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Introduction: Chronic myelomonocytic leukemia (CMML) is a hematological malignancy that is extremely variable regarding its clinical course. It may present either as a chronic disorder with mild symptoms and low disease burden for several years, thereby justifying a watch-and-wait-strategy, or may soon progress to acute myeloid leukemia (AML) leaving allogeneic stem cell transplantation as the only curative treatment option., Areas Covered: Attempts have been made to integrate clinical, cytogenetic, and molecular parameters into scoring systems aiming at providing reliable prognostic information. In this article, we discuss several prognostic parameters and validate prognostic scores in a cohort of 645 patients with CMML., Expert Opinion: We show that the CPSS (CMML prognostic scoring system) is a useful prognostic tool. The integration of molecular data into the new CPSS-mol will further improve prognostic accuracy, primarily by identifying an increased proportion of higher-risk patients.

MDS patients may present with monocytic marrow proliferation not fulfilling criteria for CMML. We analyzed MDS patients with or without a marrow monocytic proliferation by following up the amount of monocytic proliferation and characterizing their molecular profile. 315 MDS patients of Duesseldorf MDS registry were divided into two groups: A) 183 patients with monocytic esterase positive cells in marrow and monocytes between 101 and 900/μl in blood and B) 132 patients without monocytic esterase positive cells in marrow and monocytes in blood ≤100/μl. Twenty patients of each group were screened with regard to ASXL1, TET2, RUNX1, SETBP1, NRAS, and SRSF2 using Illumina myeloid panel. Group A patients were older, had significantly higher WBC, hemoglobin levels, neutrophils and platelets. CMML evolution rates were 4.9% and 1.5%, respectively (p=n.s.). TET2, NRAS and SRFS2 mutation frequencies were higher in group A and four patients had coexisting TET2 and SRFS2 mutation, which was shown to be characteristic but not specific for CMML. MDS patients with marrow monocytic proliferation have a more CMML-like pheno- and genotype and develop CMML more often. Those patients could potentially be very early stages of CMML or represent a CMML-like myeloid neoplasma with marrow adherence of the monocytic cell population., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials., (© 2016 by The American Society of Hematology.)