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Background: Observational studies suggest an anti-neoplastic effect associated with statins, metformin, dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. The aim of this study was to determine the impact of these medications in patients with myelodysplastic syndromes (MDS). Methods: A prospective Canadian national registry containing disease and patient-related characteristics enrolled patients with MDS between January 1, 2006 and December 31, 2019. The Ontario subset of the registry was linked to population-based health system administrative databases. The primary outcome was the impact of statin/oral hypoglycemic medication exposure on overall survival (OS). Cumulative medication exposure (in months) was evaluated from 1-year prior to registry enrollment to date of death or end of follow-up (March 31, 2020) as a time-varying covariate. Cox regression analysis controlling for comorbid disease burden (Aggregated Diagnosis Groups; ADG) and sociodemographic factors (age, sex, rurality, income quintile) examined the relationship between medication exposure and OS. Our secondary outcome was leukemia-free survival (LFS), in which cause-specific hazard model was used to evaluate the association between medication exposure and LFS, taking death as the competing event. Results: In total, 533 patients aged >66 years were included (395 lower-risk IPSS, 130 higher-risk IPSS). The median age was 76.0 years (IQR 72.0-81.0), 65.1% were male and 9% had secondary MDS. The mean follow-up was 2.6 years (SD+ 2.4). Starting one year prior to registry enrollment and until the end of follow-up, 49.3% used a statin, 18.9% used metformin, 9.0% used a sulfonylurea and 6.4% used a DPP4i. On univariate analysis, we identified an improved OS in the lower-risk IPSS group using DPP4i (HR 0.98, 95% CI 0.95-1.00, p=0.05), while there was no significant difference in the higher-risk IPSS group for users of DPP4i (HR 1.03, 95% CI 0.99-1.07, p=0.21). In both lower and higher-risk IPSS groups, there was no difference in mortality for statins (HR 1.00, CI 1.00-1.01, p=0.93), metformin (HR 1.00, CI 0.99-1.01, p=0.81) and sulfonylureas (HR 1.00, CI 0.99-1.02, p=0.43). Increased age (p There was no association between exposure to the studied medications and LFS in the lower-risk group: metformin (HR 0.99, 95% CI 0.96-1.02, p=0.32), sulfonylureas (HR 0.99, 95% CI 0.94-1.04, p=0.57) and statins (HR 0.99, 95% CI 0.98-1.01, p=0.41). The impact of DPP4i exposure on LFS could not be assessed in lower risk disease due to infrequent events. There was also no association in the higher-risk IPSS group: DPP4i (HR 1.06, 95% CI 1.00-1.12, p=0.05), metformin (HR 1.02, CI 0.98-1.05, p=0.34), sulfonylureas (HR 1.04, 1.00-1.08, p=0.07) and statins (HR 1.02, 1.00-1.04, p=0.12). On multivariable analysis in the lower-risk IPSS group, no associations were identified between the use of medications of interest and all-cause mortality: DPP4i (HR 0.98, 95% CI 0.95-1.00, p=0.06), metformin (HR 1.00, 95% CI 0.99-1.01, p=0.99), sulfonylurea (HR 1.00, 95% CI 0.99-1.02, p=0.65) and statins (HR 1.00, 95% CI 0.99-1.00, p=0.56). In those with known cause of death, the main cause of death amongst DPP4i users was infection (35.7%) followed by acute myeloid leukemia (AML) (21.4%) and cardiac disease (14.3%), while the main cause of death in patients not on DPP4i was progressive MDS (23.2%) followed by AML (22.5%) and infections (22.1%). Conclusions: DPP4i may confer a survival benefit in lower-risk but not higher-risk MDS that cannot be explained by a reduction in cardiovascular deaths. Metformin, sulfonylureas and statins showed no impact on OS and LFS in lower and higher-risk groups. Improved bone marrow function through exosome inhibition and increased granulocyte-macrophage colony stimulating activity is the suggested mechanism for the potential survival benefit with DPP4i in lower-risk IPSS patients. This represents the first study evaluating the impact of oral hypoglycemic mediations and statins in a large cohort of patients with MDS. Further prospective studies are required to further evaluate the effects of DPP4i in MDS. Disclosures Leber: AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Khalaf: Pfizer: Honoraria; Novartis: Honoraria; Paladin: Honoraria. Sabloff: TaiHo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Yee: Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding; Janssen: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding. Buckstein: Celgene: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; TAIHO: Research Funding; Otsuka: Research Funding.

Background: The incorporation of patient-reported outcomes with traditional disease risk classification, was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). A recently reported model, FA-IPSS(h), found that patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), among higher-risk IPSS population, further stratifies them into distinct sub-groups with different survival outcomes (Efficace et al, 2018). Compared to the IPSS, the revised IPSS (IPSS-R) is more refined in prognostic assessment and an IPSS-R score of > 3.5 may identify higher risk disease (Pfeilstocker et al, 2016). The Edmonton Symptom Self Assessment Scale (ESAS) Global Fatigue Scale (GFS), is a single-item fatigue rating scale (0-10, with 10 being the highest degree), which has been previously recommended by the National Comprehensive Cancer Network to screen for fatigue in all cancer populations. Aims: (1) to validate the FA-IPSS(h), among the Canadian MDS registry (2) investigate whether a modified index, integrating higher risk by IPSS-R with patient reported fatigue according to the GFS, is able to identify individual subgroups with divergent overall survival (OS). Methods: All adult patients diagnosed with MDS with an IPSS-R score >3.5 within 6 months before the date of registration were eligible for this analysis. Fatigue was assessed both by the QLQ-C30 questionnaire and the GFS. Frailty was assessed by the Canadian Study of Health and Aging (CSHA) 9 point Rockwood clinical frailty scale. Survival was calculated using standard Kaplan-Meier analysis. Results: This analysis included 331 patients. Median age was 73 years (range, 30-98 years), 65.7% were male, median blast % was 6% (range, 0-30), median IPSS-R score was 5.2 (range, 3.5-10) and 55% had high and intermediate-2 (Int-2) IPSS risk, 68% had high and very high IPSS-R risk disease, 66% were exposed to a hypomethylating agent. Median fatigue scores increased with Rockwood frailty scores. The median QLQ-C30 fatigue score was 33 (interquartile range (IQR), 22-55.6) and 4 (IQR, 2-6) by the GFS with 59% recording high fatigue (>4). At a median follow-up of 17 months (IQR, 9-30 months), 233 deaths were observed. The actuarial median OS was 19.3 months (95% CI, 16.5-21.7). We applied the FA-IPSS(h) using QLQ-C30 fatigue cutoffs of 45 (figure 1a) and found a significant difference in OS (p3.5 + Low Fatigue (3.5 + High Fatigue (≥45) (n=96). We found a significant difference in OS between these 2 groups, median OS 19.5 months (95% CI, 17.2-24.3) in group A versus 15.2 months (95% CI, 11.9-22.0) in group B (p=0.02) (figure 1b). We found similar results with these refinements, using the QLQ-C30 cutoff of 33 (the median in our patient population) (p4), was able to distinguish OS using the IPSS (p3.5 (p=0.005) (figure 1d). Conclusions: We were able to externally validate the FA-IPSS (h) using a threshold QLQ-C30 fatigue score of 45, as originally described and 33 (Canadian median), using both the IPSS and IPSS-R (score >3.5) classifications to define higher risk MDS. The easier to deploy ESAS GFS score of >4 further discriminates survival using the IPSS and IPSS-R. This emphasizes the power of self-reported fatigue at refining OS predictions in higher risk MDS and further bolsters the importance of considering patient related outcomes in global assessments. Disclosures Geddes: Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Keating:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees. Leber:Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leitch:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau. Shamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nevill:Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delage:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Elemary:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chodirker:Hoffman Laroche: Honoraria. Buckstein:Novartis: Honoraria; Celgene: Research Funding; Takeda: Research Funding; Celgene: Honoraria; Astex: Honoraria.

Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD.We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56.A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]).Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.).

Key Clinical Message Cyclic thrombocytopenia is often misdiagnosed as immune thrombocytopenia due to similar clinical features, a fact of significance because cyclic thrombocytopenia generally responds poorly to treatments used successfully in immune thrombocytopenia. A precise diagnosis must establish the statistical significance of periodicity of the platelet counts using statistical methods (eg, Lomb‐Scargle periodogram).

Abstract text: Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%; 90% CI 93% to 106%) to IV decitabine 20 mg/m 2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML. Methods: We used a randomized cross over design in which patients were randomized in the first 2 cycles 1:1 to either Sequence A: (decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m 2 in Cycle 2), or Sequence B: (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows: median age 71.5 years, 69% Male/31% Female, median weight 87kg (range 65-124), 25% ECOG 0, 75% ECOG 1. Population disease characteristics were: 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 10 9/L, platelets 84 x 10 9/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete Responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI); Overall Response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT). Conclusions: In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g Zeidan, et al 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients. References: Garcia-Manero, et al ASH 2019 Savona, et al, Int. MDS Symposium, 2021 Zeidan, et al, Cancer 2017: 3754-3762. Figure 1 Figure 1. Disclosures Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: 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; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. McCloskey: Pfizer: Consultancy; Takeda: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy; COTA: Other: Equity Ownership; BMS: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Griffiths: Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Genentech: Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Takeda Oncology: Consultancy, Honoraria; Novartis: Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding. Yee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Geron: Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria; Janssen: Research Funding; Onconova: Research Funding; Genentech: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; MedImmune: Research Funding; Jazz: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees. Zeidan: BeyondSpring: Consultancy; Janssen: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Ionis: Consultancy; Daiichi Sankyo: Consultancy; Epizyme: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Geron: Other: Clinical Trial Committees; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; Astellas: Consultancy; Astex: Research Funding; Jazz: Consultancy; Jasper: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patel: Agios: Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria. Sabloff: Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DeZern: Bristol-Myers Squibb: 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; Taiho: 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. Roboz: Janssen: Research Funding; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Blueprint Medicines: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Mesoblast: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.

Background: Asciminib (ASC) is a novel, first in class inhibitor specifically targeting the ABL myristate pocket. Phase 3 data comparing ASC to bosutinib have shown a higher rate of major molecular (MMR; 25.5% vs 13.2%) and complete cytogenetic response (40.8% vs 24.2%) at 6 months (mo) in CML patients (pts) in chronic phase (CP) who have failed at least two lines of TKI therapy with a favorable adverse event profile. ASC is available through a compassionate use program for heavily pre-treated CML pts. We share our real-world experience for the use of ASC in CML pts from this program across Canada. Methods: Data were collected on 22 CML pts treated with ASC from 2018 to 2021. Prior TKI history was recorded including: reason for failure to prior therapy, acquired mutations, prior cardiovascular (CV) events and outcome on ASC. BCR-ABL qPCR was performed every 3 mo at each institution. Achievement of MMR and molecular response of 2 log reduction (MR2) was assessed at 6/12 mo, and the most recent assessment. ASC dosing was also assessed at each time-point. Adverse events, resistance, and discontinuation of ASC were captured. Results: Median age was 68 years (range 20-92). 19 were in 1 st CP, 2 in accelerated phase (AP) and 1 in 2 nd CP. The median number of previous TKIs was 3 (range 2-5) with 17 pts (77%) failing at least 3 TKIs; 19 pts (86%) failing imatinib, 17 (77%) dasatinib, 12 (55%) nilotinib, 17 (77%) bosutinib, and 10 (45%) ponatinib. Median duration from first TKI to ASC was 94 mo (range 11-233). 17/22 (77%) pts had a history of a CV event including stroke, peripheral arterial disease, or coronary artery disease. 4 pts had a preexisting T315I mutation. Pts failed previous TKI therapy due to A) resistance or suboptimal response to TKI (n=15, 68%) and B) intolerance to previous TKI (n=7, 32%). With a median of 16 mo follow-up (range 1-34), MMR was noted in 3/17 (18%) and 3/8 (38%) pts evaluated at 6 and 12 mo, respectively. MR2 was noted in 7/17 (41%) and 4/8 pts (50%) at 6/12 mo (Table 1). The cumulative incidence of MMR considering competing events (i.e. ASC discontinuation) was 20.5% (95%CI: 6-41%) and 34.4% (13-57%) while MR2 was 43.8% (22-64%) and 49.4% (25-69%) at 6/12 mo (Fig 1). The proportion of pts in MMR increased from a baseline of 5% to 18%, 18%, 30%, and 38% at 3, 6, 9 and 12 mo. Pts without T315I mutation (n=18) started with a dose of 40mg bid, while pts with T315I started at either 80mg or 120mg bid, then gradually escalated aiming to 200mg bid. 4 pts discontinued the medication due to treatment failure (n=3) or grade 4 thrombocytopenia (n=1). Of those who discontinued, 2 were in AP on initiation of ASC. Side effects included myalgias (n=4), elevated lipase (n=2) and pleural/pericardial effusions (n=2). No CV events were noted in 22 pts. There was no event of disease progression to advanced disease while on ASC therapy or acquisition of new ABL1 kinase domain mutation. The MMR and MR2 rate was lower in ponatinib pre-treated pts (n=10) compared to ponatinib naïve pts (n=12) (Table 1). The MMR and MR2 rates in pts with a T315I mutation (all 4 were ponatinib pre-treated) are at least similar or better than those without T315I. No difference in MMR or MR2 rate was noted between the 2 groups of resistance/suboptimal response vs intolerant to prior TKI therapy. In a subgroup analysis of pts with a past history of a CV event (n=17), no pt discontinued ASC due to another event after a median duration of 17 mo on ASC (range 3-34). Thus, these pts with otherwise very limited options had a reasonable response to ASC without increased risk of CV toxicity (Table 1). Conclusion: In a Canadian real-world experience of ASC use within a compassionate access program in heavily-pretreated CML pts (many with a history of prior CV event), MMR and MR2 rates were comparable to that with ASC in the published literature. No new CV events were noted during ASC therapy in the present group of patients. Figure 1 Figure 1. Disclosures Busque: Novartis: Consultancy. Leber: Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaedbey: Jewish General Hospital - McGill University: Current Employment; Royal Victoria Hospital Lakeshore Hospital: Ended employment in the past 24 months; Celgene/BMS, Janssen: Honoraria; Takeda, Sanofi: Honoraria. Assouline: Johnson&Johnson: Current equity holder in publicly-traded company; Gilead: Speakers Bureau; Amgen: Current equity holder in publicly-traded company, Research Funding; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Jewish General Hospital, Montreal, Quebec: Current Employment; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Kim: Novartis: Consultancy, Honoraria, Research Funding; Bristol- Meier Squibb: Research Funding; Pfizer: Honoraria.

Background: AML is a complex disease that encompasses a huge variation of cytogenetic and mutational backgrounds, which is often complicated by age related functional deficits (Klepin et al. 2013). Given the expanding availability of reduced-intensity treatment options, patient fitness and frailty measures have become increasingly instrumental in the decision between a wide range of treatment options. Furthermore, studies have also demonstrated potential benefits in older patients who receive intensive induction chemotherapy (Julisson 2011), creating a need for additional assessments to identify suitable induction candidates. Some frailty-associated assessments including timed-up-and-go test (TUGT) and the short physical performance battery have been linked to outcomes but are not yet in broad clinical use (Kleplin et al. 2013, Khalaf et al. 2020). To minimize the burden of implementing new patient assessments, we evaluated the utility of commonly available clinical measures of frailty-associated factors including sit-to-stand test and iADL status in predicting patient outcomes. Methods: We performed a retrospective cohort study of elderly patients newly diagnosed with AML at Juravinski Cancer Center between Jan 2019 and Dec 2020. We examined a total of 44 patients aged 65+. The primary outcome was overall survival (OS). Significant risk factors were identified using the Cox proportional hazards model. Results: 43 patients had sufficient data and were included in the analysis. The median age was 70 years (range 65-89), 53% were female and 47% were male. At the time of review, 21 patients were deceased (48.8%). The median survival time was 345 days. 26 patients received full induction treatment (7+3, FLAG-IDA, or Vyxeos), and 18 received conservative treatment (LDAC, azacytidine, or supportive care). The clinical wellness of the patients at diagnosis time was assessed by baseline clinical and laboratory findings. (Table 1) The Cox regression model was used to examine these variables in predicting overall survival (Figure 1). As expected, the ELN risk group was significantly correlated with OS (HR 2.94 95%CI [1.41-6.11]), along with laboratory measures of disease burden including blood blast count (HR 1.02 [1.00-1.03]), WBC, (HR 1.02 [1.01-1.03]) and ANC (HR 1.05 [1.02-1.08]). We then assessed the influence of patient fitness factors on OS. The HCT-CI score was used as an aggregate comorbidities measure. While typically used for post-SCT prognosis, we found that HCT-CI assessed at diagnosis time was a significant predictor of OS (HR 1.22[1.04-1.45]). When added to a multivariate Cox model including ELN and age, the HCT-CI independently predicted OS (p = 0.003) and improved prediction efficiency by the Akaike information criteria (115 vs 122). This corroborates earlier findings by Sorror et al. 2017, who showed incorporation of biochemical and AML-specific variables to HCT-CI yields improved prognostic value. Within the HCT-CI, the AST and cardiac disease scores were the most associated with OS (HR 1.03[1.00-1.05] and 2.27[1.09-4.76]). While clinical and laboratory assessments were readily available, functional assessments of frailty were scarce. Previously reported frailty measures such as KPS score or TUGT were not assessed at the study center. OT/PT routinely administer sit-to-stand or standing balance tests as a part of fall risk assessment. However, this data was only available for 18 patients (41.8%). Independent sit-to-stand was not detected as a significant OS predictor (HR 0.63[0.14-2.83]), possibly related to the very limited sample size. BMI was marginally predictive (HR 1.07[0.99 - 1.08]), but unlike HCT-CI it was not an independent predictor when combined with ELN. Patient age did not significantly predict OS. Conclusion: This single center retrospective study was aimed at examining the role of existing clinical or functional measures of fitness and frailty in predicting overall survival. HCT-CI and ELN were found to be the most predictive factors amongst the variables examined, suggesting that a morbidity index such as HCT-CI could provide prognostic utility. However, functional assessments of frailty were not readily completed, limiting the ability to evaluate their usefulness. A future larger prospective study focused on optimizing and incorporating routine functional assessments of frailty is needed to address this topic. Figure 1 Figure 1. Disclosures Leber: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Khalaf: Novartis: Honoraria; Paladin: Honoraria; Pfizer: Honoraria.

Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%; 90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study. Methods: We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety. Results: Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR; CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant. Conclusions: Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC; in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population. References: Garcia-Manero, et al, ASH 2019 Savona, et al, Int. MDS Symp. 2021 Garcia-Manero, et al, Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients with Lower-Risk Myelodysplastic Syndromes. J.Clin.Onc. 2021 39:13, 1426-1436 Figure 1 Figure 1. Disclosures McCloskey: Pfizer: Consultancy; Jazz: Consultancy, Speakers Bureau; COTA: Other: Equity Ownership; Incyte: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; BMS: Honoraria, Speakers Bureau; Amgen: Speakers Bureau. Griffiths: Alexion Pharmaceuticals: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Genentech: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Boston Biomedical: Consultancy. Yee: Paladin: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Geron: Research Funding; Janssen: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan: Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Ionis: Consultancy; Astellas: Consultancy; Epizyme: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Jasper: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BeyondSpring: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Acceleron: Consultancy, Research Funding; AstraZeneca: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Gilead: Consultancy, Other: Clinical Trial Committees; Agios: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; BioCryst: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Aprea: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Astex: Research Funding. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees. Sabloff: Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy; Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Jazz: Research Funding; Astellas Health: Honoraria; Immunogen: Research Funding; Astra Zeneca: Honoraria; Aptitude Health: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: 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; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy; Mesoblast: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Consultancy; Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Astex: Consultancy; Amgen: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: 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; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding.

Introduction: Hypomethylating agents (HMAs) or DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine are established standard of care for the treatment of MDS and CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver, hence requiring intravenous infusion or subcutaneous injections daily for 5-7 days every month (m). This parenteral administration requirement adds significant burden to older cancer patients due to daily time commitment and travel to treatment centers. It also increases exposure to and infection risk with SARS-CoV-2 during the COVID-19 pandemic. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination drug of decitabine and the CDA inhibitor cedazuridine that have shown 99% (90% CI 93% to 106%) equivalent exposure to standard dose IV decitabine 20 mg/m2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present the clinical efficacy and safety results of oral decitabine/cedazuridine from 133 patient study in MDS and CMML (ASTX727-02 ASCERTAIN study). Methods: We used a randomized cross over design where patients were randomized in the first 2 cycles 1:1 to either Sequence A: decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m2 in Cycle 2, or Sequence B: IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2 to do an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days. All patients received oral decitabine/cedazuridine in all subsequent cycles from Cycle 3 onwards until disease progression or unacceptable toxicity. Patients were eligible as per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response as assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: 138 subjects were randomized, of whom 133 were treated on study. The median age was 71.0 years (range 44-88), 65% were male, 88% MDS and 12% CMML, 43% were either red blood cells (RBCs) or platelets transfusion-dependent at baseline, 25% had poor-risk cytogenetics, and 42% had baseline bone marrow blasts >5%. At the data cutoff for the response analysis, the median duration of follow up was 12.6 m (range 9.3 to 20.5 m) with median number of treatment cycles of 8 (range 1 to 18). Of the 133 treated patients the best response was complete response (CR) in 28 patients (21%; 95% CI 15-29%), marrow (m)CR with hematological improvement (HI) in 20 patients (15%), mCR without HI in 23 patients (17.3%), and HI in 10 patients (7.5%) for an overall objective response (CR+mCR+HI) in 81 patients (61%; 95% CI 52-69%). Median duration of CR was 7.5 m (range 1.6 to 17.5 m), and median time to CR was 4.3 m (range 2.1 to 15.2 m). Of the 133 treated patients 27 (20%) went on to receive allogeneic hematopoietic cell transplant. Of the 57 patients who were either RBCs or platelets transfusion-dependent at baseline, 30 (53%) became transfusion independent for both RBCs and platelets for at least 8 consecutive weeks, and 19 (33%) were both RBCs and platelets transfusion independent for at least 16 consecutive weeks. Median survival has not been reached. Most common Treatment-Emergent AEs of Grade ≥3 regardless of causality were neutropenia in 51.5%, thrombocytopenia in 50%, anemia in 40%, febrile neutropenia in 26%, leukopenia in 21%, pneumonia in 12%, and sepsis in 7% of patients treated with oral decitabine/cedazuridine (excluding the IV decitabine cycle). Summary/Conclusions: Efficacy and safety from oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days are consistent with clinical data from standard IV decitabine 20 mg/m2 daily for 5 days. Oral decitabine/cedazuridine is the only oral HMA with systemic exposure equivalent to its injectable drug. Further investigation of oral decitabine/cedazuridine in all-oral combination studies is warranted and underway. Disclosures Savona: BMS: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Ryvu: Consultancy; Boehringer Ingelheim: Patents & Royalties; Takeda: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Griffiths:Celgene/BMS: Honoraria, Research Funding; Genentech Inc: Research Funding; Boston Biomedical: Honoraria; AbbVie Inc: Honoraria; Persimmune: Research Funding; Novartis: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Astex Pharmceuticals: Research Funding. Zeidan:CCITLA: Other; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Jazz: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Aprea: Research Funding; MedImmune/Astrazeneca: Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Incyte: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria. Patel:DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy. Keating:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees. Dao:Astex Pharmaceuticals, Inc.: Current Employment. Fazal:Jansen: Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau; Karyopham: Speakers Bureau; Celgene: Speakers Bureau; Glaxosmith Kline: Consultancy, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: 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, Research Funding. Kantarjian:Abbvie: Honoraria, Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; Ascentage: Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Aptitute Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Jazz: Research Funding; Oxford Biomedical: Honoraria; Amgen: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria. DeZern:MEI: Consultancy; Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy. Roboz:Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy. Busque:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Wells:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leber:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hao:Astex Pharmaceuticals, Inc.: Current Employment. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Azab:Astex Pharmaceuticals, Inc.: Current Employment. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding.

Intro: Iron overload (IO) reflected by elevated serum ferritins is associated with increased mortality in patients with myelodysplastic syndromes (MDS) with a threshold effect seen above 1000 ug/ml (Malcovati, JCO 2005). Ferritin is elevated due to transfusions, inflammation and ineffective erythropoiesis but is an imperfect metric of true iron overload. Elevated levels of oxidatively damaging non-transferrin bound iron (NTBI) and labile plasma iron (LBI) are not easily measured but correlate with transferrin saturation (TSAT) >70% and >80% respectively (de Swart, Haematological 2018). The relationship of TSAT with ferritin and MDS-related clinical outcomes has not been well-characterized. Objectives: We aimed to describe temporal trends in TSAT according to transfusion dependence and to determine if elevated TSAT correlates with ferritin levels, and/or predicts for clinical outcomes such as survival, infectious death and cardiac death in patients with MDS. Methods: Adult patients enrolled in the Canadian national MDS registry over 11.5 years and 15 centers were evaluated retrospectively. Mean, median and ranges for ferritin and TSAT were calculated at six (+/- 3) month intervals. General linear mixed model analysis with repeated measures per subject was used to evaluate changes in ferritin and TSAT over time. Transfusion density (TD) was calculated at landmark year 1 and 2 and was defined as the total number of units transfused/months elapsed since commencing transfusion dependence, with TD-low and TD-high defined as above or below median. Log-rank tests were used to detect survival differences among three transfusion groups (transfusion independent [TI], TD-low and TD-high), among three TSAT groups (TSAT 80% at enrolment), and among three ferritin groups (≤500ug/mL, 501-1000ug/mL and >1000ug/mL at enrolment). Results: A total of 718 patients from the MDS-CAN registry were included in the analysis. Patient characteristics including demographics, clinical and laboratory characteristics are summarized in Table 1. With a median follow up of 2.1 years, actuarial OS was 2.4 years. 17% developed AML and 61% of patients have died. AML, progressive disease, infection, cardiac causes, bleeding accounted for 26%, 20%, 19%, 9.6% and 6.34% of known causes of death respectively. 56% experienced infections (median 2/patient), 7% experienced a cardiac event and 43% were hospitalized at least once. Ferritin and TSAT were moderately correlated over time (r=0.63, p < 0.0001) (Figure 1A) with only 39% of all ferritins >1000ug/mL associating with a TSAT of >80%. The relationship between the 2337 serum ferritins (recorded over 42 months) and TSAT is shown in Figure 1B. Among all patients, ferritin significantly increased from enrolment up to 42 months (p Conclusion: Among a cohort of predominantly low-intermediate risk MDS patients, TSAT correlated only moderately with serum ferritins. TD patients, and in particular high transfusion-burden TD patients have inferior clinical outcomes compared to TI or low-transfusion burden TD patients. Further analyses to probe these relationships are ongoing including the effect of TSAT and iron chelation therapy on infectious deaths, and a multivariate analysis adjusting for other covariates. Disclosures Geddes: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Keating:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Leber:Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nevill:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria. Delage:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Elemary:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chodirker:Hoffman Laroche: Honoraria. Leitch:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau. Buckstein:Astex: Honoraria; Celgene: Honoraria; Takeda: Research Funding; Celgene: Research Funding; Novartis: Honoraria.

Background: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial, named "Treatment Free Remission Accomplished By Dasatinib " (NCT#02268370), has reported 56.8% molecular relapse-free survival (mRFS) rate at 12 months after imatinib (IM) discontinuation. MMR loss occurred quickly after IM discontinuation, typically within 2-4 months, while those who lost MR4 on two consecutive measurements tended to lose their molecular response more gradually. BCR-ABL transcript doubling time (DT) after TKI discontinuation is a reciprocal concept to transcript halving time following TKI therapy. Due to inter-individual differences in DT after TKI discontinuation, DT can be used as a potential biomarker to identify those patients at high-risk for TFR failure when measured before they experience a clinically significant event of molecular relapse. The present study has not only evaluated the kinetics of BCR-ABL transcript rise after IM discontinuation, but also explored the predictive/prognostic role of DT of BCR-ABL transcript level as an early predictor of TFR failure. Patients and methods: Changes of BCR-ABL1 transcript level in each patient were assessed monthly by estimating the number of days required for BCR-ABL1 to double from the previous expression level/measurement, termed the DT. Based on the BCR-ABL1 qPCR value taken monthly in the first 6 months after IM discontinuation, DT was calculated monthly, as x = ln(2)/K, where x is the DT and K is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. K was determined as follows: K = [ln(b) - ln(a)]/t, where a is the BCR-ABL1 value of the previous measurement, b is the BCR-ABL1 at the relevant time point, and t is the number of days between measurements. The baseline qPCR level from the prior month to TKI discontinuation was referenced. The distribution of DT was assessed at each time point of DT measurement within the first 6 months. In order to define cut-off levels for BCR-ABL1 qPCR and DT for the first 6 months, multiple statistical parameters were taken into account including positive (PPV) and negative predictive value (NPV), accuracy and F1 score of DT value, resulting in the DT value of 12.75 days at 2 months as the optimal cut-off value of DT value. Patients were stratified into the 3 groups based on the DT value of 12.75 days at 2 months after IM discontinuation. The high-risk group was defined as the patients showing DT < 12.75 days but above 0, i.e. rapidly proliferating CML cells, implying a high risk for TFR failure with a shorter DT. The intermediate-risk group was defined as those patients with DT ≥ 12.75 days, i.e. more slowly proliferating CML cells implying intermediate risk for TFR failure. The low-risk group was defined as patients showing DT of zero or below, i.e. no increase in the size of the pool of cells expressing BCR-ABL, implying a low risk for TFR failure. The mRFS was analyzed for each of these risk groups at 6 monthly intervals after TKI discontinuation. Results: We compared the DT values of the patients that failed TFR with those from the patients who maintained their molecular response at last follow-up. The DT values at 2 months were much shorter in patients who failed TFR after IM cessation (median 8.32 days) compared to those who maintained molecular response (median 20.7 days; p The DT value of 12.75 days was defined as the optimal value for DT at 2 months with the NPV, PPV, accuracy and F1 score of 80.90%, 96.43%, 84.62% and 0.75, respectively, as the -log10(p-value), accuracy and F1 score reached a plateau at a DT of 12.75 days as presented in the Figure A. At a DT value of 12.75 days at 2 months after IM discontinuation, patients were stratified into 3 groups: high- (n=26), intermediate- (n=16) and low-risk groups (n=71; Figure B). With respect to mRFS rate, the high-risk group showed 7.7% mRFS rate at 12 months compared to 53.6% in the intermediate-risk group or 90.0% in the low-risk group (p Conclusion: Monthly assessment of DT based on the monthly BCR-ABL qPCR is useful to identify the patients with an imminent risk of molecular recurrence after IM cessation for TFR. Figure Disclosures Bence-Bruckler: Merck: Membership on an entity's Board of Directors or advisory committees. Keating:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Busque:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Delage:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding. Leber:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: CFI-400945 is a first-in-class, potent, selective, orally active inhibitor of Polo-like kinase 4 (PLK4) (Ki=0.26nM), a master regulator of centriole duplication, necessary for genomic integrity (Mason et al. Cancer Cell 2014; 26:163-76). CFI-400945 has activity in leukemia cell lines and primary leukemia samples including those with complex karyotype, inversion 3 and monosomy 7 (Minden. personal communications). This suggests that CFI-400945 may provide an effective treatment of patients with AML. The objectives of this phase 1 trial was to establish the safety, tolerability, and recommend phase II dose (RP2D) of CFI-400945 in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods: Patients with relapsed/refractory AML or MDS and patients with untreated AML who refused induction chemotherapy or who are not candidates for intensive chemotherapy were eligible. Dose escalation followed a standard 3+3 design with a starting dose of 64 mg orally once daily. Plasma levels of CFI-400945 free base were measured on Days 1, 2, & 29 of Cycle 1 and Day 15 on all subsequent cycles. Peripheral blood and/or bone marrow were obtained at baseline, Day 8 of Cycle 1 and Day 1 of each subsequent cycle prior to dosing for pharmacodynamic monitoring. Safety assessments using the NCI CTCAE version 4.03 were performed. Results: From May 2018 to June 2019, nine patients have been enrolled on study across three pre-defined dose levels (64 mg [n=3], 96 mg [n=4], and 128 mg [n=2]). Three patients had untreated AML, five patients had relapsed/refractory AML and one patient had myelodysplastic syndrome/myeloproliferative disorder (MDS/MPN). Patient characteristics at diagnosis are outlined in Table 1. Six (67%) patients had baseline high throughput sequencing; the most frequent mutations were TP53 (33%), TET2 (33%), KRAS (33%) and DNMT3A (33%). A total of 20 cycles were administered with a median of 1 cycle (range, 0 to 7 cycles). The most common non-hematological drug related toxicities of any grade, which occurred in over 20%, were diarrhea (44%), headache (44%), colitis (33%), vomiting (33%), bilirubin increase (22%), dizziness (22%), fatigue (22%), and nausea (22%). One patient on the 96 mg dose level was not evaluable for DLT and hence, replaced. Both patients treated at the 128 mg/day dose level developed DLTs, consisting of grade 3 colitis and grade 5 sepsis and colitis. Pharmacokinetic profile indicated low interpatient variability between patients. Maximum exposure did not correlate with toxicity Six patients were evaluable for disease response. Two (33%) achieved complete remission (CR), 3 pts (50%) had stable disease (with one patient having a 78% reduction in marrow blast count). The patient with MDS/MPN who did not complete 1 cycle of therapy progressed to AML (Figure 1). Both patients who obtained a CR had an early response within 2 cycles. One CR has been durable for 218 days with no measurable residual disease (MRD) by flow cytometry. The additional patient, who obtained a CR with incomplete platelets recovery, with subsequent best response of CR, had a sustained response for 91 days before relapse was confirmed by bone marrow examination (Figure 1). Conclusion: Single agent CFI-400945 has activity in patients with poor risk AML. The RP2D in this population is 96 mg once daily. Dose expansion is occurring at the RP2D level. A phase 2 study with CFI-400945 single agent or in combination study with azacitidine or decitabine is planned. Disclosures Leber: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bray:Treadwell Therapeutics: Current Employment; TIO Discovery: Current Employment. Gupta:Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Maze:Novartis: Honoraria; Pfizer: Consultancy; Takeda: Research Funding. McNamara:Novartis: Honoraria. Schimmer:Jazz: Honoraria; Otsuka: Honoraria; Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock ; Takeda: Honoraria, Research Funding; Novartis: Honoraria.

Introduction: Acute myeloid leukemia (AML) is driven by a subpopulation of leukemia stem cells (LSCs), which possess properties such as quiescence and self-renewal that are linked to therapy resistance and relapse. The LSC17 score was derived from genes differentially expressed between functionally validated LSC+ and LSC- fractions from 78 AML patients and is strongly associated with survival and response to standard therapy. A critical advantage of the LSC17 test over cytogenetic and molecular analysis is its rapid turnaround time (24-48h on a NanoString platform), providing clinicians with a rapid and powerful tool for upfront risk stratification. We have developed a clinical assay for the LSC17 score validated in a CAP/CLIA-lab setting. Methods: We conducted a prospective, multicenter validation and feasibility study to test the prognostic value of the LSC17 assay under real-world conditions in AML patients treated with curative intent. Patients with a possible new diagnosis of AML were eligible. Patients with a confirmed diagnosis of acute promyelocytic leukemia were excluded from analysis. Standard prognostic markers including cytogenetics, molecular studies and targeted sequencing using a standard AML panel were performed in parallel to the LSC17 score. Treatment was administered according to physician preference, based on patient history and results of standard prognostic assays, when available. Survival data was censored on June 14th, 2020. Results: 381 patients were recruited to the study between June 2016 and March 2020. 4 patients were excluded for quality control reasons (one sample had insufficient RNA and three samples failed quality control checks). 103 were excluded as they had alternative diagnoses. 84 patients were excluded because they did not receive intensive chemotherapy. LSC17 scores ranged from 0 to 1.25, and were classified as high or low according to the median score of 0.51 from a previously validated reference cohort (Ng et al, Nature 2016). Of the 190 patients included in this analysis, 84 had a low LSC17 score and 106 had a high LSC17 score. The median age was 61 years (range 18-79); 86 (45%) were female. When stratified according to ELN 2017 criteria, 48 (27%), 51 (29%), and 77 (44%) patients had favorable, intermediate, and adverse risk disease, respectively. Low LSC17 score was associated with normal cytogenetics (high vs low, 33% vs 58%; P We first considered response to induction chemotherapy (Table 1). 141 patients had standard induction chemotherapy with 3+7, 40 had Flag-IDA and 9 had CPX-351. High score patients had inferior responses to 3+7 with only 59% achieving complete remission (CR) after 1 cycle of chemotherapy compared to 96% of low score patients; responses for LSC17 high score patients were better in the Flag-IDA group with 80% achieving CR after 1 cycle. When considering overall CR rates after 2 cycles of induction, patients with a high LSC17 score were less likely to achieve CR (high vs low, 87% vs 98%; P=0.02). However, this difference was predominantly observed in patients treated with 3+7 (87% vs 99% CR rate in high vs low score patients, respectively); response rates to Flag-IDA were not significantly different between the 2 groups. Measurable residual disease (MRD) monitoring by flow cytometry was performed at the time of CR in 135 (71%) patients enrolled at Princess Margaret Cancer Centre. Patients with a high LSC17 score were significantly more likely to have MRD compared to low score patients (46% vs 10% respectively, P Conclusion: AML patients with a high LSC17 score have inferior outcomes following 3+7 induction chemotherapy. The LSC17 score should be considered as a tool to identify and stratify high-risk patients to alternative upfront therapies such as Flag-IDA. A risk adapted study is planned to validate these results. Disclosures Gupta: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Maze:Novartis: Honoraria; Takeda: Research Funding; Pfizer: Consultancy. McNamara:Novartis: Honoraria. Schimmer:Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock ; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria. Leber:Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tierens:Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees. Wang:Trilium therapeutics: Patents & Royalties: There is an existing license agreement between TTI and University Health Network and J.C.Y.W. may be entitled to receive financial benefits further to this license and in accordance with UHN's intellectual property policies. .

Background Red blood cell (RBC) transfusion dependence (TD) and anemia are associated with inferior quality of life (QOL) and survival in myelodysplastic syndromes (MDS). As part of a research programme to identify the optimal transfusion hemoglobin (Hb) threshold that translates into significantly improved QOL, we conducted a pilot randomized study of two transfusion algorithms (liberal versus restrictive) to determine the feasibility of a larger study. This trial was aligned with the REDDS study (ISRCTN26088319, Stanworth et al., BJH 2019) and followed the same pre-defined statistical analysis plan. Methods The study was undertaken at 3 cancer centers (NCT02099669). We included patients with MDS, CMML, low blast AML (20-30%) or myeloproliferative neoplasms who were TD (> 1 RBC/8 weeks x 16 weeks). Patients on disease modifying therapy for > 6 months were permitted only if they had remained stably RBC-TD with a life expectancy of > 3 months. Central randomization was to one of two RBC transfusion strategies over a 12-week period: Restrictive strategy to maintain Hb between 85 and 105g/L. To achieve this, 2 RBC units were transfused when Hb < 85 g/LLiberal strategy to maintain Hb between 110 and 120 g/L. To achieve this, 2 RBC units were transfused when Hb < 105 g/L and 1 unit for Hb 105-110 g/L. The first 4 weeks were considered a run-in period to achieve the target Hb. The primary outcomes of this feasibility study were The percentage compliance of Hb being within or above the target range of the assigned transfusion threshold (after the 4 week run-in). Feasibility was set at 70%.Achievement of at least a 15 g/L difference between the mean pre-transfusion Hb of the liberal and restrictive strategy groups. Secondary outcomes included changes and differences in QOL scores, rates of transfusion reactions and alloimmunizations, overall blood utilization and visit numbers and impact on serum ferritin. The primary analysis was intention to treat. The study was closed early due to COVID-19, with 28 patients randomized of planned 30. Results 30 patients were enrolled over 5 years and 28 patients randomized (n=15, liberal; n=13 restrictive). Median age was 74 (range 58-84), 26/28 had MDS or CMML and there were no significant imbalances in baseline disease and patient characteristics although patients in the restrictive group tended to have lower risk disease (IPSS-R very low + low 69% versus 53% liberal). Compared with the restrictive arm, liberal arm patients had more complete blood counts, were transfused more RBC units (only during the 4-week run-in) and were transfused at shorter intervals (Table 1). There were no differences in adverse events. Over the 12 weeks, the mean Hb value was 90 ± 4 g/L (restrictive) versus 101 ± 4 g/L (liberal), (p Adherence with QOL completion (minimum of 4 serial) was 93%. While sample sizes are small and comparisons exploratory, the area under the curve for several serial quality of life scores was numerically higher and the curve more stable for the liberal arm (EQ5D (figure 2), EORTC cognitive and emotional functioning). Similarly, a higher % of patients in the liberal arm achieved pre-defined clinically meaningful increases in several symptom and function domains (emotional, social, fatigue, dyspnea, financial problems). Discussion Whilst our study results did not meet our feasibility endpoints, this small randomized trial in MDS patients demonstrated clinically important differences in mean Hb achievable with different transfusion thresholds. Poor rates of compliance with Hb targets were clearly identified for patients in the liberal arm, suggesting a need to understand the barriers to protocol adherence in this arm prior to embarking on larger trials. Compared with the REDDS trial, we did not document a significant excess of RBC transfusions needed (post run-in period) to maintain the higher Hb threshold. Similar to REDDS, we did observe some signals of improved QOL with a liberal transfusion strategy. A formal analysis of pooled results with REDDS study patients is planned. (Funding, CCSRI grant QOLL-14 and MOSPI Fund 2014). Disclosures Buckstein: Novartis: Honoraria; Astex: Honoraria; Celgene: Honoraria; Celgene: Research Funding; Takeda: Research Funding. Prica:seattle genetics: Honoraria; Gilead: Honoraria; astra zeneca: Honoraria. Leber:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chodirker:Hoffman Laroche: Honoraria. Lin:Novartis: Research Funding; Pfizer: Honoraria. Callum:Octapharma: Research Funding; Canadian Blood Services: Research Funding.

Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis. The JAK1/2 inhibitor ruxolitinib blocked STAT3-phosphorylation and partially improved DEX-mediated killing of stimulated CLL cells in vitro but not in CLL patients in vivo. An automated microscopy-based screen of a kinase inhibitor library implicated an additional protective role for the PI3K/AKT/FOXO pathway. Blocking this pathway with the glycolysis inhibitor 2-deoxyglucose (2-DG) or the PI3K-inhibitors idelalisib and buparlisib increased DEX-mediated killing but did not block STAT3-phosphorylation. Combining idelalisib or buparlisib with ruxolitinib greatly increased killing by DEX. These observations suggest that glucocorticoid resistance in CLL cells may be overcome by combining JAK and PI3K inhibitors.

Objectives Achieving a major molecular response (MMR) is the goal of imatinib therapy for chronic myeloid leukemia. However, the association between gender, BCR-ABL transcript type, and age with MMR is not well understood and often controversial. Methods We retrospectively analyzed 166 patients who have been treated with imatinib for up to 10 yr. Results Men had a lower MMR rate than women (63.3% vs. 81.6%, P = 0.006) and a shorter time to relapse (median 354 vs. 675 d, P = 0.049), while patients with b3a2 or with both b3a2 and b2a2 break point transcripts had higher MMR rate than those with b2a2 (81.8%, 77.1% vs. 60.7%, P = 0.023 for b3a2 vs. b2a2, P = 0.043 for both vs. b2a2). A striking difference was found between men with b2a2 and women with both b2a2 and b3a2 in terms of MMR rate (43.8% vs. 88.9%), MMR rate within 6 months (7.1% vs. 62.5%) and the time to MMR (median d 493 vs. 159, P = 0.036). Conclusions Both gender and BCR-ABL transcript, but not age, were significantly associated with the molecular response. Men with b2a2 represent a less favorable group in their response to imatinib treatment and may need alternative therapy regimen and closer monitoring.

Current treatments that use hematopoietic progenitor cell (HPC) transplantation in acute myeloid leukemia (AML) patients substantially reduce the risk of relapse, but are limited by the availability of immune compatible healthy HPCs. Although cellular reprogramming has the potential to provide a novel autologous source of HPCs for transplantation, the applicability of this technology toward the derivation of healthy autologous hematopoietic cells devoid of patient-specific leukemic aberrations from AML patients must first be evaluated. Here, we report the generation of human AML patient-specific hematopoietic progenitors that are capable of normal in vitro differentiation to myeloid lineages and are devoid of leukemia-associated aberration found in matched patient bone marrow. Skin fibroblasts were obtained from AML patients whose leukemic cells possessed a distinct, leukemia-associated aberration, and used to create AML patient-specific induced pluripotent stem cells (iPSCs). Through hematopoietic differentiation of AML patient iPSCs, coupled with cytogenetic interrogation, we reveal that AML patient-specific HPCs possess normal progenitor capacity and are devoid of leukemia-associated mutations. Importantly, in rare patient skin samples that give rise to mosaic fibroblast cultures that continue to carry leukemia-associated mutations; healthy hematopoietic progenitors can also be generated via reprogramming selection. Our findings provide the proof of principle that cellular reprogramming can be applied on a personalized basis to generate healthy HPCs from AML patients, and should further motivate advances toward creating transplantable hematopoietic stem cells for autologous AML therapy. Stem Cells 2013;33:1839–1849

Prediction of response to erythropoietin stimulating agents (ESAs) in anemic MDS patients is often based on the Nordic score. We wished to validate the Nordic score (IWG 2006 response criteria) in a larger cohort and determine if other variables such as IPSS/IPSS-R, ferritin, LDH, and a novel European ESA response score (Santini 2013) were of prognostic importance. We analyzed 208 ESA-treated MDS patients (WHO 2008 criteria) from a prospective registry. Ninety-four and 93% had lower risk scores by IPSS (low/int − 1) and IPSS-R (low/very low), respectively. Erythroid response was achieved in 94 patients (47%); responses were similar with erythropoietin (50%) and darbepoetin (39%; p = 0.2). The Nordic and European scores were both validated on univariate analysis. Variables independently predictive of response in multivariate analysis were low-risk IPSS score (OR 0.1, p = 0.0016) and serum EPO level

Acute myeloid leukaemia (AML) is distinguished by the generation of dysfunctional leukaemic blasts, and patients characteristically suffer from fatal infections and anaemia due to insufficient normal myelo-erythropoiesis. Direct physical crowding of bone marrow (BM) by accumulating leukaemic cells does not fully account for this haematopoietic failure. Here, analyses from AML patients were applied to both in vitro co-culture platforms and in vivo xenograft modelling, revealing that human AML disease specifically disrupts the adipocytic niche in BM. Leukaemic suppression of BM adipocytes led to imbalanced regulation of endogenous haematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation. In vivo administration of PPARγ agonists induced BM adipogenesis, which rescued healthy haematopoietic maturation while repressing leukaemic growth. Our study identifies a previously unappreciated axis between BM adipogenesis and normal myelo-erythroid maturation that is therapeutically accessible to improve symptoms of BM failure in AML via non-cell autonomous targeting of the niche.

Spatial localization of primitive leukemic cells is restricted to niches shared with their normal counterparts, and their ability to retain occupancy of these niches is rivaled by normal HSPCs., Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is currently the leading strategy to manage acute myeloid leukemia (AML). However, treatment-related morbidity limits the patient generalizability of HSCT use, and the survival of leukemic stem cells (LSCs) within protective areas of the bone marrow (BM) continues to lead to high relapse rates. Despite growing appreciation for the significance of the LSC microenvironment, it has remained unresolved whether LSCs preferentially situate within normal HSC niches or whether their niche requirements are more promiscuous. Here, we provide functional evidence that the spatial localization of phenotypically primitive human AML cells is restricted to niche elements shared with their normal counterparts, and that their intrinsic ability to initiate and retain occupancy of these niches can be rivaled by healthy hematopoietic stem and progenitor cells (HSPCs). When challenged in competitive BM repopulation assays, primary human leukemia-initiating cells (L-ICs) can be consistently outperformed by HSPCs for BM niche occupancy in a cell dose-dependent manner that ultimately compromises long-term L-IC renewal and subsequent leukemia-initiating capacity. The effectiveness of this approach could be demonstrated using cytokine-induced mobilization of established leukemia from the BM that facilitated the replacement of BM niches with transplanted HSPCs. These findings identify a functional vulnerability of primitive leukemia cells, and suggest that clinical development of these novel transplantation techniques should focus on the dissociation of L-IC–niche interactions to improve competitive replacement with healthy HSPCs during HSCT toward increased survival of patients.

Background: AML is driven by a small subpopulation of leukemia stem cells (LSCs), which possess stem-cell properties such as quiescence and self-renewal that are linked to therapy resistance and relapse. The LSC17 score was derived from genes differentially expressed between functionally validated LSC+ and LSC- cell fractions from 78 AML patients. The LSC17 score was strongly associated with survival in 4 independent cohorts of AML patients treated with curative intent (n = 908), and accurately predicted initial response. Patients with high LSC17 scores had poor outcomes with standard treatment strategies. The LSC17 score remained highly significant in multivariate analyses, independent of commonly used prognostic factors. A critical advantage of the LSC17 test over cytogenetic analysis is its rapid turnaround time (24-48h on a NanoString platform), providing clinicians with a powerful tool for upfront risk stratification. To date, no RNA-based, stem cell-derived score has been transitioned into a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Study design and methods: The study consists of 2 phases. Phase 1 aims to validate the assay in a CLIA certified laboratory setting. Phase 2 aims to determine prospectively the feasibility and prognostic power of LSC17 score testing in newly diagnosed AML patients in the real-world setting. Clinical endpoints include primary induction failure rate, relapse free survival and overall survival. All patients with a suspected diagnosis of de novo or secondary AML, who are deemed fit and appropriate by their treating physician to undergo intensive induction chemotherapy, are considered for this study. Patients who received any prior anti-leukemia treatments (except hydroxyurea) and patients with a confirmed diagnosis of acute promyelocytic leukemia are excluded. Current participating centres include Princess Margaret Cancer Centre (Toronto), Juravinski Cancer Centre (Hamilton), and The Ottawa Hospital Cancer Centre (Ottawa). Pre-study sample size analysis suggests that 150 patients will be required to demonstrate a hazard ratio for death of 2.3 between patients with a high and low LSC17 score (α = 0.05, power = 0.8). The survival for the high and low LSC17 score groups will be compared using the Cox proportional hazards model. Traditional risk stratification will also be tested within a Cox proportional hazards model. Phase 1 of the study has been completed and several key quality control measures have been created. Initial derivation and validation of the LSC17 score was performed using standard chemistry on the NanoString platform; for CLIA lab validation, the assay was transitioned to Elements© chemistry, which does not require custom codeset manufacture by NanoString. The original AML reference cohort was retested using Elements© chemistry to derive an absolute median threshold for prospective LSC17 score determination in individual patients. The lab validation process compared and found no difference in LSC17 scores between samples processed by Ficoll or collected in Paxgene for ease of processing. A standardised quality assurance (QA) process was completed to identify optimal sample requirements as well as specimen storage conditions, score stability during sample storage and turnaround time for testing. An algorithm has been created using the laboratory information system to allow standardised and rapid calculation of the LSC17 score from NanoString nCounter output data. The LSC17 score can be tested on peripheral blood or bone marrow, although bone marrow samples are preferred for patients with very low peripheral blast counts. Samples are ideally stored in RNA Paxgene tubes for RNA stability and to maximize RNA yield. The prospective phase of the study (Phase 2) opened in April 2018 and as of June 2019, 233 patients have been enrolled, of which 120 received induction chemotherapy. 54 patients were excluded due to an alternative diagnosis or failed QA. The remaining patients had non-intensive therapy based on patient choice. Standard prognostic markers including cytogenetics, molecular studies and targeted sequencing using a 49-gene AML panel are performed in parallel to the LSC17 score. Treatment was administered according to physician preference, based on patient history and results of standard prognostic assays, when available. The study continues to recruit and is open to collaborations in other centres. Disclosures Ng: Celgene: Research Funding. Leber:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sabloff:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Wang:NanoString: Other: Travel and accommodation; Trilium therapeutics: Other: licensing agreement, Research Funding; Pfizer AG Switzerland: Honoraria, Other: Travel and accommodation; Pfizer International: Honoraria, Other: Travel and accommodation.

Background: More than 50% of patients with myelodysplastic syndrome (MDS) become transfusion dependent (TD) during the course of their disease and 25-30% present as TD at diagnosis. While TD is more common in IPSS/IPSS-R higher risk patients and is associated with inferior overall survival, it is unclear if achievement of transfusion independence (TI) for even short periods of time is associated with improved overall survival (OS). Objectives: Evaluate the impact of intermittent transfusion dependence and independence on OS in MDS patients and compare the OS with patients persistently TD or TI. Determine the optimal TI duration or ratio that translates into improved overall survival and the impact of developing transfusion dependence or acquiring transfusion independence after diagnosis. Methods: We extracted the detailed clinical and transfusion records of patients followed since 2010 in the national MDS registry of Canada (MDS-CAN) and assigned patients into 4 categories: TI continuous (TIcont), TD continuous (TDcont), TI followed by TD (TI/TD) and TD followed by TI (TD/TI) at any time. TD was defined as receiving at least 1 unit of packed red blood cells (PRBC) within an 8-week period for a consecutive 16 weeks. The ratio of time spent TI to total follow up period was calculated for each patient. Survival was compared between groups and an ROC curve was attempted to define the optimal ratio of TI/follow-up that translated into an overall survival benefit. Results: This study evaluated 544 patients with a median follow up of 19 months (95% CI 18-22 and actuarial OS of 28 months (95% CI 24-31). 254 (46%) were TIcont, 96 (18%) TDcont, 136 (25%) TI/TD (median time to TD 7.4 months, interquartile range (IQR) 4-19) and 58 (11%) TD/TI (median time to TI 6 months (IQR 4-10) lasting a cumulative13 months (IQR 7-29). Baseline characteristics comparing these groups are in table 1. Patients TDcont and TD/TI had higher risk IPSS/IPSS-R scores, more unfavourable karyotypes, a greater degree of frailty, higher ferritin and levels of fatigue and more deficits in instrumental activities of daily living at enrollment. 57% of TI/TD patients remained TD while 43 % converted back to TI for variable lengths of time. Among the TD/TI patients, 46% remained transfusion independent (median TI duration 12 mos, IQR 6-21) while 53% converted back to TD (median TI duration 12 mos, IQR 6-29). The TI ratio was 0.7 +/-0.4 overall. The receiver operating curve could not identify a threshold ratio or duration of transfusion independence that predicted with good sensitivity and specificity overall survival. In the 304 patients with IPSS-R very low, low and intermediate risk scores, 168 (55%) were TIcont, 27 (9%) TDcont, 81(27%) were TI/TD and 28 (9%) were TD/TI. In lower risk TI/TD patients, the development of TD within the first 6, 6-12, 12-24 and >24 mos from enrollment was associated with progressively worse OS (25, 50, 45 and 86 mos respectively, p=.0025) (figure 1a). In the 58 TD/TI patients, OS did not differ if the achievement of TI occurred < 6, 6-12 or >12 mos from enrollment (p=0.3). Of all 48 TD/TI patients with an overall survival that exceeded 12 months, there were no significant differences in OS if the duration of transfusion independence lasted a minimum of 16, 24 or 48 weeks (p=0.45). The actuarial OS for the 4 transfusion categories were 39 months (TIcont), 35 months (TI/TD), 29 months (TD/TI) and 10 months (TDcont), p Conclusion: This study validates the extremely poor prognosis associated with persistent transfusion dependence. While only 38% of patients TD at diagnosis achieve transfusion independence at any point, the achievement of transfusion independence (even if intermittent) is associated with an improved overall survival that is similar to TIcont and TI/TD within the first 2 years of follow up. For patients with TD who achieved TI, we were unable to determine a TI duration or ratio that translated into a survival benefit. While the achievement of transfusion independence may simply reflect response to therapy or better disease biology, our data suggest that we should strive for the acquisition and/or maintenance of transfusion independence as it may be a surrogate for improved overall survival. The impact of achieving or losing TI on health related quality of life is being analyzed. Disclosures Buckstein: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Geddes:Alexion: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sabloff:Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Canada: Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Novartis: Honoraria; Seattle Genetics: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees. Leber:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leitch:Alexion: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Otsuka: Honoraria; AbbVie: Research Funding; Celgene Corporation: Honoraria, Research Funding. Yee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding. St-Hilaire:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Finn:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Boehringer Ingelheim: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nevill:Paladin Labs: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Storring:Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Shamy:Amgen: Membership on an entity's Board of Directors or advisory committees; Abbie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding. Banerji:LLSC: Research Funding; Research Manitoba: Research Funding; CCMF: Research Funding; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; CIHR: Research Funding; CancerCare Manitoba/University of Manitoba: Employment; CAPhO: Honoraria; BIOGEN: Other: Licensing fee; Dana-Farber Cancer Institute: Other: Licencing fee; Janssen: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Licensing fee, Research Funding. Delage:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wells:Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Introduction: Tyrosine kinase inhibitor (TKI) therapy can result in the adverse events of prolonged anemia, thrombocytopenia and/or leukopenia via c-kit blockade in hematopoietic stem cells. Previous studies have reported that even low-grade adverse events could impair a patient's health-related quality of life. One of the benefits of TKI discontinuation is to allow patients to live drug-free, thereby preventing drug-related adverse events including cytopenias. The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported 59.1% and 21.5% molecular relapse-free survival (mRFS) rates after first and second attempts at treatment free remission (TFR) with imatinib (IM) or Dasatinib (DA) discontinuation, respectively. In the present study, we attempted to analyze the impact of TKI discontinuation on changes in hematological parameters, and its impact on TFR success after TKI discontinuation. Methods and materials: Throughout the trial, we have collected the hematoloigc parameters at 22 timepoints in 131 patients. These included Hb level, WBC count with differentials, and platelet count during IM discontinuation (7 times), DA rechallenge (10 times), and DA discontinuation (5 times). Results: With IM discontinuation, most of the hematological parameters showed a significant improvement within 3 months: Hb level rise by +10.47g/L (+8.86%; p=1.67x10-22), WBC count rise by +1.43x109/L (+30.08%; p=2.03x10-16), neutrophil rise by +0.99x109/L (36.76%; p=4.48x10-11), lymphocyte rise by +0.24x109/L (+20.64%; p=6.72x10-9), monocyte rise by +0.13x109/L (+35.9 0%; p=3.33x10-14), platelet count rise by +22.65 x109/L (+12.76%; p=1.03x10-7). Eosinophil counts were not significantly changed (p=0.475). With DA rechallenge, mixed changes were observed in hematologic parameters within 1 month: Hb level significant dropped by 11.57g/L (-8.26%; p=6.38x10-14) and platelet counts also showed a decreasing trend (-9.39x109/L or -4.57%; p=0.07), while significant increases were noted in lymphocyte (+0.41x109/L or +22.22%; p=0.00027), and monocyte counts (+0.14x109/L or +14.29%; p=0.001). No significant changes were noted in WBC counts (+0.32x109/L or +1.64%; p=0.234), neutrophil counts (-0.18x109/L or -10.42%; p=0.285), or eosinophil counts (+0.03 x109/L or 0%; p=0.185). With DA discontinuation, the Hb level rebounded by +7.08g/L within 3 months (+9.45%; p=0.0003). However, there was no significant change in the other parameters 3 months after DA discontinuation, including WBC (p=0.841), neutrophil (p=0.309), lymphocyte (p=0.995), monocyte (p=0.451), eosinophil (p=0.826) and platelet counts (p=0.533). When the changes in hematologic parameters were analyzed in correlation with mRFS, there was no association of those parameter changes with RFS after DA discontinuation. However, associations of mRFS following IM discontinuation were noted as follows: higher mRFS after IM discontinuation was observed in the group with a smaller change in Hb level (≤+1.17%, p=0.004), lymphocyte count (≤+1.06%; p=0.006), and monocyte count (≤+1.43%; 0.005) compared to those with a larger change. In other words, the group showing a rebounded Hb level after IM discontinuation showed a lower mRFS rate compared to those in whom the Hb did not rebound. A lower mRFS was noted in the group with a smaller change in neutrophil count (≤+1.07%) compared to those with a larger change (p=0.008), implying that the group with rebounded neutrophil count showed a higher mRFS compared to those not. Multivariate analysis confirmed: 1) IM treatment duration longer than 8.75 years is associated with a decrease in loss of molecular response by 13% per year (p=0.001, HR 0.871), 2) Hb level rebound above 22gm/L showed 2.8 times higher risk of molecular relapse (p=0.021, HR 2.801), 3) rebound rise of neutrophil count by 1.075% or above reduced the risk of molecular relapse by 52% (p=0.06, HR 0.485). Conclusion: Further research is warranted to explore the functional role of the hematopoietic stem cell fraction following prolonged TKI therapy in CML patients. Hematopoiesis in Ph-negative cell population could contribute to TFR after TKI discontinuation. Figure Disclosures Busque: ExCellThera: Patents & Royalties; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Delage:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber:Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: CPI-0610, a selective and potent small molecule BETi, has shown clinical activity and a wide therapeutic window in a Phase 1 lymphoma study (Blum KA, 2018). BET proteins regulate key oncogenic pathways, including NFκB and TGFβ signaling which are important drivers of pro-inflammatory cytokine (Ck) expression and bone marrow fibrosis, respectively, and are implicated in myelofibrosis (MF) pathogenesis. Ruxolitinib (rux), a Janus kinase 1/2 inhibitor (JAKi), is the only approved therapy for MF, and primarily reduces spleen volume and provides symptomatic relief. Patients (pts) receiving rux may achieve suboptimal responses or can develop treatment-emergent anemia and worsening transfusion dependence. There is no approved treatment for pts who are refractory/intolerant to rux. Preclinical studies suggest that a combination of BETi and JAKi can result in synergistic reduction of splenomegaly, bone marrow (BM) fibrosis and mutant cell burden (Kleppe, 2018). Our objective is to evaluate CPI-0610 alone or "add-on" to rux (CPI-0610 + rux) in MF pts who are refractory/intolerant or have inadequate response to rux. Method: This is a global, multicenter, open label Phase 2 study (MANIFEST) of CPI-0610 monotherapy in MF pts who are refractory/intolerant to rux (Arm 1) or CPI-0610 + rux in MF pts who have suboptimal response to rux (Arm 2). Pts are further stratified based on transfusion dependence status [transfusion dependent (TD), defined as an average of ≥2 units per month over 12 wks, or non-TD cohorts]. The starting dose of CPI-0610 is 125 mg daily on days 1-14 of a 21-day cycle in both arms. Primary endpoint: spleen volume response (SVR) for non-TD cohorts or TD to transfusion independence (TI, no transfusion for consecutive 12 wks) conversion for TD cohorts; secondary endpoints: change in total symptom score (TSS) per MFSAF v4.0, patient global impression of change (PGIC), safety and PK; additional endpoints: changes in proinflammatory Ck levels, BM morphology and mutant allele burden. Results: As of 27 June 2019, 48 pts enrolled- 12 treated with CPI-0610 monotherapy (Arm 1) and 36 with CPI-0610 + rux (Arm 2). At baseline, median age: 69 years (41-88), gender: 28 (58%) male, ECOG ≤1: 45 (94%) pts, primary MF: 33 (69%) pts, DIPSS score high: 10 (21%) pts, median platelet: 199 x 109/L (77-895), 34 (71%) pts with Hgb 18 months. Spleen volume reduction observed in 29 of 31 (94%) pts (median best change: -17% [range: -50.7, 10.2]) (Fig. 1A). TSS improvement reported in 26 of 28 (93%) pts (median best change: -46.4% [range: -95.3%, 27%]), 11 (39%) pts with ≥50% TSS improvement (Fig. 1B). PGIC improvement score in 28 of 33 (85%) pts; 21 (64%) reported much or very much improved scores. Increase in hemoglobin by 1.5 mg/dL post-baseline observed with both CPI-0610 monotherapy (4 of 8, 50%) and CPI-0610 + rux (4 of 25, 16%)). Improvement in BM fibrosis and/or reticulin by ≥1 Gr reported in 7 of 12 (58%) evaluable pts with baseline and 1 post-baseline biopsy and as early as 6-months of CPI-0610 treatment. 4 TD pts in Arm 2 treated with CPI-0610 + rux converted to TI- 2 of whom are TI for >36 wks, no longer anemic, and showed spleen volume reduction, improvement in symptom and BM fibrosis; 12 additional pts are being monitored for potential TI conversion. 41 pts remain active on treatment and 7 pts discontinued, including 1 pt, initially transplant ineligible, underwent stem cell transplantation after 6 cycles of CPI-0610 + rux treatment. Most common (≥20%) treatment-emergent adverse events (TEAE) of any Gr include diarrhea, nausea, cough and upper respiratory tract infection. Most common (≥5%) ≥3 Gr TEAE include anemia (8.3%) and thrombocytopenia (8.3%, asymptomatic, non-cumulative and generally reversible). Conclusions: Preliminary data indicate that CPI-0610 alone or "add-on" to rux is generally well-tolerated and provides clinical benefits in MF pts with inadequate responses or who are refractory to rux. Improvement in BM fibrosis and anemia responses indicate the potential for meaningful disease modification. Based on the available data, Arm 2 TD cohort has achieved proof-of-concept for TI. Further expansion of the MANIFEST study is ongoing. Updated data will be presented. Disclosures Mascarenhas: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Hoffman:Merus: Research Funding. Bose:Celgene Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Talpaz:Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Harrison:Sierra Oncology: Honoraria; Incyte: Speakers Bureau; AOP: Honoraria; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Shire: Speakers Bureau; Promedior: Honoraria; Roche: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; CTI: Speakers Bureau. Gupta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Leber:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sirhan:Celgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Kabir:Constellation Pharmaceuticals: Employment. Senderowicz:Constellation Pharmaceuticals: Employment; Puma Biotechnology: Membership on an entity's Board of Directors or advisory committees. Shao:Constellation Pharmaceuticals: Employment. Mertz:Constellation Pharmaceuticals: Employment, Equity Ownership. Trojer:Constellation Pharmaceuticals: Employment, Equity Ownership. Verstovsek: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; Gilead: Research Funding; Promedior: Research Funding.

Introduction: The Canadian trial entitled "Treatment Free Remission Accomplished By Dasatinib" (BMS CA180543, NCT#02268370) is ongoing since Jan 2015, and has completed accrual of 131 patients. The study was designed to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation following imatinib (IM) treatment. The preliminary results (ASH 2018) indicate: 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4; 3) The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months [7.9-39.5%]). Herein, we report the 4-year follow-up results with updated TFR2 after second TFR attempt following DA discontinuation. Methods and materials: This prospective clinical trial has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level above MR4.0 on 2 consecutive occasions, or an increase in BCR-ABL transcript level above MR3.0 on a single occasion. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving MR4 following a 2nd TFR attempt. Results: As of Jun 25, 2019, 58 (44.3%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 59.1% [50.1-67.0%] and 56.8% [47.8-64.8%] at 6 and 12 months, respectively. TFR using loss of MMR as an event was 69.8% at 6/12 months. Of the 58 patients who lost response, 53 patients (91.4%) lost response within 6 months after IM discontinuation: 7 (10.1%) lost response within 2 months, 20 (34.5%) within 3 months, 14 (24.1%) within 4 months, 9 (15.5%) within 5 months, and 3 (5.2%) within 5-6 months. Beyond 6 months, 5 patients (15.5%) lost response within 7, 8, 10, 20, 21 months, respectively. Only two patients experienced late relapse occuring 15 months after IM discontinuation. 54 patients started DA, of whom 49 patients (90.7%) achieved MR4.5 on DA. Median time to MMR, MR4 and MR4.5 was 0.94, 1.95, and 2.48, respectively. The incidence of MMR, MR4 and MR4.5 at 3 months was 99.0% (86.3-99.0%), 91.5% (78.4-96.7%), and 76.6% (60.9-86.0%), respectively. 32/49 patients receiving DA attained MR4.5, and discontinued DA for a 2nd TFR attempt (TFR2). 25/32 (78.1%) of these patients lost molecular response at a median of 3.67 months after DA discontinuation. The estimated TFR2 after DA discontinuation was 18.5% at 6 months [6.8-34.7%], TFR2 using loss of MMR as a definition of molecular relapse was 20.4% [7.6-37.4%], while TFR2 using two consecutive losses of MR4 was 25.4% [9.4%-45.2%]. Two patients continued to attain deep molecular response at MR4.2 and undetectable level (equivalent to MR5.5) beyond 18 months after DA discontinuation. At last follow-up of Jun 25, 2019, 30 patients are still being monitored on trial on IM discontinuation (n=20), DA rechallenge (n=4) or DA discontinuation phases (n=6). With a median follow-up duration of 36 months, risk factor analyses were performed using Cox's proportional hazard regression model suggesting a strong correlation of mRFS with total duration of IM treatment prior to IM discontinuation (p Conclusion: The 4-year follow-up results suggests that DA rechallenge after failing a first IM discontinuation attempt for TFR was safe, feasible and well tolerated. It was effective in most cases rapidly regained at least MR4. Based on the two cases who successfully discontinued DA more than 18 months after DA consolidation following achievement of deep molecular response, second generation TKI therapy after imatinib discontinuation failure is a feasible option. Further follow-up is strongly warranted in order to reach a clear conclusion on this issue. Disclosures Busque: ExCellThera: Patents & Royalties; Paladin: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Savoie:Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees. Delage:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: The Canadian tyrosine kinase inhibitor (TKI) discontinuation trial has reported a 59.1% and 21.5% molecular relapse-free survival (RFS) rate after first attempt of treatment free remission (TFR1) with imatinib (IM) discontinuation and after a 2nd attempt of TFR (TFR2) with dasatinib (DA) discontinuation, respectively. Throughout the first and second attempts of TKI discontinuation, the kinetics of BCR-ABL qPCR transcript rise were very similar after TFR1 and TFR2. This prompts us to have a better understanding of the dynamics of BCR-ABL qPCR rise after TKI discontinuation. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. We have analyzed the monthly BCR-ABL1 qPCR value and doubling time (DT) in the first 6 months following IM discontinuation. The qPCR level before IM discontinuation or the qPCR level from the prior month was used as a baseline. DT at each measurement was calculated as x = ln(2)/K, where x is the DT and k is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The distribution of DT for all patients was assessed at each timepoint of DT measurement within the first 6 months. In order to define the best cut-off levels of BCR-ABL1 qPCR and DT showing the best risk stratification power throughout the first 6 months, DT values were collected and analyzed for molecular relapse-free survival (RFS) from the time of DT measurement. Then, a binary recursive partitioning method was applied using RFS which is calculated from the time of each DT measurement. Based on the DT cut-off value, the group was divided into 2 groups. The RFS was compared according to the groups. Results: As of March 25, 2019, out of 131 patients enrolled, 58 patients (44.3%) lost a molecular response. The 6- and 12-months' molecular relapse-free survival (mRFS) rate was estimated as 59.1% (50.1-67.0%) and 56.8 % (47.8-64.8%), respectively. BCR-ABL1 qPCR transcript level after IM discontinuation showed a rapid rise between the first 2-4 months, followed by a gradual rise after 4 months. The proportion of the patients showing DT less than 12.71 days but above 0 was 3.8% at 1 mo, 25.2% at 2 mo, 15.3% at 3 mo, 12.2% at 4 mo, 2.3% at 5 mo and 2.3% at 6 mo, respectively. DT values were collected and analyzed for molecular RFS from the time of DT measurement. Binary recursive partitioning method was applied and provided 12.71 days as the best DT cutoff value to stratify the patients according to the RFS from the time of each DT measurement. In other words, the patients having DT less than 12.71 days but above 0 at any time within the first 6 months had a higher risk of failing the TFR attempt, while those with DT equal to or over 12.71 days at any time has a lower risk of losing TFR after IM discontinuation. The best result was reported in the group with stable BCR-ABL qPCR transcript level. A rapid incline of BCR-ABL qPCR transcript level was observed 2-4 months after IM discontinuation. According to the DT measured at 2 months, the group with DT less than 12.71 days but above 0 showed the lowest mRFS rate of 5.0% (0.9-14.8%) at 12 months (HR 5.74), compared to the group with DT equal to/over 12.71 days (12 months' mRFS 47.4% [23.2-68.3%]) or the group with DT equal to/less than 0 days (12 months' mRFS 87.5% [77.3-93.3%]; p Decision tree analysis was performed including 4 variables such as DT below 12.71 days, DT equal to or below 0 days, total IM treatment duration and MR4 response duration. The first node was DT below 12.71 days, and the second was DT equal to/less than 0 days. Total IM duration or MR4 duration were not identified as significant in the decision tree analysis. Multivariate analysis confirmed that grouping based on the DT at 2 months is an independent risk factor for TFR. The group with DT below 12.71 but above 0 showed 5.74 times higher risk of losing TFR after IM discontinuation independent of the total duration of IM treatment. Conclusion: DT with cut off value of 12.71 days at 2 months based on the BCR-ABL1 qPCR transcript level measured in the first 6 months after IM discontinuation is predictive of TFR failure after IM discontinuation. Figure Disclosures Busque: ExCellThera: Patents & Royalties; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Delage:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Liew:Novartis: Consultancy, Honoraria. Leber:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction: Patients with lower-risk (LR) MDS, defined as very low-, low-, and intermediate-risk by the Revised International Prognostic Scoring System (IPSS-R), have a reduced risk of progressing to acute myeloid leukemia compared with higher-risk patients, but a shortened overall survival (OS) compared with age-matched controls. MDS patients with RS have a better prognosis than those without RS, but may experience extended periods of RBC transfusion dependence. RBC transfusion dependence is associated with reduced OS in patients with LR-MDS, but studies focusing on RBC transfusion dependence and OS in RS+ MDS patients are lacking. To address this gap, data from the Canadian MDS Registry were used to assess the relationship between RBC transfusion dependence patterns and OS in this patient population. Methods: Patients with a diagnosis of RS+ MDS who were identified as transfusion dependent (TD) in the Canadian MDS Registry from 2008 to 2019 were included. Patients were considered TD if they received ≥ 1 RBC transfusion in at least one 8-week cycle. A sensitivity analysis was conducted wherein patients were considered TD if they received ≥ 1 RBC transfusion for 2 consecutive 8-week cycles. Patients were considered persistently TD (PTD) if they were TD throughout follow-up, or intermittently TD (ITD) if they were transfusion independent for periods of ≥ 8 weeks after an initial onset of TD. Covariates that were assessed included age, sex, IPSS-R risk score at enrollment, Eastern Cooperative Oncology Group performance status score at enrollment, ferritin level at first TD onset, Charlson Comorbidity Index at first TD onset, and receipt of iron chelation and anemia-treating therapies at first TD onset. Cox proportional hazards regression was used to test the association between PTD and mortality risk. Treatment patterns during follow-up were also examined. Results: Between 2008 and 2019, 191 patients had a diagnosis of RS+ MDS, of which 107 required ≥ 1 RBC transfusion over at least one 8-week cycle during follow-up. Of the 107 patients who received ≥ 1 RBC transfusion, 71 had ≥ 2 assessments for transfusion dependence and complete data on all outcomes and covariates, 36 (50.7%) of whom were classified as PTD (Table 1). Compared with ITD patients, PTD patients were older (mean age ± standard deviation [SD]: 75.11 ± 8.34 vs 69.59 ± 13.33 years) and had higher IPSS-R risk (17% of PTD patients were intermediate- or higher-risk compared with 3% of ITD patients). Median OS from first TD onset was 18.7 months (95% confidence interval [CI] 11.3-46.9) for PTD patients, compared with 48.7 months (95% CI 39.0-not evaluable) for ITD patients (Figure). After adjusting for baseline covariates, being PTD was associated with significantly greater mortality risk than being ITD (hazard ratio [HR] 2.24, 95% CI 1.18-4.25). Similar results were observed for the sensitivity analysis requiring ≥ 1 RBC transfusion for 2 consecutive 8-week cycles prior to the onset of TD (HR 2.18, 95% CI 1.13-4.21). Compared with ITD patients, PTD patients were less likely to receive iron chelation therapies (42% vs 54%), erythropoiesis-stimulating agents (25% vs 40%), and lenalidomide (14% vs 20%) during follow-up (Table 2). Conclusions: In this study, we extracted Canadian MDS Registry data on RBC transfusions and OS for MDS patients with RS+ MDS. More than half (50.7%) of the identified cohort became TD during follow-up. Among those who received RBC transfusions, PTD patients had significantly shorter OS and increased mortality risk compared with ITD patients, and RBC transfusion dependence independently predicted inferior outcomes. These conclusions are consistent with previous findings on the relationship between RBC transfusions and OS in all patients with LR-MDS. Disclosures Buckstein: Takeda: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Seattle Genetics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Leber:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sabloff:Pfizer Canada:: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Leitch:Novartis: Honoraria, Research Funding, Speakers Bureau; Otsuka: Honoraria; Alexion: Research Funding; AbbVie: Research Funding; Celgene Corporation: Honoraria, Research Funding. St. Hilaire:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Finn:Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Banerji:Janssen: Consultancy, Honoraria, Research Funding; Research Manitoba: Research Funding; CAPhO: Honoraria; BIOGEN: Other: Licensing fee; CancerCare Manitoba/University of Manitoba: Employment; CIHR: Research Funding; Dana-Farber Cancer Institute: Other: Licencing fee; CCMF: Research Funding; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; LLSC: Research Funding; Roche: Honoraria, Licensing fee, Research Funding. Liu:Celgene Corporation: Employment. Tang:Celgene Corporation: Employment, Equity Ownership. Westcott:Celgene Corporation: Employment, Equity Ownership. Huang:Celgene Corporation: Employment. Wang:Cornerstone Research Group: Employment. Cameron:Cornerstone Research Group: Employment, Equity Ownership. Morison:Celgene Corporation: Employment. Spin:Cornerstone Research Group: Employment.

Background: Hypomethylating agents (HMAs) can confer transfusion independence and prolong overall survival (OS) in patients with myelodysplastic syndromes (MDS), but response rates are < 50% and depend on sustained administration. In Ontario, 33% of higher risk MDS patients receive < 4 cycles AZA and have very short survival. Identifying the patients unsuitable for HMAs and the factors predictive of overall survival (OS)/leukemia free survival (LFS) would be of value. MDS-CAN, the national MDS registry prospectively evaluates patient-related factors in addition to disease factors in MDS, MDS/MPN, and oligoblastic AML patients. Objective: Determine the factors predictive of OS/LFS and the completion of ≥ 4 cycles of HMA, with particular focus on frailty and comorbidity. Methods: All patients who had received HMAs (azacytidine (AZA), decitabine, guadecitabine, ASTX727) were eligible. Frailty was assessed using the Rockwood clinical frailty scale (CFS) and the frailty index (FI) comprised of 42 deficits we previously developed. The MDS-FI was calculated using baseline measurements of comorbidities, laboratory values, Lawton Brody instrumental activities of daily living (LB-IADL), quality of life (EQ-5D), and 3 physical fitness tests. Patients who had ≤ 13 missing variables on the MDS-FI were included. Kaplan-Meier (KM) OS curves were calculated from treatment start date to death or last follow up. Univariable and multivariable analysis was done to identify significant predictors of OS, LFS and the receipt of ≥ 4 cycles of HMA. Results: There were 422 patients treated with an HMA (94% AZA). FI scores could be calculated in 188 patients and CFS in 169 patients. Among the 188 patients, the median age at HMA start was 73 years old (IQR 67, 79), time from diagnosis was 10 months (IQR 2, 28), 66% of patients were high/intermediate-2 risk IPSS, and 72% were high/very high risk IPSS-R. 40% were transfusion dependent, 30% had poor/very poor cytogenetics, and 10% had oligoblastic AML. Median number of HMA cycles was 7 and 76% completed ≥ 4 cycles. The median follow up was 12 months (IQR 7, 25). 19% of patients developed AML. Actuarial median OS was 17 months (95% CI: 13-20) with 50% of deaths due to AML or progressive disease. The MDS-FI score was grouped into categories of 1, 2, and 3 (scores ≤0.2, 0.2-3, and >3, respectively), with a median score of 0.3 (IQR 0.2, 0.3). The median scores for the clinical frailty scale (CFS), Charlson comorbidity index (CCI), and MDS-specific comorbidity index (CI) were 3 (IQR 2, 4), 1 (IQR 0, 2), and 0 (IQR 0, 2) respectively. 21% of patients had cardiac comorbidity(s), 53% had ≥ 1 disability (LB-IADL), and 76% had ≥ 1 impaired symptoms or function on the EQ5D, the most common being usual activities (45%) and pain/discomfort (44%). On physical testing, 56%, 30% and 88% had partial or full deficits in grip strength, 4 meter walk and the 10x chair stand tests compared with age/sex matched reference standards. Those who completed ≥ 4 cycles of AZA compared with those that did not were more likely to be younger (73 vs 78 years old, p=0.002), have lower risk disease (IPSS-R very low/low/intermediate: 29 versus 13%, p=0.044), have lower comorbidity (MDS-CI score: 0 vs 1, p=0.006), lower frailty scores (CFS: 2 versus 3, p=0.008) and performed better on grip strength (31 vs 26 kg, p=0.021) and the 10x chair stand test (28 vs 30s, p=0.045). Predictive factors from univariate analysis are presented on Table 1. There was a trend towards receiving fewer HMA cycles if patients fell within higher FI categories (8 vs 7 vs 5 cycles, p=NS). OS declined with increasing FI categories (p=0.002, Fig 1a). In subgroup analysis by IPSS or IPSS-R score, the FI further stratified the OS of patients with IPSS high/intermediate-2 (p=0.001, Fig 1b) and IPSS-R very high/high risk groups (p=0.002, Fig 1c). The best multivariate model for OS included IPSS (p=0.001), LDH (p=0.001), and MDS-CI (p Conclusions: Frailty and comorbidity provide important prognostic information for clinical outcomes in MDS patients receiving hypomethylating agents. The evaluation of patient characteristics in addition to disease parameters should be an integral part of clinical decision-making. Disclosures Wells: Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Rockwood:Alzheimer Society of Canada: Research Funding; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Canadian consortium on neurodegeneration in aging and nutricia: Membership on an entity's Board of Directors or advisory committees; Foundation Family Fund: Research Funding; Pfizer: Research Funding; Capital Health research support: Research Funding; Sanofi: Research Funding; CIHR: Research Funding; Nova Scotia Health research foundation: Research Funding. Geddes:Celgene: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sabloff:Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Novartis: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees. Leber:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leitch:Celgene Corporation: Honoraria, Research Funding; Otsuka: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Alexion: Research Funding; AbbVie: Research Funding. Yee:Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding. St-Hilaire:Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Finn:Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ipsen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Storring:Novartis: Honoraria, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Nevill:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Paladin Labs: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shamy:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Banerji:Roche: Honoraria, Licensing fee, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; LLSC: Research Funding; Research Manitoba: Research Funding; CCMF: Research Funding; CancerCare Manitoba/University of Manitoba: Employment; CAPhO: Honoraria; BIOGEN: Other: Licensing fee; Dana-Farber Cancer Institute: Other: Licencing fee; Abbvie: Consultancy, Honoraria; CIHR: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria. Delage:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Buckstein:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding.

Background: Ruxolitinib (rux), a Janus kinase 1/2 inhibitor (JAKi), is the only approved therapy for myelofibrosis (MF), a myeloproliferative neoplasm associated with bone marrow (BM) fibrosis. Rux reduces spleen volume (SVR35 in 30%-40% pts) and constitutional symptoms (≥50% in about 40% pts), two important hallmarks of MF; however, the improvement may be associated with significant cytopenia and rarely with evidence of disease modification. Synergistic therapeutic agents are needed for disease-modifying effects leading to overall improvement of MF, an unmet medical need. BET proteins are transcriptional regulators that control key oncogenic pathways, including NFκB, and TGFβ signaling, important drivers of inflammation and fibrosis, respectively, in MF. In preclinical MF models, the combination of a BETi and rux demonstrated synergistic reduction of splenomegaly, cytokine (Ck) expression, BM fibrosis and the mutant allele burden (Kleppe 2018). CPI-0610 is a selective and potent oral small molecule BETi with effects on megakaryocyte differentiation and Ck production in preclinical studies (unpublished data) and has shown antitumor activity and a wide therapeutic window in a Phase 1 lymphoma study (Blum KA, 2018). Preliminary clinical data from the Phase 2 MANIFEST study in prior JAKi treated MF pts showed that CPI-0610, as monotherapy (Arm 1) or "add on" to rux (Arm 2), was generally well-tolerated, with spleen volume reduction, symptom alleviation, hemoglobin improvement and reduction in transfusion burden as well as suppression in proinflammatory Ck and improvement in BM fibrosis (Kremyanskaya, 2019; Hoffman, 2019). Here, we present preliminary clinical data from Arm 3 in the MANIFEST study: JAKi naïve MF pts treated with CPI-0610 in combination with rux. Method: MANIFEST is a global, multicenter, open label Phase 2 study of CPI-0610 in combination with rux. Key eligibility criteria of Arm 3 include JAKi naïve MF pts with DIPSS score int-1 or higher, ECOG performance status ≤2, platelet counts ≥100 x 109/L, peripheral blood blast count Results: As of 27 June 2019, total 11 pts have been treated, all pts remain on study, 4 pts on treatment for ≥ 4 cycles (≥ 12 weeks). Baseline median age: 71 years (52-76), gender: 8 male (72.7%), ECOG ≤1: 10 (90.9%) pts, primary MF: 8 (72.7%) pts, DIPSS score: int-1/int-2/high: 2/7/2 pts, median platelet: 368 x 109/L (112-951), 9 (81.8%) pts with hemoglobin Conclusions: The combination of BETi CPI-0610 and JAKi rux was generally well-tolerated demonstrating that the safety of this combination is acceptable in JAKi naïve MF pts with anemia. Early clinical activity was observed with the combination: all 4 evaluable pts achieved both ≥35% SVR and ≥50% improvement in TSS as early as 3 months after treatment. Available data in JAKi naïve anemic MF pts, a population with poor prognosis, along-with additional information on reduction in pro-inflammatory Ck and BM fibrosis improvement in CPI-610 treated pts in rux refractory MF, collectively indicate that addition of CPI-0610 to rux may be synergistic and potentially have disease-modifying effects in JAKi naïve MF pts. Updated data will be presented. Disclosures Harrison: Incyte: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Speakers Bureau; Roche: Honoraria; Sierra Oncology: Honoraria; CTI: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Promedior: Honoraria; Celgene: Honoraria, Speakers Bureau; AOP: Honoraria. Mascarenhas:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kremyanskaya:Incyte, Celgene, Constellation, Protagonist.: Research Funding; La Jolla: Consultancy. Hoffman:Merus: Research Funding. Schiller:Agios: Research Funding, Speakers Bureau; Genzyme: Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Amgen: Other, Research Funding. Leber:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kabir:Constellation Pharmaceuticals: Employment. Senderowicz:Constellation Pharmaceuticals: Employment; Puma Biotechnology: Membership on an entity's Board of Directors or advisory committees. Mertz:Constellation Pharmaceuticals: Employment, Equity Ownership. Trojer:Constellation Pharmaceuticals: Employment, Equity Ownership. Shao:Constellation Pharmaceuticals: Employment. Gupta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Xenotransplantation of acute myeloid leukemia (AML) into immunodeficient mice has been critical for understanding leukemogenesis in vivo and defining self-renewing leukemia-initiating cell subfractions (LICs). Although AML-engraftment capacity is considered an inherent property of LICs, substrains of NOD/SCID mice that possess additional deletions such as the IL2Rγcnull (NSG) have been described as a more sensitive recipient to assay human LIC function. Using 23 AML-patient samples, 39% demonstrated no detectable engraftment in NOD/SCID and were categorized as AMLs devoid of LICs. However, 33% of AML patients lacking AML-LICs were capable of engrafting NSG recipients, but produced a monoclonal T-cell proliferative disorder similar to T-ALL. These grafts demonstrated self-renewal capacity as measured by in vivo serial passage and were restricted to CD34-positive fraction, and were defined as LICs. Molecular analysis for translocations in MLL genes indicated that these AML patient-derived LICs all expressed the MLL-AFX1 fusion product. Our results reveal that the in vivo human versus xenograft host microenvironment dictates the developmental capacity of human LICs residing in a small subset of patients diagnosed with AML harboring MLL mutations. These findings have implications both for the basic biology of CSC function, and for the use of in vivo models of the leukemogenic process in preclinical or diagnostic studies.

Introduction: A Canadian tyrosine kinase inhibitor (TKI) discontinuation trial is ongoing to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation after imatinib (IM) treatment. The preliminary result indicate : 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4. We report here the preliminary analysis of the TFR rate at 6 months after DA discontinuation for the second TFR attempt. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level < MR4.0 on 2 consecutive occasions, or a single increase in BCR-ABL transcript level < MR3.0. 100mg daily of DA is started if molecular relapse is confirmed and is discontinued 12 months after achieving > MR4 for a 2nd TFR attempt. The null hypothesis was a TFR2 rate of 17.5% while the alternative hypothesis was a TFR2 rate of 35.0% and the study was designed to reject our null hypothesis if > 28% of patients remain in TFR after DA discontinuation. Results: As of Jun 15, 2018, 53 (40.4%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 58.0% at 12 months (95% CI, 42.1-71.0%). Of the 53 patients who lost response, 51 patients received DA. The incidence of MMR, MR4 and MR4.5 at 3 months was 97.7%, 89.9%, and 84.6%, respectively. 25/ 51 patients receiving DA attained MR4.5 for 12 months or longer and discontinued it for a 2nd TFR attempt (TFR2). 21/25 (84.0%) of these patients lost molecular response at a median of 3.7 months after DA discontinuation. The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months (95% CI [7.9-39.5%], Fig 1A). Thus we cannot reject our null hypothesis based on this result. For risk factor analysis for maintaining TFR2, the variables analysed included Sokal risk score, IM duration, MR4/MR4.5 duration, monthly doubling time after IM discontinuation, time to molecular relapse after IM discontinuation, molecular relapse pattern after IM discontinuation (MMR loss vs MR4 loss), and BCR-ABL1 qPCR value prior to DA discontinuation. 1) Time to molecular relapse after IM discontinuation correlates with TFR2 (p 2) Molecular relapse pattern after IM discontinuation correlates with TFR2. The group who had loss of MMR after IM discontinuation lost molecular response faster after DA discontinuation (n=19; median 3.0 months) compared to those with two consecutive losses of MR4(n=6; 6.43 months; p=0.0435, HR 2.991; Fig 3B). 3) The group with 5.5 log reduction or deeper in BCR-ABL1 qPCR transcripts prior to DA discontinuation (n=19) showed a TFR2 rate of 28.7% at 6 months (median TFR2 duration of 4.04 months) versus 0% in the group with qPCR transcript level between 4.5 and 5.4 log reduction (n=6, median TFR2 duration of 2.89 months; p=0.017; Fig 3C). We did not identify any other risk factor for molecular relapse after DA discontinuation . The expansion kinetics of the leukemic clone after DA discontinuation is similar to that after IM discontinuation. Conclusion: These preliminary results suggest that rechallenge with DA after failing a first IM discontinuation attempt for TFR is well tolerated and effective as most cases rapidly regained at least MR4. However, more strict criteria should be considered for TFR2 attempt, including achievement of a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the 2nd TKI discontinuation attempt, and a MR4 duration of more than 12 months. Disclosures Kim: Pfizer: Consultancy; Paladin: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Bence-Bruckler:Lundbeck: Membership on an entity's Board of Directors or advisory committees. Delage:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Liew:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Laneuville:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Paladin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND Few Tx options are available for pts with inadequately controlled PV. European LeukemiaNet defined resistance/intolerance was seen in ≈25% pts treated with HU (Alvarez-Larran et al, 2012). In the HU-resistant/intolerant PV pts evaluated in the pivotal RESPONSE study (week [wk] 208), RUX was well tolerated and superior to standard therapy in achieving durable hematocrit (HCT) control, hematologic response, and spleen size and symptom reductions. This Ph 3b ETP study was planned to provide RUX Tx to HU-resistant/intolerant PV pts, who have no alternative standard Tx, and are not eligible for any ongoing clinical studies. Results from wk 24 data cutoff of this study (Devos et al) were presented at ASH 2017. Here, we report consolidated findings from the ETP study at wk 96 data cutoff (Dec 29, 2017 [final database lock]) to further support the use of RUX in this pt population with an unmet medical need. METHODS RUX Tx was initiated at a starting dose of 10 mg bid (could be titrated to a maximum of 25 mg bid). Visits were scheduled every 4 wks until wk 24 and every 12 wks thereafter; final analysis was done when all pts had been followed for 30 days after discontinuation of Tx or completion of Tx per protocol (transitioned to commercial RUX or until Dec 31, 2017, whichever date occurred first). The primary endpoint was to assess the safety of RUX. Secondary endpoints included change in HCT level, change in spleen length, and pt-reported outcomes (change in MPN-SAF TSS score). HCT control at wk 24 was defined by absence of phlebotomy (PBT) eligibility starting at wk 8 and continuing through wk 24, with no more than 1 PBT eligibility occurring after first dose date and prior to wk 8. PBT eligibility was defined by confirmed HCT >45% (at least 3 percentage points higher than HCT at baseline [BL]), or confirmed HCT >48%. Blood count remission at wk 24 was defined by HCT control, and white blood cell count RESULTS At data cutoff, 161 pts with PV were enrolled (BL characteristics similar to that presented at ASH 2017). End of Tx was reported for all 161 pts: Tx duration completed per protocol (141 pts), adverse event (AE [12 pts]), consent withdrawal (3 pts), pt decision (2 pts), disease progression (2 pts), and death (due to accident [1 pt]). The median exposure was 25.1 wks (range, 0.4-104.7), and median dose intensity of RUX was 20.0 mg/day (range, 6.7-47.7). AEs (regardless of study drug relationship) led to dose adjustment/interruption in 37.9% pts and study drug discontinuation in 8.7% pts. The most common hematologic AEs (rate=number of events per 100 pt-year exposure [pt-year exposure=110.2]; all grades]) included anemia (31.8) and thrombocytosis (10.0), while headache (24.5), diarrhea (14.5), constipation (12.7), and fatigue (12.7) were the most frequent non-hematologic AEs. For all reported grade 3/4 AEs, exposure-adjusted rate was less than 3. Thromboembolic events (all grade; Standardized MedDRA Query) were reported in 3 pts. Disease progression was reported in 4 pts (myelofibrosis=3 pts; acute myeloid leukemia=1 pt). The incidence of other neoplasms (regardless of study drug relationship) was low (leiomyoma, malignant melanoma, marginal zone lymphoma, renal cancer [1 pt each]; squamous cell carcinoma [2 pts]; basal cell carcinoma [3 pts]). Infections (all grades) were reported in 57 pts (grade 3/4 in 5 pts). At wk 24, 73 pts (45.3% [95% CI, 37.5%-53.4%]) achieved HCT control; hematologic remission was seen in 29 pts (18% [95% CI 12.4%-24.8%]). Changes in blood count parameters over time are shown in Fig. 1. In evaluable pts (N=105), use of PBT decreased from BL (39 PBTs between screening and BL) to end of Tx (5 PBTs in 12 wks prior). Best spleen response from BL for each pt by wk 96 is shown in Fig. 2. At least 50% spleen length reduction was seen in 86.7% (78/90) of pts from BL at any time in the study. Overall, 33.8% (46/136) of pts had ≥50% reduction in MPN-SAF TSS from BL at the end of Tx. CONCLUSION The observed safety profile of RUX in the ETP study was consistent with that of the RESPONSE studies. Efficacy results were close to the observed values in the RESPONSE studies. RUX Tx resulted in HCT control, hematologic remission, spleen response, and symptom reduction in this HU-resistant/intolerant pt population in need of a viable Tx option. Safety and efficacy findings from this ETP study support the use of RUX for pts with inadequately controlled PV, an unmet medical need. Disclosures Foltz: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. de Almeida:Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ranta:Novartis: Consultancy. Cartes:Novartis: Honoraria. Kiladjian:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chrit:Novartis: Employment, Equity Ownership. Yin:Novartis: Employment. Morando:Novartis: Employment, Equity Ownership. Devos:Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

Introduction: The management of CLL has been transformed in recent years by the introduction of a number of targeted agents including the BCL2 inhibitor VEN, and the Bruton's tyrosine kinase inhibitor IBR. In the US and EU, VEN is currently approved for patients who have received at least 1 prior therapy, whereas IBR has wider indications that include front-line therapy as well as R/R CLL. The mechanisms of action of VEN and IBR are complementary (Bose et al. F1000Research 2017); this has led to studies of combination therapy in patients with CLL (Wierda et al. J Clin Oncol Suppl. 2018). In addition, the documented activity of VEN in patients with IBR R/R disease (Jones et al. J Clin Oncol Suppl. 2016), together with current approvals, has resulted in VEN being suggested as a reasonable treatment choice for patients who discontinue IBR (Byrd et al. J Clin Oncol Suppl. 2018). However, the clinical benefit of IBR in patients pretreated with VEN is less clear. We present a post-hoc series, obtained after follow-up of 8 patients with R/R CLL who received IBR after fixed-duration VEN+rituximab (R) therapy in the MURANO randomized phase 3 study (NCT02005471) (Seymour et al. N Engl J Med 2018). Methods: In MURANO, 389 patients with R/R CLL were enrolled and treated with 6 cycles of VEN+R followed by VEN monotherapy once-daily for up to 2 years, or 6 cycles of bendamustine (B)+R. Progression-free survival (PFS), the primary study endpoint, was based on investigator assessment. The present case series focuses on VEN+R patients from MURANO who developed progressive disease (PD), and who subsequently received IBR. Eight patients in the VEN+R group with PD subsequently received IBR (Table 1). The number of lines of therapy prior to VEN+R ranged from 1 (n=7) to 4 (n=1; median 1). Prior to VEN+R therapy, 7 of the patients (87.5%) received fludarabine+cyclophosphamide+R (FCR); of these, 3 patients (42.8%) achieved a complete response (CR), 3 (42.8%) achieved a partial response (PR), and 1 patient (14.2%) had stable disease (SD). Of these 7 patients, 2 were considered refractory to FCR before VEN+R therapy. At baseline (before VEN+R), three of the patients (37.5%) had chromosome 17p-deletion, and two patients (25%) had baseline lymph nodes ≥5 cm- Four of the 8 patients had IBR dose interruption or modification due to neutropenia (n=2), clarithromycin treatment (n=1), or cutaneous nevus biopsy (n=1). Multiple skin abscesses were reported in 1 patient. One patient had atrial fibrillation, and 2 patients had arthralgia (1 had nearly resolved on follow-up), and there were no reports of major bleeding. Conclusions: In this series of patients with R/R CLL who received IBR following prior VEN+R in the MURANO study, IBR showed clinical activity and acceptable tolerability, with no new safety signals. Our results suggest that the use of IBR after relapse following VEN+R is a reasonable option in patients with CLL. More data will be collected from MURANO on patients progressing after VEN+R who are subsequently treated with IBR monotherapy. Disclosures Greil: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding. Fraser:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marks:BMS: Honoraria; Servier: Honoraria; Merck: Honoraria. Middeke:Roche: Membership on an entity's Board of Directors or advisory committees; 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. Schary:AbbVie: Employment. Boyer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Breuleux:Roche: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea: Patents & Royalties; Novartis: Patents & Royalties. Crompton:Roche: Employment, Equity Ownership. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Marlton:Pfizer: Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Background: Plasma levels of imatinib have been shown to be predictive of disease response in chronic phase chronic myeloid leukemia (CML). However, the ultimate site of action of imatinib is intracellular. While intracellular imatinib has been reported to be correlated with plasma imatinib, the use of intracellular imatinib for the prediction of clinical outcomes is unclear. The concentration of intracellular imatinib depends on many factors including the level of alpha-1-acid glycoprotein, which binds to imatinib and prevents intracellular uptake, and the OCT-1 transporter, which mediates the influx of imatinib across the plasma membrane of leukemic cells. We conducted the present study of newly diagnosed CML patients with the primary objective of determining if intracellular levels of imatinib two weeks after treatment initiation predicted major molecular response. The secondary objectives were to elucidate the relationships between the levels of OCT-1 and plasma imatinib with intracellular imatinib. Methods: We prospectively studied newly diagnosed chronic phase CML patients in Canada who were treated with standard dose imatinib (400 mg). We measured both intracellular and extracellular (plasma) levels of imatinib by tandem mass spectrometry at two weeks, four weeks, and twelve months after enrollment. Additionally, we measured transcript levels of OCT-1 and BCR-Abl by q-rt-PCR before treatment, at six months, and at twelve months to determine therapeutic response. Results: Eighty-one patients were screened. A total of 76 patients entered the study, and 55 completed the study per protocol. Patient information is shown in Table 1. There was a significant correlation between intracellular imatinib levels at two weeks and a 2-log reduction of BCR-Abl transcript at six months (r=0.390; 95% CI = 0.136 - 0.595; p = 0.004) (Figure 1), but not at twelve months (r=0.183; 95% CI = -0.094 - 0.434; p = 0.194). Notably, intracellular imatinib levels and plasma levels of imatinib were highly correlated at two weeks (r=0.698; 95% CI = 0.559-0.799; p Conclusions: Intracellular imatinib levels at two weeks was moderately predictive of a disease response at six months as indicated by a 2-log reduction in BCR-Abl transcript. OCT-1 transcript levels did not have utility for predicting intracellular imatinib levels. Measurement of intracellular Imatinib levels may prove to have utility in identifying patients who would benefit from adjustments to therapy. Disclosures Hillis: Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Busque:Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy; BMS: Consultancy. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Savoie:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Novel agents are frequently added to standard acute myeloid leukemia (AML) treatment backbones yet it is unclear how much additional toxicity this introduces, with the potential for adverse events (AEs) to be caused by the backbone chemotherapy or the disease itself. Glasdegib (PF-04449913) is an investigational, oral small molecule inhibitor of the Hedgehog (Hh) pathway component Smoothened (SMO), currently in clinical development for AML treatment. In a Phase 2 randomized study, addition of glasdegib to low-dose cytarabine (LDAC) improved overall survival (OS) vs LDAC alone and combination therapy was generally well tolerated with minor differences in AE rates vs chemotherapy alone. Here, we analyzed specific 'on target' AEs consistent with inhibition of the SMO component of the Hh pathway to assess impact on overall toxicity. Methods: We pooled safety data from both portions of a Phase 1b + Phase 2 multicenter study (NCT01546038), including AML patients assigned to glasdegib 100 mg QD with LDAC (non-intensive treatment) or with cytarabine/daunorubicin on a 7+3 schedule (intensive treatment) (figure 1). We assessed 'on target' all-causality treatment-emergent AEs of muscle spasms, alopecia, and dysgeusia. We also compared AE onset in defined study time-periods (non-intensive: 0-6, 6-12, or >12 months; intensive: induction, consolidation, maintenance); defining long-term treatment as >12 months for non-intensive and maintenance for intensive. Results: Across studies, 93 patients were enrolled in the non-intensive group and 80 in the intensive group. Here, we focused on patients treated with glasdegib: 89 patients in the non-intensive group and 78 in the intensive group. Table 1 shows baseline characteristics; median treatment duration was 69 days (range 3-1280) and 51 days (10-539), respectively. Rates of treatment discontinuation due to all AEs (inclusive of 'on target' and others), deemed by the investigator to be related to study drug (glasdegib and/or backbone chemotherapy) were similar (non-intensive, 10 patients [11.2%]; intensive, 15 patients [19.2%]). Frequency of muscle spasms was similar for the 2 groups; observed in 19 of the non-intensive group (21.3%) and 18 (23.1%) of the intensive group (table 1), with few grade 3 events (non-intensive 4.5%; intensive 1.3%), and the number of patients who developed muscle spasms (nearly all grade 1) when exposed to long-term treatment was small (4 non-intensive patients; 7 intensive patients) with no cases of rhabdomyolysis. Alopecia was reported for 8 (9.0%) of the non-intensive group and 16 (20.5%) of the intensive group (table 1). Alopecia had earlier time to onset in the intensive arm than in the non-intensive arm (table 1), likely reflecting the concomitant chemotherapy. Alopecia was less frequent during glasdegib maintenance monotherapy (5.3%) in the intensive arm than when given with 7+3 (16.7%). Dysgeusia was similar for the 2 groups, observed in 22 of the non-intensive group (24.7%) and 24 (30.8%) of the intensive group (table 1). For both groups, dysgeusia had similar time to onset and was less common during long-term treatment. The number of patients having a dose modification as a consequence of class-related AEs was low (for non-intensive and intensive, respectively: dose reduction, 5.6% and 2.6%; temporary discontinuation, 4.5% and 2.6%; permanent discontinuation, 1.1% and 2.6%). Conclusions: Glasdegib 'on target' AEs of muscle spasms, alopecia, and dysgeusia were mainly of mild severity, had infrequent dose modifications or permanent discontinuations, and did not appear to impair tolerability of combination treatment. In comparison, muscle spasms and dysgeusia occurred in ≤5% for the LDAC alone arm, and no alopecia was reported. Although muscle spasms and dysgeusia occurred with similar frequency, dysgeusia occurred earlier, for a shorter duration, and was more persistent at the time of discontinuation compared with muscle spasms. Similar safety profiles were observed when combining glasdegib with LDAC or 7+3, suggesting that glasdegib in combination with standard chemotherapy has a manageable safety profile and thus can be an acceptable combination partner in the treatment of AML. Our results are consistent with previously reported safety outcomes for glasdegib as monotherapy in hematologic malignancies. Clinical trials of glasdegib in combination with other standard of care AML agents are ongoing. Disclosures Cortes: Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Candoni:Pfizer: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau. Leber:Pfizer Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuko: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ma:Pfizer Inc: Employment, Equity Ownership. Gallo Stampino:Pfizer Inc: Employment, Equity Ownership. O'Connell:Pfizer Inc: Employment, Equity Ownership. Zeremski:Pfizer Inc: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

Background: Health-Related Quality of life (HRQoL) is diminished in patients with myelodysplastic syndrome (MDS). We have previously shown that HRQoL remains stable over time and low hemoglobin, transfusion dependence (TD) and age > 65 years impact QoL1. Here, we present an updated larger data set with longer follow up and consider the impact of baseline characteristics and treatments received on patient-related outcomes. Methods: MDS-CAN is a prospective database active in 15 centers across Canada, enrolling patients since April 2012. In addition to disease and patient-related characteristics, we measure HRQoL at baseline and every 6 months using the EORTC-QLQ-C30, EQ-5D, and a global fatigue scale (GFS). We examined the impact of disease related factors (IPSS, IPSS-R, karyotype, TD), patient factors (ECOG, age, gender, co-morbidity (Charlson index), frailty (Rockwood scale), disability (Lawton-Brody Independent Activities of Daily Living), and treatments received at any time (azacitidine (AZA), lenalidomide, erythropoietin-stimulating agents (ESA), iron chelation) on QoL scores. AZA-treated patients were divided into responders (where documented) or deriving benefit (if > 6 cycles) vs. non-responders. Wilcoxon rank-sum or Kruskal-Wallis nonparametric tests were used to compare scores among subgroups. Changes in QoL were assessed with a linear mixed model to account for time- dependent covariates such as TD, risk scores and treatment. Results: 594 patients were enrolled a median of 2.2 months post diagnosis (IQR: 0.8, 4.8) with a median age of 73 years , 63% male gender and performance status (ECOG) of 0-1 in 90%. IPSS scores were low/int-1 in 73% and IPSS-R scores were very low (9%), low (30%), intermediate (27%), high (20%) and very high (14% of patients). 31% were transfusion dependent at enrolment. Treatments received at any time included AZA (38%), lenalidomide (9.8%), ESA (35%) and iron chelation (12%). At a median follow up of 17 months, 329 patients (55%) died with cause of death reported as AML in 22%. Baseline assessment: Mean EQ-5D global score for the cohort was 0.75 ± 0.25 and did not significantly change over time (Figure 1). Patients with high IPSS, high/very high IPSS-R, TD, lower hemoglobin, higher ECOG, increased comorbidity, frailty and disability were more likely to have lower EQ-5D/QLQ C30 scores (inferior QoL) and higher fatigue (GFS). Age was not significantly related to QoL. Interestingly, female gender was associated with inferior QoL by EQ-5D and GFS (Figure 2). Patients scoring in the lowest quartiles for physical performance tests (grip, 4 metre walk and 10x chair sit-stand tests) also had inferior QoL scores. QoL over time: By linear mixed modelling, we did not find significant differences in QoL over time in patients treated with or without AZA, lenalidomide, or ESAs measured by the EQ-5D instrument. Iron chelation was associated with lower scores (p=0.003) although this may simply be a surrogate for transfusion dependence which is associated with inferior QoL. AZA responding/deriving benefit patients had higher QoL scores from baseline and decreased fatigue compared with those not responding or not deriving benefit (Figure 3) measured by the QLQ-C30 and GFS instruments. Patients with the highest IPSS/IPSS-R risk groups had significantly inferior QoL over time. In conclusion, this study demonstrates that HRQoL remains fairly stable over time in MDS and implementation of treatment is not at the detriment of patient related outcomes. Patients treated with AZA who respond or remain on drug for > 6 months maintain higher QoL scores over time. Disease (IPSS, IPSS-R, hemoglobin, transfusion dependence) and patient-related factors (ECOG, gender, comorbidities, disability, frailty) are associated with reduced HRQoL. The prospective assessment of QoL using a validated MDS-specific QoL instrument (QUALMS) and disease course is underway. 1 Buckstein, R., Alibhai, S.M., Lam, A., et al. The health-related quality of life of MDS patients is impaired and most predicted by transfusion dependence, hemoglobin and age. Leukemia Research. May 2011 Vol 35, Supplement 1, Pages S55-56. Disclosures Wells: Alexion Pharmaceuticals, Inc.: Honoraria, Other: Travel Support , Research Funding; Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geddes:Alexion: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zhu:Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding. Sabloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leitch:Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; AbbVie: Research Funding. Yee:Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding. St-Hilaire:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shamy:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Elemary:Roche: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Delage:Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rockwood:Pfizer: Research Funding; Lundbeck: Membership on an entity's Board of Directors or advisory committees; CHIR: Research Funding; Nova Scotia Health research foundation: Research Funding; Sanofi: Research Funding; Capital Health research support: Research Funding; Canadian consortium on neurodegeneration in aging and nutricia: Membership on an entity's Board of Directors or advisory committees; Alzheimer Society of Canada: Research Funding; Foundation Family Fund: Research Funding. Banerji:Teva: Other: Unrestricted grant received in the past; Gilead: Other: Unrestricted grant received in the past; Abbvie: Other: Unrestricted grant received in the past; Roche: Other: Unrestricted grant received in the past; Janssen: Other: Unrestricted grant received in the past. Buckstein:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The molecular basis for the unique proliferative and self-renewal properties that hierarchically distinguish human stem cells from progenitors and terminally differentiated cells remains largely unknown. We report a role for the Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) as an indispensable regulator of self-renewal in human stem cells and show that a functional dependence on Mcl-1 defines the human stem cell hierarchy. In vivo pharmacologic targeting of the Bcl-2 family members in human hematopoietic stem cells (HSCs) and human leukemic stem cells reduced stem cell regenerative and self-renewal function. Subsequent protein expression studies showed that, among the Bcl-2 family members, only Mcl-1 was up-regulated exclusively in the human HSC fraction on in vivo regeneration of hematopoiesis. Short hairpin RNA–knockdown of Mcl-1 in human cord blood cells did not affect survival in the HSC or hematopoietic progenitor cell fractions in vitro but specifically reduced the in vivo self-renewal function of human HSCs. Moreover, knockdown of Mcl-1 in ontogenetically primitive human pluripotent stem cells resulted in almost complete ablation of stem cell self-renewal function. Our findings show that Mcl-1 is an essential regulator of stem cell self-renewal in humans and therefore represents an axis for therapeutic interventions.

Peripheral T-cell lymphomas (PTL) are morphologically and immunophenotypically heterogeneous. We have examined a series of cases to determine whether this heterogeneity is reflected at the level of developmentally specific T-cell receptor (TCR) gene rearrangement. 4 of 5 cases had clonal rearrangements of TCR beta and gamma chain genes; one of these also had a probable DQ52-J immunoglobulin heavy chain gene rearrangement. 2 of the 4 TCR gamma gene rearrangements involved the most 5' J region, JP1, a characteristic of immature thymocytes. These 2 cases also had immunophenotypic features of immaturity. Taken together, our results suggest that TCR gene rearrangement is correlated with surface marker data and shows that in some cases PTL may arise from a very early stage of thymocyte maturation.

Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KIs) to identify agents that may improve venetoclax therapy in a personalized manner. Marked interpatient variability was noted for which KIs were effective; nevertheless, sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that upregulate antiapoptotic Bcl-xl, Mcl-1, and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. Although patient-specific drug responses are common, for many patients, combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax.

Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis and associated with burdensome symptoms, reduced quality of life, risk of thrombohemorrhagic complications, and risk of transformation to myelofibrosis and acute myeloid leukemia. The discovery of the JAK2 V617 mutation marked a significant milestone in understanding the pathophysiology of the disease and subsequently the diagnostic and therapeutic approaches. The current diagnostic criteria for PV are based on hemoglobin level and presence of the JAK2 V617 mutation. The treatment is geared toward prevention of thrombotic events, normalization of blood counts, control of disease-related symptoms, and potential prolongation of survival. Cytoreductive therapy is indicated in patients at increased risk of thrombosis. Hydroxyurea (HU) remains the most commonly used first-line cytoreductive therapy and is superior to phlebotomy in reducing risk of arterial and venous thrombosis. Interferon (IFN) is used either at failure of HU or in selected patients as first-line therapy. The results of pegylated IFN in phase 2 studies appear encouraging, with molecular responses occurring in some patients. Ongoing phase 3 studies of HU versus pegylated IFN will define the optimal first-line cytoreductive therapy for PV. A recent phase 3 trial has shown the superiority of the JAK1/2 inhibitor ruxolitinib in comparison to best available treatment in HU-intolerant or -resistant patients. The therapeutic landscape of PV is likely to change in the near future. In this report, we assess the potential impact of the changing landscape of PV management on daily practice.

Patients in complete cytogenetic response (CCyR) with detectable BCR-ABL1 after ≥2 years on imatinib were randomized to nilotinib (400 mg twice daily, n = 104) or continued imatinib (n = 103) in the Evaluating Nilotinib Efficacy and Safety in clinical Trials-Complete Molecular Response (ENESTcmr) trial. By 1 and 2 years, confirmed undetectable BCR-ABL1 was achieved by 12.5% vs 5.8% (P = .108) and 22.1% vs 8.7% of patients in the nilotinib and imatinib arms, respectively (P = .0087). Among patients without molecular response 4.5 (BCR-ABL1(IS) ≤0.0032%; MR(4.5)) and those without major molecular response at study start, MR(4.5) by 2 years was achieved by 42.9% vs 20.8% and 29.2% vs 3.6% of patients in the nilotinib and imatinib arms, respectively. No patient in the nilotinib arm lost CCyR, vs 3 in the imatinib arm. Adverse events were more common in the nilotinib arm, as expected with the introduction of a new drug vs remaining on a well-tolerated drug. The safety profile of nilotinib was consistent with other reported studies. In summary, switching to nilotinib enabled more patients with chronic myeloid leukemia in chronic phase (CML-CP) to sustain lower levels of disease burden vs remaining on imatinib. This trial was registered at www.clinicaltrials.gov as #NCT00760877.

Summary Resistance to temozolomide is largely mediated by the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT). We conducted a prospective multicentre study of patients with previously untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS) who were not candidates for intensive therapy. Patient selection was based on MGMT expression by Western blot. Patients with MGMT:ACTB (β-actin) ratio

During apoptosis Bid and Bax are sufficient for mitochondrial outer membrane permeabilization, releasing pro-apoptotic proteins such as cytochrome c and Smac/Diablo into the cytoplasm. In most cells, both Bid and Bax are cytoplasmic but bind to mitochondrial outer membranes to exert pro-apoptotic functions. Binding to membranes is regulated by cleavage of Bid to truncated Bid (tBid), by conformation changes in tBid and Bax, and by interactions with other proteins. At least at the peripherally bound stage, binding is reversible. Therefore, regulation of apoptosis is closely linked with the interactions of tBid and Bax with mitochondria. Here we use fluorescence techniques and cell-free systems containing mitochondria or liposomes that faithfully mimic tBid/Bax-dependent membrane permeabilization to study the dynamic interactions of the proteins with membranes. We confirm that the binding of both proteins to the membrane is reversible by quantifying the binding affinity of proteins for the membrane. For Bax, both peripherally bound (inactive) and oligomerized (active) proteins migrate between membranes but much slower than and independent of tBid. When re-localized to a new membrane, Bax inserts into and permeabilizes it only if primed by an activator. In the case of tBid, the process of transfer is synergetic with Bax in the sense that tBid ‘runs' faster if it has been ‘kissed' by Bax. Furthermore, Mtch2 accelerates the re-localization of tBid at the mitochondria. In contrast, binding to Bcl-XL dramatically impedes tBid re-localization by lowering the off-rate threefold. Our results suggest that the transfer of activated tBid and Bax to different mitochondria is governed by dynamic equilibria and potentially contributes more than previously anticipated to the dissemination of the permeabilization signal within the cell.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease. Therapeutic plasma exchange (TPE) is the most effective therapy; however, despite TPE, about one-third of TTP patients will relapse. A subset of patients with TTP has antibodies to ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) and may become resistant to conventional treatments. We describe a patient with TTP and high-titre anti-ADAMTS13 antibodies who developed a chronic, relapsing course of TTP despite frequent TPE. Once adjuvant treatment with intravenous immunoglobulin (IVIG) was added, remission was achieved. Even during remission, anti-ADAMTS13 antibodies remained elevated. We conclude that IVIG may sustain remission in some patients with chronic, relapsing TTP.

Introduction: Multiple studies have shown that tyrosine kinase inhibitor (TKI), usually imatinib (IM), can be successfully discontinued in chronic myeloid leukemia (CML) patients, achieving a 40-50% treatment free remission (TFR) rate. However, the remaining 60% of patients require reintroduction of TKI therapy. We have designed this study to answer the question if a second generation TKI, i.e. dasatinib, should be used after failing the first attempt of TKI discontinuation with IM. This prospective study attempts to evaluate whether the use of dasatinib after failure of a 1st attempt of TKI discontinuation with IM could improve TFR rate after a 2nd attempt of TKI discontinuation. Methods and materials: This is a prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) including all major CML centers across Canada (n=12). The primary objective is to determine the proportion of patients who remain in molecular remission (defined as maintaining ≥MR4.0) after dasatinib discontinuation following achieving ≥MR4.5. The present study has 3 phases: 1) IM discontinuation phase, 2) dasatinib rechallenge phase, 3) dasatinib discontinuation phase. A total of 135 patients is planned to be enrolled over 18-24 months. Key inclusion criteria include: 1) CML in chronic phase (CP), 2) total duration of IM therapy of minimum of 3 years, 3) total duration of MR4.5 or deeper response over 2 years with 2 consecutive confirmed MR4.5 or deeper response at the central lab with 3 months interval. Key exclusion criteria include prior allogeneic stem cell transplant or prior accelerated or blastic phase CML. Molecular recurrence was defined as an increase in BCR-ABL transcript level above MR4.0, on at least two consecutive occasions, or a single increase in BCR-ABL transcript level above MR3.0. Dasatinib is started at a dose of 100mg daily once molecular recurrence is confirmed. Results: The study was launched on March 2015. As of June 22 2016, 110 patients were entered into screening phase of whom 16 patients were not qualified due to 1) fluctuating transcripts (n=8) or 2) consent withdrawal (n=8). Two patients withdrew consent after losing their molecular response following IM discontinuation before starting dasatinib. Finally 75 patients were enrolled into IM discontinuation phase with 17 additional patients on screening in awaiting enrollment (Figure A). Of 67 patients evaluable for molecular relapse, 21 patients (31.3%) lost molecular response defined as loss of major molecular response (MMR; n=18) and loss of MR4 on 2 consecutive tests (n=3). The 6-month relapse free survival (RFS) rate was estimated as 58.0% (42.1-71.0%), while TFR rate using loss of MMR as an event was 64.7% (48.7-76.7%) at 6 months (Figure B) Of 21 patients who lost molecular response, 20 patients underwent dasatinib rechallenge phase, 14 of which were treated with dasatinib for at least 1 month and evaluated at least once with monthly BCR-ABL transcript monitoring (Figure C). Twelve patients achieved MMR at a median time of 56 days. The median time to achieve MR4.5 was 84 days. The incidence of MMR and MR4.5 at 3 months was 100% each (Figure D). Cox's proportional hazard regression model suggested strong correlation of RFS with total duration of IM therapy prior to IM discontinuation (p=0.001), duration of MR4 maintenance (p=0.004) or MR4.5 maintenance (p=0.006) prior to IM discontinuation, but not with time to achieve MR4 (p=0.289) or MR4.5 (p=0.330). Recursive partitioning method also defined the best cutoff for those variables: The group treated with IM for over 8.9 years (n=35) had RFS rate 81.1% vs 21.0% in those treated for less than 8.9 years (n=32; p Conclusion: Preliminary results of this Canadian TKI discontinuation trial show a RFS rate of 58-65% after IM discontinuation in CP-CML patients who attained MR4.5 for over 2 years, similar to other TKI discontinuation studies. Dasatinib can be safely administered in CML patients who lost molecular response after IM discontinuation with 100% of MMR rate at 3 months. Prolonged duration of IM treatment, or duration of MR4/MR4.5 maintenance with IM therapy could predict the chance of TFR success, but not time to achievement of MR4/MR4.5. Disclosures Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees. Savoie:Amgen: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy; Lundbeck: Consultancy. Busque:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Delage:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Laneuville:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Paladin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Liew:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Xenocostas:Janssen Inc.: Research Funding. Kamel-Reid:BMS: Research Funding. Leber:BMS Canada: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.