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Clinical Trial
. 2021 May 1;39(13):1426-1436.
doi: 10.1200/JCO.20.02619. Epub 2021 Mar 25.

Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes

Guillermo Garcia-Manero  1 , Valeria Santini  2 , Antonio Almeida  3 , Uwe Platzbecker  4 , Anna Jonasova  5 , Lewis R Silverman  6 , Jose Falantes  7 , Gianluigi Reda  8 , Francesco Buccisano  9 , Pierre Fenaux  10 , Rena Buckstein  11 , Maria Diez Campelo  12 , Stephen Larsen  13 , David Valcarcel  14 , Paresh Vyas  15 , Valentina Giai  16 , Esther Natalie Olíva  17 , Jake Shortt  18 , Dietger Niederwieser  19 , Moshe Mittelman  20   21 , Luana Fianchi  22 , Ignazia La Torre  23 , Jianhua Zhong  24 , Eric Laille  24 , Daniel Lopes de Menezes  24 , Barry Skikne  24   25 , C L Beach  24 , Aristoteles Giagounidis  26
Affiliations
Clinical Trial

Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes

Guillermo Garcia-Manero et al. J Clin Oncol. .

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01566695.

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Conflict of interest statement

Guillermo Garcia-ManeroHonoraria: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, AbbvieConsulting or Advisory Role: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Jazz Pharmaceuticals, Bristol-Myers Squibb, Helsinn TherapeuticsResearch Funding: Celgene, Astex Pharmaceuticals, Amphivena, Helsinn Therapeutics, Novartis, Abbvie, Bristol-Myers Squibb, Onconova Therapeutics, H3 Biomedicine, Merck Valeria SantiniHonoraria: Celgene/Bristol-Myers Squibb, Novartis, Janssen-CilagConsulting or Advisory Role: Celgene/Bristol-Myers Squibb, Novartis, Menarini, Takeda, Pfizer, Geron, Gilead SciencesResearch Funding: CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Celgene Antonio AlmeidaHonoraria: Novartis, CelgeneConsulting or Advisory Role: Novartis, CelgeneSpeakers' Bureau: Novartis, CelgeneTravel, Accommodations, Expenses: Bristol-Myers Squibb Uwe PlatzbeckerHonoraria: Celgene/JazzConsulting or Advisory Role: Celgene/JazzResearch Funding: Amgen, Janssen, Novartis, BerGenBio, CelgenePatents, Royalties, Other Intellectual Property: part of a patent for a TFR-2 antibody (Rauner et al. Nature Metabolics 2019)Travel, Accommodations, Expenses: Celgene Lewis R. SilvermanResearch Funding: Celgene, MedImmune, Onconova Therapeutics, BayerPatents, Royalties, Other Intellectual Property: Patent for the combination of azacitidine and rigosertib Francesco BuccisanoConsulting or Advisory Role: NovartisSpeakers' Bureau: Novartis Pierre FenauxHonoraria: CelgeneResearch Funding: Celgene Rena BucksteinHonoraria: Celgene, Taiho PharmaceuticalConsulting or Advisory Role: CelgeneResearch Funding: Celgene, Takeda, Otsuka USUncompensated Relationships: Celgene/Jazz Maria Diez CampeloHonoraria: Celgene, NovartisConsulting or Advisory Role: Celgene, Takeda, Novartis, BerGenBioTravel, Accommodations, Expenses: Celgene, Novartis David ValcarcelConsulting or Advisory Role: Celgene, Amgen, GlaxoSmithKline, Novartis, Takeda, Pfizer, Bristol-Myers Squibb, Sanofi, Jazz Pharmaceuticals, SOBISpeakers' Bureau: Celgene, Novartis, Amgen, GlaxoSmithKline, Astellas Pharma, Pfizer, Jazz Pharmaceuticals, Sanofi/Aventis, Bristol-Myers SquibbTravel, Accommodations, Expenses: Celgene, Amgen, Pfizer, GlaxoSmithKline, Jazz Pharmaceuticals Paresh VyasStock and Other Ownership Interests: OxStemHonoraria: Celgene, Pfizer, Jazz Pharmaceuticals, Abbvie, Daiichi SankyoResearch Funding: Celgene, Forty SevenPatents, Royalties, Other Intellectual Property: Patent for flow cytometric detection of leukaemic stem cells Esther Natalie OlívaHonoraria: Celgene, Novartis, Amgen, Alexion PharmaceuticalsConsulting or Advisory Role: Amgen, Celgene, NovartisSpeakers' Bureau: Celgene, NovartisPatents, Royalties, Other Intellectual Property: Royalties for QOL-E instrument Jake ShorttConsulting or Advisory Role: Astellas Pharma, NovartisSpeakers' Bureau: Bristol-Myers SquibbResearch Funding: Astex Pharmaceuticals, Amgen, Celgene/Bristol-Myers Squibb Dietger NiederwieserConsulting or Advisory Role: Cellectis, Amgen, NovartisSpeakers' Bureau: NovartisResearch Funding: Daiichi Sankyo Moshe MittelmanHonoraria: CelgeneConsulting or Advisory Role: Onconova TherapeuticsSpeakers' Bureau: NovartisResearch Funding: Novartis, Takeda, Janssen-Cilag, Roche, Medison, Abbvie, Gilead Sciences Luana FianchiConsulting or Advisory Role: SanofiTravel, Accommodations, Expenses: Celgene Ignazia La TorreEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Jianhua ZhongEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Eric LailleEmployment: Bristol-Myers Squibb, Celgene, Catalent,Stock and Other Ownership Interests: Bristol-Myers Squibb, Moderna Therapeutics, Catalent Daniel Lopes de MenezesEmployment: Celgene, Bristol-Myers SquibbStock and Other Ownership Interests: Celgene, Bristol-Myers Squibb, NovartisPatents, Royalties, Other Intellectual Property: Published and Issues patents at BMS, Novartis Barry SkikneEmployment: Celgene/Bristol-Myers SquibbConsulting or Advisory Role: Celgene/Bristol-Myers SquibbResearch Funding: Daiichi Sankyo/UCB Japan C.L. BeachEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Aristoteles GiagounidisStock and Other Ownership Interests: Novartis, RocheHonoraria: Celgene, Amgen, NovartisConsulting or Advisory Role: CelgeneNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Patient disposition. Data cutoff: January 25, 2019. LR-MDS, lower-risk myelodysplastic syndromes; RBC-TD, RBC–transfusion dependent.
FIG 2.
FIG 2.
Kaplan-Meier estimated durations of (A) RBC transfusion independence and (B) RBC transfusion reductions (≥ 4 units). Data cutoff: January 25, 2019. NR, not reached; RBC-TI, RBC transfusion independence.
FIG 3.
FIG 3.
Mean (±SE) changes from baseline in (A) hemoglobin concentrations and (B) platelet counts. BL, baseline; SE, standard error.
See this image and copyright information in PMC

Comment in

References

    1. Gangat N, Patnaik MM, Tefferi A: Myelodysplastic syndromes: Contemporary review and how we treat. Am J Hematol 91:76-89, 2016 - PubMed
    1. Greenberg P Cox C LeBeau MM, et al. : International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997 - PubMed
    1. Jansen AJ Essink-Bot ML Beckers EA, et al. : Quality of life measurement in patients with transfusion-dependent myelodysplastic syndromes. Br J Haematol 121:270-274, 2003 - PubMed
    1. Malcovati L Germing U Kuendgen A, et al. : Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25:3503-3510, 2007 - PubMed
    1. Al Ameri A Jabbour E Garcia-Manero G, et al. : Significance of thrombocytopenia in myelodysplastic syndromes: Associations and prognostic implications. Clin Lymphoma Myeloma Leuk 11:237-241, 2011 - PMC - PubMed

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