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Criteria and standards in CMML
novo) CMML.65 Although progression-free survival may not be different in these patients compared to those with de novo CMML, some of these patients progress rapidly to secondary AML. It is also worth noting that patients with therapy-related secondary CMML have a higher frequen- cy of karyotypic abnormalities compared to patients with de novo CMML.66 Eligible patients in this group should be offered allogeneic hematopoietic stem cell transplantation.
Potential pre-phases of CMML
During the past few years evidence has accumulated
suggesting that hematopoietic neoplasms, including MDS,
MPN and MDS/MPN, develop in a step-wise manner. In
the earliest phases of clonal development, patients present
without overt signs or symptoms of a hematopoietic neo-
plasm but their leukocytes carry one or more somatic
mutations, usually (early, passenger-type) mutations oth-
erwise also found in overt myeloid neoplasms (for exam-
ple TET2 mutations).67-70 In the context of MDS and other
myeloid neoplasms, these cases have been referred to as
clonal hematopoiesis of indeterminate potential (CHIP),
or, when accompanied by cytopenia, as clonal cytopenia
of unknown significance (CCUS).69-73 Since these muta-
tions are frequently detected in older individuals, the con-
dition is also called age-related clonal hematopoiesis
(ARCH).70,73 In a few healthy individuals, bona fide onco-
genic drivers (such as BCR-ABL1) are detected in a small
subset of leukocytes. Because of the oncogenic potential
of these drivers, these conditions are termed clonal
hematopoiesis with oncogenic potential (CHOP).71,73 CHIP,
CCUS and CHOP may also be the earliest clonal condi-
tions preceding CMML. For these cases, the definitions
recently proposed for CHIP, CCUS and CHOP should apply.69,71,73
Apart from somatic mutations, other factors, such as epigenetic modifications, chronic inflammation or aging- related processes, may also trigger the selection and expansion of pre-malignant neoplastic clones in myeloid neoplasms including CMML.74-76 Some of these conditions may present with persistent monocytosis without signs of an overt myeloid neoplasm and may represent pre-phases of overt CMML. In other patients, however, no or another hematopoietic neoplasm develops during follow-up. Therefore, our faculty concluded that this pre-phase should be termed idiopathic monocytosis of unknown sig- nificance, provided that the following criteria are met: (i) persistent (at least 3 months) relative (≥10%) and absolute (>0.5x109/L) monocytosis; (ii) no diagnostic dysplasia and no signs of myeloproliferation; (iii) no signs and criteria of a myeloid or other hematopoietic neoplasm fulfilled; (iv) no flow cytometric abnormalities or somatic mutations related to a myeloid, mast cell or lymphoid neoplasm detected in leukocytes; and (v) no reactive condition that would explain reactive monocytosis is detected (Table 4 and Online Supplementary Table S3). If CHIP-like mutations are found in such patients, but no hematopoietic neo- plasm can be diagnosed using the WHO criteria, the final diagnosis changes to clonal monocytosis of unknown sig- nificance (Online Supplementary Table S3). It is also worth noting that idiopathic cytopenias of unknown significance can precede CMML.64,77-79 Especially in patients with idio- pathic thrombocytopenia of unknown significance, a CMML may be detected upon deeper investigations or during follow-up.77-79 Finally, as mentioned before, oligomonocytic CMML, although proposed as a special variant of CMML, must also be regarded as a potential pre-phase of classical CMML. In this regard it is important to note that these patients should have a regular follow-up
Table 4. Overview of non-clonal and clonal conditions that may precede chronic myelomonocytic leukemia.
Pre-CMML conditions and comparison to classical CMML
Feature
Absolute monocytosis (≥0.5x109/L)
Substantial monocytosis
IMUS ICUS CCUS CHIP/CHOP
+ +/- +/- +/-
+/- - - -
- - -
CMUS O-CMML CMML
+ + +
+/- - +
+ + +
- + +
- +/- +/- <5% <20% <20% - ++ ++
-*** ++ ++
+**** ++ ++
(≥1x109/L) Relativemonocytosis +
(>10% of leukocytes)
Dysplasia* - - - -
Cytopenia(s)** - + + -
BM blasts <5% <5% <5% <5%
Flow abnormalities - - +/- +/-
Cytogenetic -*** -*** +/- +/-
abnormality (≥1)
Molecular - - + +
aberration/s****
*At least 10% of all cells in a given lineage (erythroid,neutrophilic,or megakaryocytic) are dysplastic.**Persistent cytopenia(s) recorded over a time-period of at least 4 months. ***In a subset of cases,a small clone is detectable by FISH.****A molecular aberration is defined by CMML/MDS-related mutations and an allele burden of ≥2%.The working definition for pre-CMML conditions is also ≥2% allele burden,whereas the minimal allele burden to count as a co-criterion for CMML is 10%.In most patients with overt CMML, multiple gene mutations/aberrations are found. ****Here a CHIP-like mutation is detected – if more than one CHIP-like mutations are found the question is whether the final diagnoses changes to O-CMML. CMML: chronic myelomonocytic leukemia; IMUS: idiopathic monocytosis of unknown (undetermined) significance; ICUS: idiopathic cytopenia of undetermined significance; CCUS: clonal cytopenia of undetermined significance; CHIP: clonal hematopiesis of indeterminate potential; CCUS, clonal cytopenia of undeter- mined significance; CMUS: clonal monocytosis of unknown (undetermined) significance; O-CMML: oligomonocytic CMML; MDS: myelodysplastic syndrome; BM: bone marrow; FISH: fluorescence in situ hybridization.
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