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Racial disparities in cancer care and outcomes have been well documented in various malignancies, with Black patients having the highest death rate and shortest survival of any racial/ethnic group in the United States (US) for most cancers. However, there have been limited studies on racial/ethnic disparities in myelodysplastic syndromes (MDS). Our study characterized and compared differences in baseline demographics, clinical characteristics, socioeconomic factors, and overall survival (OS) between Black and White patients with MDS in the US. We used the Surveillance, Epidemiology, and End Results (SEER) Program and included 37,562 patients (Black, 8.1 %; White, 91.9 %) diagnosed between 2001 and 2013. We observed significant differences in baseline characteristics between cohorts. In a univariate analysis, Black race was associated with longer survival (hazard ratio [HR]: 0.83; 95 % confidence interval [CI], 0.79-0.86; p 0.001). The association between race and survival was attenuated but remained significant in various models to adjust for differences in baseline characteristics (HR in multivariable analysis, 0.92; 95 % CI, 0.87-0.96); p 0.001). Subgroup analysis by histology revealed differences in the association between race and OS. Refractory anemia (RA), RA with ring sideroblasts, and MDS-not otherwise specified, a category in SEER representing a poorly defined MDS subset for 52 % of cases in our study, favored Black patients. RA with excess blasts favored White patients. The overall finding that Black race is associated with better OS outcomes, when compared with White patients, needs to be interpreted with caution and nuanced by histology. Additional research to explore these associations is warranted.

Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF β) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes.In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count13 000/μL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E), defined as a haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0·125-0·5 mg/kg vs 0·75-1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (200 IU/L, 200-500 IU/L, and500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383.Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125-1·75 mg/kg) and 31 patients in the expansion cohort (1·0-1·75 mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose luspatercept concentrations (0·75-1·75 mg/kg) achieved HI-E versus two (22% [95% CI 3-60]) of nine receiving lower dose concentrations (0·125-0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration.Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing.Acceleron Pharma.

Background: Patients with LR-MDS and anemia who have HTB have very few treatment options and represent a patient population with significant clinical unmet need. Aims: To evaluate the clinical benefit of luspatercept in HTB patients with LR-MDS from the MEDALIST trial. Methods: Eligible patients were aged ≥18 years; had IPSS-R-defined LR-MDS with ring sideroblasts (RS); were refractory, intolerant, or unlikely to respond to erythropoiesis-stimulating agents (serum erythropoietin > 200 U/L); and had anemia requiring regular RBC transfusions. All patients provided informed written consent. 229 patients were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg; titration up to 1.75 mg/kg allowed) or placebo subcutaneously every 3 weeks. HTB was defined as ≥6 RBC units transfused/8 weeks. Results: 153 patients were randomized to luspatercept and 76 to placebo; 66 and 33 had HTB at baseline, respectively. As of 01 JULY, 2019, 23/66 (34.8%) and 12/66 (18.2%) luspatercept-treated HTB patients achieved a ≥50% and ≥75% reduction in RBC units transfused over at least 24 weeks compared to baseline, respectively, versus 3/33 (9.1%; P=0.0063) and 1/33 (3.0%; P=0.0363) HTB placebo patients. 6/66 (9.1%) luspatercept-treated HTB patients and 1/33 (3.0%) placebo-treated HTB patient achieved RBC-transfusion independence (RBC-TI) ≥ 8 weeks in Weeks 1–24 (P=0.2699). Median (range) time to achieve RBC-TI was 50.0 days (1.0–100.0) with luspatercept; median (range) duration of longest RBC-TI episode in luspatercept-treated patients was 42.6 weeks (8.4–81.1). Mean number of transfusion events in Weeks 1–24 was 9.2 for luspatercept-treated patients versus 12.4 in the placebo arm (hazard ratio [95% confidence interval] 0.794 [0.660–0.956]). 65/66 (98.5%) luspatercept- and 29/33 (87.9%) placebo-treated HTB patients reported ≥1 treatment-emergent adverse event (TEAE); 11/66 (16.7%) and 3/33 (9.1%) patients, respectively, reported ≥1 TEAE leading to discontinuation. 28/66 (42.4%) luspatercept- and 15/33 (45.5%) placebo-treated patients reported ≥1 serious TEAE. The incidence of grade 3–4 TEAEs in HTB patients was similar between treatment arms (53.0% for luspatercept vs 54.5% for placebo). Conclusions: HTB patients with LR-MDS with RS receiving luspatercept had clinically significant reductions in RBC transfusion burden and reduced number of transfusion events. Luspatercept was well tolerated in HTB patients, consistent with the overall study population.

Background: Luspatercept, a first-in-class erythroid maturation agent, has been investigated in patients with LR-MDS and ring sideroblasts (RS) (MEDALIST; Fenaux and Platzbecker NEJM 2020) and in an ongoing Phase 3 trial regardless of RS status (COMMANDS, NCT03682536 ). The previously reported Phase 2 trial of luspatercept (Platzbecker Lanc Onc 2017) includes subtypes of LR-MDS with and without RS, regardless of prior ESA exposure, and various EPO levels. Aims: Evaluate the long-term safety and efficacy of luspatercept in LR-MDS. Methods: Patients were IPSS low/int-1, age ≥ 18 years, Hgb NCT01749514 ; NCT02268383 ). Results: As of 13July2019, 115 patients were enrolled, of whom 108 were treated with ≥0.75 mg/kg. 44/108 (41%) were non-RS; 47/108 (44%) had prior ESA; 45/108 (42%) had baseline transfusion burden of ≥4U RBC/8 weeks. Median duration of treatment (n=108) was 10.4 (0.7-57.3) months. IWG HI-E RR was 54% (58/108) overall; 36% (16/44) in non-RS, 68% (42/62) in RS+ (2 patients had unknown RS status); 53% (25/47) prior ESA, 54% (33/61) in ESA-naive; 54% (34/63) in 2 patients) were fatigue, headache, hypertension, arthralgia, bone pain, diarrhea, injection site erythema, myalgia, and peripheral edema. Conclusions: Consistent with previous reports, data from the long-term Phase 2 study of luspatercept in LR-MDS continues to show efficacy in a variety of subtypes and safety similar to previous and ongoing studies.

Background: Iron overload, resulting from RBC transfusions or ineffective erythropoiesis, is associated with significant morbidity in MDS. Aims: To assess changes from baseline in serum ferritin (SF) and iron chelation therapy (ICT) use in the MEDALIST trial patients ( NCT02631070 ). Methods: Patients (IPSS-R-defined lower-risk MDS with RS; ≥18 years; unsatisfactory response to or ineligible for EPO-based therapy; required regular RBC transfusions) had luspatercept (1.0 mg/kg, titration up to 1.75 mg/kg) or placebo administered subcutaneously every 3 weeks. Results: Of 153 luspatercept-treated patients, 87 (56.9%) had low and 66 (43.1%) high baseline RBC transfusion burden (LTB and HTB; Conclusion: Luspatercept treatment resulted in SF decreases, particularly in HTB patients and those with high baseline SF who experienced significant RBC transfusion reduction. Overall, ICT use was reduced with luspatercept.

Background: MEDALIST ( NCT02631070 ) is a randomized, placebo-controlled, phase 3 trial evaluating efficacy and safety of luspatercept in patients with anemia due to LR-MDS with RS. Aims: To evaluate long-term transfusion burden reduction with luspatercept in MEDALIST trial patients. Methods: Patients were aged ≥18 years; had IPSS-R-defined LR-MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs; and required RBC transfusions (≥2 units/8 weeks in the 16 weeks before randomization). Two hundred twenty-nine patients were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or placebo subcutaneously every 3 weeks. Results: As of 1 July 2019, 77/153 (50.3%) and 11/76 (14.5%) patients receiving luspatercept and placebo, respectively, achieved ≥50% RBC transfusion burden reduction over at least 24 weeks versus baseline (P Conclusions: Luspatercept demonstrated clinical efficacy in patients with LR-MDS with RS and was associated with significant reductions in RBC transfusions (≥50%) and serum ferritin.

Background: A significant proportion of patients in the MEDALIST trial (randomized, placebo-controlled, phase 3 study evaluating luspatercept, an erythroid maturation agent, for treatment of anemia in LR-MDS patients) achieved RBC transfusion independence (RBC-TI) ≥ 8 weeks (Weeks 1–24) ( NCT02631070 ). Aims: To evaluate the effect of luspatercept dose on efficacy and treatment-emergent adverse events (TEAEs). Methods: Of 229 eligible patients (IPSS-R LR-MDS with RS; age ≥ 18 years; unsatisfactory response to or ineligible for EPO-based therapy; regular RBC transfusions), 153 received luspatercept, starting at 1.0 mg/kg, subcutaneously every 3 weeks. Dose titration to 1.33 and 1.75 mg/kg was allowed in the absence of RBC-TI after ≥2 doses at the same dose level. Dose reductions/delays were used to manage excessive hemoglobin increase and safety. Response was defined as RBC-TI ≥ 8 weeks during Weeks 1–48. Results: As of May 8, 2018, 35 (22.9%), 28 (18.3%), and 90 (58.8%) patients received a maximum dose of 1.0, 1.33, and 1.75 mg/kg, respectively. Median time to dose escalation to 1.33 or 1.75 mg/kg in patients achieving RBC-TI ≥8 weeks was approximately twice (105 and 171 days) that of non-responders (43 and 91 days). Of the 69 luspatercept-treated responders, 47 (68.1%) achieved their first response at 1.0 mg/kg, 5 (7.2%) at 1.33 mg/kg, and 7 (10.1%) at 1.75 mg/kg. The majority of patients with baseline transfusion burden ≤ 6 units/8 weeks were responders (63/108; 58.3%). Of these 63 patients, the maximum dose was 1.0 mg/kg in 24 (38.1%) patients, 1.33 mg/kg in 14 (22.2%), and 1.75 mg/kg in 25 (39.7%); first response occurred at 1.0 mg/kg in 47 (74.6%) patients, at 1.33 mg/kg in 2 (3.2%), and at 1.75 mg/kg in 5 (7.9%); 9 patients received luspatercept at ≥2 dose levels during first response. As of July 1, 2019, 74 (48.4%) and 9 (5.9%) luspatercept-treated patients experienced ≥1 dose delay and ≥1 dose reduction, respectively. New onset of luspatercept-related TEAEs generally did not increase with dose increases from 1.0–1.75 mg/kg. Conclusions: The dose range of 1.0–1.75 mg/kg was well tolerated in LR-MDS patients. Dose escalations contributed to maintenance of response or achievement of multiple response episodes.