Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial.

Abstract

Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1γ, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. This trial is registered at EudraCT (eudract.ema.europa.eu) as #2008-000470-21 and www.clinicaltrials.gov as #NCT01098084.

• Authors: Thorsten Braun, Raphael Itzykson, Aline Renneville, Benoit de Renzis, François Dreyfus, Kamel Laribi, Krimo Bouabdallah, Norbert Vey, Andrea Toma, Christian Recher, Bruno Royer, Bertrand Joly, Anne Vekhoff, Ingrid Lafon, Laurence Sanhes, Guillaume Meurice, Cédric Oréar, Claude Preudhomme, Claude Gardin, Lionel Ades, Michaela Fontenay, Pierre Fenaux, Nathalie Droin, Eric Solary, Groupe Francophone des Myélodysplasies
• Journal: Blood (Blood) Vol. 118 Issue 14 Pg. 3824-31 (Oct 06 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21828134 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Decitabine
• Azacitidine

Topics

• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (therapeutic use)
• Azacitidine (analogs & derivatives, therapeutic use)
• Decitabine
• Female
• Gene Expression Regulation, Leukemic
• Humans
• Leukemia, Myelomonocytic, Chronic (diagnosis, drug therapy, genetics)
• Male
• Middle Aged
• Mutation
• Prognosis
• Survival Analysis