ALBERT

Description: Introduction Sex represents a major source of diversity among patients in terms of pathophysiology, clinical presentation, prognosis and response to therapy, and therefore sex (gender)-informed medicine is becoming a new paradigm to refine clinical decision making process in different human diseases. Myelodysplastic syndromes (MDS) are heterogeneous disease characterized by ineffective hematopoiesis and risk of leukemic evolution. We aimed to study clinical effect of sex in MDS as a basis to improve patient prognostication and personalized treatment. Material and Methods We analysed three MDS populations from disease-specific registries (Italian registry n=3015, Dusseldorf registry, n=1185 and Spanish registry, n=7678). Results We first analysed the association of sex with clinical and biological disease-specific features. These analyses were conducted on Italian MDS cohort. Considering WHO categories, female patients showed higher prevalence of single lineage dysplasia and MDS with del(5q), while males were characterized by higher frequency of multilineage dysplasia and excess blasts (P

Description: Introduction: Anemia is the predominant cytopenia observed in patients with myelodysplastic syndromes (MDS), with many patients requiring regular red blood cell (RBC) transfusions. Erythropoiesis-stimulating agents (ESAs) remain a standard of care among patients with lower-risk MDS (LR-MDS), defined by International Prognostic Scoring System-Revised (IPSS-R) as Very Low-, Low-, or Intermediate-risk MDS, and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L. Recent studies of epoetin alfa and darbepoetin alfa have demonstrated efficacy among patients with LR-MDS, but the patient population in whom a clinically significant effect is seen may be limited (Fenaux P, et al. Leukemia 2018;32:2648-2658; Platzbecker U, et al. Leukemia 2017;31:1944-1950). A novel therapeutic option that increases the frequency of response and the duration of RBC transfusion independence (TI) in patients with LR-MDS would provide an important clinical benefit in this patient population. Luspatercept is a first-in-class erythroid maturation agent with a mechanism of action distinct from ESAs (Suragani RNVS, et al. Nat Med 2014;20:408-414). It is now approved in both the US and EU for patients with LR-MDS with ring sideroblasts (RS) who require RBC transfusions and are refractory, intolerant, or ineligible to receive ESAs on the basis of results from a phase 3 study (Fenaux P, Platzbecker U, et al. N Engl J Med 2020;382:140-151). Luspatercept may also be beneficial in treating anemia in patients with ESA-naive, LR-MDS who require RBC transfusions. In a phase 2 study in anemic patients with LR-MDS, 63% of patients receiving luspatercept (0.75-1.75 mg/kg) achieved a modified hematologic improvement - erythroid (mHI-E) response (Platzbecker U, et al. Lancet Oncol 2017;18:1338-1347); when analyzed by RS status, 69% of patients with ≥ 15% RS and 43% of patients with 〈 15% RS achieved mHI-E response. Study Design and Methods: The COMMANDS trial is a phase 3, open-label randomized study to compare the efficacy and safety of luspatercept versus epoetin alfa in anemic patients with IPSS-R defined LR-MDS, either with or without ≥ 15% RS, who are ESA naive, and who require regular RBC transfusions. Eligible patients must be aged ≥ 18 years at time of consent, have a documented diagnosis of IPSS-R defined LR-MDS with 〈 5% blasts in the bone marrow, have sEPO levels 〈 500 U/L, and require RBC transfusions (defined as an average transfusion requirement of 2-6 RBC units/8 weeks for ≥ 8 weeks immediately prior to randomization). Exclusion criteria include prior use of ESAs (≤ 2 doses of prior epoetin alfa permitted if ≥ 8 weeks from randomization date and sEPO confirmed as ≤ 500 U/L), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for the treatment of febrile neutropenia; disease-modifying agents (e.g. lenalidomide), or hypomethylating agents; and presence of del(5q) cytogenetic abnormality. A total of approximately 350 eligible patients will be randomized in a 1:1 ratio to receive either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg) subcutaneously (SC) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg with titration up to 1,050 IU/kg) SC once every week, for a minimum of 24 weeks (Figure). Best supportive care, including RBC transfusions, may be used in combination with study treatment in both arms. Randomization will be stratified by baseline RBC transfusion burden (〈 4 vs ≥ 4 RBC units per 8 weeks), RS status (with RS+ defined as RS ≥ 15%, or ≥ 5% [but 〈 15%] if SF3B1 mutation is present), and baseline sEPO level (≤ 200 U/L versus 〉 200 U/L). In addition, ≥ 40% and ≤ 60% of randomized patients will be RS+, and ≥ 25% will have sEPO 〉 200 U/L. The primary endpoint is the proportion of patients who achieve RBC-TI for 12 weeks within the first 24 weeks on study, with a concurrent mean hemoglobin (Hb) increase of ≥ 1.5 g/dL compared with baseline. Key secondary endpoints include duration of RBC-TI, change in Hb levels, achievement of HI-E response per International Working Group (IWG) 2006 criteria, and safety. The COMMANDS trial is registered at ClinicalTrials.gov (NCT03682536) and EudraCT (number 2017-003190-34). Disclosures Platzbecker: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria. Santini:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding. Komrokji:Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Description: Luspatercept is a recombinant fusion protein that binds and sequesters several endogenous transforming growth factor-beta superfamily ligands, including growth differentiation factor 11, thereby diminishing Smad2/3 signaling in target cells involved in erythropoiesis. Luspatercept, and its murine analog RAP-536, have been shown to act as erythroid maturation agents via their effects on late-stage erythropoiesis by inducing erythroblast maturation, leading to increases in red blood cells (RBCs) and hemoglobin (Hb). This study demonstrated that thalassemic (th3/+) reticulocytes are unstable, and that RAP-536, in addition to its function as an erythroid maturation agent, modulates the maturation of wild-type (WT) and th3/+ reticulocytes. Furthermore, RAP-536 treatment increased RBCs and decreased bilirubin in a mouse model of alpha-thalassemia (129S-Hba-a1tm1Led/J). To examine whether acute RAP-536 treatment acts on reticulocytes and alters reticulocyte levels in blood, the blood of WT mice was analyzed 3, 12, and 24 hours, and 2, 3, 4, and 7 days after a single dose of RAP-536 (10 or 30 mg/kg) or vehicle. RAP-536 treatment increased RBCs, Hb, and hematocrit significantly at all time points, compared with vehicle. However, in mice treated with RAP-536, reticulocytes in blood decreased significantly on Days 2, 3, and 4 and returned to normal baseline levels on Day 7. Analysis of reticulocyte subpopulations in blood 3 days after RAP-536 treatment showed that the relative percentages of immature reticulocytes (CD71+ or high RNA content) within the blood reticulocyte population decreased, suggesting that reticulocytes released from the bone marrow (BM) were more mature and/or reticulocytes matured faster in blood. A quantitative pharmacology (QP) model was developed to explore which RAP-536-induced modulations of erythropoiesis in WT mice can simulate the experimental observations. The model represents erythroblast, reticulocyte, and RBC (erythrocyte) maturation stages in BM, peripheral blood, and spleen, in the presence or absence of a RAP-536 effect. The QP model consists of a system of ordinary differential equations, with homeostatic parameter values assigned from literature or experimental measures, and RAP-536-perturbed parameter values regressed by fitting the model to erythropoiesis data of RAP-536-treated WT mice. Comparison of model parameters for homeostatic versus RAP-536-perturbed states indicated that RAP-536 leads to an increase in the erythroblast-to-reticulocyte and reticulocyte-to-RBC conversion rates, the transfer of BM reticulocytes to blood, and a delayed increase in erythroblast production. To directly test whether RAP-536 treatment affects reticulocyte development in blood, comparative blood transfusion experiments were performed. Biotinylated GFP+ blood from WT mice (C57BL/6-Tg(UBC-GFP)30Scha/J) and biotinylated GFP− blood from th3/+ beta-thalassemic mice (B6.129P2-Hbb-b1tm1Unc Hbb-b2tm1Unc/J) were co-transfused into GFP− WT recipient mice (C57BL/6J), which were subsequently treated with RAP-536 or vehicle. In the donor reticulocyte population, th3/+ reticulocyte percentage decreased continuously up to 3 days after transfusion, suggesting that many of the th3/+ reticulocytes were eliminated before they could form RBCs. However, compared with vehicle, RAP-536 treatment led to increased persistence of the relative percentages of th3/+ reticulocytes (Figure A). Consequently, 7 days after transfusion, when most reticulocytes have matured to RBCs, the percentage of th3/+ RBC among donor RBCs was higher with RAP-536 (Figure B). Finally, treatment of an alpha-thalassemia mouse model (129S-Hba-a1tm1Led/J) with RAP-536 10 mg/kg for 8 weeks increased RBCs and hematocrit and reduced serum bilirubin, compared with vehicle. These results suggest that RAP-536 is, as previously shown, an erythroid maturation agent, which also modulates reticulocyte maturation in blood. In WT mice, RAP-536 modulated blood reticulocyte dynamics consistent with faster maturation. RAP-536 also prolonged the persistence of th3/+ reticulocytes and maintained a higher frequency of th3/+ RBCs. These data, together with the finding that RAP-536 reduces hemolysis in an experimental alpha-thalassemia disease model, suggest that luspatercept has the potential to improve anemias associated with hemolysis and/or reticulocytosis. Disclosures Acar: Bristol Myers Squibb: Ended employment in the past 24 months. Jupelli:Bristol Myers Squibb: Current Employment. Abbiati:Bristol Myers Squibb: Current Employment. Ramanathan:Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Santini:Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Ratushny:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dunshee:Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech Inc.: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. MacBeth:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Suragani:Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Loos:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Schwickart:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Description: Background: Therapy options for pts with HR-MDS or AML who are not candidates for intensive chemotherapy (IC) or hematopoietic stem cell transplantation (HSCT) are limited, and clinical outcomes are poor. Novel, effective and tolerable therapies are urgently needed. TIM-3 is an inhibitory receptor that regulates both adaptive and innate immune responses. It is expressed on immune cells and on leukemic stem cells (LSCs) and blasts, but not on normal hematopoietic stem cells, making it a promising target in MDS and AML. Sabatolimab is a high-affinity, humanized, anti-TIM-3 IgG4 (S228P) antibody that simultaneously targets TIM-3 on immune and myeloid cells; this may restore immune function while also directly targeting LSCs and blasts. In preclinical studies, sabatolimab enhanced immune cell-mediated killing of AML cells in vitro. In early results from a ph 1b study (NCT03066648), sabatolimab + hypomethylating agents (HMAs; decitabine [Dec] or azacitidine [Aza]) demonstrated encouraging overall response rates in pts with high-/very high-risk MDS (+ Dec, 61%; + Aza, 57%) and newly diagnosed AML (+ Dec, 47%; + Aza, 29%), and a favorable safety profile. Study Design and Methods: The STIMULUS clinical trial program currently includes 3 trials evaluating the efficacy and safety of sabatolimab combination therapy in pts with HR-MDS or AML who are ineligible for IC or HSCT: STIMULUS-MDS1 (NCT03946670; ph 2) in pts with HR-MDS, STIMULUS-MDS2 (NCT04266301; ph 3) in pts with HR-MDS or chronic myelomonocytic leukemia-2 (CMML-2), and STIMULUS-AML1 (NCT04150029; ph 2) in pts with AML. STIMULUS-MDS1 is a randomized, double-blind, placebo-controlled ph 2 study evaluating the addition of sabatolimab to HMA in pts with HR-MDS. The 2 primary endpoints are complete remission (CR) rate and/or progression-free survival. Secondary endpoints include overall survival (OS), event-free survival (EFS), leukemia-free survival, duration of CR, transfusion independence, safety, pharmacokinetics (PK), and immunogenicity. Approximately 120 pts will be randomized 1:1 to receive sabatolimab 400 mg or placebo IV Q2W (D8 and D22 of each 28-d cycle), + Dec 20 mg/m2 IV on D1-D5 or Aza 75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9, of each 28-d cycle. STIMULUS-MDS2 is a randomized, double-blind, placebo-controlled ph 3 study of sabatolimab in combination with Aza in pts with HR-MDS or CMML-2; the primary endpoint is OS. Secondary endpoints include measures related to pt quality of life, such as time to definitive deterioration of fatigue, improvement of fatigue, transfusion-free intervals, and physical/emotional functioning, as well as additional efficacy and safety parameters. Approximately 500 pts will be randomized 1:1 to sabatolimab 800 mg or placebo IV Q4W at D8 of each 28-d cycle + Aza using the same Aza dosing schedule as in STIMULUS-MDS1. Eligible pts for STIMULUS-MDS1 or -MDS2 are treatment-naïve adults with HR-MDS (Revised International Prognostic Scoring System [IPSS-R] intermediate-/high-/very high-risk MDS). Pts with intermediate-risk MDS enrolling in STIMULUS-MDS1 are also required to have ≥5% bone marrow blasts at baseline. Pts with CMML-2 are eligible for STIMULUS-MDS2 only. STIMULUS-AML1 is a single-arm ph 2 study evaluating the safety and efficacy of sabatolimab in combination with Aza and venetoclax in pts with AML who are not candidates for IC or HSCT. Primary endpoints are incidence of dose-limiting toxicities (safety run-in) and CR rate. Secondary endpoints include safety and tolerability, CR/CRi rate, measurable residual disease-negative rate, durability of CR, relapse-free survival, EFS, OS, PK, transfusion independence, and immunogenicity. Eligible pts for STIMULUS-AML1 are adults with newly diagnosed AML who are not candidates for IC or HSCT, based on comorbidities (including renal and hepatic impairments, cardiac and pulmonary comorbidities), age (≥75 years old), or Eastern Cooperative Oncology Group performance status of 2 or 3. STIMULUS-AML1 will enroll approximately 86 pts. Part 1 consists of a safety run-in (≈18 pts) across 2 escalating sabatolimab dose levels (400/800 mg IV Q4W on D8 of each 28-d cycle) in combination with Aza (75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9) and venetoclax 400 mg PO QD. If this triple combination is assessed to be safe, part 2 (expansion) will open and enroll approximately 68 additional pts who will receive sabatolimab 800 mg Q4W in combination with Aza and venetoclax. Disclosures Zeidan: Incyte: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; CCITLA: Other; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Kim:SL VaxiGen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, 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; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Yuhan: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; BL&H: Research Funding; Sanofi Genzyme: Honoraria; Abbvie: Honoraria. Miyazaki:Novartis Pharma KK: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Platzbecker:Amgen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Malek:Novartis: Current Employment. Scott:Novartis: Current Employment. Niolat:Novartis: Current Employment. Peyrard:Novartis: Current Employment. Ma:Novartis: Current Employment. Kiertsman:Novartis: Current Employment. Stegert:Novartis AG: Current Employment, Current equity holder in publicly-traded company. Hertle:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; 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.

Description: Introduction: LR-MDS are characterized by ineffective erythropoiesis that leads to anemia and red blood cell (RBC) transfusion dependence. Luspatercept is a first-in-class erythroid maturation agent that binds to select TGF-β superfamily ligands and enhances late-stage erythropoiesis. MEDALIST is a phase 3, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of luspatercept in pts with LR-MDS (IPSS-R-defined Very low-, Low-, and Intermediate-risk) with ring sideroblasts who required RBC transfusions and were ineligible for, intolerant of, or refractory to erythropoiesis-stimulating agents. Clinical benefit (CB; defined as RBC transfusion independence [RBC-TI] ≥ 8 weeks and/or modified hematologic improvement-erythroid [mHI-E] per IWG 2006 criteria) in the primary MEDALIST treatment phase (Weeks 1-24) was achieved by 58.2% of pts in the luspatercept arm and 21.1% in the placebo arm (P 〈 0.0001). The objective of the study was to investigate the effect of luspatercept treatment on erythropoiesis biomarkers and their relationship to CB in the primary MEDALIST treatment phase (Weeks 1-24). Methods: In the MEDALIST trial, 229 pts were randomized to receive either luspatercept (N = 153) or placebo (N = 76). Reticulocyte count was determined in blood samples collected at baseline and during the primary treatment phase. Serum biomarkers (soluble transferrin receptor 1 [sTfR1], erythroferrone [ERFE], and erythropoietin [EPO]) were measured by ELISA. Bone marrow (BM) erythroid precursors (EP) were determined by cytomorphology from BM aspirates. Biomarker levels were compared between baseline and Week 25 within treatment arms and between pts with CB and without CB in the luspatercept arm using a paired 2-tailed t-test and unpaired t-test (parametric method). Results: In the luspatercept arm, mean reticulocyte count increased from baseline, starting at 8 days after first dose (55.1 vs 34.5 × 109/L at baseline, P 〈 0.0001), and remained elevated throughout the evaluation period (Figure). Mean EPO levels increased significantly within 6 weeks after first dose (440.1 vs 220.4 IU/L at baseline, P 〈 0.0001) and remained elevated up to Week 25. Similarly, levels of sTfR1 (P 〈 0.0001), ERFE (P 〈 0.0001), and EP (P = 0.0010) were elevated at Week 25 relative to baseline (Table). The mean transfusion burden (within 16 weeks) was significantly reduced at Week 25 compared with baseline (7.2 vs 11.0 units, P 〈 0.0001). In contrast, in the placebo arm, reticulocyte count, EPO levels, and 16-week transfusion burden remained largely unchanged, while levels of sTfR1 (P 〈 0.0001), ERFE (P = 0.0431), and EP (P = 0.0010) were significantly lower at Week 25 relative to baseline. In the luspatercept arm, mean baseline EP were higher in 87 pts with CB (31.3%) compared with 63 pts without CB (26.5%; P = 0.0298). No statistically significant differences in baseline EPO, ERFE, sTfR1, reticulocyte count, and 16-week transfusion burden were observed in either group. At Week 25, pts with luspatercept and CB had a significantly greater increase of reticulocyte count (2.7 vs 1.8 mean fold increase from baseline, P = 0.0017), but not EPO levels (2.9 vs 4.3 mean fold increase from baseline, P = 0.1370) compared with pts without CB. Changes in erythropoiesis-related biomarkers (EP, ERFE, and sTfR1) did not differ significantly between pts with and without CB. To investigate whether luspatercept affects erythroid maturation, the ratio of reticulocyte/sTfR1 was calculated. This ratio was reasoned to be an approximation of the ratio of late-stage erythropoiesis (reticulocytes) within total erythropoiesis (sTfR1). Luspatercept increased the mean ratio of reticulocyte/sTfR1 in pts with CB (2.2 in Week 25 vs 1.5 at baseline, P 〈 0.0001) and no CB (1.9 in week 25 vs 1.3 at baseline, P = 0.0071). Conclusions: Luspatercept-treated pts in the MEDALIST trial had an increase of erythropoiesis-associated biomarkers. Luspatercept-mediated CB (RBC-TI ≥ 8 weeks and/or mHI-E) was associated with increased blood reticulocyte counts and was higher in pts with expanded BM erythropoiesis (as measured by EP) at baseline. Together with the observation that the ratio of reticulocytes/sTfR1 increased during luspatercept treatment, this suggests that the luspatercept mechanism of efficacy in pts with LR-MDS is associated with an increase of erythroid maturation and reticulocytes. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding. Zhu:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ha:Bristol Myers Squibb: Current Employment. Risueño:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Named in BMS (before Celgene) patent filings related to predictive patient response biomarkers in hematological malignancies. Chan:Bristol Myers Squibb: Current Employment. Zhang:BMS: Current Employment. Dunshee:Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech Inc.: Current Employment, Current equity holder in publicly-traded company. Acar:Bristol Myers Squibb: Ended employment in the past 24 months. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. MacBeth:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Santini:Menarini: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Acceleron: Consultancy; Novartis: Consultancy, Honoraria; Johnson & Johnson: Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Garbowski:Imara: Consultancy; Vifor Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fenaux:BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Schwickart:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Description: 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.

Description: Introduction: Patients (pts) with MDS/MPN-RS-T have limited treatment options for anemia due to ineffective erythropoiesis. Luspatercept, the first-in-class erythroid maturation agent that enhances late-stage erythropoiesis, is approved by the FDA for treatment of anemia in adult pts with lower-risk (LR) MDS with ring sideroblasts (RS) or MDS/MPN-RS-T after erythroid-stimulating agent (ESA) failure. In the randomized, double-blind, phase 3 MEDALIST study, luspatercept significantly reduced transfusion burden vs placebo in pts with LR-MDS (NCT02631070; Fenaux P, et al. N Engl J Med 2020;382:140-51). Here, we assess the efficacy and safety of luspatercept in pts with MDS/MPN-RS-T enrolled in the MEDALIST study. Methods: Eligible pts were ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs (serum erythropoietin 〉 200 U/L); and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or placebo administered subcutaneously every 3 wks. The primary endpoint was achievement of RBC transfusion independence (RBC-TI) ≥ 8 wks during Wks 1-24. Results: A retrospective analysis identified 23/229 (10.0%) pts enrolled in the MEDALIST trial who had MDS/MPN-RS-T, per WHO 2016 criteria (Arber DA, et al. Blood 2016;127:2391-405); 14 received luspatercept and 9 received placebo. Pts in this subgroup received a median of 4.0 RBC units/8 wks (range 2.0-11.5) during the 16 wks prior to treatment. At baseline, pts had a median hemoglobin (Hb) level of 7.7 g/dL (range 7.0-9.0), a median leukocyte count of 5.1 × 109/L, a median platelet count of 447.0 × 109/L, and 18 (78.3%) pts had serum erythropoietin levels 〈 200 U/L (Table). In the luspatercept arm, 9/14 (64.3%) pts with MDS/MPN-RS-T achieved the primary endpoint of RBC-TI for ≥ 8 wks during Wks 1-24, compared with 2/9 pts (22.2%) receiving placebo (odds ratio 11.3; 95% confidence interval [CI] 1.19, 106.12; P = 0.028). Pts receiving luspatercept were significantly more likely to achieve clinical benefit (achieving RBC-TI ≥ 8 wks and/or modified hematologic improvement-erythroid [mHI-E] per IWG 2006 criteria [≥ 4 units/8 wks reduction in RBC transfusion in pts with ≥ 4 units/8 wks baseline RBC transfusion burden; Hb increase by ≥ 1.5 g/dL] during Wks 1-24 in pts with 〈 4 units/8 wks baseline RBC transfusion burden), compared with pts receiving placebo (78.6% vs 33.3%; P = 0.034). Median time from the start of clinical benefit response to end of treatment was 94.6 wks (range 8.0-150.0) in the luspatercept arm and 23.9 wks (range 23.7-57.9) in the placebo arm. During Wks 1-24, mHI-E was achieved by 10 luspatercept pts (6 were high transfusion burden [HTB; defined as baseline transfusion burden ≥ 4 units/8 wks] and 4 were low transfusion burden [LTB; defined as baseline transfusion burden 〈 4 units/8 wks]) and 1 placebo pt (1/5 HTB). RBC-TI ≥ 8 wks was achieved by 4/8 HTB pts receiving luspatercept (vs 0/5 placebo) and 5/6 LTB pts (vs 2/4 placebo). After 24 wks, pts in the luspatercept arm had a mean Hb increase of +1.7 g/dL compared with an increase of +0.9 g/dL in pts in the placebo arm (least squares [LS] mean difference +0.85 g/dL; 95% CI −1.13, +2.82). Greater reductions from baseline in mean serum ferritin levels were seen with luspatercept (−121.8 μg/L) compared with placebo (−91.9 μg/L) over Wks 9-24 (LS mean difference −90.1; 95% CI −758.4, 578.2). Pts in the luspatercept arm had median platelet counts of 467.5 × 109/L and median leukocyte counts of 6.5 × 109/L post 24 wks of treatment, compared with pts in the placebo arm with 514.0 × 109/L and 6.2 × 109/L, respectively. The incidence of specific TEAEs (occurring in ≥ 1 patient) are as follows: fatigue (1/14 [7.1%] luspatercept vs 1/9 [11.1%] placebo), dizziness (7/14 [50.0%] vs 0/9), dyspnea (3/14 [21.4%] vs 0/9), nausea (6/14 [42.9%] vs 2/9 [22.2%]), arthralgia (1/14 [7.1%] vs 0/9), diarrhea (6/14 [42.9%] vs 1/9 [11.1%]), and hypertension (3/14 [21.4%] vs 0/9). In the luspatercept arm, 1/14 (7.1%) pts experienced ≥ 1 thromboembolic event (transient ischemic attack) and 1/9 (11.1%) pts in the placebo arm progressed to AML (as of July 1, 2019). Conclusions: Luspatercept demonstrated clinical efficacy in pts with MDS/MPN-RS-T with a generally well-tolerated safety profile. These data support the clinical benefits of luspatercept in this patient population with otherwise limited treatment options. Disclosures Komrokji: Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Platzbecker:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Fenaux:BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mufti:Abbvie, Novartis: Consultancy; BMS, Novartis: Research Funding. Santini:Janssen: Research Funding; BMS, J&J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: 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. Finelli:BMS: 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, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Jurcic:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Daiichi-Sankyo: 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; Arog Pharmaceuticals: Research Funding; Astellas: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Kura Oncology: Research Funding; PTC Therapeutics: Research Funding. Greenberg:BMS: Research Funding; Aprea: Research Funding; Notable Labs: Research Funding; H3 Biotech: Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zeidan:Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Leukemia and Lymphoma Society: Other; CCITLA: Other; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; Taiho: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other; Agios: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. DeZern:Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy; Abbvie: Consultancy. Savona:Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Ryvu: Consultancy; Boehringer Ingelheim: Patents & Royalties; Astex: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Zhang:BMS: Current Employment. Ha:BMS: Current Employment. Sinsimer:BMS: Current Employment, Current equity holder in publicly-traded company. Backstrom:BMS: Current equity holder in publicly-traded company; Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; Medpacto: Research Funding; stelexis: Current equity holder in private company.

Description: Introduction: Patients with myelodysplastic syndromes (MDS) experience severe anemia, which is commonly managed with frequent red blood cell transfusions (RBCT) in patients refractory to erythropoiesis-stimulating agents. At diagnosis, 85% of patients have anemia and 30-50% depend on RBCT. The administration of RBCT itself provides transient relief in anemia-related symptoms. Per protocol, MEDALIST investigators were advised to transfuse for symptoms related to anemia at the investigators' discretion. Hence, cessation or reduction of RBCT may increase anemia-related symptoms and negatively impact health-related quality of life (HRQoL). Luspatercept is a first-in-class erythroid maturation agent providing clinically meaningful reduction in transfusion burden in patients with transfusion-dependent anemia due to Revised International Prognostic Scoring System (IPSS-R)-defined Very low-, Low-, or Intermediate-risk MDS with ring sideroblasts in the phase 3 MEDALIST trial (NCT02631070). However, the impact of luspatercept on patients' HRQoL has not been evaluated. This analysis aimed to evaluate the effect of luspatercept versus placebo on HRQoL of patients treated for MDS from baseline through Week 25 of the MEDALIST study. Methods: Patients received luspatercept or placebo every 3 weeks for 24 weeks, plus best supportive care (BSC), including tailored amounts of RBCT. Effects of luspatercept versus placebo on HRQoL were evaluated as secondary and exploratory endpoints in the MEDALIST study. In the primary analysis, mean change from baseline to Week 25 (clinical assessment visit) in the European Organisation for Research and Treatment of Cancer's core quality of life questionnaire, version 3.0 (EORTC QLQ-C30) and in the QoL assessment in MDS questionnaire (QOL-E) was determined using mixed-effects repeated measures analysis. Clinically meaningful change within each treatment arm was defined as a ≥ 10-point change in patient-reported outcome (PRO) score from baseline for all EORTC QLQ-C30 domains, and ≥ 0.5 standard deviation of the baseline domain score for all QOL-E domains. Differences between luspatercept and placebo were considered clinically meaningful if the change from baseline between treatment arms exceeded the threshold for a clinically meaningful difference. In an exploratory analysis, patient-reported impact of transfusion dependence and overall side effects on their daily life was estimated using the QOL-E instrument. Results: A total of 229 patients were randomized; 153 patients to luspatercept and 76 to placebo. The HRQoL-evaluable population, consisting of patients with ≥ 1 post-baseline HRQoL score, was 149 patients in the luspatercept arm and 76 patients in the placebo arm. Questionnaire compliance rates among patients remaining on treatment were similar between luspatercept and placebo treatment groups at Week 25 (EORTC QLQ-C30, 88.2% vs 79.4% and QOL-E, 72.5% vs 69.7%). At baseline, MEDALIST patients had a clinically meaningfully worse HRQoL compared with the general population in 5 of 15 EORTC QLQ-C30 domains: physical functioning, role functioning, social functioning, fatigue, and dyspnea. Through Week 25, there was no clinically meaningful difference in change from baseline between and within the luspatercept and placebo arms across all EORTC QLQ-C30 (Global health status shown in Figure A) and QOL-E domains. A greater proportion of patients in the luspatercept arm relative to placebo reported improvements in daily life from the impact of transfusion burden (Figure B). Relative to baseline, the proportion of patients reporting a lower impact of transfusion dependence on their daily life was 39% versus 22% in luspatercept versus placebo at Week 25; in contrast, the proportion of patients reporting a higher impact of transfusion dependence on their daily life was 12% versus 22% in luspatercept versus placebo. Impact of treatment side effects on patients was comparable between luspatercept and placebo. Conclusions: Luspatercept with BSC reduced RBCT burden and patient-reported transfusion impact on their daily life, while maintaining other aspects of HRQoL from baseline through Week 25 in the MEDALIST study. Disclosures Oliva: Alexion: Consultancy; BMS: Consultancy, Honoraria, Patents & Royalties, Speakers Bureau; Novartis: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Apellis: Consultancy. Platzbecker:Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding. Mufti:BMS, Novartis: Research Funding; Abbvie, Novartis: Consultancy. Santini:Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Acceleron, BMS, Menarini, Novartis: Consultancy; BMS, J&J, Novartis: Honoraria. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Komrokji:BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Novartis: Honoraria. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Guo:BMS: Consultancy. Zhang:BMS: Current Employment. Ha:Bristol Myers Squibb: Current Employment. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Lord-Bessen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Backstrom:BMS: Current equity holder in publicly-traded company; Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Fenaux:Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.