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

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.
Highlights • TET2mut/ASXL1wt genotype predicts higher complete response rate and prolonged survival in CMML with hypomethylating agents. • Conversely, RUNX1mut and CBLmut genotypes are associated with poorer outcome, independently of higher leukocyte count. • CPSS and GFM prognostic scores showed modest performance when calculated at initiation of hypomethylating agents. Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML. Response and survival in MDS and AML patients treated with HMAs is difficult to predict. We explore the predictive role of recurrent somatic mutations in a large retrospective cohort of 174 HMA-treated CMMLs. Consistent with MDS studies, we report a higher response rate in TET2mut/ASXL1wt patients. We also identify a CMML-specific molecular pattern (RUNX1mut or CBLmut) associated with shorter survival. Our results can inform treatment decision in CMML, for instance by using HMAs prior to transplant in TET2mut/ASXL1wt patients.