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P. Valent et al.
CMML with rearranged PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2
In these patients, persistent substantial monocytosis (≥1.0x109/L) is detected and all other consensus criteria for classical CMML (see previous paragraphs) are also met, except the following specific exclusion criteria: CMML to be excluded in the presence of a well-characterized diag- nosis of myeloid/lymphoid neoplasm with rearranged PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2 (Table 2). Except for neglecting the above-mentioned criteria, our proposal is otherwise fully in agreement with all of the other tenets postulated by the WHO classification.14,15 In relation to neoplasms with rearranged PDGFRA/B, FGFR1 or PCM1-JAK2, the WHO’s definition of ‘myeloid/lym- phoid neoplasms’ is too generic and there is a clinical need to know whether the underlying myeloid neoplasm is an aggressive disease, like AML, or a chronic neoplasm such as CMML or chronic eosinophilic leukemia.20,21 Our facul- ty is of the opinion that (unlike in previous times) the pres- ence of one criterion-confirmed myeloid neoplasm should not a priori exclude the presence of another (second con- comitant) myeloid or lymphoid neoplasm. Hence, when CMML is encountered in the context of another molecu- larly defined myeloid/lymphoid neoplasm (as a final diag- nosis), it should be delineated as a specific subtype of the myeloid/lymphoid neoplasm with eosinophilia along with the specific associated gene rearrangement (PDGFRA/B or FGFR1 or PCM1-JAK2).
CMML with JAK2 V617F
In these patients the situation is different. First, JAK2
V617F itself may be considered as a criterion of myelopro- liferation in MDS/MPN, e.g. in cases with MDS/MPN with ring sideroblasts and thrombocytosis. In the context of CMML, the JAK2 mutation is also typically associated with other signs of myeloproliferation (including BM fibrosis) and with the ´myeloproliferative variant´ of CMML.39,42,43 Therefore, our faculty concludes that JAK2 V617F should also count as a molecular co-criterion of MDS/MPN and thus for CMML. Second, the presence of a JAK2-mutated MPN does not exclude the presence of a concomitant CMML if diagnostic criteria for both neo- plasms are fulfilled. If this is not the case because the size of the MPN-like clone carrying JAK2 V617F is too small and/or other MPN features are clearly missing, the final diagnosis will be CMML with JAK2 V617F. On the other hand, in patients in whom the JAK2 allelic burden is high and clinical and laboratory features argue for an overt MPN rather than CMML (e.g., polycythemia and/or BM fibrosis without dysplasia and without molecular or flow cytometry-based signs of CMML) the final diagnosis will be JAK2 V617F+ MPN with monocytosis.43 In a third group of patients, diagnostic criteria for both a distinct MPN and CMML are fulfilled and the mutation status confirms the presence of an overt JAK2-mutated MPN (usually with high allelic burden). These patients are suffering from both MPN and CMML or from a gray zone disease dis- playing hybrid features between MPN and CMML.44,45 Our faculty concludes that it is therefore important to measure the JAK2 V617F allele burden in all patients with CMML.39,42,43 Other drivers, such as BCR-ABL1, are rarely found in patients with CMML. However, although in clas- sical CMML, the presence of BCR-ABL1 must be exclud- ed, it may be detected in rare patients, suggesting the exis- tence of a special variant of CMML (defined by a co-exist-
ing chronic myeloid leukemia). In some of these cases, the chronic myeloid leukemia clone may be small. In other patients, however, the chronic myeloid leukemia may even mask the CMML at the initial diagnosis.46
The management and therapy of patients with special variants of CMML depend on the subtype of the disease and the molecular driver involved, e.g., FIP1L1/PDGFRA, other gene abnormalities involving PDGFRA or PDGFRB, KIT D816V or JAK2 V617F. Therefore, it is of crucial importance to screen for all these drivers in all patients with CMML. The type of therapy to consider in these patients depends on clinical features, the histopathological diagnosis, the size of the mutated clone(s) and the type of driver. The type of driver is of considerable importance since novel treatments directed against these drivers, are often extremely effective.47-50 For example, imatinib can induce long-lasting molecular and hematologic complete remissions in patients with FIP1L1/PDGFRA-rearranged myeloid neoplasms with features of CMML or MPN.47-49 Even in patients who develop CMML and secondary AML in the context of FIP1L1/PDGFRA, the disease may respond to imatinib.50 It is, therefore, important to diag- nose all patients based on molecular markers and to define the major drivers and therapeutic targets expressed by malignant cells in order to provide optimal management and therapy.
CMML associated with lymphoid neoplasms
In a small group of patients with CMML, a co-existing lymphoproliferative neoplasm is diagnosed, such as a lym- phocytic leukemia, non-Hodgkin lymphoma or multiple myeloma.51-60 In most patients, the lymphoid neoplasm is detected first, and CMML is considered to develop as treat- ment-induced, secondary, leukemia.51,57 In other patients, CMML is diagnosed first and later a lymphoid neoplasm is detected during follow-up.52-56 It is worth noting that in patients with CMML, polyclonal hypergammaglobuline- mia is often recorded: this must be distinguished from the monoclonal gammopathy of concomitant myeloma, mon- oclonal gammopathies of undetermined significance and both low-count and high-count monoclonal B lymphocy- toses which represent pre-malignant conditions.
The management and treatment of lymphoid neo- plasms presenting with concomitant (secondary) CMML is a clinical challenge. In non-transplantable cases, both diseases require separate treatment plans. Because of the high risk of transformation to AML, allogeneic hematopoietic stem cell transplantation should be consid- ered in young, fit patients, especially when it can be expected that the lymphoid neoplasm will also be eradi- cated by this approach.
Treatment-related CMML and other secondary forms of CMML
Our faculty concluded that both the classical form of CMML and the special variants of CMML should be divided into primary (de novo) CMML and secondary CMML. The latter group includes patients who (i) received chemotherapy and/or radiation therapy in the past (therapy-related CMML) or (ii) have a history of a preceding MDS, MPN or another indolent myeloid or mast cell neoplasm prior to their diagnosis of CMML.51,57,58,61-64 Recent data suggest that patients with therapy-related secondary CMML may have shorter over- all survival compared to that of patients with primary (de
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haematologica | 2019; 104(10)