Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission.

Administration, Oral Aged Aged, 80 and over Antimetabolites, Antineoplastic / administration & dosage Antineoplastic Combined Chemotherapy Protocols / therapeutic use Azacitidine / administration & dosage Double-Blind Method Drug Administration Schedule Female Humans Leukemia, Myeloid, Acute / drug therapy Maintenance Chemotherapy / adverse effects Male Middle Aged Nausea / chemically induced Quality of Life Remission Induction Survival Analysis

Journal

The New England journal of medicine

ISSN: 1533-4406

Titre abrégé: N Engl J Med

Pays: United States

ID NLM: 0255562

Informations de publication

Date de publication:
24 12 2020

Historique:

entrez: 28 12 2020

pubmed: 29 12 2020

medline: 15 1 2021

Statut: ppublish

Résumé

Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor. We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life. A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment. CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).

Sections du résumé

BACKGROUND

Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.

METHODS

We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.

RESULTS

A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment.

CONCLUSIONS

CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).

Identifiants

DOI: 10.1056/NEJMoa2004444 PMID: 33369355

pubmed: 33369355

doi: 10.1056/NEJMoa2004444

doi:

Substances chimiques

Antimetabolites, Antineoplastic 0

cc-486 0

Azacitidine M801H13NRU

Banques de données

ClinicalTrials.gov

['NCT01757535']

Types de publication

Clinical Trial, Phase III Journal Article Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

2526-2537

Investigateurs

Andrew Wei (A)

Paula Marlton (P)

Michael Harvey (M)

Matthew Wright (M)

Devendra Hiwase (D)

Peter Presgrave (P)

James Gray (J)

Daniela Zantomio (D)

William Stevenson (W)

Peter Tan (P)

Ashanka Beligaswatte (A)

Michael Pfeilstöcker (M)

Klaus Geissler (K)

Peter Valent (P)

Heinz Sill (H)

Dominik Selleslag (D)

Philippe Mineur (P)

Radu Mihnea Firescu (R)

Jordana Ramires Aragão (J)

Eduardo Munhoz (E)

Celso Arrais Rodrigues da Silva (C)

Nelson Hamerschlak (N)

Laura Fogliatto (L)

Lalit Saini (L)

Andre Schuh (A)

Sean Dolan (S)

John Storring (J)

Ines Chamakhi (I)

Jaroslav Cermak (J)

Jiri Mayer (J)

Kimmo Porkka (K)

Hervé Dombret (H)

Thorsten Braun (T)

Stéphane De Botton (S)

Sophie Rigaudeau (S)

Bérengère Gruson (B)

Xavier Thomas (X)

Emilie Lemasle (E)

Hartmut Döhner (H)

Felicitas Thol (F)

Dominik Wolf (D)

Uwe Martens (U)

Daniela Heidenreich (D)

Stefan Krause (S)

Heinz-A Horst (HA)

Hans-Günter Derigs (HG)

Jörg Westermann (J)

Cristoph Röllig (C)

Katharina Götze (K)

Volker Runde (V)

Peter Staib (P)

Helen Enright (H)

Yishai Ofran (Y)

Dina Ben-Yehuda (D)

Itai Levi (I)

Valentina Giai (V)

Lorenza Borin (L)

Germana Beltrami (G)

Chiara Frairia (C)

Maria Teresa Voso (MT)

Valeria Santini (V)

Luana Fianchi (L)

Anna Candoni (A)

Francesco Passamonti (F)

Fabrizio Pane (F)

Maurizio Musso (M)

Francesco Fabbiano (F)

Cristina Papayannidis (C)

Giorgina Specchia (G)

Agostino Cortelezzi (A)

Esther Oliva (E)

Roberto Foà (R)

Benedetto Bruno (B)

Nicola Di Renzo (N)

Daniela Cilloni (D)

Pierangelo Spedini (P)

Agostino Tafuri (A)

Giuseppe Visani (G)

Jun-Ho Jang (JH)

Sang Kyun Sohn (SK)

Kim Hee-Je (K)

Ho-Jin Shin (HJ)

Ligita Malciute (L)

Roberto Ovilla Martinez (R)

Eduardo Emir Cervera-Cebal (EE)

Justyna Rybka (J)

Tadeusz Robak (T)

Andrzej Hellmann (A)

Jaroslaw Czyz (J)

Aida Botelho (A)

Antonio Almeida (A)

Ana Crisostomo (A)

Isabel Oliveira (I)

Boris Afanasiev (B)

Andrey Zaritsky (A)

Olga Samoilova (O)

Pau Montesinos (P)

Jose Falantes (J)

Teresa Bernal Del Castillo (T)

Angela Figuera Alvarez (A)

Albert Oriol Rocafiguera (A)

Josefina Serrano (J)

Celina Benavente (C)

Patricia Font Lopez (P)

Ming-Chung Wang (MC)

Tsai-Yun Chen (TY)

Su-Peng Yeh (SP)

Wen-Chien Chou (WC)

Mehmet Turgut (M)

A I Emre Tekgunduz (AI)

Hakan Goker (H)

Ayse Tuglular (A)

Christopher Pocock (C)

Timothy Chevassut (T)

Paul Greaves (P)

Ghulam Mufti (G)

Panos Kottaridis (P)

Michael Dennis (M)

Eduardo Olavarria (E)

Evangelia Dimitriadou (E)

Hamid Sayar (H)

Jane Liesveld (J)

Hana Safah (H)

William Tse (W)

Christopher Seet (C)

Lewis Silverman (L)

Delong Liu (D)

Brenda Cooper (B)

Jose Cruz (J)

Michael Robert Savona (MR)

Thomas Boyd (T)

Russell Baur (R)

Aref Al-Kali (A)

Maxim Norkin (M)

Deepa Jeyakumar (D)

Gail Roboz (G)

Farhad Ravandi-Kashani (F)

Tara Lin (T)

Peter Byeff (P)

Ian Flinn (I)

Eric Cheung (E)

Suman Kambhampati (S)

David Gordon (D)

Prapti Patel (P)

James McCloskey (J)

Danielle Shafer (D)

Daniel Landau (D)

Don Stevens (D)

Commentaires et corrections

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