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Criteria and standards in CMML
Table 3. Proposed minimal diagnostic criteria for oligomonocytic chronic myelomonocytic leukemia.*
A. Prerequisite criteria (all must be fulfilled)
- Persistent (3 months) peripheral blood monocytosis 0.5-0.9x109/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 <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 CMML/MDS context include, among other, TET2, SRSF2, ASXL1 and SETBP1. Minimal allele burden proposed to count as a co-criterion: ≥10%. CMML: chronic myelomonocytic leukemia; MPN: myeloproliferative neoplasm(s); MDS: myelodysplastic syndrome(s); FISH: fluorescence in situ hybridization.
Table 3. Patients with oligomonocytic CMML should be managed and followed clinically in the same way as patients with classical CMML.
CMML associated with KIT D816V+ systemic mastocytosis
According to WHO criteria, systemic mastocytosis (SM) can be divided into: (i) indolent SM (ISM), which is assocaiated with a normal life expectancy; (ii) smoldering SM (SSM), in which signs of BM dysplasia, myeloprolif- eration and/or splenomegaly are found but survival and prognosis are still favorable; and (iii) advanced SM, defined by a poor prognosis.33-36 Advanced SM is further divided into aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL).33-36 The most frequent AHN detected in patients with SM-AHN is CMML.6-8,36 In these patients the SM component of the diseases may present as ISM, ASM or, rarely, as MCL. Our faculty concludes that diagnostic WHO criteria for SM and diagnostic criteria for classical CMML (except exclusion of SM) must be fulfilled to diag- nose SM-CMML.
Patients with SM may present with monocytosis resem- bling oligomonocytic CMML. However, the clinical fea- tures of SSM and advanced SM overlap largely with those found in patients with oligomonocytic CMML. Especially in SSM, myeloproliferation, dysplasia and splenomegaly are diagnostic criteria.33-35 Therefore, our faculty is of the opinion that such patients should be classified as having ISM, SSM or ASM with monocytosis rather than SM with oligomonocytic CMML.
In patients with CMML, a concomitant SM is often overlooked, especially when the disease does not present with cutaneous lesions. In other patients, CMML is diag-
nosed long before SM is detected by chance or after KIT D816V is identified: even though it is tempting to call these conditions CMML-SM, our faculty agreed that the classical terminology should be SM-CMML which is also in line with the WHO classification34,35 and that the sub- type of SM and of CMML should be defined in the final diagnosis (e.g., ISM-CMML-1 or ASM-CMML-2) with recognition that in the SM-context, CMML is always regarded as a secondary neoplasm.6,36 Furthermore our fac- ulty is of the opinion that it should be standard practice to examine BM and blood leukocytes for the presence of KIT D816V in all patients with (suspected) CMML. In almost all patients with SM-CMML, neoplastic monocytes dis- play KIT D816V.7 In these monocytes, mutated KIT is not expressed on the cell surface but acts as a cytoplasmic driver. In line with this hypothesis drugs targeting KIT D816V can sometimes induce a major decrease in mono- cyte counts in patients with ASM-CMML.37
Therapy of SM-CMML should be based on a bi-direc- tional strategy: in fact the SM component of the disease should be treated as if no CMML was diagnosed and CMML should be treated as if no SM had been found, with recognition of drug-drug interactions and the possi- bility of drug-induced anaphylaxis.33-35 In many cases (ISM- CMML) the SM component of the disease is only treated symptomatically.33-35
CMML associated with mutated JAK2, rearranged PDGFRA/B or other drivers
Patients with CMML may present with the JAK2 muta- tion V617F, a rearranged PDGFRA or PDGFRB, often in the context of hypereosinophilia, or other drivers related
to distinct hematopoietic neoplasms as defined by the WHO.5,9-11,38-43
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