Dataset Information

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

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.

SUBMITTER: Duchmann M

PROVIDER: S-EPMC6013781 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Duchmann Matthieu M Yalniz Fevzi F FF Sanna Alessandro A Sallman David D Coombs Catherine C CC Renneville Aline A Kosmider Olivier O Braun Thorsten T Platzbecker Uwe U Willems Lise L Adès Lionel L Fontenay Michaela M Rampal Raajit R Padron Eric E Droin Nathalie N Preudhomme Claude C Santini Valeria V Patnaik Mrinal M MM Fenaux Pierre P Solary Eric E Itzykson Raphael R

EBioMedicine 20180425

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 nex ...[more]

PMID: 29728305

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Project description:Background: The consequences of infectious toxicity of hypomethylating agents (HMAs) on overall survival (OS) of patients diagnosed with high-risk myeloid neoplasms have not been thoroughly investigated. Objectives: We aimed to evaluate whether infectious events (IEs) negatively influenced the results of HMA treatment in a real-world setting. Design: Observational study. Methods: We obtained data from 412 non-selected consecutive patients from 23 Spanish hospitals who were diagnosed with high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia and were treated with HMA. HMAs received after chemotherapy or stem cell transplant were excluded. All IEs were recorded. Outcomes included OS, modifications to the pre-planned treatment, incidence and characteristics of IEs, hospitalization, red blood cell transfusions, and factors associated with infection. Results: The rate of infection was 1.2 per patient/year. Next-cycle delay (p = 0.001) and hospitalizations (p = 0.001) were significantly influenced by IEs. Transfusion requirements during each cycle were significantly higher after infection compared with cycles without infection (coefficient = 1.55 [95% confidence interval (CI) = 1.26–1.84], p < 0.001). The median number of cycles was lower in patients experiencing any infection during the first four cycles (5 [3–8] versu 8 [5–16], p < 0.001). In the multivariable analysis, factors associated with lower OS were having any infection during the first four cycles (hazard ratio (HR) = 1.43 [95% CI = 1.09–1.88], p = 0.01), bone marrow blasts ⩾30% (HR = 2.13 [95% CI = 1.14–3.96], p = 0.01), adverse cytogenetics (HR = 1.70 [95% CI = 1.30–2.24], p < 0.001), and platelet count <50 × 109/l (HR = 1.69 [95% CI = 1.3–2.2], p < 0.001). BM blasts >20% (HR = 1.57 [95% CI = 1.19–2.01], p < 0.001) and adverse cytogenetics (HR = 1.7 [95% CI = 1.35–2.14], p < 0.001) were associated with infection, whereas hemoglobin >9 g/dl (HR = 0.65 [95% CI = 0.51–0.82], p < 0.001) and higher platelet count (HR = 0.997 [95% CI = 0.996–0.998], p = 0.016) protected from it. Conclusion: HMA infectious toxicity worsens OS, hinders the adherence to antineoplastic treatment and results in significant morbidity. Preventive strategies are fundamental in vulnerable patients.

Dataset Information

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

Publications

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

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