Contemporary Risk Stratification and Treatment of Chronic Myelomonocytic Leukemia

Abstract

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by absolute monocytosis, one or more lineage dysplasia, and proliferative features including myeloid hyperplasia, splenomegaly, and constitutional symptoms. Because of vast clinical heterogeneity in presentation and course, risk stratification is used for a risk-adapted treatment strategy. Numerous prognostic scoring systems exist, some of which incorporate mutational information. Treatment ranges from observation to allogeneic hematopoietic stem cell transplantation. Therapies include hydroxyurea for cytoreduction, hypomethylating agents, and the JAK1/2 inhibitor ruxolitinib to address splenomegaly and constitutional symptoms. Recently, oral decitabine with cedazuridine was approved and represents a convenient treatment option for CMML patients. Although novel therapeutics are in development for CMML, further work is needed to elucidate possible targets unique to the CMML clone. In this review, we will detail the pathophysiology, risk stratification, available treatment modalities, and novel therapies for CMML, and propose a modern treatment algorithm. IMPLICATIONS FOR PRACTICE: Chronic myelomonocytic leukemia (CMML) is a clinically heterogenous disease, which poses significant management challenges. The diagnosis of CMML requires bone marrow biopsy and aspirate with thorough evaluation. Risk stratification and symptom assessment are essential to designing an effective treatment plan, which may include hypomethylating agents (HMAs) in intermediate or high-risk patients. The recently approved oral decitabine/cedazuridine provides a convenient alternative to parenteral HMAs. Ruxolitinib may be effective in ameliorating proliferative symptoms and splenomegaly. Allogeneic stem cell transplantation remains the only treatment with curative potential; however, novel therapies are in clinical development which may significantly alter the therapeutic landscape of CMML.

Keywords: Chronic myelomonocytic leukemia; MDS/MPN; Monocytosis; Overlap.

Figure 1

Pathologic findings in chronic myelomonocytic leukemia. (A): The biopsy shows hypercellular marrow with myeloid hyperplasia and mononuclear cells consistent with monocytes. The inset shows increased numbers of monocytes highlighted by CD163 immunohistochemical . (B): Aspirate smear shows myeloid hyperolasia and increased number of monocytes with spectrum of mostly mature monocytes. The smear also shows dysplastic granulocytes characteristic by hypogranulation and abnormal nuclear lobulation. (C): A dysplastic megakaryocytes with widely spaced nuclei. (D): A promonocyte with dysplastic erythroid precursors and dysplastic myeloid cells.

Figure 2

Commonly mutated genes in chronic myelomonocytic leukemia (CMML) categorized by oncogenic mechanisms with potential targets. Multiple pathways contribute to the pathogenesis of CMML that can be therapeutically exploited. These include apoptosis, epigenetic targets including the spliceosome, and the JAK‐STAT pathway.

Figure 3

Comparison of chronic myelomonocytic leukemia (CMML) prognostic stratification scoring system. Five CMML prognostic stratification scoring systems are compared and contrasted via the individual risk factors recognized by each. Abbreviations: AMC, absolute monocyte count; ASXL1, additional sex combs like‐1; BM, bone marrow; CPSS, CMML‐specific prognostic scoring system; FAB, French‐American‐British; GFM, Groupe Français des Myélodysplasies; Hgb, hemoglobin; NRAS, neuroblastoma RAS; Plt, platelet; RBC, red blood cell; RUNX1, Runt‐related transcription factor 1; SETBP1, SET binding protein 1; WBC, white blood cell; WHO, World Health Organization.

Figure 4

Proposed treatment algorithm for patients with chronic myelomonocytic leukemia. Although this does not capture every clinical scenario, it should be used as a guide for clinicians. Importantly, clinical trial enrollment is encouraged, if available, in all patients. Abbreviations: AlloSCT, allogeneic stem cell transplantation; ESA, erythropoietic stimulating agent; HMA, hypomethylating agent; WBC, white blood cell.