Chronic myelomonocytic leukemia: 2024 update on diagnosis, risk stratification and management

Abstract

Disease overview: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, characterized by prominent monocytosis and an inherent risk for leukemic transformation (~15%-20% over 3-5 years).

Diagnosis: Newly revised diagnostic criteria include sustained (>3 months) peripheral blood (PB) monocytosis (≥0.5 × 10⁹/L; monocytes ≥10% of leukocyte count), consistent bone marrow (BM) morphology, <20% BM or PB blasts (including promonocytes), and cytogenetic or molecular evidence of clonality. Cytogenetic abnormalities occur in ~30% of patients, while >95% harbor somatic mutations: TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), RAS pathway (~30%), and others. The presence of ASXL1 and DNMT3A mutations and absence of TET2 mutations negatively impact overall survival (ASXL1^WT/TET2^MT genotype being favorable).

Risk stratification: Several risk models serve similar purposes in identifying high-risk patients that are considered for allogeneic stem cell transplant (ASCT) earlier than later. Risk factors in the Mayo Molecular Model (MMM) include presence of truncating ASXL1 mutations, absolute monocyte count >10 × 10⁹/L, hemoglobin <10 g/dL, platelet count <100 × 10⁹/L, and the presence of circulating immature myeloid cells; the resulting 4-tiered risk categorization includes high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor), and low (no risk factors); the corresponding median survivals were 16, 31, 59, and 97 months. CMML is also classified as being "myeloproliferative (MP-CMML)" or "myelodysplastic (MD-CMML)," based on the presence or absence of leukocyte count of ≥13 × 10⁹/L.

Treatment: ASCT is the only treatment modality that secures cure or long-term survival and is appropriate for MMM high/intermediate-2 risk disease. Drug therapy is currently not disease-modifying and includes hydroxyurea and hypomethylating agents; a recent phase-3 study (DACOTA) comparing hydroxyurea and decitabine, in high-risk MP-CMML, showed similar overall survival at 23.1 versus 18.4 months, respectively, despite response rates being higher for decitabine (56% vs. 31%).

Unique disease associations: These include systemic inflammatory autoimmune diseases, leukemia cutis and lysozyme-induced nephropathy; the latter requires close monitoring of renal function during leukocytosis and is a potential indication for cytoreductive therapy.

Figure 1:

A schematic approach to the differential diagnosis of sustained peripheral blood monocytosis *: Peripheral blood abnormalities include unexplained anemia, thrombocytopenia, thrombocytosis, leukocytosis, eosinophilia, granulocytic dysplasia (pseudo Pelger Huët cells), circulating immature myeloid cells such as myelocytes, metamyelocytes and promyelocytes, promonocytes and blasts. Monocyte repartitioning flow cytometry specifically designed to detect classical (M01; CD14+/CD16−), intermediate (M02, CD14+/CD16+) and nonclassical monocytes (M03; CD14−/CD16+), with CMML cases demonstrating a M01 fraction of >94%. Peripheral blood NGS (next generation sequencing) can be carried out at times while evaluating cytopenias or cytosis. If myeloid driver mutations commonly seen in CMML are encountered, such as TET2, ASXL1, SRSF2, SETBP1, and oncogenic RAS pathway mutations among others, then further work is recommended. **: FISH – fluorescence in-situ hybridization, PDGFRA and PDGFRB: Platelet-derived growth factor – A and Platelet-derived growth factor – B, FGFR1- Fibroblast growth factor receptor 1, JAK2- Janus associated kinase 2. FISH testing for PDGFRA and PDGFRB rearrangements is highly recommended if the peripheral blood monocytosis is associated with concomitant eosinophilia. The ETV6-PDGFRB fusion oncogene can give rise to clonal monocytosis mimicking CMML but is in fact a unique molecularly defined myeloid neoplasm (not to be diagnosed as CMML). Similarly, PDGFRA fusions are commonly associated with eosinophilia, but rarely can have associated monocytosis. Most PDGFRA fusions occur due to the karyotypically occult CHIC2 deletion (not detectable by metaphase cytogenetics) resulting in the FIP1L1-PDGFRA fusion oncogene. The World Health Organization also mandates FISH testing for FGFR1, JAK2, FLT3 and the ETV6::ABL1 rearrangements, however, these abnormalities usually give rise to eosinophilia and are very uncommonly associated with monocytosis. These gene rearrangements are classified as myeloid and lymphoid neoplasms with tyrosine kinase fusions. *** While estimating peripheral blood blasts in a patient with CMML, the blasts must be summated with promonocytes.

Figure 2:

Monocyte repartitioning flow cytometry demonstrating a normal M01 fraction (CD14+, CD16−) in a healthy control (84.95%) patient in the left scatter plot, while the right scatter plot shows an expanded M01 fraction (94.6%) in a patient with an established diagnosis of chronic myelomonocytic leukemia.

Figure 3:

Peripheral blood and bone marrow morphology, immunohistochemistry and cytochemical analysis in chronic myelomonocytic leukemia (CMML). A. Peripheral blood smear of a patient with CMML demonstrating promonocytes (black arrow) along with dysplastic granulocytes (grey arrow). Wright-Giemsa 200 X magnification. B. Bone marrow aspirate of the same patient with CMML demonstrating minimal/subtle granulocytic dysplasia. Wright-Giemsa 1000 X magnification. C. Bone marrow core biopsy of a patient with CMML demonstrating a relatively hypercellular marrow (patient aged 81 years) with dysplastic megakaryocytes (black arrow). Hematoxylin and Eosin 100 X magnification. D. Bone marrow core biopsy of a patient with CMML demonstrating a plasmacytoid dendritic cell nodule (black circle), with an adjacent image at a higher magnification (both hematoxylin and eosin stain) and the same nodule brightly positive for CD123 by immunohistochemistry (1000 X magnification). E. Peripheral blood smear of a patient with CMML with blast transformation (secondary AML), demonstrating promonocytes (black arrow) and myeloblasts (red arrow). Wright-Giemsa 400 X magnification. F. Cytochemical analysis on a bone marrow aspirate in a patient with CMML using the dual esterase stain (alpha napthyl butyrate esterase and choloroacetate esterase) demonstrating dysplastic monocytes taking up both colors (blue and brick red). Normal granulocytes stain bright blue, while normal monocytes stain brick red. 400 X magnification.

Figure 4:

Spectrum of monocytes and monocytic precursors that can be encountered in chronic myelomonocytic leukemia (CMML). A. Peripheral blood smear of a patient with CMML demonstrating mature monocytes with nuclear segmentation, mature clumped chromatin, and pale cytoplasm. Wright-Giemsa stain 1000 X magnification. B. Peripheral blood smear of a patient with CMML demonstrating promonocytes with less distinct nuclear segmentation, tissue-paper-like nuclear folds, and immature open chromatin. Wright-Giemsa stain 1000 X magnification. C. Bone marrow aspirate of a patient with CMML demonstrating blasts/ monoblasts devoid of nuclear segmentation, with occasional nuclear folds, and very immature open chromatin with occasional nucleoli. Wright-Giemsa stain 1000 X magnification. D. Bone marrow core biopsy of a patient with CMML demonstrating extensive reticulin fibrosis (black arrow). Hematoxylin and eosin stain 100 X magnification. E. Bone marrow core biopsy of a patient with CMML demonstrating extensive reticulin fibrosis (black arrow). Trichrome stain 100 X magnification. F. Peripheral blood smear of a patient with CMML demonstrating dysplastic bilobed neutrophils (black arrow) with Dohle-like bodies (peripheral light blue cytoplasmic inclusion). Wright Giemsa 1000 X magnification G. Peripheral blood smear of a patient with CMML demonstrating dysplastic monolobate neutrophils (black arrow) with Dohle-like bodies (peripheral light blue cytoplasmic inclusion). Wright Giemsa 1000 X magnification H. Peripheral blood smear of a patient with CMML demonstrating dysplastic neutrophils with markedly hypogranular cytoplasm (black arrow) with Dohle-like bodies (peripheral light blue cytoplasmic inclusion). Wright Giemsa 1000 X magnification.

Figure 5:

Schematic representation of patterns of clonal hematopoiesis and clonal evolution in chronic myelomonocytic leukemia (CMML). Abbreviations: HSPC- hematopoietic stem and progenitor cell, CMP- common myeloid progenitor, SCNA- somatic copy number alterations, dCMML- myelodysplastic CMML, pCMML- myeloproliferative CMML, CN-LOH- copy neutral loss of heterozygosity.

Figure 6:

Lysozyme immunohistochemistry of a kidney biopsy specimen demonstrating renal tubular epithelial cells with lysozyme accumulation. Lysozyme IHC 1000 X magnification.

Figure 7:

How we diagnose and treat CMML. CMML risk stratification was conducted using the Mayo Molecular Model. Abbreviations: CMML- chronic myelomonocytic leukemia, HSCT- hematopoietic stem cell transplant, MP- myeloproliferative CMML, MD- myelodysplastic CMML, DNMTi- DNA methyltransferase inhibitors, ESA- erythropoiesis stimulating agent therapy, MMF- mycophenolate mofetil.