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 = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P = .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 = .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 = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 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.

Antonio e Biagio e Cesare Arrigo Hospital Alessandria Italy

Bristol Myers Squibb Princeton New Jersey

Celgene a Bristol Myers Squibb Company Boudry Switzerland

Department of Leukemia University of Texas MD Anderson Cancer Center Houston TX

Fondazione Policlinico Universitario A Gemelli IRCCS Rome Italy

Grande Ospedale Metropolitano Bianchi Melacrino Morelli Reggio Calabria Italy

Hematology Fondazione PTV Policlinico Tor Vergata Rome Italy

Hematology Unit Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico Milan Italy

Hôpital St Louis Assistance Publique Hôpitaux de Paris and Université de Paris Paris France

Hospital da Luz Lisboa Lisbon Portugal

Hospital Universitari Vall d'Hebron Barcelona Spain

Hospital Universitario de Salamanca Salamanca Spain

Hospital Universitario Virgen del Rocio Seville Spain

Icahn School of Medicine at Mount Sinai New York NY

Leipzig University Hospital Leipzig Germany

Marienhospital Düsseldorf Düsseldorf Germany

MDS Unit Hematology AOU Careggi University of Florence Florence Italy

Medical Department Hematology Charles University General University Hospital Prague Czech Republic

Monash University and Monash Health Melbourne Australia

MRC Molecular Haematology Unit and Oxford Biomedical Research Centre University of Oxford and Oxford University Hospitals Oxford United Kingdom

Royal Prince Alfred Hospital Sydney Australia

Sackler School of Medicine Tel Aviv University Tel Aviv Israel

Sunnybrook Health Sciences Centre Toronto Canada

Tel Aviv Sourasky Medical Center Tel Aviv Israel

University of Kansas Medical Center Kansas City KS

University of Leipzig Leipzig Germany

J Clin Oncol. 2021 Sep 20;39(27):3091-3092. doi: 10.1200/JCO.21.01126. PubMed

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NCT01566695