Contributions
Abstract: PB1619
Type: Publication Only
Session title: Myelodysplastic syndromes - Clinical
Background
Patients (pts) with myelodysplastic syndromes (MDS) often suffer from anemia and other consequences of regular red blood cell (RBC) transfusions. Erythropoiesis-stimulating agents (ESAs) are a standard of care for pts with lower-risk MDS (LR-MDS). Epoetin alfa and darbepoetin alfa have shown efficacy among pts with LR-MDS, but the pt population in whom a clinically significant effect is seen may be limited. An important clinical benefit in this LR-MDS pt population would be to increase the frequency of response and the duration of RBC transfusion independence (TI). Luspatercept, a first-in-class erythroid maturation agent with a mechanism of action distinct from ESAs, is now approved in both the EU and the USA for pts with LR-MDS with ring sideroblasts (RS) who require RBC transfusions and are refractory, intolerant, or ineligible to receive ESAs. Luspatercept may also be beneficial in treating anemia in pts with ESA-naive, LR-MDS who require RBC transfusions. In a phase 2 study in anemic pts with LR-MDS, 63% of pts receiving luspatercept (0.75–1.75 mg/kg) achieved a modified hematologic improvement–erythroid (mHI-E) response; when analyzed by RS status, 69% of pts with ≥15% RS and 43% of pts with <15% RS achieved mHI-E response (Platzbecker U, et al. Lancet Oncol 2017;18:1338−1347).
Aims
The COMMANDS is a phase 3, open-label, randomized trial comparing the efficacy and safety of luspatercept vs epoetin alfa in anemic pts with IPSS-R-defined LR-MDS, with or without ≥15% RS, who are ESA naive, and who require regular RBC transfusions.
Methods
To be eligible, pts must be ≥18 years old, have a diagnosis of IPSS-R-defined LR-MDS with <5% blasts in the bone marrow, serum erythropoietin (sEPO) levels <500 U/L, and require RBC transfusions (defined as transfusion requirement of 2–6 RBC units/8 weeks for ≥8 weeks immediately prior to randomization). Exclusion criteria include prior use of ESAs (≤2 doses of prior epoetin alfa permitted if ≥8 weeks from randomization date and sEPO confirmed as ≤ 500 U/L), granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, unless administered for treatment of febrile neutropenia; disease-modifying agents (e.g. lenalidomide), or hypomethylating agents; and presence of del(5q) cytogenetic abnormality. Eligible pts (N≈350) will be stratified and randomized 1:1 to either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg) subcutaneously (s.c.) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg with titration up to 1,050 IU/kg) s.c. once every week, for a minimum of 24 weeks (Figure). Best supportive care, including RBC transfusions, is permitted in combination with study treatment in both arms. Stratification factors include: baseline RBC transfusion burden (<4 vs ≥4 RBC units/8 weeks), baseline sEPO level (≤200 U/L vs >200 U/L), and RS status (with RS+ defined as RS ≥15%, or ≥5% [but <15%] if SF3B1 mutation is present). Additionally, ≥40% and ≤60% of randomized pts will be RS+, and ≥25% will have sEPO >200 U/L.
Results
The primary endpoint is defined as achievement of RBC-TI for 12 weeks during Weeks 1–24 of study, with a concurrent mean hemoglobin (Hb) increase of ≥1.5 g/dL compared to baseline. Key secondary endpoints include duration of RBC-TI, change in Hb levels, achievement of HI-E (per International Working Group [IWG] 2006), and safety.
Conclusion
The COMMANDS trial is registered at EudraCT (number 2017-003190-34) and ClinicalTrials.gov (NCT03682536).
This abstract was presented previously (Della Porta et al. Blood 2020;136(suppl 1):1−2).
Keyword(s): Anemia, Clinical trial, MDS
Abstract: PB1619
Type: Publication Only
Session title: Myelodysplastic syndromes - Clinical
Background
Patients (pts) with myelodysplastic syndromes (MDS) often suffer from anemia and other consequences of regular red blood cell (RBC) transfusions. Erythropoiesis-stimulating agents (ESAs) are a standard of care for pts with lower-risk MDS (LR-MDS). Epoetin alfa and darbepoetin alfa have shown efficacy among pts with LR-MDS, but the pt population in whom a clinically significant effect is seen may be limited. An important clinical benefit in this LR-MDS pt population would be to increase the frequency of response and the duration of RBC transfusion independence (TI). Luspatercept, a first-in-class erythroid maturation agent with a mechanism of action distinct from ESAs, is now approved in both the EU and the USA for pts with LR-MDS with ring sideroblasts (RS) who require RBC transfusions and are refractory, intolerant, or ineligible to receive ESAs. Luspatercept may also be beneficial in treating anemia in pts with ESA-naive, LR-MDS who require RBC transfusions. In a phase 2 study in anemic pts with LR-MDS, 63% of pts receiving luspatercept (0.75–1.75 mg/kg) achieved a modified hematologic improvement–erythroid (mHI-E) response; when analyzed by RS status, 69% of pts with ≥15% RS and 43% of pts with <15% RS achieved mHI-E response (Platzbecker U, et al. Lancet Oncol 2017;18:1338−1347).
Aims
The COMMANDS is a phase 3, open-label, randomized trial comparing the efficacy and safety of luspatercept vs epoetin alfa in anemic pts with IPSS-R-defined LR-MDS, with or without ≥15% RS, who are ESA naive, and who require regular RBC transfusions.
Methods
To be eligible, pts must be ≥18 years old, have a diagnosis of IPSS-R-defined LR-MDS with <5% blasts in the bone marrow, serum erythropoietin (sEPO) levels <500 U/L, and require RBC transfusions (defined as transfusion requirement of 2–6 RBC units/8 weeks for ≥8 weeks immediately prior to randomization). Exclusion criteria include prior use of ESAs (≤2 doses of prior epoetin alfa permitted if ≥8 weeks from randomization date and sEPO confirmed as ≤ 500 U/L), granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, unless administered for treatment of febrile neutropenia; disease-modifying agents (e.g. lenalidomide), or hypomethylating agents; and presence of del(5q) cytogenetic abnormality. Eligible pts (N≈350) will be stratified and randomized 1:1 to either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg) subcutaneously (s.c.) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg with titration up to 1,050 IU/kg) s.c. once every week, for a minimum of 24 weeks (Figure). Best supportive care, including RBC transfusions, is permitted in combination with study treatment in both arms. Stratification factors include: baseline RBC transfusion burden (<4 vs ≥4 RBC units/8 weeks), baseline sEPO level (≤200 U/L vs >200 U/L), and RS status (with RS+ defined as RS ≥15%, or ≥5% [but <15%] if SF3B1 mutation is present). Additionally, ≥40% and ≤60% of randomized pts will be RS+, and ≥25% will have sEPO >200 U/L.
Results
The primary endpoint is defined as achievement of RBC-TI for 12 weeks during Weeks 1–24 of study, with a concurrent mean hemoglobin (Hb) increase of ≥1.5 g/dL compared to baseline. Key secondary endpoints include duration of RBC-TI, change in Hb levels, achievement of HI-E (per International Working Group [IWG] 2006), and safety.
Conclusion
The COMMANDS trial is registered at EudraCT (number 2017-003190-34) and ClinicalTrials.gov (NCT03682536).
This abstract was presented previously (Della Porta et al. Blood 2020;136(suppl 1):1−2).
Keyword(s): Anemia, Clinical trial, MDS