Prognostic Role of Gene Mutations in Chronic Myelomonocytic Leukemia Patients Treated With Hypomethylating Agents

EBioMedicine. 2018 May;31:174-181. doi: 10.1016/j.ebiom.2018.04.018. Epub 2018 Apr 25.

Abstract

Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7 cycles of azacitidine (n = 68) or decitabine (n = 106). Sequencing data before treatment initiation were available for all patients, from Sanger (n = 68) or next generation (n = 106) sequencing. Overall response rate (ORR) was 52%, including complete response (CR) in 28 patients (17%). In multivariate analysis, ASXL1 mutations predicted a lower ORR (Odds Ratio [OR] = 0.85, p = 0.037), whereas TET2mut/ASXL1wt genotype predicted a higher CR rate (OR = 1.18, p = 0.011) independently of clinical parameters. With a median follow-up of 36.7 months, overall survival (OS) was 23.0 months. In multivariate analysis, RUNX1mut (Hazard Ratio [HR] = 2.00, p = .011), CBLmut (HR = 1.90, p = 0.03) genotypes and higher WBC (log10(WBC) HR = 2.30, p = .005) independently predicted worse OS while the TET2mut/ASXL1wt predicted better OS (HR = 0.60, p = 0.05). CMML-specific scores CPSS and GFM had limited predictive power. Our results stress the need for robust biomarkers of HMA activity in CMML and for novel treatment strategies in patients with myeloproliferative features and RUNX1 mutations.

Keywords: Chronic myelomonocytic leukemia; Hypomethylating agents; Prognosis; Somatic mutations.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Aged
  • Azacitidine / administration & dosage*
  • Azacitidine / analogs & derivatives*
  • Core Binding Factor Alpha 2 Subunit* / genetics
  • Core Binding Factor Alpha 2 Subunit* / metabolism
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Decitabine
  • Dioxygenases
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / pathology
  • Male
  • Mutation*
  • Proto-Oncogene Proteins* / genetics
  • Proto-Oncogene Proteins* / metabolism
  • Repressor Proteins* / genetics
  • Repressor Proteins* / metabolism

Substances

  • ASXL1 protein, human
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • RUNX1 protein, human
  • Repressor Proteins
  • Decitabine
  • Dioxygenases
  • TET2 protein, human
  • Azacitidine