Consultancy, Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; syros: Honoraria; medimmune: Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:plexxikon: Research Funding; novartis: Consultancy, Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; incyte: Consultancy, Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy.

Introduction: Venetoclax (VEN) is approved for the treatment of acute myeloid leukemia (AML) in combination with hypomethylating agents (HMAs) or low-dose cytarabine and commonly used for patients (pts) unfit for intensive chemotherapy. Prophylaxis with triazole antifungals (azoles) during induction treatment in pts with AML has decreased mortality and is the standard of care for pts receiving treatment regimens associated with prolonged myelosuppression (Cornely et al, 2007). Azoles inhibit CYP3A4 (CYP3A4i), the enzyme responsible for the metabolism of VEN, and p-glycoprotein to varying degrees, which VEN is a substrate. Based on this interaction and the results of a small pharmacokinetic study, significant VEN dosage reductions are recommended (Agarwal et al, 2017). Little real-world data exists to demonstrate the tolerability of VEN in combination with azoles during induction treatment with VEN and HMAs. Methods: All pts with newly diagnosed AML treated at our institution with VEN and HMAs from 11/2014-1/2019 were retrospectively reviewed. Pts were treated as standard of care or as part of clinical trial in combination with azacitidine (NCT02203773) or decitabine (NCT03404193; NCT02203773). Pts who received concomitant antifungal for >5 days while also receiving VEN for >7 days were included. VEN 100mg daily with posaconazole or voriconazole (strong CYP3A4i) and VEN 200mg daily with isavuconazole or fluconazole (moderate CYP3A4i) were considered 400mg equivalent dosages. Higher doses of VEN in these combinations were considered >VEN 400mg equivalent. To determine the clinical impact of concomitant azoles, time to absolute neutrophil count (ANC) and platelet (PLT) recovery after induction was analyzed, in addition to response rates, episodes of febrile neutropenia (FN) and documented infections. Results:One-hundred twenty-one pts treated with HMA and VEN were identified (Table 1). The median age was 72 years (48-86) and 35% were > 75 years. Forty pts (33%) had secondary AML, and 10% had therapy-related AML. Most were treated with decitabine 20mg/m2 administered for 10 days (67%) or 5 (22%). VEN was administered for a median of 23 days (7-30) at a 400mg daily dose equivalent in 74 pts (62%) and >400mg dose equivalent in 40 pts (33%). Eighty-nine (74%) received a concomitant azole with VEN including posaconazole (38%), isavuconazole (21%), voriconazole (13%), or fluconazole (2%). Following induction therapy with VEN and HMA, 37% achieved a complete response (CR) and 22% achieved a CR with incomplete blood count recovery (CRi). An additional 10% achieved a morphologic leukemia free state (MLFS) (Table 2). Prior to cycle 2, 55% of pts achieved ANC>500 cells/mm3 and 64% achieved PLT>50,000 cells/mm3 after a median of 34 days and 24 days, respectively. No difference in response was observed based on VEN dosage or duration (Table 3). Pts achieving CR/CRi received VEN for a median of 22 days (7-29), and 38% at the 400mg equivalent VEN dosage with an azole. When analyzing VEN dosage by the use of an azole, duration of neutropenia (ANC0.05) (Table 4). Number of pts achieving PLT>50,000 cells/mm3 was not affected by concomitant antifungal or VEN dosage, but duration of thrombocytopenia was. Time to PLT>50,000 cells/mm3 was significantly longer for pts receiving VEN 400mg equivalent with an azole (25 vs 20 days, p=0.01) as well as time to PLT>100,000 cells/mm3 (27 vs 22 days, p=0.03). Despite prolonged cytopenias, all pts receiving the VEN 400mg equivalent dosage had similar rates of FN, documented infections, and hospital duration regardless of the use of an azole (Table 4). Those receiving >400mg VEN equivalent had numerically higher rates of FN, infections, and duration of hospitalization. Conclusion: The combination of VEN with HMA is an effective treatment option in pts with newly diagnosed AML. VEN is associated with significant myelosuppression which can be enhanced by concomitant CYP3A4i, such as the azoles. The combination of VEN and azoles resulted in prolonged cytopenias, namely thrombocytopenia, compared to the use of VEN without an azole. This did not result in higher rates of FN, infections, or duration of hospitalization, therefore the concomitant use of VEN and azole appear to provide a clinically safe and effective therapeutic regimen. Higher doses of VEN do not appear to be advantageous in this setting. Disclosures DiNardo: daiichi sankyo: Honoraria; jazz: Honoraria; syros: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria. Maiti:Celgene: Other: research funding. Kadia:Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; Arvinas: Research Funding; Oncoceutics: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Agensys: Research Funding. Pemmaraju:affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; incyte: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding. Kantarjian:Astex: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding. Konopleva:Astra Zeneca: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Agios: Research Funding; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding.

Introduction Since the advent of tyrosine kinase inhibitors (TKIs) in 2001, the treatment goals in the management of chronic myeloid leukemia (CML) have evolved according to international recommendations. The 2009 European LeukemiaNet (ELN) proposed a category of "suboptimal response". The 2013 recommendations introduced a "warning response" category that saw some "suboptimals" in 2009 becoming failures in 2013. The clinical implications of this intermediate category and the difference in categorizations has not been fully explored. As new recommendations are being prepared, we seek to compare the outcomes of patients with suboptimal/warning using 2009 and 2013 guidelines. Methodology We analyzed 730 patients treated with front-line TKIs in various clinical trials and identified patients who meet the criteria for suboptimal response at 3, 6 and 12 months according to the 2009 ELN guidelines and/or warning criteria according to 2013 ELN criteria. We computed descriptive statistics for patients at each of the above criteria at the 3 time points. Kaplan-Meier product limit method, was used to estimate the median for overall survival (OS), event-free survival (EFS), failure-free survival (FFS) and transformation-free survival (TFS). Results Of the 730 CML patients evaluated, using the 2009 ELN guidelines, 2%, 3% and 5% of the patients met the 3, 6 and 12 months definition of suboptimal response, respectively. Analysis of baseline characteristics show a median age of 44.1, 42.1 and 44.4 years, respectively for the three time lines with a predominantly male and white population. Using the 2013 guidelines 4%, 10% and 17% of the patients met the 3, 6 and 12 months definition of warning, respectively. Patients were again predominantly male and white with a median age at diagnosis of 41.5, 44.1 and 47 years respectively. With regard to achieving complete cytogenetic response (CCyR), a higher percentage of patients achieved CCyR using the 2013 guidelines (55.2%, 80.8% and 98%, for warning cohorts at 3, 6 and 12 months, respectively) compared to using the 2009 guidelines (35.3%, 56.5% and 81.1%, respectively). Similarly, for best molecular response, a higher percentage of patients achieved MR4.5 using the 2013 guidelines (10.7%, 20.8% and 44.2%, for warning cohorts at 3, 6 and 12 months, respectively) compared to using the 2009 guidelines (13.3%, 4.5% and 24.2%, for suboptimal cohorts respectively). With respect to survival outcomes, patients classified as warning per the 2013 guidelines had better outcomes than those with suboptimal response using the 2009 guidelines. For example, for EFS, median survival was longer for the 2013 warning cohort compared to the 2009 suboptimal cohort (29 months vs. 18 months, by 3 months assessment). For FFS, the median survival was longer for the 2013 warning cohort compared to the 2009 suboptimal cohort (68 months vs. 11 months, by 6 months assessment). Using the 2013 guidelines median survival could not be reached for most of the survival outcomes. Conclusion Our assessment reveal that survival outcomes were better for the warning cohort using the ELN 2013 recommendations compared to the suboptimal cohort of the 2009 recommendations. This represents a stage migration by moving the subset of patients with the worse outcome away from this intermediate category and into the failure. An important, still unanswered question, is the optimal management of patients in this intermediate category or of those that migrate from one category to the next based on a change in definitions. Disclosures Kantarjian: Ariad: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Novartis: Research Funding. Borthakur:Eli Lilly and Co.: Research Funding; NKarta: Consultancy; PTC Therapeutics: Consultancy; Cyclacel: Research Funding; Eisai: Research Funding; Janssen: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Bayer Healthcare AG: Research Funding; BMS: Research Funding; AbbVie: Research Funding; Merck: Research Funding; GSK: Research Funding; Incyte: Research Funding; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Polaris: Research Funding; Cantargia AB: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; Strategia Therapeutics: Research Funding. Verstovsek:Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Incyte: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Novartis: Consultancy, Research Funding. Kadia:BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Pemmaraju:abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; incyte: Consultancy, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Agios: Research Funding; Ablynx: Research Funding; Astra Zeneca: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ascentage: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; jazz: Honoraria; medimmune: Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Cortes:Immunogen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding.

Background: Ibrutinib (IBR), a BTK inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are approved for patients (pts) with CLL. The rationale for combining IBR and VEN includes: 1) preclinical models showing synergism, 2) non-overlapping toxicities; 3) non-overlapping mechanisms of action. We recently reported results of the first-line cohort of an investigator-initiated phase II trial of combined IBR and VEN for pts with CLL (Jain N et al. NEJM 2019). Here we report results of the 80 pts from the R/R CLL cohort of the trial (NCT02756897). Methods: Pts with R/R CLL meeting 2008 IWCLL treatment criteria were enrolled. Pts received IBR monotherapy (420 mg daily) for 3 cycles followed by addition of VEN (weekly dose-escalation to the 400mg daily target dose). Combined therapy was administered for 24 cycles. Pts with bone marrow (BM) undetectable MRD (U-MRD) (multi-color flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy stopped both VEN and IBR; MRD+ pts could continue IBR. Response assessments were performed using blood, BM and CT imaging (2008 IWCLL criteria) at the following time-points (after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of combined therapy). Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death. Overall survival (OS) was assessed as the time from the start of study drug to death. Results: A total of 80 pts were enrolled. The median age was 61.5 yrs (32-79). The baseline characteristics are shown in Table 1. Overall, 30 (38%) pts had a TP53 aberration. The median follow-up for all pts is 22.3 months. Of the 80 pts, 1 pt was later reclassified as splenic marginal zone lymphoma and is excluded from further analyses. Five pts came off study during IBR monotherapy phase (reasons listed below). 74 pts initiated VEN. Serial BM MRD responses are shown in Figure 1. One pt with a prior allo-SCT had no marrow disease at screening and is therefore excluded from serial MRD analyses. After 3 cycles of IBR monotherapy, none of the 73 pts achieved BM U-MRD. After addition of VEN, increasing proportions of pts achieved BM U-MRD remission. After 3 cycles of the combination, 7/68 (10%) achieved BM U-MRD remission. After 6 cycles of the combination, 15/67 (22%) achieved BM U-MRD remission. After 12 cycles of the combination, 29/60 (48%) achieved BM U-MRD remission. After 24 cycles of the combination, 16/24 (67%) achieved BM U-MRD remission. To assess the incremental benefit of the combined IBR and VEN beyond the first 12 cycles, we analyzed the MRD for pts who had received 24 cycles of combined therapy (n=24). Among these 24 pts, 13 were MRD+ at end of 12 cycles; 4/13 (31%) became U-MRD at end of 18 cycles of combination. Similarly, among these 24 pts, 9 were MRD+ at end of 18 cycles of combination; only 1/9 (11%) achieved U-MRD after 24 cycles of combination. PFS and OS are shown in Figure 2. Two pts had CLL progression after completing 24 cycles of combined therapy. 1 pt was in U-MRD remission at 24 cycles and stopped both IBR and VEN per study design; he relapsed 3 months later and responded to IBR monotherapy. The second pt was MRD+ at 24 cycles of combined therapy and continued IBR monotherapy after 2 yrs per study design; he relapsed few months later and is now in remission post CD19 CAR-T. One pt developed Hodgkin's transformation. Two pts died; both due to infectious complications during the IBR monotherapy. One pt developed severe cytopenias during the VEN dose escalation, was non responsive to multiple therapies for worsening cytopenias, then underwent an allogeneic stem cell transplant. One pt, with prior FCR therapy developed MDS. A total of 15 (19%) pts have come off trial; 5 pts came off study during IBR monotherapy (death from infection, n=2; skin rash, n=1; insurance issue, n=1; pt decision, n=1). Three pts came off trial during VEN ramp up (cytopenias, n=2; noncompliance, n=1). Four pts came off trial during the combination phase of IBR and VEN (arthralgia, n=1; Hodgkin's transformation, n=1; renal cancer, n=1; MDS, n=1). Three pts came off trial after completing 24 cycles of combined therapy (CLL progression, n=2; pt decision to continue VEN beyond 24 cycles, n=1). Grade 3-4 neutropenia occurred in 29% pts. Grade 3-4 thrombocytopenia occurred in 3% pts. Atrial fibrillation occurred in 7 (9%) pts. Conclusions: Combined VEN and IBR is an effective well-tolerated chemotherapy-free oral regimen for pts with R/R CLL. Disclosures Jain: Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Thompson:Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Research Funding. Burger:Gilead Sciences: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; Aptose Biosciences, Inc: Research Funding; BeiGene: Research Funding; AstraZeneca: Honoraria. Borthakur:Cyclacel: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; AbbVie: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Eisai: Research Funding; Janssen: Research Funding; GSK: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Bose:Constellation: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; CTI BioPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Blueprint Medicine Corporation: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Konopleva:Ablynx: Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Forty-Seven: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. DiNardo:medimmune: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; jazz: Honoraria. Pemmaraju:samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Pharmacyclics LLC: Research Funding; KITE pharma: Research Funding; Acerta Pharma Inc: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved

Background: We have previously shown that CMR predicts better outcomes in Ph+ ALL. The lack of achievement of CMR and particularly major molecular response (MMR) at 3 months may confer poor outcomes. We sought to investigate the outcomes of pts who did not achieve CMR at 3 months as best response in terms of progression free survival (PFS) and overall survival (OS), and the role of allogeneic stem cell transplant (ASCT) in this population. Methods: We reviewed 204 pts with newly diagnosed Ph+ ALL treated at our institution between January 2001 and June 2019 with the combination of Hyper-CVAD plus tyrosine kinase inhibitors (TKI); dasatinib (n=88, 43%), ponatinib (n=72, 35%) and imatinib (n= 44, 22%). PFS was defined from the start of therapy to relapse or death. OS was defined from diagnosis to death or last follow-up. Backward multivariate Cox regression was used to identify prognostic factors for PFS and OS after variable selection at a p-value cutoff of 0.200. Time to ASCT was handled as a time-dependent variable. Survival curves were estimated by Kaplan-Meier method. Landmark analysis at the median time to ASCT was analyzed to evaluate the impact of ASCT. Results: We identified 94 pts (46%) who did not achieve 3-month CMR. Of pts treated with imatinib, 29 (66%) did not achieve 3-month CMR and 16 pts (36%) achieved 3-month MMR. Of pts treated with dasatinib, 42 (48%) did not achieve 3-month CMR and 29 pts (33%) achieved 3-month MMR. Of pts treated with ponatinib, 23 (32%) did not achieve 3-month CMR and 17 pts (24%) achieved 3-month MMR. Patient characteristics are summarized in table 1. Median age was 54 years (range: 21-80). The TKI administered was dasatinib, imatinib and ponatinib in 42 (45%), 29 (31%) and 23 (24%) pts, respectively. Overall, ASCT was performed in 28 pts (30%); 21 out of 62 pts (34%) with 3-month MMR, and 7 out of 32 pts (22%) who did not achieve MMR, within a median time of 5 months (range, 2.3-12.3). After a median follow-up of 97 months, median PFS was 21 months and median OS was 46 months. There was no difference in survival by TKI choice. The 5-year PFS and OS rates were 52% and 23% (p=0.001) (Figure 1A), and 58% and 26% (p=0.001) (Figure 1B) for pts with and without 3-month MMR, respectively. In multivariate analysis (table 2), 3-month MMR predicted longer PFS (p A 5-month landmark analysis was performed to assess the effect of ASCT on survival by 3-month MMR status. In pts who achieved 3-month MMR, 5-year PFS and OS rates were 60% and 58% (p=0.64) (Figure 2A) and 64% and 64% (p=0.73) (Figure 2B) in pts with and without ASCT, respectively. In contrast, among pts who did not achieve a 3-month MMR, there was a tendency for better PFS (5-PFS, 43% vs 21%; p=0.25) (Figure 2C) and OS (5-year OS, 43% vs. 26%; p=0.57) (Figure 2D) in favor of ASCT. Conclusions: The lack of achievement of MMR at 3 months predicted worse outcomes in Ph+ ALL. Higher survival rates were seen when ASCT was performed in pts who do not achieve 3-month MMR. Innovative targeted strategies aimed to eradicate minimal residual disease are needed to further improve long term outcomes. Disclosures Kantarjian: Cyclacel: Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding. Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Cortes:Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:AstraZeneca: Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; AbbVie: Research Funding; Bayer Healthcare AG: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agensys: Research Funding; Eisai: Research Funding. Verstovsek:Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding. Daver:Agios: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Genentech: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Celgene: Consultancy; Immunogen: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Servier: Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Jain:Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva:F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding. O'Brien:Eisai: Consultancy; Gilead: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Verastem: Consultancy; Vaniam Group LLC: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy. Ravandi:Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding. Jabbour:Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding.

Background: The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs) are Philadelphia negative myeloid neoplasms with overlapping clinicopathological features of both MPNs and MDS. Ruxolitinib (RUX), a JAK 1/2 inhibitor is FDA approved for primary myelofibrosis. The hypomethylating agents, azacitidine (AZA) and decitabine, are approved for MDS. The independent activity of RUX and AZA in patients with MPNs and MDS, respectively, and their non-overlapping toxicity profiles suggest that the combination of these two agents administered sequentially and at lower doses may be tolerable and efficacious in patients with MDS/MPNs. Herein we present updated results from a Phase II trial. Methods: This is a single-arm Phase II trial of RUX in combination with AZA for patients (pts) with MDS/MPNs. Eligible pts included adults > 18 years with newly diagnosed or previously treated (excluding previous therapy with RUX or AZA) MDS/MPNs with intermediate-1, intermediate-2, or high risk according to the DIPSS criteria for PMF. RUX at 15-20 mg orally twice daily was to be given alone in 28 day cycles for the first 3 cycles. AZA was to be added from cycle 4 onward at 25 mg/m2 days 1-5, and could be gradually up-titrated to 75 mg/m2 days 1-5 over subsequent cycles if clinically indicated. AZA could be initiated prior to cycle 4 in pts with proliferative disease or high bone marrow blasts. The primary objective was to determine the response rate per the 2015 IWG MDS/MPN response criteria. The secondary objective was to determine the safety and tolerability of the combination therapy. Results: Forty-five pts were enrolled between May 2013 and June 2019. The median age was 68 years; 64% were ≥65 years, 77.7% were int-2 or high risk by DIPPS. Twenty one (46.6%) pts had splenomegaly and 16 (35.5%) pts had EUMNET MF-2 or MF-3. JAK2V617F mutation was present in 16 pts (35.5%). Thirteen pts had pre-therapy BM blasts >5%. The pts. characteristics are in Table 1. Fourty three pts were evaluable for response at the time of this report. AZA was given to 41/45 pts (91.1%), with 26 (63%) pts initiating the AZA before cycle 4 due to increased of bone marrow blast or proliferative disease. After a median follow-up of 30.8 months (mo), 19 pts are still alive. 24 pts (56%) achieved an objective IWG 2015 response. The median time to IWG response was 1.8 mo (0.4-5.5). A ≥50% palpable spleen length reduction was seen in 64% (9/14) of evaluable pts with a median time to response of 1.0 mo. 8/13 (62%) evaluable pts achieved a BM blast reduction to The most common possibly related non-hematological adverse events were grade I-II constipation (22.2%), nausea (15.5%) and pain (15.5%). Significant possibly related hematological AEs included grade III-IV anemia (35.5%), neutropenia (22.2%) and thrombocytopenia (53.3%), these were usually transient and only 2 pts had to discontinue protocol therapy due to cytopenias. All possibly related adverse events are listed in Table 3. Five pts progressed to AML, with a median time to progression of 13.8 mo. Overall, the median OS was 25.4 mo with 1-year and 3-year OS rates of 86% and 40%. Pts with MDS/MPN-U had a better median OS compared with CMML and aCML (31.8 mo vs. 16 mo vs. 1.5 mo; p=0.009). Figure 1 depicts OS by diagnosis. The 1-year and 3-year OS rates for pts with MDS/MPN-U were 100% and 46%, respectively. The median duration of response was 8.35 mo (range 2.1-14.6 mo).The median OS of 31.8 mo among MDS/MPN-U pts compares favorably to a median OS of 16.1 mo from the previously published historical cohort of MDS/MPN-U patients treated with AZA alone (N = 36) at our institution (DiNardo C et al, Leukemia 2014). Conclusions: RUX in combination with AZA was safe and effective and may be a therapeutic option to consider, especially in pts with MDS/MPN-U. Transient grade III-IV myelosuppression was frequently seen, but only 2 pts (4.4%) required treatment discontinuation, which is similar to discontinuation rates with single agent RUX in MF in COMFORT studies (8-9%). Overall response rate was 56%. Additionally 63% BM remissions were noted among pts with ≥5% blast at baseline. The clinical trial is still recruiting (NCT01787487) and focussed on enrolling MDS/MPN-U pts. Disclosures Kantarjian: BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Astex: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Cortes:Merus: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Pemmaraju:novartis: Consultancy, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; celgene: Consultancy, Honoraria; plexxikon: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; cellectis: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. DiNardo:syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria. Borthakur:Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AbbVie: Research Funding; Bayer Healthcare AG: Research Funding; GSK: Research Funding. Wierda:GSK/Novartis: Research Funding; Genentech: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Acerta Pharma Inc: Research Funding; AbbVie: Research Funding; Juno Therapeutics: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Pharmacyclics LLC: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Takahashi:Symbio Pharmaceuticals: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Jain:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Konopleva:Forty-Seven: Consultancy, Honoraria; Astra Zeneca: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. Verstovsek:Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding. Daver:Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Agios: Consultancy; Incyte: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Servier: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Ruxolitinib a JAK1/2 is approved for the treatment of MF and PV HMA decitabine and azacitidine are approved for MDS This trial is combining azacitidine and ruxolitinib in MDS/MPNs

Background: Outcomes in patients (pts) with relapsed/refractory (R/R) myelofibrosis (MF) post JAK inhibitor are poor [overall survival (OS) 13-14 months] (Newberry K, Blood 2017; Kuykendall A, Ann Hematol 2018). There are no approved therapies beyond JAK inhibitors for pts with MF. In certain clinical situations, such as severe thrombocytopenia, administration of JAK inhibitors may be difficult or even contraindicated. SMAC mimetics (or IAP antagonists), a novel class of anti-cancer therapeutics, lead to apoptotic cancer cell death through targeting of IAPs. Because these agents are hypothesized to be particularly effective in a TNFα-rich micro-environment, such as in pts with MF, a group known to have markedly increased cytokines including TNFα (Fleischman A Blood 2011; Heaton W, Leukemia 2018; Tefferi A, JCO 2011), we conducted an investigator-initiated phase 2 clinical trial with LCL161 in pts with intermediate to high risk PMF or post-ET/PV MF. Objectives: Primary: overall response rate (ORR) by IWG-MRT 2013; secondary and exploratory: time to response, response duration, safety, improvement in symptom burden by MPN-SAF TSS, measurement of cIAP1/2, XIAP, and mutational profiling via next-generation sequencing. Clinical Trial Design: LCL161 is an oral monovalent SMAC mimetic, administered once weekly, starting dose 1500 mg with 2 dose level reductions (DL-1, 1200mg; DL-2, 900 mg) in pts with MF. One cycle was 28 days. Pts age ≥18, PS 0-2, who were not candidates for, intolerant to, or R/R to JAK inhibitors were eligible. After 3 cycles, bone marrow biopsy/response evaluations were performed. There was no minimum platelet count for eligibility, and prior allogeneic stem cell transplant (SCT) was allowed. Results: The study has completed enrollment. A total of 47 pts were treated with a median age of 72 years [56-85]. The median baseline platelet count was 51 x 109/L [6-1365]. The median baseline spleen size was 12 cm among 28 pts with enlarged spleen at baseline. 70% of the pts had ≥2 prior therapies; 55% had a prior JAK inhibitor, 2 pts had prior SCT. 75% were IPSS high-risk. Driver mutations: 64% JAK2 V167F; 13% CALR; 11% MPL W515L; 5 pts had triple negative MF. Mutation analysis revealed the three most common additional mutations: ASXL1 (23%); TET2 (15%); DNMT3a (11%). ORR was 32% (15/47 pts); 15 pts exhibited a total of 19 objective responses (4 pts met criteria for 2 separate IWG 2013 responses): Clinical improvement (CI) symptoms (n=11); CI anemia (n=6); CI spleen (n=1), cytogenetic response (n=1). At a median follow-up of 21.1 months (mo) [3.9-49.7+], the median number of cycles received was 5 [1-52+], the median time to response was 1.4 mo [0.9-9.1] and median response duration (mo) was 31.5 [3.6-48.8+]. Long-term responders: n=8 for ≥1 year; n=4 for ≥2 years/ongoing. Importantly, median OS is not yet reached on this study (Figure). The most common non-hematologic toxicities (grade 1/2): nausea/vomiting (60%); fatigue syndrome (49%), dizziness/vertigo (32%); non-hematologic Grade 3/4: syncope (n=2); nausea/vomiting (n=1). Hematologic toxicities (grade 3/4): thrombocytopenia n=3 (6%); anemia n=2 (4%). 36% pts had a dose reduction; the most common cause was fatigue (n=10). Overall, 81% pts are now off study [Stable disease/no objective response (n=16); progressive disease (n=9); toxicity (n=5), pt's choice/other (n=6), proceeded to SCT (n=2)]. Correlative analysis: Preliminary analysis demonstrates on-target inhibition of cIAP1 observed in all responding pts analyzed; high levels of XIAP and/or XIAP increases were observed in many pts with resistance/disease progression. Anemia responders: 6 pts achieved CI anemia (n=4 hemoglobin responses, n=2 achievement of transfusion independence). Among these 6 pts: median time to response (mo): 3.1 [0.9-9.1]; median response duration (mo): 8.4 [5.5-28.6]. Conclusion: In an older group of pts with 70% with ≥2 prior therapies (55% JAK inhibitor-exposed), median baseline platelet count of 51, ASXL1-mutated in 23%, we observed a 32% ORR. The median OS has not yet been reached. Oral SMAC mimetics may represent a possible option for older pts, those who have failed prior JAK inhibitor, and those with thrombocytopenia limiting entry onto other trials. Future directions include combination studies with hypomethylating agents and JAK inhibitors for pts with myeloid malignancies. This clinical trial is registered at ClinicalTrials.gov as NCT02098161. Figure Disclosures Pemmaraju: sagerstrong: Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; novartis: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; incyte: Consultancy, Research Funding; affymetrix: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding. Carter:Amgen: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding. Cortes:Sun Pharma: Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Bose:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Garcia-Manero:Merck: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding. Bueso-Ramos:Incyte: Consultancy. DiNardo:jazz: Honoraria; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Konopleva:Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Borthakur:Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Strategia Therapeutics: Research Funding; Xbiotech USA: Research Funding; Tetralogic Pharmaceuticals: Research Funding; GSK: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Cantargia AB: Research Funding; AbbVie: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Cyclacel: Research Funding; Polaris: Research Funding; NKarta: Consultancy; Agensys: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Oncoceutics: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: LCL161- not yet FDA approved drug; investigational agent = SMAC mimetic /IAP antagonist

INTRODUCTION: AML with myelodysplasia related changes (AML-MRC) is a heterogeneous disorder defined by multilineage dysplasia, presence of myelodysplastic syndrome (MDS)-related karyotype, or history of prior MDS. Defining the outcomes within this heterogeneous subgroup of pts is necessary to select optimal therapy. METHODS: We evaluated all pts with AML-MRC diagnosed and treated at our institution from 2013 to 2018. All cases where reviewed by 2 hematopathologists to establish diagnosis of AML-MRC following WHO 2017 criteria. Patients with therapy-related myeloid neoplasms were excluded. Sequencing data was obtained by use of an 81-gene targeted, next generation sequencing (NGS) platform. Pts were classified into 4 categories: 1) AML-MRC was based on cytogenetic abnormalities (AML-MRC-C) in pts with definitory cytogenetic abnormalities; 2) AML-MRC with history of prior MDS or MDS/myeloproliferative neoplasm (MDS/MPN) in 103 (25%) pts (AML-MRC-H); 3) AML-MRC with history of prior therapy for antecedent MDS or MDS/MPN (AML-MRC-S) and 4) AML-MRC with presence of >50% dysplasia in 3 lineages (AML-MRC-M) in pts with compatible morphologic features but none of the prior. We reviewed response and survival outcomes based on subgroup, therapy, and clinic-pathologic factors. RESULTS: A total of 415 pts with AML-MRC where identified. Median age at diagnosis was 70 years (range 18-94). A total of 243 (59%) pts had AML-MRC-C, 47 (11%) had AML-MRC-H, 28 (7%) had AML-MRC-S and 97 (23%) had AML-MRC-M. Among pts with a prior history of MDS or MDS/MPN, 23 (22%) had received therapy with hypomethylating agents, 1 (1%) with lenalidomide and 3 (3%) with ruxolitinib and 1 with 7+3 (1%) (these were categorized as AML-MRC-S). Median bone marrow blast percentage on aspirate was 35% (range 1-97%). Among pts with AML-MRC-C the defining cytogenetic abnormality included: complex karyotype in 186 (77%), monosomy 5 or del(5q) in 14 (6%), monosomy 7 or del(7q) in 38 (16%), concurrent chromosome 5 or 7 abnormalities in 2 (1%), del(13q) in 2 (1%) and i(17) in 1 (0.5%) pt. Data on NGS was available in 95 pts. Identified mutations are shown in Figure 1A. Mutations in TP53 where more commonly observed in pts with AML-MRC-C (p=0.001). Prior publications (Lindsley et al Blood 2015) have shown that secondary-type mutations (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2) identify a subset of pts with AML with worse than expected outcomes. Among evaluable pts, a total of 37 (39%) pts had secondary-type mutations. Based on variant allele frequency of identified mutations, mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. A total of 73 (18%) pts received therapy with single agent hypomethylating agents (HMA), 67 (16%) with HMA in combination with investigational drugs, 86 (21%) with low-dose cytarabine (LDAC) based therapies and 119 (29%) with intensive chemotherapy. Response outcomes on evaluable pts are shown in Figure 1B. With a median follow up of 28.3 months (95% CI 25.7-30.9 months) the median overall survival (OS) was 10.5 months (95% CI 9.1-12.0 months). Pts with AML-MRC-M and AML-MRC-H had significantly better outcomes than those with AML-MRC-C or AML-MRC-S (overall p CONCLUSION: AML-MRC is a heterogeneous group of AML with diverse mutational abnormalities and outcomes. Selection of therapy should be based on cytogenetic abnormalities and AML-MRC subtype. Figure 1 Disclosures Sasaki: Pfizer: Consultancy; Otsuka: Honoraria. Ravandi:Xencor: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:celgene: Consultancy, Honoraria; jazz: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; medimmune: Honoraria; daiichi sankyo: Honoraria; syros: Honoraria; abbvie: Consultancy, Honoraria. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Borthakur:GSK: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; NKarta: Consultancy; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Xbiotech USA: Research Funding. Konopleva:Calithera: Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding. Bueso-Ramos:Incyte: Consultancy. Kantarjian:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Astex: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding. Garcia-Manero:Celgene: Consultancy, Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION: Outcomes of pts with lower-risk MDS is heterogeneous as shown by validated prognostic scales such as the MD Anderson lower risk prognostic scoring system (MDA-LRPSS) (Garcia-Manero, et al, Leukemia, 2008). We have previously shown that use of lower doses of HMA in lower-risk MDS is safe and can be effective (Jabbour, et al, Blood, 2017). Determining long-term benefit of early intervention with HMA in pts with lower-risk MDS is necessary. METHODS: We report the long-term follow up of a phase 2 study of azacitidine (AZA) or decitabine (DAC) for pts with MDS and chronic myelomonocytic leukemia (CMML) with low or intermediate-1 IPSS risk score. A Bayesian response-adaptive design was used to assign pts to either DAC 20mg/m2 intravenously (i.v.) for 3 days or AZA 75mg/m2 i.v. or subcutaneous for 3 days. Courses were repeated every 4 weeks. Response was evaluated following IWG 2006 criteria. Next-generation sequencing was performed using targeted PCR-based sequencing. Sanger sequencing for SF3B1, SRSF2, U2AF1 and ZRSR2 was performed on a subset of pts. Kaplan-Meier product limit method was used to estimate survival outcomes for each clinical/demographic factor. Univariate Cox proportional hazards regression was used to identify any association with each of the variables and survival outcomes. RESULTS: A total of 113 pts were treated: 73 with decitabine and 40 with azacitidine. Pt characteristics are shown in Figure 1A. Median age was 70 years (44-88). By the MDA-LRPSS 13 (11%) pts had low risk, 52 (46%) intermediate and 48 high (42%). Identified mutations are detailed in Figure 1B. The median number of cycles was 15 (3-74) and the median number of cycles to best response was 2.2 months (1-19.5 months). Response outcomes are shown in Figure 1C. Overall, DAC-treated pts were more likely to show response than AZA-treated (OS = 2.24, 95% C.I. 0.95-5.35, p = 0.047). Median follow-up is 59 months (95% CI 55.7-62.3). Median overall survival (OS) was 33.4 months with no significant difference based on treatment arm (DAC 38 months vs AZA 31 months, p=0.435). A total of 13 (12%) pts suffered transformation to acute myeloid leukemia (AML). Based on the MDA-LRPSS, pts with intermediate risk had worse survival than low-risk, but this was not statistically significant (HR 2.5, p=0.09). High-risk pts had significantly worse survival than low-risk (HR 3.5, p = 0.017) (Figure 1D). To determine if survival outcomes were improved compared to expected based on the MDA-LRPSS, we compared observed outcomes (continues lines in Figure 1E) to reported outcomes in the original MDA-LRPSS cohort (dashed lines in Figure 1E). Median OS compared favorably with expected outcomes in pts with intermediate and high-risk with no significant differences in patients with low risk category. The number of mutations did not correlate with outcomes but DNMT3A (HR 4.1, p=0.003), TP53 (HR 3.6, p=0.002) and U2AF1 (HR 2.1, p=0.018) mutations correlated with poor OS. U2AF1 mutations correlated with shorter transformation free survival (TFS) (HR 6.3, p=0.002). TP53 mutations correlated with shorter event-free survival and response duration (HR 3.9, p=0.006). On multivariate analysis, age, U2AF1, TP53, and DNMT3A mutations all correlate with poor OS. By univariate analysis there were no differences in OS, TFS, or duration of response by HMA. Mutations had similar effects on OS regardless of HMA used. Pts with SF3B1 mutations had a median OS which was not reached at the time of follow up (Figure 1F). Treatment was overall well-tolerated in both arms with most adverse events being grade 1 or 2. CONCLUSIONS: Low-doses of HMA in pts with lower-risk MDS are safe and can improve outcomes compared to historical data in pts with intermediate or high risk features by the MDA-LRPSS. Figure 1 Disclosures Jabbour: AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Eli Lilly and Co.: Research Funding; Cyclacel: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; Oncoceutics: Research Funding; Oncoceutics, Inc.: Research Funding; Janssen: Research Funding; BMS: Research Funding; Polaris: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; NKarta: Consultancy; GSK: Research Funding; Incyte: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Cortes:Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Komrokji:JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau; Novartis: Speakers Bureau. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Steensma:Arrowhead: Equity Ownership; Onconova: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Aprea: Research Funding; Astex: Consultancy; Summer Road: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Daiichi-Sankyo: Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Garcia-Manero:Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding.

Treatment of older patients with newly diagnosed AML remains challenging, limited by modest response rates with low-intensity therapy and higher levels of toxicity with intensive therapy. We previously reported on a low-intensity backbone of cladribine + LDAC (CLAD/LDAC)alternating with decitabine for older patients with AML, yielding higher rates of CR and improved outcomes compared to historical experience with hypomethylating agents (HMAs) in this setting (Lancet Haematology 2018). Recently, the combination of the BCL-2 inhibitor venetoclax with HMAs demonstrated significant improvements in response rates and survival over experience with HMAs alone. We hypothesized that the addition of venetoclax to the CLAD/LDAC backbone may further improve response rates and outcomes for this group of patients. We designed a phase II clinical trial studying the combination of venetoclax with CLAD/LDAC alternating with 5-azacytidine (AZA) in older (age ≥ 60y) or unfit patients with newly diagnosed AML (excluding APL). Induction was cladribine 5 mg/m2 IV over 30 minutes on days 1-5 followed by araC 20mg SQ BID on days 1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV over 30 minutes on days 1-3 + araC 20 mg SQ BID on days 1-10 alternating with 2 cycles of AZA 75 mg/m2 on days 1-7, for up to 18 cycles. Venetoclax was added on days 1-21 of each cycle with dose adjustments (50-400 mg) for concomitant CYP3A inhibitors. One cycle was 4 weeks and up to 2 cycles of induction were allowed. All patients underwent pre-treatment cytogenetic analysis and mutational testing using a customized 81-gene next generation sequencing panel. MRD was assessed using multiparameter flow cytometry in the marrow at the time of remission. Twenty-six patients have been treated on study, with a median age of 69 yrs (57-84); 11 (42%) pts were ≥ 70 yrs and 1 pt < 60 yrs who was unfit for intensive chemotherapy was enrolled. The baseline patient characteristics are summarized in Table 1. Among 24 evaluable pts, 18 (75%) achieved a complete remission (CR), 3 (13%) had a CR with incomplete platelet recovery (CRp), and 1 (4%) had CR with incomplete neutrophil recovery (CRn) for a CR/CRp rate of 88% an overall response rate of 92%. The median number of cycles to response was 1 (1-3) and 83% of pts were negative for MRD by multi-parameter flow cytometry at the time of CR. Among 9 evaluable pts with diploid karyotype, the CR rate was 100% with full count recovery. Rates of CR/CRp/CRn among other genetic subgroups are summarized in Table 2. The regimen was well tolerated, with a 4-week mortality of 0%. The median time between cycle 1 and 2 was 32 days. The most frequent grade 3/4 non-heme adverse events were neutropenic fever (n=12), lung infection (7), decreased urine output (2), and acute kidney injury (1). Four (18%) of the 22 responding pts went on for allogeneic stem cell transplant, 1 pt (4%) relapsed, 2 (8%) did not respond, and 19 pts continue on treatment. With a median follow-up of 4 months, the median remission duration and overall survival (OS) have not been reached, with an estimated 3- and 6-month OS rate of 95% (Figure). The combination of venetoclax with CLAD/LDAC alternating with AZA is a lower intensity, well-tolerated, and highly effective regimen for older patients with newly diagnosed AML, producing high rates of MRD negative remission and meaningful blood count recovery. Further study of this approach is warranted. Disclosures Kadia: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding. Konopleva:Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Agios: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. Borthakur:AbbVie: Research Funding; Janssen: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; Incyte: Research Funding; Merck: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Eli Lilly and Co.: Research Funding; Eisai: Research Funding; Oncoceutics: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Strategia Therapeutics: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; NKarta: Consultancy; Oncoceutics, Inc.: Research Funding; Arvinas: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; cellectis: Research Funding; Daiichi-Sankyo: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; sagerstrong: Research Funding. Daver:Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Agios: Consultancy; Forty-Seven: Consultancy; Abbvie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy; Novartis: Consultancy, Research Funding; Servier: Research Funding; Glycomimetics: Research Funding; NOHLA: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. DiNardo:abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; syros: Honoraria. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Andreeff:Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; CPRIT: Research Funding; NIH/NCI: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Ravandi:Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding. Kantarjian:Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Pfizer: Honoraria, Research Funding.

Background: Inotuzumab ozogamicin (INO) and blinatumomab both improve survival in relapsed or refractory acute lymphoblastic leukemia (ALL) compared to conventional chemotherapy. The combination of INO with reduced-intensity mini-hyper-CVD chemotherapy in older adults with newly diagnosed ALL is safe and highly effective (Kantarjian H et al, Lancet Oncol 2018;19(2):240-8). The addition of blinatumomab to this regimen may further improve outcomes. Methods: Patients (pts) ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B-cell ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. In order to decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). Results: 64 pts have been treated, 5 of whom were in complete remission (CR) at enrollment. Pt characteristics are summarized in Table 1. Median age was 68 years (range, 60-81 years); 27 pts (42%) were ≥70 years. 28% were positive for TP53 mutation, 19% were CRLF2 positive, and 27% had adverse-risk karyotype. 33/58 pts (57%) were CD20+ and received rituximab. Among 59 pts evaluable for morphologic response, 58 (98%) responded (CR, n=51; CRp, n=6; CRi, n=1). MRD negativity by 6-color flow cytometry was achieved in 48/62 pts (77%) after 1 cycle and 59/63 pts (94%) overall. There were no early deaths, and the 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 63 pts who achieved remission, 9 (14%) relapsed, 3 (5%) underwent allogeneic SCT in first remission, 30 (48%) remain on treatment or have completed maintenance, and 21 (33%) died in CR/CRp. The rate of death in CR/CRp was higher in pts ≥70 years of age vs. 60-69 years (50% vs. 22%; P=0.02). Causes of death for pts in CR/CRp included: sepsis (n=7; all in pts 70 years and older), VOD (n=3), gunshot wound (n=1), dementia and deconditioning (n=1), end stage renal disease (n=1), MDS/AML (n=4; 3 in pts 70 years and older) and unknown causes (n=4). 6 pts (9%) developed VOD, 1 after subsequent allogeneic SCT. The rate of VOD was 6/64 (9%) with no difference in VOD in pts who did or did not receive blinatumomab. With a median follow-up of 37 months (range, 2-85 months), 34 pts (53%) were alive, 30 of whom (47%) were in CR and MRD negative status. The 3-year continuous remission and OS rates were 76% and 54%, respectively (Figure 1A). The 3-year continuous remission rate was 69% and 87% for pts age 60-69 and ≥70 years, respectively (P=0.25), and the 3-year OS rate was 63% and 42%, respectively (P=0.13; Figure 1B). The trend for worse survival in the pts ≥70 years was driven predominantly by the increased rate of death in CR/CRp in this older group. The outcomes of pts who did or did not receive blinatumomab were similar. Compared to a similar historical cohort of older pts treated with hyper-CVAD ± rituximab (n=77), mini-hyper-CVD + INO ± blinatumomab resulted in significantly higher 3-year OS (54% vs 32%; P=0.007). Conclusion: Reduced-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, is safe and effective in older adults with newly diagnosed Ph-negative ALL, with an overall response rate of 98% and 3-year OS rate of 54%. Further optimization of this regimen with less chemotherapy in patients 70 years and older is warranted to further decrease the rate of death in remission. Disclosures Short: Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Ariad: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jain:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Daver:Otsuka: Consultancy; Astellas: Consultancy; NOHLA: Research Funding; Jazz: Consultancy; Forty-Seven: Consultancy; Agios: Consultancy; Immunogen: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Servier: Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Pemmaraju:sagerstrong: Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; incyte: Consultancy, Research Funding. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Konopleva:Ablynx: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Astra Zeneca: Research Funding; Agios: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Merck: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Eisai: Research Funding; Oncoceutics, Inc.: Research Funding; AbbVie: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; NKarta: Consultancy; Bayer Healthcare AG: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Strategia Therapeutics: Research Funding; Incyte: Research Funding; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding. Burger:BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria. Wierda:Genentech: Research Funding; Juno Therapeutics: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; GSK/Novartis: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; AbbVie: Research Funding; Gilead Sciences: Research Funding. DiNardo:syros: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. O'Brien:Astellas: Consultancy; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Kite: Research Funding; Aptose Biosciences, Inc: Consultancy; Acerta: Research Funding; Verastem: Consultancy; GlaxoSmithKline: Consultancy; Eisai: Consultancy; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding; Regeneron: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy. Jabbour:AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. OffLabel Disclosure: The use of inotuzumab ozogamicin and blinatumomab as frontline therapy for older patients with ALL

Background: Cytogenetic abnormalities have prognostic implications in acute lymphoblastic leukemia (ALL). High risk cytogenetics include complex karyotype (≥ 5 anomalies), low-hypodiploidy / near-triploidy, 14q32/IGH rearrangements and 11q23/KMT2A rearrangements. The most frequent gene partner involved in KMT2A-rearranged ALL is AFF1 located on chromosome 4q21. ALL with t(4;11)(q21;q23) - KMT2A-AFF1 has a very poor outcome and patients (pts) with this translocation are offered allogeneic stem cell transplantation (HSCT) in first complete remission (CR1). More than 130 gene partners have been described in KMT2A rearrangements. The frequency and prognostic signification of these various gene partners in KMT2A-rearranged ALL is unknown and it is uncertain whether pts harboring these translocations should be offered HSCT in CR1. Methods: We retrospectively reviewed 1102 pts with newly diagnosed ALL treated at our institution between 1984 and 2019 to identify pts with KMT2A rearrangement. Presence of t(11;v)(q23;v) was assessed by conventional cytogenetics with G-banding and/or by fluorescence in situ hybridization (FISH). Clinical and laboratory data were collected retrospectively. We analyzed the pts characteristics at baseline and evaluated remission rates, overall survival (OS) and relapse-free survival (RFS). The survival curves were estimated using the Kaplan-Meier method and differences between groups were evaluated with the log-rank test. Univariate Cox proportional hazard ratio were used for estimation of hazard ratios (HR). HSCT in CR1 was considered as a time-dependent covariate. Results: We identified 51 cases (5%) of ALL with KMT2A rearrangement or amplification. Two cases (4%) were cryptic KMT2A rearrangements identified by FISH, but with a normal karyotype. The most common KMT2A rearrangement was t(4;11)(q21;q23) in 42/51 (82%) pts. Four (8%) pts had t(11;19)(q23;p13) in which KMT2A can be partnered with MLLT1 or ELL, 1 (2%) pt had t(9;11)(p21;q23) - KMT2A-MLLT3, 1 (2%) pt had t(11;15)(q32;q26) with unknown gene partner, 1 (2%) pt had hsr(11)(q23) with KMT2A amplification, and 2 (4%) pts had an unknown gene partner (identification by FISH). Sixteen (31%) pts had additional chromosomal abnormalities, with i(7q) (3/51, 6%) and + X (2/51, 4%) the only identified in more than one case. The pts' clinical characteristics are summarized in table 1. All but one were B-cell ALL. The median age at diagnosis was 45 year-old (range, 18 - 78). The median white blood cell count (WBC) at diagnosis was 107.0 x 109/L (range, 0.5 - 1573.0) and 29/51 (57%) pts had hyperleukocytosis with WBC ≥ 100 x 109/L. None of the cases of B-ALL had CD20 expression, but 32/41 (78%) had CD22 expression (median of 59%; range 0 - 99%). Pts were treated with various regimens, with most pts receiving the Hyper-CVAD regimen (n=35), or one of its variation including addition of anti-CD20 monoclonal antibody (n=2), blinatumomab (n=1), nelarabine for T-cell ALL (n = 1) or dose adjusted regimen with omission of doxorubicin (mini-Hyper-CVD, n = 4). The complete remission rate was 88% (45/51) with 5 (10%) deaths during induction and 1 (2%) refractory disease. The measurable residual disease (MRD) negativity rate was 57% (17/30 evaluable pts). With a median follow-up of 63 months, the median OS and RFS were 14 months (95% confidence interval [CI], 10 - 39] and 10 months (95% CI, 6 - 17), respectively. The 5-year OS and RFS rates were 17% (95% CI, 9 - 35%) and 15% (95% CI, 7 - 33%), respectively. Comparing the 42 pts with t(4;11) and the 9 pts with other KMT2A abnormalities, no difference in OS (HR 0.94, p = 0.89) and RFS (HR 1.00, p = 0.99) were observed (Figure 1A-1B). HSCT in CR1 was associated with a better outcome in terms of OS (HR 0.49, 95% CI 0.24 - 0.99, p = 0.049) and RFS (HR 0.44, 95% CI 0.22 - 0.92). In the 17 (33%) pts who underwent HSCT in CR1 (16 with t(4;11) and 1 with other KMT2A rearrangement), the 5-year OS and RFS rates were 30% (95% CI, 14 - 68%) and 24% (95% CI, 9 - 62%), respectively, versus 10% (95% CI, 3 - 35%) and 9% (95% CI, 3 - 34%), respectively, in the 34 (67%) pts who did not undergo HSCT. The only 2 pts with KMT2A rearrangements other than t(4;11) who remain alive are the only 2 who have undergone HSCT: 1 in CR1 and 1 in CR2. Conclusion: Patients with KMT2A-rearranged ALL have a poor prognosis, which do not differ based on the gene partner involved. These patients benefit from HSCT in CR1. Disclosures Kantarjian: BMS: Research Funding; Astex: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria. Khoury:Kiromic: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding. Jain:Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. DiNardo:medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; jazz: Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria. Takahashi:Symbio Pharmaceuticals: Consultancy. Borthakur:Xbiotech USA: Research Funding; Eisai: Research Funding; AstraZeneca: Research Funding; Cantargia AB: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding. Konopleva:Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Agios: Research Funding; Astra Zeneca: Research Funding; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:H3 Biomedicine: Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Pragmatist: Consultancy; Constellation: Consultancy; Protaganist Therapeutics: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

Background: Aplastic anemia is an autoimmune disease of the bone marrow (BM) characterized by defective and decreased regulatory T cells (Tregs) which results in unchecked cytotoxic T cell mediated bone marrow suppression [1]. In a xenogeneic model of induce BM aplasia, adoptive therapy with cord blood (CB) Tregs reverses such a defect (Fig 1A). Furthermore, as compared to peripheral blood (PB), CB Tregs show a higher expression of Helios, a marker of thymic derived Tregs (Fig 1B) and CB Tregs exert a superior suppression of proliferating conventional T-cells in CFSE assay (Fig 1C). In a xenogeneic mouse model of GVHD, CB Tregs can exert suppression across HLA barrier resulting in survival benefit (Fig 1D); and in another xenogenic lupus model, a single dose of CB Tregs results in significant decrease in circulating effector T cells (Fig 1E) up to 8 weeks. Furthermore, under stressful conditions of continued culture in the presence of inflammatory cytokines including IL15 and IL23, CB Tregs do not secrete IL-17 or express RORγt, a concern of plasticity that plagues PB Tregs (Fig 1F). In fact, CB Tregs increase their secretion of the suppressor cytokine, IL-10 in response to inflammatory stress, which supports our hypothesis, that CB Tregs based adoptive therapy can have wide application and can be used to treat inflammatory disorders. Therefore, we hypothesized that adoptive therapy with CB Tregs can be utilized as treatment for the inflammatory bone marrow failure (BMF) disorders including aplastic anemia, hypoplastic myelodysplasia and primary myelofibrosis. Study Design and Methods: We have now launched a phase I clinical trial examining the role of single infusion of CK0801, an allogeneic, fresh CB Treg product, utilizing novel process development that consist of well-defined qualification criteria for the starting material (cord blood units), parameters for manufacturing and culture-expansion; and well-defined analytic testing and lot release criteria, for the treatment of BMF, where 3 doses are examined: i) dose level I: 1x106 cells/kg; ii) dose level II: 3x106 cells/kg and iii) dose level III: 10x106 cells/kg (NCT03773393). The study follows 3+3 phase I design where 3 patients will be treated at dose level I. If no DLT is observed, then the dose will be escalated to dose level II and if no DLT is observed, then the dose will be escalated to dose level III. If 1 DLT is observed at a dose level, then 3 additional patients will be treated at that level. If no additional DLTs, then that dose level will be defined as MTD. If ≥2DLTs are observed at dose level II or III, then prior dose level is defined as MTD. If ≥2DLTs at dose level I, then DSMB will review and evaluate for study continuation. MTD will be decided when 6 patients are treated at a dose level with < 2 DLTs. The eligibility criteria include: i) diagnosis of aplastic anemia, myelodysplastic syndrome or myelofibrosis, ii) Age > 18 years, iii) cord blood unit matched at HLA 3 out of 6 with the patient for generation of CK0801. The primary endpoint includes dose limiting toxicity (DLT) as defined by i) severe (grade 3 or 4) infusion toxicity within 24 hours; ii) regimen related death within 30 days or iii) severe (grade 3 or 4) cytokine release syndrome within 30 days. The secondary endpoints include i) disease-specific response including complete remission, transfusion independence and hematologic improvement and ii) duration of response. The exploratory endpoints include assessment of PB and BM immune reconstitution and inflammatory cytokines at baseline and scheduled follow ups of Days 0, +1, +3, +7, +14, +21, +30, +60, +90, +180 and +365 in the post-treatment setting. These studies will include T cell compartment analysis: Treg, Effector T cells, T-cell anti-viral activity. Serum will be analyzed for inflammatory cytokines: IL1, IL2, IL4, IL6, IL7, IL8, IL10, IL17, IFN-gamma, ST2, REG3a, OPN, Follistatin, Elafin, TGF-beta. Optional exploratory cytokines: SCF, G-CSF, GM-CSF, HGF, VEGF, SDF1a, MCP1, MCP2, TARC, MIP3a, TECK, CTACK, CCL28, FGF, PDGF, EGF, TGF-α, TLR. The first patient is already consented with a planned total of 9 patients. References: 1. Kordasti S, Costantini B, Seidl T, et al., Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment. 2016 Sep 1;128(9):1193-205 Figure 1 Disclosures Kadia: AbbVie: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. DiNardo:abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Iyer:Rhizen: Research Funding; Seattle Genetics: Research Funding; Trillium Therapeutics: Research Funding; Merck: Research Funding; Spectrum: Research Funding. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Jabbour:BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Borthakur:Novartis: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Agensys: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Eisai: Research Funding; Strategia Therapeutics: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; GSK: Research Funding; NKarta: Consultancy; Cantargia AB: Research Funding; Cyclacel: Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

Background: Although the JAK1/2 inhibitor RUX provides significant benefits to patients with myelofibrosis (MF), activation of non-JAK pathways could lead to therapeutic resistance, suggesting a need for rationally developed therapeutic combinations. We hypothesized that the combination of RUX and AZA would target distinct clinical and pathological manifestations of MF, resulting in synergistic efficacy. Updated phase II study results are presented in this abstract. Methods: This is a single-arm Phase II trial of RUX in combination with AZA for pts with MF. Eligible pts included adults >18 years with newly diagnosed or previously treated (excluding previous therapy with RUX or AZA) MF with int-1, int-2, or high risk according to the DIPSS criteria. RUX at 15-20 mg orally twice daily (BID) was given alone in 28 day cycles for the first 3 cycles. AZA was added from cycle 4 onwards at 25 mg/m2 days 1-5, and could be gradually up-titrated to 75 mg/m2 days 1-5 over subsequent cycles if clinically indicated. AZA could be initiated prior to cycle 4 in pts with proliferative disease or high bone marrow blasts. The primary objective was to determine the response rate per the IWG MRT 2013 criteria. Secondary objectives included safety and tolerability. Results: 60 pts were enrolled (58 evaluable, 2 too early) between May 2013 and June 2019. Pt characteristics are in Table 1. The median age was 66 years (range, 46-87). Forty pts (67%) had int-2/high DIPSS score, 9 (15%) had ≥10% blasts. JAK2V617Fwas detected in 35 pts (58%). Among 44 pts with comprehensive molecular panel, 21 (48%) had additional mutations (ADD mut), with the most frequent being ASXL1 and TET2 (8 pts each, 18%; Table 1), followed by IDH, TP53 and DNMT3A. AZA was given to 53 pts (88%), with 6 (11%) pts initiating AZA earlier than cycle 4. Median (med) follow-up was 35 months (range, 1-70+) with a med of 26 cycles (range, 1-70) administered. 20 pts (33%) are still on RUX AZA therapy, with a med of 47 cycles (range, 1-70), including 7 pts who have received >65 cycles. Twenty nine (48%) and 16 (30%) pts required RUX and AZA dose reduction and/or treatment interruption, respectively. Med dose of RUX was 15 mg BID (range, 5-25). Among 58 evaluable pts, 43 (74%) achieved IWG-MRT 2013 objective response (OR) on study (Table 2), with a med time to response of 2.0 months (range, 0.7-19.0). Among 43 pts with baseline splenomegaly ≥5 cm, 30 (70%) and 25 (58%) had palpable spleen reduction ≥50% at any time on study and at week 24, respectively. Thirty percent of responses (13/43), including responses in spleen (10/30), occurred only after the addition of AZA (Table 2). Med time to response after the addition of AZA was 4.0 months (range, 0.5-17.0). Median overall survival (OS) was not reached, with 1-year and 3-year OS rates of 89% and 66%, respectively. Improvement in bone marrow morphology (fibrosis, collagen and/or osteosclerosis), was noted in 21 (61%) of 35 sequentially evaluated patients (Figure 1, bone marrow improvements at 24 months and at any time on a study). The med time to response was 12.0 months (range, 6.0-18.0), and responses have been sustained in all but 1 patient. Updated results will be presented at the meeting. The med duration of responses (DoR) was not reached for OR, ≥50% spleen length reduction, or symptom response. Patients with ≥1 ADD mut appeared to have shorter DoR spleen (≥50% spleen length reduction) than those with no ADD mut; 47 months vs NR (p=0.05). Patients with TP53 and IDH1/2 mutation had shorter DoR (DoR [OR] 18.5 and 13.0 months, respectively) than those with no ADD mut, ASXL mut, or any other single ADD mut (DoR [OR] 46.0, 45.0 months and NR). The most common possibly therapy related non-hematological adverse events (AEs) were infections (28%) and constipation (11%). Significant hematological AEs included grade III-IV anemia (37%), neutropenia (18%) and thrombocytopenia (27%), these were transient and did not require therapy interruption in most cases. Only 4 pts discontinued therapy due to drug-related AEs (cytopenia in 4 pts). Table 3 summarizes AEs on study. Conclusion: Concomitant RUX with AZA appears safe and effective. Myelosuppression was manageable with only 4 pts (7%) requiring study discontinuation due to cytopenias, a similar rate to single agent RUX in phase III trials (7-9%). A 2013 IWG-MRT objective response and ≥50% spleen reduction were achieved in ≥ 70% of pts at any time on study; and responses appear durable. The study is ongoing (NCT01787487). Disclosures Verstovsek: Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Bose:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Constellation: Research Funding; Kartos: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding. Pemmaraju:affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Borthakur:Agensys: Research Funding; Novartis: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; PTC Therapeutics: Consultancy; AstraZeneca: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; Cyclacel: Research Funding; Bayer Healthcare AG: Research Funding; Incyte: Research Funding; BMS: Research Funding; GSK: Research Funding; AbbVie: Research Funding; NKarta: Consultancy; Janssen: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; AbbVie: Consultancy, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. DiNardo:celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; syros: Honoraria; jazz: Honoraria; daiichi sankyo: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria. Ravandi:Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Bueso-Ramos:Incyte: Consultancy. Kantarjian:Jazz Pharma: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Ariad: Research Funding.

INTRODUCTION The introduction of 20 years ago of imatinib, the first tyrosine kinase inhibitor (TKI), has drastically improved the survival of patients (pts) with Chronic Phase (CP) Chronic Myeloid Leukemia (CML), with a life expectancy similar to that of the general population. First used in patients after interferon (IFN) failure, imatinib and other TKIs have become standard frontline therapy. This analysis was done to investigate a 20-year outcome of Imatinib in pts Interferon-alpha failure. METHODS The long term outcome of 154 patients treated at our Institution with imatinib 400 mg after interferon failure from 1999-2000 was analyzed. RESULTS The median age was 44 (16 to 79yrs). 16 pts (11%) had prior malignancies 6 (38%) breast cancer, 3 (19%) skin cancer, 2 (12%) each prostate cancer and lymphoma, and 1 patient (6%) each lung cancer, colon cancer, and hairy cell leukemia. At the time of this analysis, 26 pts (17%) remained on imatinib of whom 22 pts (85%) had decreased their dosage. The median dose at last follow-up (FU) was 400mg (100-400mg). 128 pts (83%) discontinued imatinib permanently. Among them, 47 pts (37 %) changed to second generation TKIs, including 27 pts (58%) to dasatinib, 13 pts (28%) to nilotinib, and 7 (15%) to bosutinib.28 (60 %) received therapy with only 2 TKIs, and 19 (41%) received more than two TKIs. 81 pts (64%) did not receive a second TKI. Of these, 29 (36%) died, 23 (29%) were lost to follow up, 4 pts (12%) transformed to blast phase, 6 (8%) had stem cell transplant, 6 (8%) received farnesyltransferase inhibitor, 2 (3%) hyper-CVAD, 2 (3%) gemtuzumab ozogamicin, 1 (2%) homoharringtonine, 1(2%) with decitabine, and 7 (9%) had elective treatment discontinuation. All these 7 pts have remained treatment-free with a median follow up after discontinuation of 11.8 months. At baseline 13.6% had cardiac/vascular comorbidities and none had renal comorbidities. At 5-years, 8.4% had cardiac/vascular adverse events (AEs) and 1.2% had renal AEs. At last follow up, 13.4% had developed cardiac/vascular AEs and 3.8% renal AEs. 12 pts (8%) acquired second cancers after the start of imatinib. Of those, 2 pts each (16%) had esophageal, prostate, breast, and pancreatic cancers, and one each glioblastoma, basal cell cancer, lung cancer, and melanoma each had 1 patient (6%). At the time of this report, intention to treat (ITT) responses are available for 63 patients. The median FU for these pts was 232 months, with a median overall survival (OS) of 51%. At three months, the ITT responses were: 35% for MCyR, 13% for CCyR. At 6 months they were 54% MCyR, 25% CCyR, and 2% each for MR4, MR4.5, and CMR (undetectable transcripts with ≥100,000 copies ABL). At one year they were 73% MCyR, 39% CCyR, and 3% for MMR, MR4, and MR4.5, respectively. At 18 months, responses were 67% MCyR, 38% CCyR, 5% for MMR, MR4, and MR4.5, respectively, and 2% for CMR. At three years, best responses included 71% MCyR, 49% CCyR, 40% MMR, 24% MR4 and MR4.5, and 13% CMR. At five years best responses were 83% MCyR, 70% CCyR, 43% MMR, 23% MR4, 19% MR4.5, and 11% CMR. At ten years, best responses were 66% for MCyR and CCyR, 63% for MMR, 46% for MR4, 41% for MR4.5, and 12% for CMR. Lastly, at fifteen years, best responses were 72% for MCyR and CCyR, 66% for MMR, and 59% for MR4 and MR4.5, and 34% for CMR. The overall best response rates (at any time) for these 63 pts was 87% for MCyR, 79% for CCyR, 62% for MMR, 51% for MR4 and MR4.5, and 33% for CMR (Table). The median duration of sustained MR4.5 for 21 pts was 139 months, and only 3 pts (15%) lost it while on therapy. The one year, five years, and nineteen years survival outcomes are: Overall Survival (OS) 98%, 89%, and 50%, respectively; Failure free survival (FFS) 68%, 31%, and 20%, respectively; Event Free Survival (EFS) 86%, 53%, and 40%, respectively. Treatment Free Survival (TFS), 90%, 81%, and 70%, respectively. CONCLUSION These results represent the longest follow-up of imatinib therapy available to date and demonstrate the long-term benefit of TKIs even in the setting of IFN failure. Figure Disclosures Kantarjian: Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Jazz Pharma: Research Funding. Borthakur:Incyte: Research Funding; Oncoceutics, Inc.: Research Funding; Bayer Healthcare AG: Research Funding; NKarta: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Agensys: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; Cantargia AB: Research Funding; Merck: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Janssen: Research Funding; BMS: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; GSK: Research Funding; Eisai: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy. Verstovsek:Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Promedior: Research Funding; Sierra Oncology: Research Funding; Ital Pharma: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Pragmatist: Consultancy; Protaganist Therapeutics: Research Funding; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Constellation: Consultancy; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Wierda:Cyclcel: Research Funding; Sunesis: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Miragen: Research Funding; Loxo Oncology Inc.: Research Funding; GSK/Novartis: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding.

Background: Therapy-related myeloid neoplasms (t-MNs) occur after exposures to chemotherapies and/or radiation therapies (CRT). However, true etiological association between CRT exposures and t-MN development is not clearly understood. We and others have recently revealed that selection of preleukemic mutant clones (TP53, PPM1D and others) under the selective pressure of CRT might play an important role in t-MN development (Wong et al. Nature 2014, Takahashi et al. Lancet Oncology 2017, Hsu et al. Cell Stem Cell 2018). For instance, PPM1D-mutated clone exhibited preferential expansion over wild-type clone only when exposed to cisplatin or etoposide, likely due to reduced apoptosis of mutant cells upon exposure to DNA damaging agents. In support of these findings, PPM1D-mutated t-MN patients had significantly frequent prior exposures to platinum and etoposide (Hsu et al. Cell Stem Cell 2018). These data led us to systematically analyze correlations between t-MN genotypes and prior exposures. Methods: We studied 471 patients (pts) with t-MNs (t-AML N = 188 and t-MDS N = 283) whose bone marrow or peripheral blood samples were analyzed by targeted next-generation sequencing. We performed extensive chart review to obtain history of prior exposures and analyzed correlation between CRT exposures and t-MN genotype. Results: Median age at diagnosis was 68 years (IQR:17-91) and the median latency from CRT exposures was 6 years (IQR: 0.1-45). (Table 1). The most frequent prior malignancies were breast cancer (20.8%), non-hodgkin's lymphoma (NHL) (20.3%) and prostate cancer (11.6%). Pts with NHL and multiple myeloma (MM) had significantly increased likelihood of developing t-MDS than t-AML (t-MDS vs. t-AML, 73.4% vs. 28.1%, P = .008 for NHL, 94.2% vs. 5.7%, P = < 0.001 for MM), whereas breast cancer pts developed t-AML more frequently than t-MDS (t-MDS vs. t-AML 43.8% vs. 56.1%, P < 0.001). Two hundred and eight (44.1%) pts had exposures to chemotherapy alone, 185 pts (39.2%) to chemo-radiotherapy, and 78 pts (16.5%) to radiotherapy alone. Eighty (16.9%) pts underwent autologous hematologic stem-cell transplant (auto-SCT). At least 1 driver mutation was detected in 392/471 (83.2%) t-MN pts and TP53 (36.3%), PPM1D (19.4%), TET2 (14.9%) and DNMT3A (14.6%%) were among the most frequently detected mutations. TP53 mutations were significantly more frequent in t-MDS than t-AML (43.8% vs. 25%; P=.000), while FLT3, NPM1, IDH1/2 mutations were more frequent in t-AML (14.9%, 7.4%, 9% respectively) than t-MDS (1.8%, 0%, 5.3%, 3.5% respectively) Correlation analysis of genotype and exposures confirmed previously known associations such as PPM1D mutations and platinum (log odds ratio [OR] 1.1, P = 0.01, false discovery rate [FDR] = 0.10), 11q23 rearrangement and topoisomerase II inhibitors (log OR 0.40, FDR = 0.71), and chromosome 7 abnormalities and alkylating agents (log OR 0.48, FDR =0.08). We found significant associations between TP53 mutations and immunomodulatory imide drugs (IMiDs, log OR = 0.98, , FDR =0.03); negative associations of alkylating agents with TET2 (log OR -0.93, FDR= 0.01) and NPM1 (log OR -3.31, FDR=0.003); and SRSF2 mutations with auto-SCT (log OR -2.24, FDR=0.03) and topoisomerase II inhibitors (log OR -2.42, FDR= 0.02). (Figure 1 Univariate analysis) We adjusted for the confounding effect from multiple exposures by multivariate logistic regression analysis (MLR) with modelbuilding by stepwise AIC or BIC selection criteria. MLR revealed a significant association of TP53 mutations with IMiDs (log OR = 1.07, P = 0.001), platinum (log OR = 0.61, P = 0.02), and vinca alkaloid (log OR = 0.62, P = 0.01). As well as a significant association between EZH2 mutations and vinca alkaloid (Log OR = 1.68, P = 0.009, Table 2). Conclusions: Comprehensive analysis of genotype and prior exposures in a large cohort of t-MNs revealed previously unknown associations, such as EZH2 mutations and vinka alkaloids, and TP53 mutations and IMiDs. The connection between TP53 mutations and IMiDs is consistent with the clonal selection of TP53 mutant clone with lenalidomide in 5q- syndrome (Jädersten et al. JCO 2011). These data provide a rationale for studying the mechanism of clonal selection of TP53-mutant or EZH2-mutant cells under IMiDs or vinka alkaloids. Further, this knowledge might be clinically useful for cancer pts with specific clonal hematopoiesis in reducing the risk of t-MNs by avoiding exposures to certain drugs. Disclosures DiNardo: notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; jazz: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria. Konopleva:Eli Lilly: Research Funding; Ascentage: Research Funding; Forty-Seven: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Agios: Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; Astra Zeneca: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria. Borthakur:Oncoceutics: Research Funding; Novartis: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Eli Lilly and Co.: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare AG: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Agensys: Research Funding; Strategia Therapeutics: Research Funding; Xbiotech USA: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.

Cyclin dependent kinases (CDKs) are critical for cell cycle regulation and transcriptional elongation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased survival. CYC065 is a potent and orally‐available inhibitor of CDK2 and CDK9. CDK9 regulates transcription of genes through phosphorylation of RNA polymerase II (RNAP II) C-terminal domain (CTD). Through inhibition of CDK9, CYC065 suppresses CDK9-dependent gene expression and reduces the level of MCL1, a key anti-apoptotic protein. In the first-in-human study, CYC065 was administered by 4-hour infusion every 3 weeks in patients with advanced cancers. Biomarkers related to CYC065 target inhibition, e.g. phosphorylation of RNAP II CTD Ser2, a direct substrate of CDK9, and protein levels of downstream targets, such as MCL1, were determined in patient's peripheral blood mononuclear cells (PBMCs). Durable MCL1 suppression was observed after a single dose in 11 out of 13 patients treated at the recommended phase 2 dose (RP2D) of 192 mg/m2. Five of these 13 patients achieved stable disease lasting ≥ 6 cycles (Do, KT et al, AACR Annual Meeting 2018 Abs CT037). Acute myeloid leukemia (AML) frequently relapses after initial treatment by intensive or low-intensive therapy. Drug resistance has been attributed to dysregulation in apoptotic pathways. AML cells often upregulate pro-survival members of the BCL2 family, such as BCL2 and MCL1, to avoid apoptosis (Grundy M et al, Oncotarget, 2018). Suppression of MCL1 triggered rapid apoptosis in AML, and cured AML-afflicted mice (Glaser SP et al, Genes Dev. 2012). Preclinically, CYC065 has demonstrated potent anti-tumor effect in various AML cell lines, including those with MLL rearrangements, and xenograft models (Frame S et al, AACR, 2010 Abs 3886; Frame S et al, SOHO, 2014 Abs 209). Venetoclax has modest single agent activity in AML. MCL1 dependence appeared to correlate with resistance to venetoclax (Konopleva M et al, Cancer Discovery, 2016). Preclinical study confirmed synergy of CYC065 and venetoclax, suggesting that the suppression of both BCL2 and MCL1 may be more beneficial than inhibiting either one alone (MacKay C et al. AACR-NCI-EORTC 2015 Abs B182). Based on the above rationale, a clinical study (NCT04017546) has been initiated to evaluate a combination of CYC065 with venetoclax in relapsed/refractory AML and MDS. CYC065 will be administered intravenously via 4-hour infusion on Day 1 and Day 15 in combination with daily venetoclax every 4 weeks. Initial dose escalation is 33% and then 25% upon occurrence of the first dose limiting toxicity (DLT). RP2D is the highest dose level at which less than one-third of at least 6 patients experience a DLT during the first treatment cycle. Eligible patients are ≥18 years with previously treated AML or MDS and ≥10% blasts in bone marrow or peripheral blood; adequate bone marrow, renal and liver functions are required. All patients will be asked to participate in the pharmacokinetic and pharmacodynamic studies. Plasma levels of CYC065 and its metabolites as well as venetoclax will be determined. PBMCs will be collected to assess MCL1 levels and the phosphorylation and protein levels of other downstream targets of CDK9 inhibition. Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and bone marrow aspirate/biopsy will be performed to assess response according to standard criteria. Disclosures Borthakur: AbbVie: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; GSK: Research Funding; Polaris: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; Janssen: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Oncoceutics, Inc.: Research Funding; Strategia Therapeutics: Research Funding; PTC Therapeutics: Consultancy; BMS: Research Funding; Oncoceutics: Research Funding; Eisai: Research Funding; NKarta: Consultancy; Xbiotech USA: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Agensys: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Arvinas: Research Funding. Kadia:BMS: Research Funding; Bioline RX: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Al Azzawi:Cyclacel LTD: Research Funding. Zheleva:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Blake:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Chiao:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties.

Background: PLX2853 is an orally available, non-benzodiazepine BET (bromodomain and extraterminal domain) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g. MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profile in solid tumor patients revealed a short half-life (< 3 hour) enabling high peak plasma concentrations and nearly complete elimination from the plasma 9 hour post dose. Since strong and prolonged suppression of BET proteins have often untoward effects in normal tissues, the PLX2853 PK profile is hypothesized to be associated with improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: We are conducting an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily in adult patients with relapsed or refractory acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) using a modified continuous reassessment model (mCRM) with escalation with overdose control (EWOC) to determine the recommended phase 2 dose (RP2D). Up to 36 patients are expected to enroll. The dosing cycle and dose limiting toxicity window (DLT) is 21 days. Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments in various tissues. Enrollment through Cohort 2 (40 mg QD) is ongoing as of July 2019. Results: Five subjects with relapsed or refractory AML (median age 65 years) have received PLX2853 in escalating doses from 20 to 40 mg QD. Among these first 5 patients treated, the most common treatment emergent adverse events (AEs) regardless of causality in > 1 patient: decreased appetite (n=3), nausea (n=2), diarrhea (n=2), peripheral edema (n=2), cough (n=2), oropharyngeal pain (n=2), blood bilirubin increase (n=2), anemia (n=2), febrile neutropenia (n=2), fatigue (n=2), bacteremia (n=2), headache (n=2), dyspnea (n=2), and hypertension (n=2). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patient included: anemia (n=2), febrile neutropenia (n=2) and hypertension (n=2). No treatment-related serious AEs or DLTs have been observed. Following a 20 mg daily dose of PLX2853, median time to reach maximal plasma concentrations (Tmax) is 1 hour and the absorption half-life (T1/2) is < 3 hours. Conclusions: In an ongoing Ph1b study, PLX2853 has now completed its first dosing cohort for patients with relapsed or refractory AML or high risk MDS, and no DLT has been observed yet. As dose escalation continues, PK, PD, preliminary safety and efficacy data will be assessed further to determine the clinical significance of target engagement. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Pemmaraju: mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Borthakur:Polaris: Research Funding; Arvinas: Research Funding; Agensys: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Merck: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; NKarta: Consultancy; Incyte: Research Funding; Janssen: Research Funding; GSK: Research Funding; PTC Therapeutics: Consultancy. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Zhang:Plexxikon Inc.: Employment. Powell:Plexxikon Inc.: Employment. Severson:Plexxikon Inc.: Employment. Inokuchi:Plexxikon Inc.: Employment. Matusow:Plexxikon Inc.: Employment. Halladay:Plexxikon Inc.: Employment. Hsu:Daiichi Sankyo, Inc.: Employment. Watkins:Plexxikon Inc.: Employment. Walling:Myovant Sciences: Consultancy; Nurix: Consultancy; Aduro Biotech: Consultancy; Plexxikon: Consultancy; CytomyX: Consultancy; Flag Therapeutics: Consultancy; Aminex: Consultancy; Immunext: Consultancy; SensenBio: Consultancy; Harpoon Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Employment. Mims:PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Deregulated transcription, one of the key features of acute myelogenous leukemia (AML), remains largely unactionable by recently approved therapies. Preclinical studies indicate that targeting Cyclin Dependent Kinase 8 (CDK8) may be a novel therapeutic strategy for AML. CDK8 and its paralog CDK19, restrain activation of super-enhancer-associated tumor suppressors and lineage commitment genes in AML cells. SEL120 is a first-in-class, specific and selective inhibitor of CDK8/CDK19 and has shown activity in preclinical AML models. Preclinical characterization of SEL120 demonstrated a unique mechanism of action, related to known functions of CDK8 in the regulation of transcription. Cells sensitive to SEL120 show enrichment for leukemia stem cells (LSCs) signatures and higher signal transducer and activator of transcription 5 (STAT5) levels. Treatment with SEL120 reduced STAT5 phosphorylation in sensitive cell lines both in vitro and in vivo. Transcriptomic analysis of AML cells revealed that SEL120 regulated genes involved in lineage controlling functions. Specifically, trimethylation of lysine 27 on histone H3 (H3K27me3) by the polycomb repressive complex 2 (PRC2), was proposed to maintain the stemness of LSCs by preventing differentiation. Derepression of lineage commitment genes marked with H3K27me3, was one of the earliest transcriptional events in sensitive cells treated with SEL120. Consistent with its transcriptional effects, SEL120 induced differentiation of AML cells. Additionally SEL120 significantly repressed the MYC Proto-Oncogene-dependent transcriptomic signatures. Efficacy of SEL120 in AML was confirmed in models with high translational potential, including patient-derived AML cells (PDC) in vitro and in vivo. PDCs treated with SEL120 showed reduced viability, induction of apoptotic cell death and differentiation commitment. Administration of SEL120 in orthotopic AML patient-derived xenograft models reduced tumor burden to the level undetectable by flow cytometry, decreased splenomegaly and resulted in partial bone marrow recovery. CLI120-001 is a first-in-human, open-label, multi-center, modified 3+3 dose escalation phase Ib study of SEL120 with a dose-escalation cohort (DC) followed by an enrichment cohort (EC) in adult patients with AML or high-risk myelodysplastic syndrome who have relapsed or refractory disease and have received no more than 3 prior lines of therapy. Other key inclusion criteria are Eastern Cooperative Oncology Group performance status of 0-2, white blood cell (WBC) count 10000/µL, adequate organ function defined as: aspartate aminotransferase and alanine aminotransferase ≤3x the upper limit of normal (ULN), total bilirubin ≤1.5x ULN, creatinine clearance ≥60 ml/min, left ventricular ejection fraction ≥40%. Major exclusion criteria include Q to T wave interval corrected for heart rate (QTc) ≥450 ms, taking concomitant medications that are known to be strong inhibitors or inducers of cytochrome P450 1A2 or that can prolong QTc and/or cause torsade de pointes. The primary objective of the study is to assess safety and tolerability of SEL120 and to establish the recommended dose (RD) for further clinical development. Secondary objectives include evaluation of preliminary anti-leukemic activity and characterization of the pharmacokinetic profile of SEL120. The exploratory objective is to assess pharmacodynamics of SEL120 by using relevant biomarkers, including STAT5 pS726, transcriptional profiling by RNAseq and immunophenotypic changes related to stemness and differentiation of AML cells. SEL120 is administered as a single oral dose every other day for a total of 7 doses i.e. on days 1, 3, 5, 7, 9, 11 and 13, in a 21-day treatment cycle. Patients receive SEL120 until disease progression, unacceptable toxicity, or withdrawal of consent. The DC is now enrolling patients who are treated at dose levels defined by a modified Fibonacci sequence, and will end with selection of the RD based on all available study data. In the EC, additional patients will be treated at the RD to further support the evaluation of the RD of SEL120 monotherapy. The study is currently running in the United States and is planned to be completed in 2020. The ClinicalTrials.gov Identifier: NCT04021368. Disclosures Borthakur: Eli Lilly and Co.: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Eisai: Research Funding; Oncoceutics: Research Funding; Oncoceutics, Inc.: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; Strategia Therapeutics: Research Funding; BMS: Research Funding; PTC Therapeutics: Consultancy; Xbiotech USA: Research Funding; AbbVie: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Merck: Research Funding; AstraZeneca: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Abboud:Jazz Pharma: Speakers Bureau; Novartis: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017), Research Funding; Agios: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017); Tetraphase Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NKarta: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Nazha:Abbvie: Consultancy; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Mazan:Selvita S.A.: Employment. Majewska:Selvita S.A.: Employment. Wiklik:Selvita S.A.: Employment. Golas:Selvita S.A.: Employment. Bialas:Selvita S.A.: Employment. Windak:Selvita S.A.: Employment. Juszczynski:Selvita S.A.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chrom:Selvita S.A.: Employment. Rzymski:Selvita S.A.: Employment, Equity Ownership. Brzózka:Selvita S.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.