Luspatercept: From Bench to Bedside and Beyond in the Management of Ineffective Erythropoiesis.

A Systematic Literature Review on the Burden of Illness in Lower-Risk Transfusion-Dependent Myelodysplastic Syndromes

Background:β-thalassemia is a hereditary blood disorder resulting in ineffective erythropoiesis and anemia. Management of anemia with regular blood transfusions is associated with complications including iron overload. Here, we report long-term safety and efficacy results of the first clinical study of luspatercept in β-thalassemia, initiated in 2013, enrolling adults with both nontransfusion-dependent (NTD) and transfusion-dependent (TD) β-thalassemia.Objectives:The objective was to report long-term safety data, for up to 5 years of treatment, for 64 patients with TD or NTD β-thalassemia, and long-term efficacy data for a subset of 63 patients with β-thalassemia who received high-dose luspatercept (0.6–1.25 mg/kg): 31 NTD and 32 TD patients.Design:The study was a phase 2, noncontrolled, open-label trial comprising a dose-finding base phase and a 5-year extension phase.Methods:Endpoints include safety; erythroid response over a continuous 12-week period [NTD: hemoglobin increase from baseline ⩾1.0 or ⩾1.5 g/dl; TD: red blood cell (RBC) transfusion burden reduction, ⩾20%, ⩾33%, or ⩾50%]; and changes in biomarkers of ineffective erythropoiesis, iron metabolism parameters, Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) scores, and 6-min walking distance.Results:Median duration of luspatercept exposure for NTD and TD patients was 910 days (range, 40–1850) and 433 days (range, 21–1790), respectively. Seventeen of 31 (54.8%) NTD patients achieved a mean hemoglobin increase of ⩾1.5 g/dl and 19 of 32 (59.4%) TD patients achieved ⩾50% reduction in RBC transfusion burden, during any continuous 12-week period. Median cumulative duration of response was 1126 days (range, 127–1790) for NTD patients and 909 days (range, 87–1734) for TD patients. The most common treatment-related adverse events of any grade were bone pain, headache, and myalgia.Conclusion:Long-term assessment of patients with β-thalassemia showed luspatercept was associated with sustained increases in hemoglobin levels in NTD patients and sustained transfusion burden reductions in TD patients.Trial registration:(ClinicalTrials.gov Identifiers: NCT01749540 and NCT02268409).Plain Language SummaryLong-term safety and erythroid response with luspatercept treatment in patients with β-thalassemiaBackground: β-thalassemia is a genetic blood disorder caused by mutations in the β-globin gene, which encodes one of the proteins that comprise hemoglobin, a key constituent of red blood cells. Patients with β-thalassemia experience anemia, the main treatment for which is blood transfusions. Long-term repeated blood transfusions lower patients’ quality of life, use hospital resources, and the resulting accumulation of excess iron can cause organ failure and decrease life expectancy. The severity of the anemia experienced by patients with β-thalassemia varies; patients with transfusion-dependent β-thalassemia require regular blood transfusions, compared with those with nontransfusion-dependent β-thalassemia who require infrequent transfusions, or even none at all, to manage their symptoms. Luspatercept (Reblozyl®) is an agent that stimulates the production of red blood cells and is used to treat anemia caused by β-thalassemia. However, the long-term effects of luspatercept treatment on patients with β-thalassemia are not known.Objective: In this study, we report the long-term safety of luspatercept in 64 adult patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, and the long-term efficacy of high-dose luspatercept (0.6–1.25 mg/kg) in a subset of 63 patients.Results: The average time period that patients were treated with luspatercept was 910 days for nontransfusion-dependent β-thalassemia and 433 days for transfusion-dependent β-thalassemia. We report that in patients with nontransfusion-dependent β-thalassemia, luspatercept treatment was associated with sustained increases, just over 3 years, in hemoglobin levels. Likewise, in transfusion-dependent β-thalassemia, luspatercept treatment was associated with a sustained reduction, 2.5 years, in the amount of blood transfusion required to manage their anemia. Long-term treatment with luspatercept was not associated with any new side effects compared with previous short-term treatment studies. The most common side effects were headache (27 patients), bone pain (20 patients), and muscle pain (14 patients) with more than 90% of these patients experiencing these side effects as mild severity.Conclusion: The results of this study show that in patients with either transfusion-dependent or nontransfusion-dependent β-thalassemia, luspatercept provides lasting reduction in anemia with mostly mild and predictable side effects.

7002 Background: ESAs, the first line treatments of anemia in non del 5q lower risk MDS, yield only 40-50% responses. LEN gives RBC transfusion independence (TI) in about 25% of ESA resistant (or relapsing) TD lower risk MDS without del 5q (Raza, Blood, 2008), and a gene expression signature can predict response (Ebert, Plos Med 2008). We randomized in this patient population LEN alone and LEN+EPO. Methods: In this prospective multicenter open-label phase II study (NCT01718379), lower risk MDS patients without del 5q, with TD (≥4 RBC units during the previous 8 weeks (w)) with ESA resistance or relapse after a response were randomized between LEN alone, 10mg/d x 21 d/4 w (L arm) or LEN (same schedule) + EPO beta, 60 000 U/w (LE arm). The primary endpoint was erythroid response (HI-E, IWG 2006 criteria) after 4 treatment cycles. Secondary objectives included identification of biomarkers of response. Results: Between July 2010 and June 2012, 132 patients (pts, 66 / arm), median age 73 (range 46-88), M/F: 88/44 were enrolled. Median TD was 6 RBC units/8w (range 2-18). IPSS was Low in 45% and Int-1 in 55% pts. Pretreatment characteristics did not differ between the 2 groups. All but 3 pts, who withdrew consent (2L+1LE), were evaluable for response. In this ITT population, HI-E was obtained in 15 pts (23.4%) in L arm and 26 (40.0%) in LE arm (RR= 1.7, p= 0.043, chi2 test), and TI in 9 (14.1%) versus 16 (24.6%) pts (RR=1.7, p= 0.13). In the 99 pts who completed 4 treatment cycles, 41 achieved HI-E, including 15/49 (30.6%) in L arm versus 26/50 (52.0%) in LE arm (p= 0.03), and TI in 9 (18.4%) versus 16 (32.0%) pts (RR= 1.7, p=0.12). Side effects (cytopenias and 1 DVT/arm) were similar in the 2 arms. A 29-gene expression profile signature predicting HI-E to L or LE, different from that previously published, was identified and a polymorphism in the CRBN gene (Kosmider, submitted) was significantly associated with HI-E in the entire cohort (p=0.034). Conclusions: LEN + EPO yielded a significantly better erythroid response than LEN alone in lower risk MDS patients with anemia resistant to ESA alone. A gene expression signature and a CRBN gene polymorphism correlated with the erythroid response. Clinical trial information: NCT01718379.

The Commands Trial: A Phase 3 Study of the Efficacy and Safety of Luspatercept Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low-, Low-, or Intermediate-Risk MDS in Erythropoiesis Stimulating Agent-Naive Patients Who Require RBC Transfusions

Treatment of Anemia with Darbepoetin Alfa in Patients with Low and Intermediate-1 Risk Myelodysplastic Syndromes. Results from the ARAMYS Study

Interim Results of A Randomized Phase II Trial of Azacitidine (AZA) +/− Epo In Lower Risk Myelodysplastic Syndrome (MDS) Resistant to An Erythropoietic Stimulating Agent (ESA) Alone

Real-World Impact of Luspatercept on Patients with Myelodysplastic Syndromes Requiring Red Blood Cell Transfusions and with Prior Exposure to Erythropoietin-Stimulating Agents: A United States Healthcare Claims Database Study

Direct Medical Care Cost Associated with β-Thalassemia Care in Turkey

Sustained Erythroid Response Associated With Red Cell Transfusion and Progressive Growth Factor Independence Is Feasible With Adjuvant Sertraline In Low-Risk Myelodysplastic Syndrome (LR-MDS)

Clinical and Economic Burden of Transfusion-Dependent β-Thalassemia in Adult Patients in the United States

Dyserythropoiesis Evaluated By Red Score and Hepcidin/Ferritin Levels Predicts Response to Epoetin Zeta in Lower Risk MDS

Durable Clinical Benefit with Ker-050 Treatment: Findings from an Ongoing Phase 2 Study in Participants with Lower-Risk MDS

A Systematic Review and Meta-Analysis of Luspatercept for Anemia Treatment in Low Risk Myelodysplastic Syndrome with Ring Sideroblast Subtype in Phase II and Phase III Clinical Trials

Patients with transfusion-dependent (TD) β-thalassemia require long-term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health-related quality of life (HRQoL). The impact of luspatercept, a first-in-class erythroid maturation agent, versus placebo on HRQoL of patients with TD β-thalassemia was evaluated in the phase 3 BELIEVE trial. HRQoL was assessed at baseline and every 12 weeks using the 36-item Short Form Health Survey (SF-36) and Transfusion-dependent Quality of Life questionnaire (TranQol). Mean change in HRQoL was evaluated from baseline to week 48 for patients receiving luspatercept + best supportive care (BSC) and placebo + BSC and between luspatercept responders and non-responders. Through week 48, for both groups, mean scores on SF-36 and TranQol domains were stable over time and did not have a clinically meaningful change. At week 48, more patients who achieved clinical response (≥50% reduction in RBCT burden over 24 weeks) in the luspatercept + BSC group had improvement in SF-36 Physical Function compared with placebo + BSC (27.1% vs. 11.5%; p = .019). Luspatercept + BSC reduced transfusion burden while maintaining patients' HRQoL. HRQoL domain improvements from baseline through 48 weeks were also enhanced for luspatercept responders.

A Phase 2, Single-Arm, Open-Label Trial To Evaluate the Effectiveness of Darbepoetin alfa for the Treatment of Anemia in Patients with Low-Risk Myelodysplastic Syndrome.