Abstract: Leprosy is a chronic but treatable infectious disease caused by the intracellular pathogen Mycobacterium leprae . Host immunity to M. leprae determines the diversity of clinical manifestations seen in patients, from tuberculoid leprosy with robust production of Th1-type cytokines to lepromatous disease, characterized by elevated levels of Th2-type cytokines and a suboptimal proinflammatory response. Previous reports have indicated that M. leprae is a poor activator of macrophages and dendritic cells in vitro. To understand whether M. leprae fails to elicit an optimal Th1 immune response or actively interferes with its induction, we have examined the early interactions between M. leprae and monocytes from healthy human donors. We found that, in naïve monocytes, M. leprae induced high levels of the negative regulatory molecules MCP-1 and interleukin-1 (IL-1) receptor antagonist (IL-1Ra), while suppressing IL-6 production through phosphoinositide-3 kinase (PI3K)-dependent mechanisms. In addition, low levels of proinflammatory cytokines were observed in association with reduced activation of nuclear factor-κB (NF-κB) and delayed activation of IL-1β-converting enzyme, ICE (caspase-1), in monocytes stimulated with M. leprae compared with Mycobacterium bovis BCG stimulation. Interestingly, although in itself a weak stimulator of cytokines, M. leprae primed the cells for increased production of tumor necrosis factor alpha and IL-10 in response to a strongly inducing secondary stimulus. Taken together, our results suggest that M. leprae plays an active role to control the release of cytokines from monocytes by providing both positive and negative regulatory signals via multiple signaling pathways involving PI3K, NF-κB, and caspase-1.

Abstract: Interactions between host immune cells and gut microbiota are crucial for the integrity and function of the intestine. How these interactions regulate immune cell responses in the intestine remains a major gap in the field. Aim We have identified the signalling lymphocyte activation molecule family member 4 (SLAMF4) as an immunomodulator of the intestinal immunity. The aim is to determine how SLAMF4 is acquired in the gut and what its contribution to intestinal immunity is. Methods Expression of SLAMF4 was assessed in mice and humans. The mechanism of induction was studied using GFP tg bone marrow chimaera mice, lymphotoxin α and TNLG8A-deficient mice, as well as gnotobiotic mice. Role in immune protection was revealed using oral infection with Listeria monocytogenes and Cytobacter rodentium . Results SLAMF4 is a selective marker of intestinal immune cells of mice and humans. SLAMF4 induction occurs directly in the intestinal mucosa without the involvement of the gut-associated lymphoid tissue. Gut bacterial products, particularly those of gut anaerobes, and gut-resident antigen-presenting cell (APC) TNLG8A are key contributors of SLAMF4 induction in the intestine. Importantly, lack of SLAMF4 expression leads the increased susceptibility of mice to infection by oral pathogens culminating in their premature death. Conclusions SLAMF4 is a marker of intestinal immune cells which contributes to the protection against enteric pathogens and whose expression is dependent on the presence of the gut microbiota. This discovery provides a possible mechanism for answering the long-standing question of how the intertwining of the host and gut microbial biology regulates immune cell responses in the gut.

Abstract: Introduction: Lower-risk MDS is characterized by anemia and ineffective erythropoiesis leading to RBC transfusion dependence. Effective treatment for anemia remains an unmet medical need. Patients with MDS may also experience additional cytopenias that may complicate treatment and contribute to infections and bleeding events. Here, we report hematologic improvement (HI) outcomes for patients in the MEDALIST trial (ClinicalTrials.gov identifier: NCT02631070), a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent that binds select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. Methods: Eligible patients in the MEDALIST trial were adults with anemia due to Very low-, Low-, or Intermediate-risk MDS with RS according to the Revised International Prognostic Scoring System; were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents (ESAs); and required RBC transfusions. Patients received luspatercept (starting dose of 1.0 mg/kg and titration up to 1.75 mg/kg, if needed) or placebo subcutaneously every 3 weeks for ≥ 24 weeks. Platelet and neutrophil counts were assessed by the central laboratory. Secondary endpoints included HI-neutrophil (HI-N) and -platelet (HI-P) responses, using International Working Group 2006 criteria, over any consecutive 56-day period. Mean changes from baseline in platelets and neutrophils were also evaluated. Results*: A total of 94.8% patients in the luspatercept arm and 97.4% in the placebo arm had refractory cytopenia with multilineage dysplasia and RS at baseline. Mean neutrophil and platelet counts at baseline for patients in the luspatercept arm were 2.8 x 109/L and 259 x 109/L, respectively, and in the placebo arm were 2.7 x 109/L and 252 x 109/L, respectively. Neutropenia ( 〈 1 x 109/L) was confirmed at baseline in 15 (9.8%) and 10 (13.2%) patients in the luspatercept and placebo arms, respectively. Fifty-one (33.3%) patients in the luspatercept arm and 22 (28.9%) in the placebo arm received granulocyte colony-stimulating factor in combination with ESAs prior to randomization. A total of 8 (5.2%) and 6 (7.9%) patients receiving luspatercept and placebo, respectively, had baseline thrombocytopenia ( 〈 100 x 109/L); no patients received prior platelet transfusions. Fifteen (9.8%) and 10 (13.2%) patients in the luspatercept and placebo arms, respectively, were evaluable for HI-N (i.e. baseline neutrophils 〈 1 x 109/L); 3/15 (20%) of those receiving luspatercept and 1/10 (10%) of those receiving placebo achieved HI-N in Weeks 1-48. Among patients who were evaluable for HI-P (i.e. baseline platelets 〈 100 x 109/L), 5/8 (62.5%) of those receiving luspatercept and 2/6 (33%) of those receiving placebo achieved HI-P in Weeks 1-48 (Table). None of the luspatercept HI-P responders received platelet transfusions. Mean changes from baseline in neutrophils of 0.94 x 109/L with luspatercept and 0.04 x 109/L with placebo were observed at Week 15, with early increases reported for luspatercept by Day 8 (0.86 vs 0.08 x 109/L for placebo). Mean increases in neutrophils at Day 8 occurred in both luspatercept responders (by MEDALIST primary endpoint; 1.0 x 109/L) and non-responders (0.8 x 109/L). Mean changes from baseline in platelets of 29 x 109/L were observed with luspatercept and 0.9 x 109/L with placebo by Week 12, but early increases were observed with luspatercept by Day 8 (18 vs 3 x 109/L for placebo) and mean increases in platelets at Day 8 occurred in both luspatercept responders (21.4 x 109/L) and non-responders (16.5 x 109/L). No patients in either arm experienced grade 3 or 4 treatment-emergent thrombocytopenia. Treatment-related grade 3 or 4 neutropenia was reported in 1 (0.7%) patient receiving luspatercept and 1 (1.3%) patient receiving placebo. Conclusions: Although only a minority of patients were evaluable for HI-P/HI-N response based on entry criteria for the study, luspatercept treatment resulted in a mean increase from baseline in platelet and neutrophil counts in most patients overall vs placebo, regardless of response status. These improvements were observed early following treatment initiation and then stabilized. Luspatercept did not contribute to the worsening of cytopenias vs placebo. *Data cutoff: May 8, 2018. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Mufti:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Buckstein:Takeda: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Santini:Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria. Díez-Campelo:Celgene Corporation: 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, Research Funding. Finelli:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Ito:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Rampersad:Celgene Corp: Employment, Equity Ownership. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Linde:Fibrogen, Inc.: Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Platzbecker:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Komrokji:Alexion: Speakers Bureau; Incyte: Consultancy; Janssen: Consultancy; Agios: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Jazz: Speakers Bureau; DSI: Consultancy; Novartis: Speakers Bureau. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Abstract: Introduction: β-thalassemia is an inherited hemoglobinopathy characterized by ineffective erythropoiesis and anemia. Luspatercept is a first-in-class erythroid maturation agent that binds to select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. We aim to evaluate in detail the number of response episodes, duration of clinical benefit, and safety in luspatercept responders during the phase 3 BELIEVE study (NCT02604433). Methods: Eligible pts were aged ≥ 18 years, with β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed), requiring regular transfusions of 6-20 RBC units in the 24 weeks (wks) prior to randomization, with no transfusion-free period & gt; 35 days. Pts were randomized 2:1 to luspatercept 1.0 mg/kg (up to 1.25 mg/kg allowed), or placebo, subcutaneously every 3 wks for ≥ 48 wks. Pts in both treatment arms continued RBC transfusions to maintain baseline Hb level and iron chelation therapy. Achievement and number of response episodes (defined as ≥ 33% reduction in RBC transfusion from baseline over any consecutive 24 wks) were assessed at a median follow-up of 64.1 wks. Duration of clinical benefit, defined as the time of first response (≥ 33% reduction in RBC transfusion over any 24 wks) to discontinuation due to any cause at that episode, was also assessed. Results:A total of 336 pts were randomized. In the ITT population, 224 pts in the luspatercept arm had a median baseline RBC transfusion burden in the 12 wks prior to randomization of 6.12 U RBCs (average 0.51 U/wk; range 3-14) and the 112 pts in the placebo arm had a median baseline transfusion burden of 6.27 U (average 0.52 U/wk; range 3-12). A total of 194 (57.7%) luspatercept and 65 (58%) placebo pts had prior splenectomy. As of the May 11, 2018 cutoff date, 92/224 (41.1%) luspatercept-treated pts and 3/112 (2.7%) placebo-treated pts had achieved ≥ 33% reduction in RBC transfusion over any 24 wks; of these luspatercept responders, 55 (59.8%) had ≥ 2 separate responses (over the treatment period up to data cutoff), 42 (45.7%) had ≥ 3, 29 (31.5%) had ≥ 4, and 19 (20.7%) had ≥ 5. Three (1.3%) pts receiving luspatercept re-responded at the same dose level after initially losing response. Median duration of clinical benefit (as defined above) for luspatercept responders was 53.5 wks (range 24-93.7). Forty-seven (21.0%) pts receiving luspatercept had no loss of response within the entire study period. Five luspatercept responders achieved RBC transfusion independence for ≥ 24 wks (median total duration was 60.1 wks) and 3 achieved RBC transfusion independence for ≥ 48 wks (median duration was 66 wks). The average number of RBC units saved over any 24 wks in all luspatercept responders was 6.55 U (0.27 U/wk) and was 8.16 U (0.34 U/wk) with transfusion burden & gt; 15 U/24 wks, compared to baseline. As of the May 11, 2018 cutoff date, the safety population consisted of 243 pts (including 92 pts who crossed over from the placebo arm to the luspatercept arm). Frequent adverse events (AEs) in the luspatercept and placebo arms included bone pain (19.7% vs 8.3%, respectively), arthralgia (19.3% vs 11.9%), and dizziness (11.2% vs 4.6%). The safety profile for pts who crossed over from placebo to luspatercept was consistent with that observed for pts receiving luspatercept from baseline. The incidence of bone pain, arthralgia, and dizziness was largely non-severe grade 1-2, tended to decrease over time during the study, was not associated with dose level, and was not associated with treatment modification or discontinuation. Pts continue to be monitored for safety outcomes. Conclusions: Most β-thalassemia pts who were luspatercept responders experienced multiple response periods and had durable clinical benefit over the 64.1 wk follow-up period. The incidence of frequent AEs was consistent with the previously reported 48 wk safety profile for luspatercept, was not associated with dose level, and decreased over time with no impact on treatment modification or continuation. Disclosures Viprakasit: Celgene Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Protagonist: Consultancy, Research Funding; Vifor: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Ionis: Consultancy, Research Funding; La Jolla: Consultancy, Research Funding. Taher:Celgene Corporation: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Abfero: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; La Jolla Pharmaceuticals: Consultancy, Research Funding; Ionis Pharmaceuticals: Consultancy. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding. Porter:Vifor: Honoraria; Agios: Consultancy, Honoraria; Protagonist: Honoraria; La Jolla: Honoraria; Bluebird Bio: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Silence Therapeutics: Honoraria. Piga:Acceleron Pharma: Research Funding; Celgene Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Coates:agios pharma: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study; apo pharma: Consultancy, Honoraria, Speakers Bureau; vifor: Consultancy, Honoraria. Voskaridou:Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Perrotta:Acceleron Pharma: Research Funding; Novartis: Honoraria, Research Funding. Kattamis:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Shetty:Celgene Corporation: Employment, Equity Ownership. Kuo:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene International: Employment. Zinger:Celgene Corporation: Employment. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Linde:Acceleron Pharma: Employment, Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership; Fibrogen, Inc.: Equity Ownership. Cappellini:CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Abstract: 7554 Background: Anemic pts with LR-MDS and high baseline RBC transfusion burden (HTB) have very few treatment options and constitute a pt population with significant clinical unmet need. In this secondary analysis of the MEDALIST trial (NCT02631070), we sought to evaluate the clinical benefit of luspatercept in this pt population. Methods: MEDALIST is a randomized, placebo (PBO)-controlled, phase 3 study evaluating the efficacy and safety of luspatercept in pts with anemia due to LR-MDS with ring sideroblasts (RS) (Fenaux & Platzbecker et al. NEJM. 2020;382:140-51). Pts were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to erythropoiesis-stimulating agents (serum erythropoietin 〉 200 U/L); and had anemia requiring regular RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg; titration up to 1.75 mg/kg allowed) or PBO subcutaneously every 3 weeks. HTB was defined as ≥ 6 RBC units transfused/8 weeks. Results: 153 pts were randomized to luspatercept and 76 to PBO. As of July 1, 2019, 23/66 (34.8%) and 12/66 (18.2%) HTB pts receiving luspatercept achieved a ≥ 50% and ≥ 75% reduction from baseline in RBC transfusion burden over ≥ 24 weeks, respectively, vs 3/33 (9.1%; P = 0.0063) and 1/33 (3.0%; P = 0.0363) pts receiving PBO. 6/66 (9.1%) luspatercept-treated HTB pts and 1/33 (3.0%) PBO-treated HTB pt achieved RBC-transfusion independence (TI) ≥ 8 weeks in Weeks 1–24 ( P = 0.2699). The median (range) time to achieve RBC-TI with luspatercept was 50.0 days (1.0–100.0) and median (range) duration of RBC-TI in the luspatercept arm was 42.6 weeks (8.4–81.1). Mean number of transfusion events in Weeks 1–24 was 9.2 in the luspatercept arm vs 12.4 in the PBO arm (hazard ratio [95% confidence interval] 0.794 [0.660–0.956] ). 65/66 (98.5%) luspatercept- and 29/33 (87.9%) PBO-treated HTB pts reported ≥ 1 treatment-emergent adverse event (TEAE); 11/66 (16.7%) and 3/33 (9.1%) pts, respectively, reported ≥ 1 TEAE leading to discontinuation. 28/66 (42.4%) luspatercept- and 15/33 (45.5%) PBO-treated pts reported ≥ 1 serious AE. Incidence of grade 3–4 TEAEs in HTB pts was similar between arms (53.0% luspatercept vs 54.5% PBO). Conclusions: Luspatercept treatment resulted in clinically significant reductions in transfusion burden and reduced number of transfusion events in HTB pts with LR-MDS with RS, with an acceptable safety profile consistent with the overall population. Clinical trial information: NCT02631070 .

Abstract: 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 & gt; 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 & lt; 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 & lt; 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 & lt; 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.