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Criteria and standards in CMML
(usually mild to moderate) has been reported in CMML
cases, with several recent studies attempting to determine
the prognostic value of this finding.42,90,91 Indeed, although
the data are not yet conclusive, the presence of marrow
fibrosis in CMML seems to be of prognostic impor- tance.42,90,91
The application of immunhistochemical markers is rec- ommended in all patients with (suspected) CMML. The minimal immunohistochemistry panel includes CD14 (monocytes), CD34 (progenitors), CD117/KIT (progeni- tors and mast cells), tryptase (mast cells), and a megakary- ocyte marker (CD41, CD42 or CD61) (Online Supplementary Table S5).86,92,93 In unclear cases or when a co-existing (second) BM neoplasm is suspected, addition- al lineage-specific antibodies such as CD3, CD20, or CD25 (suspected mastocytosis) should be applied (Online Supplementary Table S4). When employing CD34 as a pro- genitor-related immunhistochemical marker, it is impor- tant to know that endothelial cells also express this anti- gen. Another important point is that blasts may some- times be CD34-negative. In such cases, KIT/CD117 is applied as an alternative marker (Online Supplementary
Table 6. Commonly mutated genes detectable in patients with classical chronic myelomonocytic leukemia.
Table S4). For the immunohistochemical detection of monocytic cells, CD14 is a preferred antigen.71,86 Tryptase and CD117 are useful immunhistochemistry markers for detecting and quantifying mast cells.92,93 When spindle- shaped mast cells form compact clusters in the BM and express CD25, these cells usually also display KIT D816V – in these cases the final diagnosis is always SM-CMML.93 In other cases, the pathologist will ask for JAK2 V617F, based on an abnormal morphology and distribution of megakaryocytes. As in MDS, megakaryocytes may also express CD34 in patients with CMML.
Karyotyping in CMML: current recommendations and standards
Clonal cytogenetic abnormalities are detected in 20- 30% of all patients with CMML. The most frequently identified aberrations are trisomy 8, abnormalities of chro- mosome 7 (especially monosomy 7 and deletion of 7q), and loss of the Y chromosome (‐Y) (Online Supplementary Table S6).94-97 Compared to MDS, isolated del(5q) and com- plex abnormal karyotypes are rarely detected in CMML. Our faculty is of the opinion that conventional karyotyp- ing of BM cells should be performed in all patients with known or suspected CMML or a suspected pre-CMML condition. At least 20 metaphases should be examined.98 In the case of a clear-cut result, even 10-20 metaphases may be sufficient to define the karyogram. Reporting of karyotypes should be performed using the International System for Human Cytogenetic Nomenclature (ISCN) guidelines.99 A clone is defined by two or more metaphas- es showing the same gain or structural rearrangement (deletion, inversion, translocation) of chromosomal mate- rial or at least three metaphases showing a monosomy of the same chromosome.99 Several of the cytogenetic anom- alies in CMML may be difficult to detect by conventional karyotyping. Therefore, we are of the opinion that fluo- rescence in situ hybridization (FISH) should be performed in all patients with (suspected) CMML, at least in those in whom no karyotype anomaly was detected by conven- tional karyotyping. The FISH probes should cover all rele- vant regions, including 5q31, cep7, 7q31, 20q, cep8, cepY and p53. Special consideration should be directed to cryp- tic deletions of TET2 (in 4q24), NF1 (17q11), and ETV6 (12p13) which can occur in up to 10% of CMML patients10 and are only detectable by interphase FISH (Online Supplementary Table S6). It is worth noting that NF1 dele- tions may occur during progression/karyotype evolution in CMML. The limitation of FISH is that is does not detect all karyotypic abnormalities. In some patients with CMML, clonal evolution is found. Subclones are defined by additional chromosomal defects (apart from the pri- mary chromosomal defect) in at least two cells (or 3 cells for monosomies) and the absence of these additional chro- mosomal defects in the other clonal cells.99 A complex karyotype is defined by at least three chromosome defects in one clone.99 As in MDS, a complex karyotype in CMML is indicative of a poor prognosis. Overall, cytogenetic studies are of prognostic significance in CMML and have been used to optimize prognostic scoring systems.97,100-102 In some patients with CMML, clonal evolution is observed over time and may then also be an adverse prognostic sign. Therefore, we recommend that chromosome analy- ses are performed each time a BM investigation is done in the follow-up in order to detect (or exclude) clonal evolu- tion.
Gene name abbreviation
ASXL1
EZH2
TET2
DNMT3A
IDH1 IDH2 CBL NRAS
KRAS PTPN11 FLT3
SRSF2 SF3B1 U2AF1 ZRSR2 RUNX1
SETBP1 TP53 PHF6
Gene class and function
Epigenetic regulation Histone modification
Epigenetic regulation
Histone modification
Epigenetic regulation DNA methylation
Epigenetic regulation
DNA methylation Epigenetic regulation Epigenetic regulation Signaling
Signaling
Signaling Signaling Signaling
Pre‐mRNA splicing Pre‐mRNA splicing Pre‐mRNA splicing Pre‐mRNA splicing Gene transcription
Gene transcription DNA damage Chromatin adaptor
Relative frequency in CMML
40%*
5%
60%*
5%
1% 5-10% 15% 15%
10% 5% <5%
50%* 5-10% 5-10% 5% 15%
15% 1% 5%
Clinical impact
Poor prognosis** CHIP/ARCH***
CHIP/ARCH***
Poor prognosis**
CHIP/ARCH***
Drug target
Drug target
RAS pathway
Poor prognosis**
RAS pathway
RAS pathway
RAS pathway
AML-related Drug target
Poor prognosis**
AML-related Poor prognosis** Poor prognosis**
*These mutations can be regarded as CMML-related mutations, but only SRSF2 mutations do not, in addition, also count as classical CHIP/ARCH mutations. **Mutations in these genes are independent adverse prognostic factors regarding survival in CMML. ***These genes are fre- quently detected in individuals with clonal hematopoiesis of indeterminate potential (CHIP) also known as age-related clonal hematopoiesis (ARCH).Therefore,the diagnostic impact of these mutations may be regarded as somehow lower compared to that of other (CMML-related and other) mutations. CMML: chronic myelomonocytic leukemia; AML: acute myeloid leukemia.
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