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MF is a life-threatening myeloproliferative neoplasm. The JAKi ruxolitinib and fedratinib are the only FDA approved treatment options for MF. Despite benefits reported with ruxolitinib in the front-line setting, a high proportion of patients (pts) discontinue treatment (Abdelrahman 2015), and the median overall survival (OS) is 13-16 months (Kuykendall 2018; Newberry 2017; Schain 2019; Palandri 2019; Mcnamara 2019), highlighting a great unmet need for pts non-responsive to a JAKi treatment. Imetelstat, a first-in-class telomerase inhibitor, has shown meaningful clinical improvement in IMbark, a Phase 2 study in pts with Int-2 or high-risk MF who have relapsed after or are refractory to JAKi (Mascarenhas EHA 2020, ASH 2020). Treatment with imetelstat 9.4 mg/kg resulted in 32.2% symptom response (total symptom score [TSS] reduction ≥50%) at Week 24 and median OS of 28.1 months with overall study follow up of 42 months. Dose-dependent inhibition of telomerase with imetelstat resulted in on-target activity that correlated with clinical benefits; dose-dependent reduction in variant allele frequency of MF driver mutations indicated targeting of the underlying malignant clone. The Phase 2 results support continued study of imetelstat 9.4 mg/kg in a Phase 3 randomized controlled study. Study MYF3001 (IMpactMF; NCT04576156) is an open label, randomized (2:1), multicenter, Phase 3 study of imetelstat compared with BAT in ~320 pts with Int-2 or high-risk MF refractory to JAKi treatment. Pts will be randomized to receive imetelstat 9.4 mg/kg IV every 21 days or investigator selected BAT (including hydroxyurea, thalidomide, interferon, danazol, hypomethylating agents, chemotherapy, or other non-JAKi containing therapy as appropriate). Eligible pts will be stratified based on a) Int-2 or high-risk per Dynamic International Prognostic Scoring System; b) platelet count at entry (platelets ≥ 75 and < 150 x 10 9/L vs ≥ 150 x 10 9/L). Pts who meet progressive disease criteria and discontinue BAT may be eligible to crossover to imetelstat. The primary endpoint is OS, and one interim analysis is planned when >70% of death events have occurred. Secondary endpoints include symptom and spleen response rates at Week 24, progression-free survival, clinical response assessment per modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment criteria, time to and duration of response, reduction in degree of bone marrow fibrosis, safety, pharmacokinetics, and patient-reported outcomes. Biomarkers and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones. Approximately 180 sites are planned in North and South America, Europe, Middle East, Australia, and Asia. The study is open for enrollment. Disclosures Mascarenhas: Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, 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; Prelude: Consultancy; Geron: Consultancy, Research Funding; Geron: Consultancy; Galecto: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: 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, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merus: Research Funding. Harrison: Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: 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; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian: Taiho Oncology, Inc.: Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Komrokji: BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Koschmieder: Abbvie: Other: Travel support; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Shire: Honoraria, Other; CTI: Membership on an entity's Board of Directors or advisory committees, Other; Alexion: Other: Travel support; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Geron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Image Biosciences: Other: Travel support; Baxalta: Membership on an entity's Board of Directors or advisory committees, Other; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support), Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: (e.g. travel support); Karthos: Other: Travel support. Vannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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. Berry: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sherman: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Verstovsek: Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Roche: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Imetelstat, a first-in-class telomerase inhibitor, is undergoing clinical development but is not approved for treatment of MF

Introduction: Imetelstat is a first-in-class telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase (hTERT) expression, characteristics observed in MDS patients (pts) across all disease stages. IMerge (MDS3001, NCT02598661) is a Phase 2/3 global study of imetelstat for red blood cell (RBC) transfusion dependent (TD) pts with non-del 5q LR-MDS ESA-R/R, who have limited treatment options. The results from the Phase 2 part indicated that imetelstat achieved durable transfusion independence (TI) with a manageable safety profile. Among 38 pts with median follow-up of 24 months, ≥8-week (w), ≥24-w, ≥1-year (y) TI rates were 42%, 32% and 29%, respectively (Steensma JCO 2020, Platzbecker ASH 2020). Aims: To assess the correlation between imetelstat's on-target activity with clinical benefits and safety data as of 10-May 2021 in the Phase 2 part of IMerge. Methods: Peripheral blood samples pre and after 1 and 2 cycles of imetelstat administration were collected to analyze hTERT level by Taqman RT-PCR assay. ≥50% hTERT reduction by imetelstat was considered optimal pharmacodynamic (PD) effect. Correlation analyses between the optimal PD and efficacy, including TI rates ≥8-w, ≥24-w, and ≥1-y, duration of the longest TI, and OS, as well as hematological and liver function lab parameters were performed. Results: hTERT analyses on 35/38 pts with matched pre- and post-1 to 2 cycles of treatment samples available demonstrated on-target activity/optimal PD effect of imetelstat in 54.3% (19/35) of pts. Pts who achieved optimal PD had significantly higher rates of TI compared to pts who did not achieve optimal PD: 63.2% (12/19) vs 25% (4/16) had ≥8-w TI (p=0.0411); 57.9% (11/19) vs 12.5% (2/16) had ≥24-w TI (p=0.0125); and 52.6% (10/19) vs 6.3% (1/16) had ≥1-y TI (p=0.0125) (Fig A). Pts who achieved optimal PD effect had a greater reduction in transfusions (both absolute change in transfusion units and % of change in transfusion burden) in the best 8-week interval compared to pts who did not. In addition, pts who achieved optimal PD had a significantly longer median TI duration (68.4 w, 95% CI 4.9, 92.4) compared to those who did not (5.5 w, 95% CI 2.3, 6.6) with a hazard ratio of 0.364 (95% CI 0.167, 0.794, log-rank p value=0.0087, Fig B). Furthermore, median OS was 57.0 months (95% CI 34.6, -) in pts who achieved optimal PD vs 40.7 months (95% CI 26.9, -) in pts who did not, and the 4-year OS rate was 58.4% vs 31.0%, respectively, although not statistically significant. Pts who achieved optimal PD also had lower rates of Grade 3+neutropenia (52.6%), thrombocytopenia (57.9%), or liver function elevations (5.3%) compared to pts who did not achieve optimal PD (68.8%, 68.8% and 18.8%, respectively), although the differences were not statistically significant. Conclusion: Optimal PD effect of imetelstat treatment was demonstrated by ≥50% hTERT reduction. A significant correlation was observed between optimal PD effect of imetelstat and durable TI and improved 4-year OS rate, effectively linking imetelstat activity to clinical efficacy. Additionally, pts who achieved an optimal PD effect by imetelstat treatment did not have higher rates of cytopenias or liver enzyme elevations compared to pts without optimal PD effect. Enrollment is ongoing for the Phase 3 part of IMerge, a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo. Figure 1 Figure 1. Disclosures Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: 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, Research Funding. Fenaux: JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Raza: Celgene Inc: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Kura Oncology: Research Funding; Janssen R&D: Research Funding; Syros Pharmaceuticals: Research Funding; Onconova Therapeutics: Research Funding, Speakers Bureau. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria. Font: CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses; GILEAD: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Abbvie: Other: Travel, accomodations, expenses. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sherman: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Platzbecker: Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Celgene/BMS: Honoraria. OffLabel Disclosure: Imetelstat, a first-in-class telomerase inhibitor, is under clinical development but not approved for treatment of MDS

Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm characterized by splenomegaly and debilitating symptoms, such as fatigue, pruritus, night sweats, fever, bone pain, and weight loss that impact quality of life (QoL). Imetelstat, a first-in-class telomerase inhibitor, demonstrated clinical benefits in terms of symptom response and potential improvement in overall survival in a pilot study in MF patients (pts) (Tefferi et al, NEJM 2015) and in IMbark, a Phase 2 study in MF pts relapsed or refractory (R/R) to a Janus associated kinase (JAK) inhibitor (Mascarenhas et al, ASH 2018 #685). Aims: We assessed the effects of imetelstat on MF symptom burden and QoL in IMbark, and the correlations of MF-related symptoms measured by modified Myelofibrosis Symptom Assessment Form (MFSAF) 2.0 and other patient-reported outcome (PRO) endpoints. Methods: IMbark (MYF2001; NCT02426086) is a two-dose, randomized, single-blinded, Phase 2 study of imetelstat in R/R intermediate-2/high-risk MF pts, who received imetelstat 9.4 mg/kg or 4.7 mg/kg IV every 3 weeks. Symptom response, one of the co-primary endpoints, was defined as ≥50% reduction in total symptom score (TSS) from baseline to Week 24 as measured by the modified MFSAF 2.0 e-diary. The TSS was calculated as the 7-day average of daily TSS, which is the summation of 6 individual symptom scores (night sweats, itchiness, abdominal discomfort, pain under ribs on left side, early satiety, bone or muscle pain). Correlation of TSS with other PROs was explored: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Brief Pain Inventory (BP-I), and Patient Global Impression of Change (PGIC). Results: All 107 pts enrolled in IMbark were symptomatic, with baseline mean TSS scores of 25.7 in the 9.4 mg/kg arm (N=59) and 24.6 in the 4.7 mg/kg arm (N=48), indicating a high symptom burden. Pts in both arms had ≥96.5% mean compliance rates with completion of the e-diary. Treatment with imetelstat demonstrated a statistically significant dose-related improvement in TSS symptom response rate at Week 24 for 9.4 mg/kg vs 4.7 mg/kg (32.1% vs 6.3%, p=0.001) and at any time (52.5% vs 27.1%, p=0.010). A higher proportion of pts in the 9.4 mg/kg arm than in the 4.7 mg/kg arm achieved ≥50% reduction in 5 individual symptoms, including night sweats, itchiness, abdominal pressure, pain under left ribs, and early satiety. Based on EORTC QLQ-C30, improvements at Week 24 relative to baseline were seen in the imetelstat 9.4 mg/kg arm for global health status, all 5 function subscales, and all 3 symptoms. Notably for fatigue (a common MF symptom which was not measured in MFSAF v2.0), pts in the 9.4 mg/kg arm had improvement at Week 24 relative to baseline, compared to the pts in the 4.7 mg/kg arm (LS means -13.3 vs -3.1, p=0.042). The TSS symptom responses were shown to correlate with other PROs. Compared to pts in the 4.7 mg/kg arm, TSS symptom responders in the 9.4 mg/kg arm achieved significantly greater improvements in the global health status (p=0.004), fatigue (p=0.009), pain (p=0.033), and most of the functional scales in EORTC QLQ-C30. Pain scores per the modified MFSAF v2.0 correlated with the pain scores in EORTC QLQ-C30 and BP-I (correlation coefficients 0.5-0.6). More than 90% of TSS symptom responders in the 9.4 mg/kg arm also characterized their condition as having had either "very much improvement" (36.4%) or "somewhat improvement" (54.6%) in PGIC. Conclusion: These data show a dose-related, clinically meaningful improvement in overall and individual MF symptoms as measured by MFSAF 2.0 with imetelstat treatment in pts who are JAK inhibitor R/R. TSS symptom responders treated with imetelstat 9.4 mg/kg also had improvement in QoL as measured by EORTC QLQ-C30. The data further support the robustness of overall and individual symptom improvement in pts with MF as evidenced by the correlation of modified MFSAF v2.0 with other PROs such as EORTC QLQ-C30, PGIC, and BP-I. Disclosures Mascarenhas: Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy. Komrokji:Geron: Honoraria; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Niederwieser:Novartis: Speakers Bureau; Amgen: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi: Research Funding. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Scott:Agios, BMS: Honoraria; BMS, Novartis: Research Funding; Alexion, Incyte, Novartis, Regeneron: Consultancy. Baer:AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Hoffman:Dompe: Research Funding; Protagonist: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees.

Background: Imetelstat is a first-in-class telomerase inhibitor currently in clinical development for hematologic myeloid malignancies. IMbark (MYF2001; NCT02426086) was a 2-dose (9.4 mg/kg or 4.7 mg/kg IV every 3 weeks), randomized Phase 2 study of imetelstat in intermediate-2/high-risk myelofibrosis (MF) relapsed or refractory to prior Janus kinase inhibitor treatment. Comparing the 9.4 mg/kg arm to the 4.7 mg/kg arm, the rate of symptom response (total symptom score [TSS] reduction ≥50%) at Week 24 was 32.2% and 6.3%, respectively (Mascarenhas et al, ASH 2018 #685), and median overall survival (OS) was 28.1 months (mos) (95% confidence interval [CI]: 22.8, 31.6) for the 9.4 mg/kg arm and 19.9 mos for the 4.7 mg/kg arm (95% CI: 17.1, 33.9) with an overall study follow up of 42 mos (Mascarenhas et al, EHA 2020, EP1107). Dose-dependent on-target pharmacodynamic (PD) activity of imetelstat was observed and it correlated with clinical responses and longer OS (Mascarenhas et al, EHA 2020 EP1098). Here we report the results of imetelstat exposure-response analyses from IMbark to further evaluate the benefit/risk profile and justify 9.4 mg/kg every 21 days as the optimal dosing regimen for the planned Phase 3 study of imetelstat in refractory MF. Methods: The average plasma concentration (Cavg) of imetelstat was used to define the exposure. The Cavg values of 107 patients (pts) were grouped into 4 quartiles (Q1-4) representing different levels of imetelstat exposure regardless of the protocol-specified dose arm assignment. Optimal PD effect of imetelstat was defined as ≥50% reduction in telomerase activity or human telomerase reverse transcriptase (hTERT) from baseline. The exposure-response relationships between exposure quartiles and PD effect, symptom response, OS, and laboratory safety parameters were assessed. Results: The association between the 4 exposure quartiles and dose levels showed that 89% of pts in Q1 (the lowest exposure quartile) were treated with 4.7 mg/kg, while 96% of pts in Q4 (the highest exposure quartile) were treated with 9.4 mg/kg. The pts in the 4.7 mg/kg arm who had higher exposure in Q3 and Q4 were mainly those with dose escalation to 9.4 mg/kg, and pts in the 9.4 mg/kg arm who had lower exposure in Q1-Q2 were mainly those with dose delay, reduction, or interruption. 51.9% of pts in Q1, 63% in Q2 (vs Q1, p=0.5826), 77.8% in Q3 (vs Q1, p=0.0861), and 80% in Q4 (vs Q1, p=0.0439) achieved the optimal PD effect, respectively, indicating exposure-dependent on-target activity of imetelstat. The symptom response rate for pts in exposure quartile Q1, Q2, Q3, and Q4 was 7.4%, 18.5% (vs Q1, p=0.4203), 18.5% (vs Q1, p=0.4203), and 38.5% (vs Q1, p=0.0091), respectively. Median OS was 18.9 mos in Q1, 23.6 mos in Q2 (hazard ratio [HR]=0.663; 95% CI: 0.350, 1.259; log-rank p=0.2097), 24.6 mos in Q3 (HR=0.656; 95% CI 0.348, 1.236; p=0.1920) and 30.6 mos in Q4 (HR=0.467; 95% CI: 0.236, 0.925; p=0.0260), respectively. The exposure-response analyses showed that pts in the highest exposure quartile were more likely to have better clinical outcome. The relationship between exposure quartiles and hematological and liver function safety parameters was assessed. There were no significant differences between each imetelstat exposure quartile group on the change from baseline in hemoglobin concentration, platelet count, and neutrophil counts; or in the rate of Grade 3+ neutropenia, thrombocytopenia, and elevations in alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, and bilirubin. Pts with higher imetelstat exposure had similar rates of Grade 3+ adverse events as pts with lower exposure, suggesting that the lower dose does not improve safety. Conclusions: In summary, the exposure-response analysis results indicated 9.4 mg/kg and 4.7 mg/kg covered the therapeutic window of imetelstat in MF pts. Imetelstat 9.4 mg/kg every 21 days treatment yielded higher exposure, leading to higher rate of pts achieving the optimal PD effect, consistently better clinical benefits, such as higher symptom response and significantly longer median OS, and had a similar safety profile as 4.7 mg/kg with regard to hematologic and liver function parameters. This exposure-response analysis of benefit/risk profile supports 9.4 mg/kg every 21 days as the optimal dosing regimen for the planned imetelstat Phase 3 study in refractory MF. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Komrokji:Acceleron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; Geron: Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Niederwieser:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Daiichi: Research Funding; Cellectis: Membership on an entity's Board of Directors or advisory committees. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Scott:Agios, BMS: Honoraria; Alexion, Incyte, Novartis, Regeneron: Consultancy; BMS, Novartis: Research Funding. Baer:AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Hoffman:Protagonist: Consultancy; Dompe: Research Funding; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, 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; Incyte: Other: Institutional research funding; Astra Zeneca: Research Funding; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company.

Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm. Ruxolitinib, a Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor and fedratinib, a JAK2/FLT3 inhibitor, are the only approved treatment options for MF. Despite the benefits reported with ruxolitinib in the front-line setting, a high proportion of patients discontinue treatment, the 1-, 2-, and 3-year discontinuation rates are 49%, 71%, and 86%, respectively (Abdelrahman et al, 2015). For patients who discontinue treatment with ruxolitinib, the median overall survival (OS) is dismal and ranges from 13 to 16 months (Kuykendall et al, 2018; Newberry et al, 2017; Schain et al, 2019; Palandri et al, 2019; Mcnamara et al, 2019). There remains a great unmet need for patients who are non-responsive to and have discontinued treatment with a JAK inhibitor. Imetelstat, a first-in-class telomerase inhibitor, has shown meaningful clinical improvement in symptom response and improved OS in IMbark, a Phase 2 study in patients with intermediate-2 or high-risk MF who have relapsed after or are refractory to JAK inhibitors (Mascarenhas et al, ASH 2018 #685; Mascarenhas et al, EHA 2020 #EP1107). Nineteen (32.2%) patients in the 9.4 mg/kg arm and 3 (6.3%) patients in the 4.7 mg/kg arm achieved symptom response (total symptom score [TSS] reduction ≥50%) at Week 24. As of clinical cutoff (7 February 2020), with an overall study follow up of 42 months, median OS was 28.1 months for the 9.4 mg/kg arm (95% confidence interval [CI]: 22.8, 31.6) and 19.9 months for the 4.7 mg/kg arm (95% CI: 17.1, 33.9). The improvement in OS for patients treated with 9.4mg/kg imetelstat was further supported by analyses of IMbark patients with closely matched real world controls (Kuykendall et al, EHA 2019 #PS1456). Taken together, these findings support continued study of imetelstat 9.4 mg/kg dose in a well-designed Phase 3 randomized controlled study in patients with refractory MF. Methods: Study MYF3001 is an open label, randomized (2:1), multicenter, Phase 3 study of imetelstat compared with best available therapy (BAT) in approximately 320 patients with intermediate-2 or high-risk MF (primary MF, post-essential thrombocythemia-MF, or post-polycythemia vera-MF) who are refractory to JAK inhibitor treatment. Approximately 214 patients will be randomized to Arm A to receive imetelstat, and approximately 106 patients will be randomized to Arm B to receive BAT. Eligible patients will be stratified based on: a) intermediate-2 or high-risk per Dynamic International Prognostic Scoring System (DIPSS); and b) platelet count at study entry (platelets ≥75 x 109/L and The primary endpoint of the study is OS. Secondary endpoints include symptom response rate at week 24, progression-free survival, spleen response rate at week 24, clinical response assessment per modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG MRT) criteria, time to and duration of response, reduction in the degree of bone marrow fibrosis, safety, pharmacokinetics, and patient-reported outcomes. One interim analysis based on OS is planned. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with OS and clinical responses. Mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. The study will be conducted at approximately 150 centers in North and South America, Europe, Asia, and Middle East. Disclosures Mascarenhas: Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy. Harrison:Promedior: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Sierra Oncology: Honoraria; Shire: Honoraria, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Roche: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau. Mesa:Promedior: Research Funding; Genentech: Research Funding; Samus Therapeutics: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Sierra Oncology: Consultancy. Komrokji:Incyte: Honoraria; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau. Koschmieder:Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Geron Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte/Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; CTI Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; AOP Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Promedior: Other. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Verstovsek:PharmaEssentia: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding.

Background: Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Both cytogenetic abnormalities and gene mutations in MF carry prognostic significance. Development of novel agents for treatment of MF to target the underlying malignant clones remains a significant area of unmet need. IMbark (MYF2001; NCT02426086) is a randomized Phase 2 study of imetelstat (9.4 mg/kg or 4.7 mg/kg) in intermediate-2/high-risk MF relapsed/refractory to prior Janus kinase inhibitor treatment. Comparing the 9.4 mg/kg arm to the 4.7 mg/kg arm, the rate of symptom response (total symptom score [TSS] reduction ≥50%) was 32.2% and 6.3%, respectively (Mascarenhas et al ASH 2018 #685), and median overall survival (OS) was 28.1 months (mos) (95% confidence interval [CI]: 22.8, 31.6) and 19.9 mos (95% CI: 17.1, 33.9) with an overall study follow up of 42 mos (Mascarenhas et al, EHA 2020, EP1107). Dose-dependent target inhibition as evaluated by reduction of telomerase activity and human telomerase reverse transcriptase level correlated with clinical responses and longer OS; also, reduction in variant allele frequency (VAF) of driver mutations by imetelstat was reported (Mascarenhas et al EHA 2020 #EP1098). Aims: To evaluate imetelstat activity on depletion of malignant cells (cytogenetically abnormal clones and mutation burden); to assess the relationships between baseline cytogenetic status and change in mutation VAF with clinical benefits such as spleen volume reduction, symptom response, bone marrow fibrosis improvement, and OS. Methods: Cytogenetic analyses were performed on bone marrow aspirates. Peripheral blood samples pre and post imetelstat administration were collected and granulocytes were isolated to analyze mutations and VAF by next-generation sequencing (NGS) using the Illumina TruSight Myeloid Sequencing Panel. Bone marrow fibrosis was assessed by a central pathologist. Results: 83 patients (pts) had baseline cytogenetic results available; 45 (54.2%) had an abnormal karyotype, including 32 (71.1%) with a sole abnormality, the most prevalent being deletions 13q- (24.4%) and 20q- (8.8%), and 5 (11.1%) with a complex karyotype. Spleen and symptom responses were observed in pts with or without abnormal karyotype. Of the 24 pts that had identified cytogenetic abnormalities at baseline and with matched post-treatment cytogenetic results available, 5 (20.8%) achieved ≥50% reduction in their cytogenetically abnormal clones, and interestingly they all had sole deletion 13q-. 49 pts had matched pre- and post-imetelstat treatment (3-14 mos) NGS data and had at least one mutation at baseline. 46.2% of pts (12/26) in the 9.4 mg/kg vs 17.4% (4/23) in the 4.7 mg/kg arm (p=0.0321) achieved ≥20% VAF reduction in any of the mutated genes present at baseline. In addition, pts who achieved ≥20% VAF reduction had higher rates of spleen response (12.5% vs 3%), symptom response (31.3% vs 24.2%) or bone marrow fibrosis improvement (54.4% vs 25%) compared to pts who did not have VAF reduction regardless of dose level (Fig. 1A). Furthermore, a prolonged median OS was seen (Fig. 1B) in pts who achieved ≥20% VAF reduction (31.6 mos, 95% CI: 21.5, NE) vs those with no VAF reduction (22.8 mos, 95% CI: 17.1, 31.6). The 3-year survival rate was 45.5% for pts who achieved ≥20% VAF reduction vs 14.9% for pts with no VAF reduction. Conclusions: Clinical responses to imetelstat treatment were observed regardless of baseline cytogenetic status, and a subset of pts achieved ≥50% reduction in cytogenetically abnormal clones. Significant dose-dependent reductions of mutation burden by imetelstat were noted and correlated with improved overall clinical benefits including higher rates of spleen and symptom responses, bone marrow fibrosis improvement, and prolonged OS. Together with the clinical data that suggest improvement in median OS in these pts, the data presented here further demonstrate that imetelstat has disease-modifying activity by targeting malignant cells, as evidenced by depletion of cytogenetically abnormal clones and reduction in mutation burden. These results will be confirmed in the planned Phase 3 study in refractory MF. Figure Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Komrokji:Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Acceleron: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Incyte: Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Niederwieser:Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Daiichi: Research Funding. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Scott:Alexion, Incyte, Novartis, Regeneron: Consultancy; BMS, Novartis: Research Funding; Agios, BMS: Honoraria. Baer:Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding; AbbVie: Other: Institutional research funding. Hoffman:Protagonist: Consultancy; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding. 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; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Other: Institutional research funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company.

BACKGROUND Clonal stem cell derived myeloproliferative neoplasms (MPNs) have a propensity to evolve to acute myeloid leukemia (AML). Deregulation of the innate immune deaminase associated with RNA1 (ADAR1) has been linked to malignant progression and therapeutic resistance. Increased expression of the stem cell gene, human telomerase reverse transcriptase (hTERT), has also been linked with malignant transformation. However, the combinatorial role of ADAR1 and hTERT in the evolution of MPN stem cells to therapy resistant acute myeloid leukemia stem cells (LSCs) and the capacity of a telomerase inhibitor, imetelstat, to prevent survival and self-renewal of pre-LSC and LSC had not been established. Recent clinical trials show early signs of efficacy of imetelstat in treatment of myelofibrosis (MF). However, its role in selectively inhibiting pre-LSC transformation to self-renewing LSC has not been elucidated. Here we show that targeting telomerase activity prevents pre-LSC and LSC maintenance both in vitro and in vivo, suggesting telomerase inhibition as an effective strategy for preventing MPN progression. METHODS To quantify hTERT level and ADAR1 activity in the setting of normal HSPC and MPN stem cell evolution, whole genome sequencing (WGS) analysis was performed on 76 normal and MPN blood CD34+ cells and matching saliva samples. Results were compared with RNA-seq of 100 FACS purified young, aged, MPN and AML CD34+CD38- stem cells and CD34+CD38+ progenitor cells. Confocal fluorescence microscopic evaluation of stem cell ADAR1 and hTERT localization, telomere length by Flow-FISH and telomerase activity by TRAP assays, lentiviral ADAR1 overexpression and shRNA knockdown were performed. In vitro stromal co-cultures, and humanized immunocompromised mouse models were established to determine the impact of imetelstat (a oligonucleotide inhibitor of telomerase) on normal, MPN stem cell and LSC maintenance. RESULTS Combined hTERT overexpression, ADAR1 activation and a significant reduction in telomere length correlated with accelerated stem cell aging during MPN progression to AML. Increased ADAR1 mediated adenosine to inosine (A-to-I) transcript editing coincided with accelerated telomere shortening in high risk MPN stem cells. Moreover, lentiviral ADAR1 overexpression enhanced pre-LSC engraftment. Treatment with imetelstat reduced MPN stem cell and LSC propagation in stromal co-cultures as well as in humanized mouse models commensurate with reduced hTERT expression levels and telomerase activity and decreased ADAR1 editing activity. Specifically, stromal co-culture assays revealed that combined treatment with dasatinib at 1 nM, and imetelstat at 1 µM or 5 µM significantly inhibited survival and replating of blast crisis (BC) CML progenitors compared with aged bone marrow progenitors (p < 0.001, ANOVA). As a single agent, imetelstat (5 µM) inhibited survival and replating of pre-LSC derived from myelofibrosis compared with normal bone marrow progenitor samples (p < 0.001, ANOVA). In pre-LSC MPN NSG-SGM mouse models established from 4 different MF samples, a significant reduction in proliferation of human CD45+ cells (p < 0.01, t test) was observed in bone marrow and spleen, when compared with vehicle control. Treatment of humanized LSC mouse models, established with 5 different BC CML, with 30 mg/kg of imetelstat, 3 times a week for 4 weeks resulted in a significant reduction in proliferation of malignant progenitors and human CD45+ cells (p < 0.001, ANOVA). As measured by a Flow-FISH assay, abnormal telomere length was reversed by imetelstat treatment compared with mismatch control (p < 0.05, ANOVA). In addition, FACS analysis revealed a significant reduction in activated beta-catenin expression after imetelstat treatment of LSC engrafted mice compared with vehicle control (p < 0.01, ANOVA). Finally, RNA-seq analysis performed on human CD34+ cells from imetelstat treated LSC mouse models revealed a significant reduction in LSC harboring malignant ADAR1-mediated A-to-I editing at doses that spared normal hematopoietic stem cells. CONCLUSIONS Combined WGS and RNA-Seq analyses, lentiviral ADAR1 overexpression, stromal co-culture assays and humanized pre-LSC and LSC mouse model studies reveal that pre-LSC evolution into LSC coincides with both ADAR1 and hTERT activation, which can be prevented with imetelstat. Disclosures Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Jamieson:Forty Seven Inc: Patents & Royalties; Bristol-Myers Squibb: Other.

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study (Tefferi et al, Blood Cancer J 2016) supported initiation of a study in TD LR MDS patients. The Phase 2 part of IMerge demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 32%, with median duration of TI being 88 weeks. The responses were seen across different subtypes of LR MDS (Platzbecker et al, EHA 2020, S183). No new safety signal was identified. These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrolment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 130 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of hematologic improvement-erythroid (HI-E), the amount and relative change in RBC transfusions, rate of complete response or partial response, overall survival, progression of MDS, pharmacokinetics, and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Fenaux:Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Steensma:CRISPR: Current equity holder in publicly-traded company; Aprea Therapeutics: Research Funding; Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; H3 Biosciences: Research Funding; Astex Pharmaceuticals, Otsuka: Consultancy; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company. Font:Abbvie: Other: Travel, accommodations, expenses; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Jang:Bristol Myers Squibb: Research Funding; Abbvie: 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; Amgen: Honoraria, Research Funding. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Johnson & Johnson: Honoraria.

This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), and doxorubicin 50 mg/m(2), all IV day 1, prednisone 100 mg/m(2) orally days 1-5, plus either bortezomib 1.3 mg/m(2) IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m(2) (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; P = .80), overall response rate (93.4%, 98.6%; OR, 0.21; P = .11), progression-free survival (hazard ratio [HR], 1.12; P = .76), or overall survival (HR, 0.89; P = .75). Rates of grade ≥3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade ≥3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871.

The major limitation for the development of curative cancer therapies has been an incomplete understanding of the molecular mechanisms driving cancer progression. Human models to study the development and progression of chronic myeloid leukemia (CML) have not been established. Here, we show that BMI1 collaborates with BCR-ABL in inducing a fatal leukemia in nonobese diabetic/severe combined immunodeficiency mice transplanted with transduced human CD34+ cells within 4-5 months. The leukemias were transplantable into secondary recipients with a shortened latency of 8-12 weeks. Clonal analysis revealed that similar clones initiated leukemia in primary and secondary mice. In vivo, transformation was biased toward a lymphoid blast crisis, and in vitro, myeloid as well as lymphoid long-term, self-renewing cultures could be established. Retroviral introduction of BMI1 in primary chronic-phase CD34+ cells from CML patients elevated their proliferative capacity and self-renewal properties. Thus, our data identify BMI1 as a potential therapeutic target in CML.

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by 1 or more peripheral blood cytopenias.Anemia is the most common cytopenia associated with low-grade MDS (based on the International Prognostic Scoring System). Erythropoiesis-stimulating agents (ESA) are commonly used as frontline treatment of anemia in patients (pts) with low-grade MDS; red blood cell transfusions are also important in supportive care. The present database analysis was conducted to understand the transfusion burden and outcomes among pts in the United States who were diagnosed with low- or unspecified-grade MDS and treated with ESA. Methods: A retrospective analysis of theOptum integrated claims and Electronic Medical Record database ("Optum Database") identified pts aged ≥ 18 years with an index diagnosis of MDS (low-grade, ICD 9 code: 238.72; high-grade, ICD 9 code: 283.73; del(5q), ICD 9 code: 238.74; or unspecified-grade, ICD 9 code: 238.75) between 2006 and 2014 who had 365 days of retrospective data preceding index diagnosis. Pts with baseline acute myeloid leukemia were excluded. Demographics and clinical outcomes were analyzed by descriptive summary. Kaplan-Meier survival analysis was performed to define overall survival (OS) and time to transfusion dependence or transfusion independence. Results: Among the 8,493 pts in the Optum Database who met the inclusion criteria, MDS was categorized as low-grade in 2,136 (25.2%), high-grade in 367 (4.3%), del(5q) in 198 (2.3%), and unspecified-grade in 5,792 (68.2%); median follow-up was 2.3 years. In each MDS category, roughly half of pts were male, and the majority were white and non-Hispanic. Median ages at diagnosis were 75, 74, 74, and 76 years, and 977 (46%), 224 (61%), 83 (42%), and 2,071 (36%) received ≥ 1 treatment in the low-grade, high-grade, del(5q), and unspecified-grade MDS categories, respectively. Frontline therapy with ESA was the mainstay of treatment for pts with low-grade (n = 732; 75%) and unspecified-grade (n = 1,284; 62%) MDS. Average durations of frontline treatment with ESA were 228.1 and 204.5 days in pts with low-grade and unspecified-grade MDS, respectively. Median OS among low- and unspecified-grade MDS pts receiving frontline ESA was 5.4 and 4.6 years, respectively. Of the pts who received frontline ESA, 53 (7.2%) with low-grade and 107 (8.3%) with unspecified-grade MDS were transfusion dependent (≥ 2 transfusions in the 16 weeks prior to treatment initiation). Transfusion dependence in pts receiving frontline ESA was associated with shorter median OS vs transfusion independence (1.7 years vs 5.7 years in low-grade MDS, P < 0.0001; 1.7 years vs 5.2 years in unspecified-grade MDS, P < 0.0001;Figure 1). Among the 160 frontline ESA pts with low-/unspecified-grade MDS who were transfusion dependent, 108 (68%) became transfusion independent (defined as ≥ 60 days without transfusion; 37 of 53 with low-grade MDS; 71 of 107 with unspecified-grade MDS); median time to transfusion independence was 137 and 139 days in pts with low-grade and unspecified-grade MDS, respectively. Most pts with low- or unspecified-grade MDS who received frontline ESA (52% and 51%, respectively) went on to receive second-line treatment, and treatment with ESA was the most common second-line therapy (42% and 40%, respectively). 163 (8.7%) of post-front-line ESA pts were transfusion dependent. Among pts with low-/unspecified-grade MDS who received second-line therapy, median OS was shorter for those who were transfusion dependent after frontline treatment with ESA vs those who were transfusion independent (1.97 years vs 4.5 years, respectively, P < 0.001). 92 (56%) of these transfusion-dependent pts became transfusion independent in a median of 181 days. Conclusions: ESA therapy was the most common treatment approach, both frontline and second-line, for pts with low- or unspecified-grade MDS; however, treatment with ESA did not always eliminate the need for transfusion. Similar to previous reports in pts with low-grade MDS, survival outcomes were substantially worse if pts were transfusion dependent prior to frontline or second-line treatment or became transfusion dependent following frontline treatment. These data indicate the critical importance for treatments to reduce transfusion burden among pts with MDS, in both the frontline and relapsed settings. Disclosures Mehra: Janssen: Employment, Equity Ownership. Potluri:Janssen Research & Development, LLC: Other: Contracted to perform research; SmartAnalyst, Inc.: Employment. He:Janssen Global Services, LLC: Employment, Equity Ownership. Rizo:Janssen Research & Development, LLC: Employment, Equity Ownership. Mundle:Janssen Research & Development, LLC: Employment, Equity Ownership. Bussolari:Janssen Research & Development, LLC: Employment, Equity Ownership.

Introduction MCL is an aggressive B-cell lymphoma with a poor overall prognosis. For patients who fail initial therapy, conventional chemotherapy achieves only short-term remissions. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase that has been shown to be highly active for previously treated MCL patients (overall response rate [ORR] ~65%; complete response [CR] ~20%) in single-arm phase 2 studies. Temsirolimus has demonstrated significantly longer progression-free survival (PFS) vs investigator's choice. In this phase 3, randomized, open-label study (MCL3001 [RAY]), ibrutinib was compared with temsirolimus in patients with relapsed or refractory (R/R) MCL who had received ≥1 prior rituximab-containing therapy. Methods Patients were randomized at a 1:1 ratio to receive oral ibrutinib (560 mg once-daily) or intravenous temsirolimus (175 mg: Days 1, 8, and 15 of Cycle 1; 75 mg: Days 1, 8, and 15 of subsequent cycles). Stratification factors were number of prior lines of therapy (1-2 vs ³3) and simplified MCL international prognostic index (sMIPI) risk (low [0-3] vs intermediate [4-5] vs high [6-11]). Patients in both arms received treatment until disease progression or unacceptable toxicity. Primary end point of the study was PFS, as assessed by an independent review committee (IRC). Secondary end points included ORR, overall survival (OS), time to next treatment (TTNT), time to worsening of lymphoma symptoms (measured by FACT-Lym lymphoma subscale), and safety. Results Overall, 280 patients were randomized to ibrutinib (n = 139) or temsirolimus (n = 141). Baseline disease characteristics and demographics were generally well balanced. Median age (range) was 68 years (34-88) and median number (range) of prior lines of therapy was 2 (1-9). Approximately two-thirds of the patients had intermediate- or high-risk disease. At the time of this analysis, median follow-up was 20.0 months. Ibrutinib was superior to temsirolimus for the primary end point of IRC-assessed PFS, with a statistically significant 57% reduction in the risk of progression or death (Figure 1). The median PFS was 14.6 months for the ibrutinib arm and 6.2 months for the temsirolimus arm, respectively. At a landmark of 2 years, the PFS rate is 41% in the ibrutinib arm vs 7% in the temsirolimus arm. PFS results were consistent across most assessed subgroups. Investigator-assessed PFS was consistent with the IRC results. IRC-assessed ORR was significantly higher for ibrutinib vs temsirolimus (71.9% vs 40.4%; p < 0.0001) with a CR rate of 18.7% vs 1.4%, respectively. Median OS was not reached with ibrutinib vs 21.3 months with temsirolimus, showing a positive trend toward patients in the ibrutinib arm (reduced risk of death by 24% [HR, 0.76; 95% CI, 0.53-1.09]). However, these results may have been confounded by 23% of patients that initially received temsirolimus crossing over to receive ibrutinib. A greater proportion of patients treated with ibrutinib vs temsirolimus avoided worsening of lymphoma symptoms throughout the study; 27% of ibrutinib patients had worsening vs 52% of temsirolimus patients. Median TTNT was not reached with ibrutinib vs 11.6 months with temsirolimus. Median treatment duration was 14.4 months for ibrutinib and 3.0 months for temsirolimus. Overall, 6.5% of subjects discontinued treatment due to AEs in the ibrutinib arm and 25.5% of subjects discontinued treatment due to AEs in the temsirolimus arm. The most common TEAEs with ibrutinib were diarrhea, fatigue, and cough, whereas with temsirolimus, thrombocytopenia, anemia, and diarrhea were most commonly observed (Table 1). Grade ³3 TEAEs were reported for 67.6% of ibrutinib patients vs 87.1% of temsirolimus patients; most frequent were thrombocytopenia, anemia, and neutropenia. When adjusted for exposure, TEAE incidence was consistently lower for the ibrutinib arm vs the temsirolimus arm. Conclusions Ibrutinib is superior to temsirolimus for PFS and ORR, and showed preferable tolerability. The results of this phase 3 trial confirm the efficacy and favorable safety profile of ibrutinib shown in phase 2 studies. Future concepts will investigate ibrutinib-based combination approaches for patients with R/R MCL. Disclosures Rule: Gilead: Research Funding; Celgene: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Roche: Consultancy, Other: Travel reimbursement. Rusconi:Roche: Honoraria. Joao:Celgene, Novartis: Consultancy; Janssen, Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Honoraria, Research Funding; Roche: Honoraria. Hess:Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Balasubramanian:Janssen: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Bandyopadhyay:Janssen: Employment. Sun:Janssen/J&J: Employment, Equity Ownership. Goldberg:Janssen: Employment. Bothos:Janssen: Employment. Traina:Janssen: Employment. Enny:Janssen: Employment. Rizo:Janssen: Employment. Vermeulen:Janssen: Employment.

Introduction: Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase is highly effective in relapsed or refractory mantle cell lymphoma (MCL) patients with an ORR of 68% (Wang M, et al. N Engl J Med. 2013;369:507-516). Similar efficacy results were observed in a recent phase 2 study in MCL patients who progressed after rituximab containing chemotherapy and bortezomib therapy (SPARK study, NCT01599949). However, despite the very promising efficacy data, some patients with MCL do not respond to ibrutinib. Here, we report analyses of potential mechanisms associated with primary resistance to ibrutinib therapy in the SPARK study. Methods: In this phase 2, international, multicenter, single-arm study, patients with MCL received 560 mg/day oral ibrutinib continuously until progressive disease (PD) or unacceptable toxicity. Patients who had PD at the first disease evaluation were considered to have primary resistant disease. DNA was extracted from baseline/pretreatment tumor samples (biopsy or CD19-enriched cells from PBMC) and enriched libraries were constructed with probesets specific for the coding region of 97 genes possibly involved in ibrutinib response and resistance, using the Ovation Target Enrichment system (NUGEN). Deep sequencing (150bp, single end reads) was performed on an Illumina HiSeq instrument . Sequences were aligned to the hg19 reference genome, variants were called using samtools and filters were applied to identify possible somatic mutations (minor allele frequency < 1% in dbSNP, > 5% and < 95% variant allele, > = 10 total reads). Results: Twenty five (22.7%) of the 120 patients enrolled in this study had Independent Review Committee (IRC)-confirmed disease progression. In these primary treatment resistant patients, the median number of prior lines of systemic therapy was 3 (range 1-5 lines); 37% of patients had high risk MIPI score; 64% had bulky disease (longest diameter ≥ 5 cm), 52% had extranodal disease; 32% had bone marrow involvement and 20% had blastoid subtype. None of these baseline clinical parameters were found to be predictive for primary treatment resistance. The median duration of treatment was 1.54 months. Sequence data could be collected from 23 of the 25 patients, with an average of 9 million reads. After data filtering as described above, 27 genes were found with nonsynonymous variants in at least 2 or more patients. The majority of these variants were previously unreported in dbSNP or COSMIC databases. No mutations previously described in chronic lymphocytic leukemia (CLL) patients with acquired resistance to ibrutinib (BTK C481S, PLCg2 R665W) were seen in these patients, although one patient had a different mutation in PLCg2. Genes previously implicated in diffuse large B-cell lymphoma (DLBCL) pathogenesis (Pasqualucci L, et al. Nature Genetics. 2011;43:830-837) such as MLL2 and CREBBP were also found to be mutated in these patients. In addition, mutations in PIM1 and ERBB4 kinase genes were more frequent in patients with PD compared with those non-resistant to therapy. PIM1 kinase has been associated with increased proliferation, survival, and migration of tumor cells, and somatic mutations in this gene have been described in several cancers including hematologic malignancies. Interestingly, several of the mutations detected affect NF-kB signalling inhibition which is thought to contribute to ibrutinib’s mechanism of action. These results will be updated at the time of final presentation. Conclusion: Sequence analyses were conducted on tumor DNA from the fraction of patients with primary resistance to ibrutinib treatment in this study. These studies have revealed a number of known and novel mutations, including genes involved in NF-kB signalling. Among others, the mutational status of PIM1 kinase and ERBB4 kinase genes may be of interest with respect to primary resistance to ibrutinib therapy in MCL. Disclosures Balasubramanian: Janssen R&D: Employment, Equity Ownership. Schaffer:Janssen: Employment. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Davis:Janssen: Employment. Aquino:Janssen R&D: Employment. Yuan:Johnson & Johnson : Employment, Equity Ownership. Kranenburg:Janssen Biologics: Employment; Johnson & Johnson: Equity Ownership. Dreyling:Janssen, Pfizer (support of IITs (institutional): Research Funding; Janssen, Pfizer (speaker's honoraria): Honoraria. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang:Pharmacyclics, Janssen, Celgene, Onyx, OnyPep, : Research Funding; Onyx, Janssen: Honoraria. Zhuang:Johnson & Johnson: Employment, Equity Ownership. Rizo:Janssen R&D: Employment, Equity Ownership. Lenz:Janssen: Membership on an entity's Board of Directors or advisory committees.

Introduction: Despite recent advances, mantle cell lymphoma (MCL) remains difficult to treat with frequent chemoresistance in the relapsed or refractory setting. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, demonstrated durable single-agent efficacy in a previous phase 2 study of patients with MCL who had received 1 to 5 prior therapies (Wang M, et al. N Engl J Med. 2013;369:507-516). In that study, the investigator-assessed overall response rate was 68% (complete response rate, 21%). The current study reports on the efficacy and safety of single-agent ibrutinib specifically in patients with MCL who had received a rituximab-containing regimen and had progressed after at least 2 cycles of bortezomib therapy. Methods: In this phase 2, multicenter, single-arm study, patients received 560 mg/day oral ibrutinib continuously until progressive disease or unacceptable toxicity. The primary end point was the overall response rate (ORR) in response evaluable patients, as assessed by an Independent Review Committee (IRC). Secondary end points, also assessed by IRC, included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: 120 patients in this international multicenter study were enrolled. The median age was 67.5 years, ranging from 35 to 85 years with 62.5% ≥ 65 years. Most patients had stage IV disease at study entry (77.5%), and 9.2% were reported as blastoid variant (per investigator). 76.3% of patients had an intermediate or high risk simplified MIPI score, and 52.5% had bulky disease (longest diameter ≥ 5 cm). Forty two (35.0%), 67 (55.8%) and 11 patients (9.2%) had an ECOG score of 0, 1 and 2, respectively. The median number of prior lines of systemic therapy was 2 (range 1-8 lines) with almost half of the patients (47.5%) receiving 3 or more prior lines of therapy. Overall, 33% of patients had received prior stem cell transplantation. At the time of clinical cut-off for the primary analysis (29 April, 2014), median follow-up was 14.9 months with median treatment duration of 8 months (range: 0.5-20.9 months). The main reasons for treatment discontinuation were disease progression in 53 patients (44.2%) and an adverse event (AE) in 8 patients (6.7%). The ORR for response evaluable patients was 62.7% (95% confidence interval [CI]: 53.7%-71.8%) with a complete response rate of 20.9%. Subgroup analysis suggested that the ORR was independent of age, gender, geographic region, number of prior lines of therapies, baseline extranodal disease, simplified MIPI score, bulky disease, and stage of MCL. Median DoR by IRC was 14.9 months and the median time to first response was 2.1 months, ranging from 1.3 to 6.3 months. Median PFS was 10.5 months and 47% of the patients remained progression-free at 1 year. The OS rate at 18 months was 61%. The most common AEs were fatigue (any grade, 43.3%; grade 3 or 4, 3.3%) and diarrhea (any grade, 42.5%; grade 3 or 4, 2.5%). The most common grade 3 or higher AEs were neutropenia (20.8%), thrombocytopenia (13.3%), and pneumonia (12.5%). Any-grade hemorrhagic events were reported in 45 patients (37.5%), including 3 (2.5%) with major hemorrhagic events. The median time to initial hemorrhagic event was 84 days (range 1-515 days), with a median duration of 22 days (95% CI: 8-31 days). Atrial fibrillation was reported in 13 patients (10.8%), which was grade 3 or 4 in 6 patients (5%). AEs led to dose reductions in 8 patients (6.7%). Conclusion: Single agent ibrutinib is highly efficacious and well tolerated, with an acceptable toxicity profile in patients with MCL who progressed after rituximab-containing chemotherapy and bortezomib therapy. These results are consistent with previous ibrutinib studies, with no new safety signals. Disclosures Wang: Pharmacyclics, Janssen, Celgene, Onyx, OnyPep, : Research Funding; Onyx, Janssen: Honoraria. Goy:Janssen/Pharmacyclics: Honoraria, Speakers Bureau; Clinical Trials through Institution: Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Martin:Janssen: Honoraria. Popat:Janssen: Honoraria. Advani:Seattle Genetics, Genetech, (Uncompensated): Membership on an entity's Board of Directors or advisory committees; Janssen, Pharmacyclics, Seattle Genetics: Research Funding. Le Gouill:Roche: Consultancy; Janssen: Consultancy. Yuan:Johnson & Johnson: Equity Ownership; Johnson & Johnson: Employment. Kranenburg:Johnson&Johnson: Equity Ownership; Janssen Biologics: Employment. Rizo:Janssen R&D: Employment, Equity Ownership. Zhuang:Johnson & Johnson: Employment, Equity Ownership. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Hematopoietic stem cells (HSCs) are able to self-renew and differentiate into cells of all hematopoietic lineages. Because of this unique property, they are used for HSC transplantations and could serve as a potential source of cells for future gene therapy. However, the difficulty to expand or even maintain HSCs ex vivo has been a major limitation for their clinical applications. Here, we report that overexpression of the Polycomb group gene Bmi-1 in human cord blood-derived HSCs can potentially overcome this limitation as stem/progenitor cells could be maintained in liquid culture conditions for over 16 weeks. In mouse studies, it has been reported that increased expression of Bmi-1 promotes HSC self-renewal, while loss-of-function analysis revealed that Bmi-1 is implicated in maintenance of the hematopoietic stem cells (HSC). In a clinically more relevant model, using human cord blood CD34+ cells, we have established a long-term ex-vivo expansion method by stable overexpression of the Bmi-1 gene. Bmi-1-transduced cells proliferated in liquid cultures supplemented with 20% serum, SCF, TPO, Flt3 ligand, IL3 and IL6 for more than 4 months, with a cumulative cell expansion of more then 2×105-fold. The cells remained cytokine-dependent, while about 4% continued to express CD34 for over 20 weeks of culture. The cultured cells retained their progenitor activity throughout the long-term expansion protocol. The colony-forming units (CFUs) were present at a frequency of ~ 30 colonies per 10 000 cells 16 weeks after culture and consisted of CFU-GM, BFU-E and high numbers of CFU-GEMM type progenitors. After plating the transduced cells in co-cultures with the stromal cell line MS5, Bmi-1 cells showed a proliferative advantage as compared to control cells, with a cumulative cell expansion of 44,9 fold. The non-adherent cells from the co-cultures gave rise to higher numbers of colonies of all types (~70 colonies/10.000 cells) after 4 weeks of co-culture. The LTC-IC frequencies were 5-fold higher in the Bmi-1-transduced cells compared to control cells (1/361 v.s. 1/2077, respectively). Further studies will be focused on in-vivo transplantation of the long-term cultured cells in NOD/SCID mice to test their repopulating capacity. In conclusion, our data implicate Bmi-1 as an important modulator of human HSC self-renewal and suggest that it can be a potential target for therapeutic manipulation of human HSCs.