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Criteria and standards in CMML
immunophenotype, can identify CMML with a sensitivi- ty of >90% and a specificity of >95%.127,129,131 Moreover, during successful therapy, the distribution of MO1, MO2, and MO3 monocytes changes back to near normal or nor- mal.128 Therefore, our faculty recommends that the per- centages of MO1 monocytes are quantified in the PB by MFC in all cases with suspected or known CMML at diagnosis and during follow-up.
In many cases with CMML, neoplastic monocytes aberrantly display CD2, CD5, CD10, CD23, and/or CD56.121-124 Of all aberrantly expressed surface markers, CD56 is most commonly detected on CMML monocytes.121-124 CD5 is only (very) weakly expressed on neoplastic monocytes in most cases with CMML. The most frequently underexpressed antigens may be CD14 and CD15. Overall, however, the use of decreased expression of these markers as a diagnostic test in CMML is limited by a relatively low sensitivity. An abnormal monocyte immunophenotype is also seen in other myeloid neoplasms, including MDS. On the other hand, phenotypically aberrant monocytes (as described above) are typically neoplastic cells (unless the patient has been treated with growth factors). Therefore, our faculty rec- ommends that MFC studies in patients with (suspected) CMML employ antibodies directed against aberrantly expressed surface markers, including CD2 and CD56. Additionally, as mentioned before, several surface mark- ers are ‘under-expressed’ on CMML monocytes com- pared to their levels on normal blood monocytes. These antigens include, among others, CD13, CD14, CD15, CD33, CD38, CD45, and CD64.121-124,129,131
Other cell types may also express aberrant markers detectable by MFC in CMML. For example, myeloid pro- genitor cells may express CD56 in CMML and often exhibit the same phenotypic abnormalities as in MDS; this also holds true for neutrophils and erythroid cells (Online Supplementary Table S8). Other cell types that may show aberrant phenotypes are dendritic cells and mast cells. Mast cells are of particular importance as these cells may be indicative of the presence of a concomitant mas- tocytosis (SM-CMML). In these cases, mast cells almost invariably express CD25 in MFC analyses (Online Supplementary Table S8).134 Overall, our faculty is of the opinion that MFC studies should be performed on mono- cyte subsets, myeloid progenitors, neutrophils, erythroid cells and mast cells in (suspected) CMML. An overview of immunophenotypic aberrancies detectable in CMML is given in Online Supplementary Table S8.
Differential diagnoses of CMML: reactive and clonal mimickers
A number of conditions can mimick CMML and must be taken into account when patients with unexplained monocytosis are evaluated. Reactive disorders mimicking CMML include certain chronic bacterial infections (exam- ples: tuberculosis or subacute endomyocarditis), fungal infections, chronic auto-immune processes and non- hematologic neoplasms. There are also hematologic malignancies that may present as a CMML-like disease. For example, Philadelphia chromosome-positive chronic myeloid leukemia usually presents with (absolute) mono- cytosis and can also show signs of dysplasia. Particularly high monocyte counts are recorded in chronic myeloid leukemia cases expressing BCR-ABL1p190. When cryptic variants of BCR-ABL1 are expressed by leukemic cells, it
can be difficult to exclude CMML. Myeloid neoplasms (MDS or MPN) in progression and myelomonocytic or monocytic AML may also resemble CMML. The reactive and clonal mimickers of CMML are listed in Online Supplementary Table S9.
Scoring systems in CMML: recommended standards
Although several prognostic variables have been identi- fied in CMML regarding survival and AML evolution, accurate prediction of the clinical course and survival remains a clinical challenge. A first step in prognostication is grading into CMML-0, CMML-1 and CMML-2. To delineate the prognosis in CMML more accurately, a num- ber of scoring systems have been developed in the past.29,117-121,135-138 Until 2012, the International Prognostic Scoring System (IPSS) served as the gold standard for prognostication in MDS and (dysplastic) CMML.135
However, a number of more specific scoring systemic taking CMML-related features into account have also been proposed.117-120,136-138 During the past few years, researchers have successfully started to integrate cytoge- netic and molecular variables into these scoring models.117- 121 Our faculty concludes that these novel approaches should be followed and developed into clinical applica- tion.
Management strategies and therapeutic options in CMML
Several new treatment strategies for CMML have been
developed during the past 15 years. A detailed description
of therapeutic options is beyond the scope of this article.
The reader is referred to a series of excellent published
review articles.139-146 A disappointing fact is that all drug
therapies are still non-curative. The only curative therapy
in CMML remains allogeneic hematopoietic stem cell
transplantation.147,148 For most young and eligible patients
with acceptable transplant-related risk, allogeneic
hematopoietic stem cell transplantation is therefore rec-
ommended. All other forms of treatment are cytoreduc-
tive, experimental or palliative in nature. Some of these
drugs, such as the hypomethylating agents (5-azacytidine,
decitabine) may induce long-term disease control in a sub-
set of patients with classical CMML.139-145 In general,
cytoreductive and palliative drugs should be used accord-
ing to available recommendations provided by major soci-
eties.145,148 Similarly, treatment response assessment should
be performed in line with available (accepted) guide- lines.146,150
Specific therapy may work in those patients who suffer from a special variant of CMML. For example, in CMML patients with a transforming PDGFRA/B mutation, treat- ment with imatinib or other similar tyrosine kinase inhibitor usually induces major responses or even long- lasting remissions.47-49,151 In patients with SM-CMML, midostaurin may result in disease control, especially when the CMML portion of the disease exhibits KIT D816V. However, in many cases, relapses occur. Treatment options in CMML and its variants are summarized in Online Supplementary Table S10.
Concluding remarks and future perspectives
CMML is a unique and rare hematopoietic neoplasm with a complex biology and pathology. In the past 10
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