Myelodysplastic syndromes, primarily affecting older adults, are a heterogeneous group of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis that manifest clinically as anemia, neutropenia, and/or thrombocytopenia of variable severity; these often result in RBC- transfusion dependent (TD) anemia, increased risk of infection, and/or hemorrhage, as well as a potential to progress to acute myeloid leukemia (AML).
Lenalidomide is approved for red blood cell transfusion-dependent (RBC TD) anemia due to low-risk myelodysplastic syndromes (MDS) with a chromosome 5q deletion (del5q) with or without additional cytogenetic abnormalities. About one third of patients are refractory/resistant/intolerant and will require further treatment options.
Luspatercept (ACE-536), an erythroid maturation agent, is a recombinant fusion protein consisting of a modified form of the extracellular domain (ECD) of the human activin receptor type IIB (ActRIIB) linked to the Fc portion of human immunoglobulin G1 (IgG1-Fc). Luspatercept acts on endogenous inhibitors of late-stage erythropoiesis (eg, growth differentiation factor 11, GDF11) to increase release of mature erythrocytes into circulation. Nonclinical data have demonstrated that luspatercept binds to negative regulators governing late-stage erythroid development to inhibit their action, thereby promoting the maturation of erythrocytes in the bone marrow.
Luspatercept is indicated for the treatment of adult patients with transfusion-dependent anaemia associated with beta-thalassaemia and due to very low, low and intermediate-risk MDS with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based-therapy. It is not indicated for other MDS subtypes. Unfortunately, patients with MDS with del5q refractory/resistant/intolerant to lenalidomide are excluded from clinical trials that evaluate novel treatments for the anemia of RBC TD lower risk MDS. Therefore, treatment of anemia in such patients is an unmet need.
QOL-ONE Phoenix is a Phase 2, multicenter, single arm, prospective study. The primary objective of the study is to evaluate the effect of luspatercept on RBC TI in subjects with MDS with del5q with IPSS-R very low, low, or intermediate risk and \< 5% bone marrow blasts, resistant/refractory/intolerant to lenalidomide and who require RBC transfusions.
The study is divided into a Screening Period, a 2-year Treatment Period and a 3-year Follow-up Period.
Primary objective is to evaluate the effect of luspatercept on RBC TI (lack of transfusions for 8 consecutive weeks within the first 24 weeks) in subjects with MDS with del5q with IPSS-R very low, low, or intermediate risk and \< 5% bone marrow blasts, resistant/refractory/intolerant to lenalidomide and RBC TD.
Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
Documented diagnosis of MDS with del5q according to 2018 WHO classification
< 5% blasts in bone marrow
Peripheral blood WBC count <13,000/μL
P53 mutation at screening
Prior therapy with disease modifying agents for underlying MDS disease (hypomethylating agents)
subjects who previously received HMA may be enrolled at the investigator's discretion contingent that the subject received no more than 1 dose of HMA). The last dose must be ≥ 5 weeks from the date of screening.
Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)
Single group
Luspatercept Injection [Reblozyl]
DrugEligible subjects will receive luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg (with a maximum total dose of 168 mg). All subjects who have received at least one dose of luspatercept should undergo follow-up evaluations after day 169 with Assessment visits every 24 weeks (168 days) up to 2 years to evaluate evidence of clinical benefit.
RBC Transfusion Independence
Proportion of subjects who are RBC TI for 8 weeks over the first 24 weeks from trial entry
Safety and tolerability of Luspatercept measured as frequency and severity of adverse events occurred and assessed by CTCAE v. 5.0
Type, frequency, severity of AEs. The adverse events occurring in the subjects enrolled in the study will be evaluated according to CTCAE v5.0 Furthermore, the relationship between adverse events and treatment with luspatercept will be evaluated
RBC-TI in long term
Proportion of subjects who are RBC TI for 8 weeks over the first 48 weeks from trial entry and over the 30 months
Duration of RBC-TI
Maximum duration of RBC transfusion independence for subjects who achieve RBC TI ≥ 8 weeks
Reduction in RBC transfusions
Mean change in total pRBC units transfused over a rolling 8-week period and proportion achievieng HI-E (reduction in ≥ 4 units in the preceding 8 weeks in those with baseline transfusion burden of ≥8 units in 8 preceding weeks)
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