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Criteria and standards in CMML
Table 1. Minimal diagnostic criteria for classical chronic myelomonocytic leukemia.*
A. Prerequisite criteria (all must be fulfilled)
- Persistent (3 months) peripheral blood monocytosis ≥1x109/L and relative monocytosis of ≥10% of circulating peripheral blood leukoyctes - Exclusion of BCR-ABL1+ leukemia, classical MPN and all other bone marrow neoplasms that could serve as a primary source of chronic
persistent monocytosis
- Blast cell count of <20% in peripheral blood and bone marrow smears and exclusion of all other histopathological, morphological, molecular and
cytogenetic features that count as evidence of the presence of acute myeloid leukemia**
B. Morphological criterion = Dysplasia
- Dysplasia in at least 10% of all cells in one of the following lineages in the bone marrow smear: erythroid; neutrophilic; megakaryocytic
C. Co-criteria (for patients fulfilling A but not B, and otherwise showing typical clinical features of CMML such as splenomegaly)
- Typical chromosome abnormalities by conventional karyotyping or FISH***
- Abnormal findings in histological and/or immunohistochemical studies of bone marrow biopsy sections supporting the diagnosis of CMML****
- Abnormal immunophenotype of bone marrow and blood cells by flow cytometry, with multiple CMML-associated phenotypic aberrancies indicating the presence of an abnormal/dysplastic population of monocytic and other myeloid cells*****
- Evidence of a clonal population of myeloid cells determined by molecular (sequencing) studies revealing CMML-related mutations******
*The diagnosis of classical CMML can be established when all prerequisite criteria (A) and either morphological dysplasia (B) or one or more of the co-criteria (C) are fulfilled. **Examples:Auer rods,overt acute myeloid leukemia (AML) by histology and immunohistochemistry;presence of AML-specific diagnostic cytogenetic and/or molecular mark- ers (e.g., inv16). ***Typical cytogenetic abnormalities found in CMML (Online Supplementary Table S6). ****Leukemic infiltration of CD14+ monocytes and exclusion of AML. *****Utilizing a cutoff value of >94% MO1 monocytes,phenotyping can identify CMML cases with a sensitivity of >90% and a specificity of >95%,and a decrease in MO3 mono- cytes is even as diagnostic as an increase in circulating MO1 cells.127,129,131 ******Genes that are often mutated in the context of CMML/MDS include,among others,TET2,SRSF2, ASXL1 and SETBP1.The minimal allele burden proposed to count as co-criterion: ≥10%. CMML: chronic myelomonocytic leukemia; MPN: myeloproliferative neoplasm(s); MDS: myelodysplastic syndrome(s); FISH: fluorescence in situ hybridization.
in CMML patients in the context of certain infections. Furthermore, most of these mimickers do not produce persistent monocytosis. Proof of clonality by molecular and cytogenetic studies, and other disease-specific param- eters, together with global and specific laboratory (e.g., microbial screen) tests should easily lead to the conclusion that the patient is suffering from reactive monocytosis but not from (or also from) CMML.
The a priori exclusion of AML as a criterion should apply to both the classical and the special variants of CMML, whereas the a priori exclusion of other indolent hematopoietic neoplasms should only apply to the classi- cal variant of CMML and oligomonocytic CMML but not to other special CMML variants. This is because several previous and more recent studies have shown that CMML may be accompanied by (or may accompany) other myeloid or lymphoid neoplasms, such as systemic masto- cytosis. In several of these patients, the CMML clone is dominant and the additional sub-clone is smaller in size and usually not relevant clinically, even if these smaller clones express certain driver mutations, such as KIT D816V or a rearranged PDGFRA or PDGFRB. Rarely, a Philadelphia chromosome-positive chronic myeloid leukemia may develop as an additional small-sized (sub)clone in a patient with CMML. Our faculty is of the opinion that the presence of additional (chronic) myeloid, mast cell, or lymphoid neoplasms does not exclude a diag- nosis of CMML, provided that diagnostic WHO criteria for CMML are fulfilled. Moreover, these concomitant neo- plasms should not exclude a diagnosis of CMML even when the driver of the concomitant disease (e.g., KIT D816V) is detectable in CMML monocytes. Thus, where- as the occurrence of AML is always regarded as transfor- mation of CMML, the occurrence of indolent myeloid, mast cell, or lymphoid neoplasms should be regarded as concomitant disorders. Co-existing myeloid neoplasms
and CMML may be derived from the same original founder clone.
There are also patients in whom a certain driver of another BM neoplasm is present, such as a mutated JAK2, PDGFRA/B, or FGFR1, but only the diagnostic criteria for CMML (not those of the other BM neoplasm) are fulfilled. Our faculty concludes that these cases should also be regarded and diagnosed as special variants of CMML. This strategy is in line with the current WHO classification. In fact, whereas the primary molecular diagnosis is often based on a mutated form of JAK2, PDGFRA/B or other classical driver, the underlying or additional diagnosis may well be CMML.20,21
Grading of CMML
The grading system of CMML proposed by the WHO is regarded as standard in clinical hematology. Our faculty recommends the use of this grading system as the initial prognostic tool in classical CMML. In fact, classical CMML should be split into CMML-0, CMML-1 and CMML-2 based on the blast cell count (Online Supplementary Table S2).15-19 In addition, CMML can be divided into a dysplastic variant and a proliferative variant based on leukocyte counts (threshold: 13x109/L) (Online Supplementary Table S2). The resulting grading system defines six distinct CMML variants with variable clinical outcome.17 However, grading may sometimes be challeng- ing. For example, blast cell counts obtained from BM smears may differ from those obtained in the PB so that the grade is questionable. Our faculty recommends that in patients in whom results from BM and PB smears would not fit into one distinct grade of CMML (e.g., BM blasts 4% and PB blasts 6%) grading should be based on the higher blast cell percentage (Online Supplementary Table S2). It is worth noting that initial prognostication by grad- ing does not include all essential prognostic parameters.
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