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P. Valent et al.
nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distin- guish between ´normal´, pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.
Introduction
Chronic myelomonocytic leukemia (CMML) is a myeloid stem cell disease characterized by an abnormal production and accumulation of monocytic cells, often in association with other signs of myeloproliferation, sub- stantial dysplasia in one or more hematopoietic cell line- ages, and an increased risk of transformation into second- ary acute myeloid leukemia (AML).1-5 As per definition, the Philadelphia chromosome and its related BCR-ABL1 fusion gene are absent in CMML. Other disease-related drivers, such as the JAK2 mutation V617F or the KIT mutation D816V, may be detected and may indicate a spe- cial variant of CMML, such as CMML associated with systemic mastocytosis (SM-CMML).6-8 However, most somatic mutations identified in CMML patients, such as mutations in SRSF2, TET2, or RAS, are not disease-specif- ic, but are also detected in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or AML.8-11
For many years, CMML was listed as a separate variant among the MDS in the classification of the French- American-British (FAB) working group.2,12 However, in 2001, the World Health Organization (WHO) reclassified CMML into a newly created MDS/MPN overlap group, defined by the presence of both MDS-related and MPN- related morphological and clinical features.13 Depending on the leukocyte count, CMML can be divided into a ‘dys- plastic’ variant (leukocyte count ≤13x109/L) and a ‘prolif- erative’ variant (leukocyte count >13x109/L).2 In 2001 and 2008, the WHO also proposed a split into CMML-1 and CMML-2, based on the percentage of blast cells in the blood and bone marrow (BM).13,14 In the most recent updates of the WHO 2016 classification, CMML is again listed amongst the MDS/MPN overlap disorders.15,16 Based on the percentage of blasts, CMML is now divided into CMML-0, CMML-1, and CMML-2.15-19 Moreover, con- trasting the 2008 WHO classification, the diagnosis of CMML now requires both an absolute monocytosis (≥1×109/L) and relative monocytosis (≥10% of leukocytes) in the peripheral blood (PB).15-19 In the 2008 and 2016 update of the WHO classification, CMML can only be diagnosed per definition when rearrangements in PDGFRA, PDGFRB or FGFR1 genes have been excluded, and in the 2016 update, the PCM1-JAK2 fusion gene was added as an excluding criterion.14-16,19 These molecular aber- rations are commonly found in eosinophilia-associated neoplasms such as chronic eosinophilic leukemia.20,21 However, CMML is also listed as an underlying variant in these molecular ‘entities’ in the WHO classification sys- tem.20,21
Over the past two decades, our knowledge about the molecular features and mechanisms in CMML has increased substantially.4-11,22-26 Moreover, new diagnostic criteria, prognostic markers, and therapeutic concepts have been developed.26-29 Nevertheless, a number of ques-
tions remain concerning basic diagnostic standards, prog- nostication, optimal management and therapeutic options. Furthermore, there is a need to define clinically relevant pre-phases of CMML and distinct CMML vari- ants by clinical variables, histomorphological features, flow cytometric phenotypes, molecular markers and cyto- genetic findings. It is also important to separate CMML and pre-CMML conditions from diverse mimickers. To address these unmet needs, an international consensus group discussed open questions and issues around CMML, its variants and pre-CMML entities in a Working Conference held in August 2018. The outcomes of this meeting are summarized in this article and include pro- posed diagnostic criteria and a classification of pre-CMML conditions as well as updated minimal diagnostic criteria for CMML and its variants. In addition, diagnostic stan- dards and diagnostic algorithms are proposed. Details con- cerning the conference format, pre- and post-conference discussion and consensus-finding are described in the Online Supplement.
Definition of CMML and minimal diagnostic criteria
The diagnostic criteria of CMML, as defined by the WHO,15,16 are depicted in Online Supplementary Table S1. Our faculty is of the opinion that these criteria are valid in general for the classical form of CMML, but need adjust- ments for special variants of CMML. Based on consensus discussion, the following concept is proposed.
The classical form of CMML is defined by the following pre-requisite criteria: (i) persistent (at least 3 months) absolute PB monocytosis (≥1×109/L) and relative monocy- tosis (≥10% of PB leukocytes); (ii) exclusion of BCR-ABL1+ leukemia, classical MPN and all other hematologic neo- plasms that may serve as a primary source of monocyto- sis; and (iii) a blast cell count of 0-19% in PB and/or BM smears and exclusion of all (other) histopathological, mor- phological, phenotypic, molecular and cytogenetic signs that qualify as evidence of AML. In addition, morpholog- ical and/or histopathological evidence for diagnostic dys- plasia in one or more of the three major BM cell lineages (≥10% of megakaryocytes and/or erythroid precursor cells and/or neutrophilic cells) must be present. If dysplasia is absent or not diagnostic (<10%), the presence of cytoge- netic or molecular lesions (mutations) typically found in CMML and/or the presence of CMML-related flow cytometry abnormalities may be employed as co-criteria and may lead to the diagnosis of CMML, provided that the pre-requisite criteria listed above are fulfilled. Pre-req- uisite criteria and co-criteria of the classical form of CMML are presented in Table 1.
The exclusion of various reactive states producing monocytosis (and sometimes even dysplasia) was also dis- cussed and regarded as being of great importance. However, these mimickers cannot a priori exclude the presence of a concomitant CMML, but may indeed occur
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haematologica | 2019; 104(10)