TY - JOUR
T1 - Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes
AU - Garcia-Manero, Guillermo
AU - Santini, Valeria
AU - Almeida, Antonio
AU - Platzbecker, Uwe
AU - Jonasova, Anna
AU - Silverman, Lewis R.
AU - Falantes, Jose
AU - Reda, Gianluigi
AU - Buccisano, Francesco
AU - Fenaux, Pierre
AU - Buckstein, Rena
AU - Campelo, Maria Diez
AU - Larsen, Stephen
AU - Valcarcel, David
AU - Vyas, Paresh
AU - Giai, Valentina
AU - Oliva, Esther Natalie
AU - Shortt, Jake
AU - Niederwieser, Dietger
AU - Mittelman, Moshe
AU - Fianchi, Luana
AU - Torre, Ignazia La
AU - Zhong, Jianhua
AU - Laille, Eric
AU - De Menezes, Daniel Lopes
AU - Skikne, Barry
AU - Beach, C. L.
AU - Giagounidis, Aristoteles
PY - 2021
Y1 - 2021
N2 - PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n 5 107) or placebo (n 5 109). The median age was 74 years, median platelet count was 25 3 109/L, and absolute neutrophil count was 1.3 3 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P5.0002), with median durations of 11.1 and 5.0 months. Reductions of $ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had $ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC- 486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P 5 .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC- 486, n 5 16; placebo, n 5 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 3 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.
AB - PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n 5 107) or placebo (n 5 109). The median age was 74 years, median platelet count was 25 3 109/L, and absolute neutrophil count was 1.3 3 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P5.0002), with median durations of 11.1 and 5.0 months. Reductions of $ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had $ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC- 486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P 5 .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC- 486, n 5 16; placebo, n 5 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 3 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.
KW - Myelodysplastic Syndromes
KW - Myelodysplastic Syndromes
UR - http://hdl.handle.net/10807/302165
U2 - 10.1200/JCO.20.02619
DO - 10.1200/JCO.20.02619
M3 - Article
SN - 1527-7755
VL - 39
SP - 1426
EP - 1436
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
ER -