Lack of Gdf11 does not improve anemia or prevent the activity of RAP-536 in a mouse model of β-thalassemia

Guerra, Amaliris; Oikonomidou, Paraskevi Rea; Sinha, Sayantani; Zhang, Jianbing; Presti, Vania Lo; Hamilton, Callum R.; Breda, Laura; Casu, Carla; La, Ping; Martins, Ana C.; Sendamarai, Anoop K.; Fleming, Mark D.; Rivella, Stefano

doi:10.1182/blood.2019001057

Cited by 57 publications

(59 citation statements)

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“…This finding was consistent with the results of the phase 2 study, which included patients without ring sideroblasts and in which 38% of the patients in the luspatercept group had a response. 30 Although the precise mechanism of action of luspatercept on SMAD2 and SMAD3 signaling remains incompletely understood, 34,35 the rapid onset of treatment effect, extended duration of transfusion * Adverse events during the trial were not adjusted for treatment exposure. † At least one serious adverse event occurred: nausea (in one patient receiving luspatercept), back pain (in three receiving luspatercept), dyspnea (in one receiving luspatercept), bronchitis (in one receiving luspatercept), and urinary tract infection (in one receiving placebo).…”

Section: Discussionmentioning

confidence: 99%

Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes

et al. 2020

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BACKGROUND Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspaterceptassociated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesisstimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.)

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Section: Discussionmentioning

confidence: 99%

Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes

et al. 2020

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“…Luspatercept is a chimera between the extracellular domain of activin receptor and human IgG1 Fc portion serving as a TGFβ ligand trap ( Figure 1 ). Though initially thought to exert its activity via inactivating GDF11, recent genetic studies called into question this mechanism of action ( Guerra et al., 2019 ). A number of other TGFβ ligands, including BMPs, activins, and GDF8 may play role ( Verma et al., 2020 ).…”

Section: Current Therapiesmentioning

confidence: 99%

Targeting the Microenvironment in MDS: The Final Frontier

et al. 2020

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Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders of hematopoietic stem and progenitor cells (HSPC), mainly characterized by ineffective hematopoiesis leading to peripheral cytopenias and progressive bone marrow failure. While clonal dominance is nearly universal at diagnosis, most genetic mutations identified in patients with MDS do not provide a conspicuous advantage to the malignant cells. In this context, malignant cells alter their adjacent bone marrow microenvironment (BME) and rely on cell extrinsic factors to maintain clonal dominance. The profoundly disturbed BME favors the myelodysplastic cells and, most importantly is detrimental to normal hematopoietic cells. Thus, the MDS microenvironment not only contributes to the observed cytopenias seen in these patients but could also negatively impact the engraftment of normal, allogeneic HSPCs in patients with MDS undergoing bone marrow transplant. Therefore, successful therapies in MDS should not only target the malignant cells but also reprogram their bone marrow microenvironment. Here, we will provide a synopsis of how drugs currently used or on the verge of being approved for the treatment of MDS may achieve this goal.

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“…This erythroid maturation agent increased hemoglobin levels in mouse models 13,14 by a mechanism that is not yet fully understood. 13,15,16 Luspatercept increased hemoglobin levels in a phase 1 study involving healthy postmenopausal women. 15 In a subsequent open-label, dose-ranging, phase 2 study, the transfusion burden (the total number of red-cell units transfused) during any 12-week interval was reduced by at least 20% from baseline in 26 of 32 patients with transfusion-dependent β-thalassemia (81%) who received luspatercept at a dose of 0.60 to 1.25 mg per kilogram of body weight.…”

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confidence: 98%

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia

Cappellini¹,

Viprakasit²,

Taher³

et al. 2020

N Engl J Med

201

255

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BACKGROUND Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was −348 μg per liter (95% confidence interval, −517 to −179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.)

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Lack of Gdf11 does not improve anemia or prevent the activity of RAP-536 in a mouse model of β-thalassemia

Abstract: There is a Blood Commentary on this article in this issue.

Cited by 57 publications

References 25 publications

Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes

Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes

Targeting the Microenvironment in MDS: The Final Frontier

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia

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