Diagnostics

Chronic myelomonocytic
leukemia (CMML)

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Classification
Diagnostics
Prognosis

Based on the current guidelines and the current state of research, there are different diagnostic recommendations for patients with chronic myelomonocytic leukemia. We have summarized the most important information on classification and diagnostic methods at the MLL. In addition, we provide further links on the prognosis in CMML, so that you can inform yourself in more detail.

CMML: Classification

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder and is characterized by overlapping features of a myeloproliferative disorder and a myelodysplastic neoplasia, respectively. CMML is considered a myelodysplastic/myeloproliferative neoplasm according to the 2022 WHO classification. CMML is classified based on leukocyte count into the subgroups myelodysplastic CMML (MD-CMML) with <13x10⁹/L leukocytes and myeloproliferative CMML (MP-CMML) with ≥13x10⁹/L (WHO 2022).

Table 1: Diagnostic criteria of CMML (WHO 2022)

Prerequisite criteria:

1. Persistent absolute (≥0,5x10⁹/L)and relative (≥ 10%) peripheral blood monocytosis

2. Blasts constitute <20% of the cells in the peripheral blood and bone marrow

3. Not meeting diagnostic criteria of chronic myeloid leukemia or other myeloproliferative neoplasms

4. Not meeting diagnostic criteria of myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangements (e.g. PDGFRA, PDGFRB, FGFR1 or JAK2)

Supporting criteria:

1. Dysplasia involving ≥ 1 myeloid lineages

2. Acquired clonal cytogenetic or molecular abnormality

3. Abnormal partitioning of peripheral blood monocyte subsets

Requirements for diagnosis:

· Pre-requisite criteria must be present in all cases

· Monocytosis ≥ 1 × 10⁹/L: one or more supporting criteria must be met

· Monocytosis < 1 × 10⁹/L: supporting criteria 1 and 2 must be met

Subtyping criteria:

· MD-CMML: WBC count < 13x10⁹/L

· MP-CMML: WBC count ≥ 13x10⁹/L

Subgrouping criteria (based on percentage of blasts and promonocytes):

· CMML-1: <5% in peripheral blood and <10% in bone marrow

· CMML-2: 6-19% in peripheral blood and 10-19% in bone marrow

Diagnostics of CMML

Characteristic of CMML is monocytosis in the peripheral blood with a monocyte count ≥0.5x10⁹/L, typically at 2-5x10⁹/L but can reach values >80x10⁹/L, and ≥10% monocytes. Depending on the total leukocyte count, two variants are distinguished in CMML: the so-called dysplastic form (MD-CMML, total leukocyte count <13x10⁹/L) and the proliferative form (MP-CMML, total leukocyte count ≥13x10⁹/L). Immature monocytes are frequently present in peripheral blood. Smears of peripheral blood in MP-CMML patients cannot always be distinguished morphologically from those of CML. The number of circulating immature myeloid cells (promyelocytes, myelocytes, metamyelocytes) is significantly higher in MP-CMML. Dysplasia signs of granulopoiesis, large platelets and nucleated red blood cells may be present (WHO 2022).

Most CMML patients have a hypercellular bone marrow in which myelomonocytes predominate and the number of erythroid progenitors is relatively low. Dysgranulopoiesis is often more pronounced in the bone marrow than in the peripheral blood and is more common in MD-CMML. Monocytes in the bone marrow are usually increased and a left shift is seen (WHO 2022).

It is recommended to perform cytochemical staining, especially of myeloperoxidase and especially of nonspecific esterase, with which monocytes can be well distinguished from other cells. However, in the case of a weak reaction with nonspecific esterase, the differential blood count and the ratios counted there are ultimately decisive.

Depending on the number of blasts, CMML can be divided into the following groups (WHO 2022):

· CMML-1: <5% blasts in peripheral blood and <10% blasts in bone marrow

· CMML-2: 6-19% blasts in peripheral blood and 10-19% blasts in bone marrow

Immunophenotyping is helpful in differentiating CMML from benign reactive monocytosis. It has been shown that a proportion of ≥94% of so-called classical monocytes (MO1: CD14⁺, CD16^-) in peripheral blood with a specificity and sensitivity of more than 90% each differentiates CMML from reactive monocytosis (Selimoglu-Buet et al. 2015, WHO 2022). The cut-off value of 94% was confirmed in a recent study (Wagner-Ballon et al. 2023). The expansion of classical monocytes is also helpful in differentiating CMML from myelodysplastic neoplasms and other myelodysplastic/myeloproliferative neoplasms (WHO 2022).

The CD34+ myeloid blast population in CMML frequently exhibits aberrations such as increased antigen expression of CD13, CD34, CD117, and CD123 and decreased antigen expression of CD38. In addition, aberrant expressions of CD2, CD5, CD7, CD19, and CD56 have been described, as well as asynchronous expression of mature myelomonocytic markers such as CD15 and CD64 (Shen et al. 2015, WHO 2022).

Chromosomal analysis should be performed in the presence of CMML. Approximately 70% of CMML patients have a normal karyotype when examined by classical chromosome analysis. The incidence of clonal cytogenetic aberrations ranges from 23% to 34% (WHO 2022). In blasts as defined by CMML-2, the aberration rate is higher (Such et al. 2011). In most scoring systems (see Prognosis in CMML), chromosomal aberrations play a crucial role, so chromosomal analysis is required to assess prognosis here. Common aberrations include trisomy 8, monosomy 7 or 7q deletion, loss of the Y chromosome, and trisomy 21 (WHO 2022). However, these alterations are not CMML-specific, but are also observed in other hematologic neoplasms.

FISH can be used as an adjunct to chromosome analysis or to clarify typical changes. FISH can make a contribution to follow-up examinations and the determination of residual disease after therapy. In addition, cytogenetic cryptic alterations (TET2 deletion, NF1 deletion, ETV6 deletion) can be detected by FISH (Valent et al. 2019).

Over 90% of CMML patients have at least one molecular mutation, some of which have prognostic relevance (Patnaik & Tefferi 2022). Table 1 summarizes common mutations for which mutational analysis is recommended at diagnosis (panel according to ELN/EHA guidelines). The same genes are also recommended for molecular profiling according to the WHO 2022 classification. These are epigenetic alterations (e.g. ASXL1 and TET2), splicing mutations (e.g. SRSF2) and alterations affecting cellular signal transduction (e.g. K/NRAS, CBL, JAK2). A constellation of mutations in the ASXL1/SRSF2/TET2 genes is particularly common at diagnosis and is also expressed overall in the mutation frequency of these genes (see Table 2). Table 3 lists the prognostically relevant genes used for risk assessment (prognostic panel).

Table 2: Frequent mutations in CMML (Itzykson et al. 2018, Patnaik & Tefferi 2022)

Frequency	Gene
>40%	ASXL1, TET2, SRSF2
5-15%	EZH2, BCOR, DNMT3A, IDH2, JAK2 V617F, CBL, NRAS, KRAS, PTPN11, SF3B1, U2AF1, RUNX1, SETBP1
<5%	IDH1, NF1, FLT3, NPM1, ZRSR2

Table 3: Prognostically relevant mutations in CMML (Elena et al. 2016)

Gene

ASXL1, NRAS, RUNX1, SETBP1

In addition, to differentiate from rare cases with CML (usually with BCR::ABL1 breakpoint e1a2) or with myeloid/lymphoid neoplasms with eosinophilia that may have CMML-like features, analysis to exclude the following gene rearrangements is recommended:

· BCR::ABL1

· ETV6::PDGFRB

· FIP1L1::PDGFRA

· PCM1::JAK2

· ZNF198::FGFR1

· ETV6::ABL1

Mutations in the genes TET2, SRSF2, ASXL1, or SETBP1 may also be age-associated (clonal hematopoiesis of undetermined potential, CHIP), so interpretation in conjunction with the other diagnostic criteria is required.

CMML: Prognosis

The median survival of patients with CMML is 2-3 years and the risk of AML transformation is 15-30% (WHO 2022). During the course of the disease, expansion of genetic alterations as well as the appearance of further genetic aberrations may occur, so that the investigation of changes in the karyotype as well as somatic mutations is also recommended during the course, as it may bring therapeutic consequences (Onkopedia guideline CMML).

Prognosis can be assessed using the CPSS (CMML-specific prognostic scoring system) (Such et al. 2013) and the CPSS-molecular (Elena et al. 2016), or the Düsseldorf score if cytogenetic and molecular genetic data are not available (Onkopedia guideline CMML). Among others, the cytogenetic risk group (low: normal karyotype, loss of the Y chromosome; intermediate: other anomalies; high: trisomy 8, complex karyotype, anomalies of chromosome 7) or the mutation status of the ASXL1, NRAS, RUNX1 and SETBP1 genes is taken into account.

Here you can access the online calculators for the CPSS-Score and the CPSS-Mol-Score.

Elena C et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood 2016;128(10):1408-1417.

Itzykson R et al. Diagnosis and Treatment of Chronic Myelomonocytic Leukemias in Adults: Recommendations From the European Hematology Association and the European LeukemiaNet. Hemasphere 2018;2(6):e150.

Onkopedia Leitlinie „Chronische Myelomonozytäre Leukämie“ 2023; DGHO 2023.

Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2022 update on diagnosis, risk stratification, and management. Am J Hematol 2022;97(3):352-372.

Selimoglu-Buet D et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood 2015;125(23):3618-3626.

Shen Q et al. Flow cytometry immunophenotypic findings in chronic myelomonocytic leukemia and its utility in monitoring treatment response. Eur J Haematol 2015;95(2):168-176.

Such E et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 2011;96(3):375-383.

Such E et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood 2013;121(15):3005-3015.

Valent P et al. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica 2019;104(10):1935-1949.

Wagner-Ballon O et al. ELN iMDS flow working group validation of the monocyte assay for chronic myelomonocytic leukemia diagnosis by flow cytometry. Cytometry B Clin Cytom 2023;104(1):66-76.

WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: https://tumourclassification.iarc.who.int/chapters/63.

Status: October 2023

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Chronic myelomonocytic leukemia (CMML)

CMML: Classification

Diagnostics of CMML

Cytomorphology

Immunophenotyping

Chromosome analysis

Fluorescence in situ hybridisation (FISH)

Molecular genetics

CMML: Prognosis

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Chronic myelomonocytic
leukemia (CMML)