Chronic Myelomonocytic Leukemia: 2024 Update on Diagnosis, Risk Stratification and Management

Abstract

Disease Overview:

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), characterized by prominent monocytosis and an inherent risk for leukemic transformation (~15-20% over 3-5 years).

Diagnosis:

Newly revised diagnostic criteria include sustained (>3 months) peripheral blood (PB) monocytosis (≥0.5 x 10⁹/L; monocytes ≥10% of leukocyte count), consistent bone marrow (BM) morphology, <20% BM or PB blasts (including promonocytes), and cytogenetic or molecular evidence of clonality. Cytogenetic abnormalities occur in ~ 30% of patients, while >95% harbor somatic mutations: TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), RAS pathway (~30%), and others. The presence of ASXL1 and DNMT3A mutations and absence of TET2 mutations negatively impact over-all survival (ASXL1^WT/TET2^MT genotype being favorable).

Risk stratification:

Several risk models serve similar purposes in identifying high risk patients that are considered for allogeneic stem cell transplant (ASCT) earlier than later. Risk factors in the Mayo Molecular Model (MMM) include presence of truncating ASXL1 mutations, absolute monocyte count >10 × 10⁹/L, hemoglobin <10 gm/dl, platelet count <100 × 10⁹/L, and the presence of circulating immature myeloid cells; the resulting 4-tiered risk categorization includes high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor) and low (no risk factors); the corresponding median survivals were 16, 31, 59, and 97 months. CMML is also classified as being “myeloproliferative (MP-CMML)” or “myelodysplastic (MD-CMML), based on the presence or absence of leukocyte count of ≥13 x 10⁹/L.

Treatment:

ASCT is the only treatment modality that secures cure or long-term survival and is appropriate for MMM high/intermediate-2 risk disease. Drug therapy is currently not disease-modifying and includes hydroxyurea and hypomethylating agents; a recent phase-3 study (DACOTA) comparing hydroxyurea and decitabine, in high-risk MP-CMML, showed similar overall survival at 23.1 vs 18.4 months, respectively, despite response rates being higher for decitabine (56% vs 31%).

Unique disease associations:

Systemic inflammatory autoimmune diseases, leukemia cutis; lysozyme-induced nephropathy; the latter requires close monitoring of renal function during leukocytosis and is a potential indication for cytoreductive therapy.

DISEASE OVERVIEW

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem and progenitor cell (HSPC) disorder characterized by the presence of sustained (>3 months) peripheral blood (PB) monocytosis (≥0.5 x 10⁹/L; monocytes ≥10% of white blood cell count), with bone marrow (BM) dysplasia, with an inherent risk to transform to acute myeloid leukemia ( AML; 15-20% over 3-5 years).^1-3 Secondary to overlapping features of both, myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), the classification of CMML as a unique myeloid neoplasm has undergone several iterations dating back to the original French-American-British (FAB) co-operative group effort in 1982.⁴ Due to renewed evidence demonstrating clinical, morphological and molecular differences, the revised 4^th edition of the World Health Organization (WHO) classification of myeloid neoplasms recommended categorization of CMML into “myeloproliferative” (MP-CMML) and “myelodysplastic” (MD-CMML) sub-types; based on a white blood cell count of ≥13 x 10⁹/L for MP-CMML.^3,5,6 In 2022, two slightly divergent classification systems for myeloid neoplasms emerged, the International Consensus Classification (ICC) system and the 5^th edition of the WHO classification system.^1,2 Both systems recommended lowering the diagnostic absolute monocyte count (AMC) threshold from ≥1 x 10⁹/L, to ≥0.5 x 10⁹/L.^1,2 This was based on data demonstrating that patients with sustained AMC values between 0.5-1.0 x 10⁹/L, with CMML-like clonal changes in HSPC, shared phenotypic overlaps and had similar outcomes⁷. This category of patients had previously been designated as oligomonocytic CMML (O-CMML). In addition, the 5^th edition of the WHO classification and the ICC removed CMML-0 as a subcategory, due to limited risk stratification and restored categorization based on PB and BM blast % into b) CMML-1 (<5% PB blasts including promonocytes and <10% BM blasts) and c) CMML-2 (5-19% PB blasts including promonocytes and 10-19% BM blasts and/or when any Auer rods are present).^1-3 Please refer to table 1 to review the details and differences between the ICC and the 5^th edition of the WHO classification systems for CMML.

Table 1:

International Consensus Classification and the 5^th edition of the World Health Organization Classification systems for diagnosis of chronic myelomonocytic leukemia (CMML).

Variable	ICC Classification	5th Edition of the WHO Classification
Absolute monocyte count	AMC ≥0.5 x 109/L, with monocytes being ≥10% of the WBC differential.	*AMC ≥0.5 x 109/L, with monocytes being ≥10% of the WBC differential.
Cytopenias	MDS-defining cytopenias.	Not specified.
Clonality	Abnormal karyotype, or myeloid driver mutations with a variant allele fraction ≥10%. Without a clonal marker the AMC≥1.0 x 109/L, along with ≥5% BM blasts, or BM dysplasia, or an abnormal immunophenotype.	**Abnormal karyotype and/or presence of a myeloid driver mutation.
CMML categorization	$ CMML-1: <5% PB blasts and <10% BM blasts CMML-2: 5-19% PB blasts and 10-19% BM blasts, or the presence of Auer rods WBC< 13 X109/L- MD-CMML WBC≥ 13 X109/L- MP-CMML	$ CMML-1: <5% PB blasts and <10% BM blasts CMML-2: 5-19% PB blasts and 10-19% BM blasts, or the presence of Auer rods. WBC< 13 X109/L- MD-CMML WBC≥ 13 X109/L- MP-CMML
Bone marrow aspirate and biopsy	Hypercellular marrows with increased BM monocytosis. No features of AML or MPN <20% blasts	**Dysplasia present in ≥1 cell lineage. *<20% blasts
Monocyte repartition-based flow cytometry	Not included	**Presence of classical monocytes (M01) >94%
Exclusionary criteria	BCR::ABL1 Myeloid/lymphoid neoplasms with tyrosine kinase fusions	*BCR::ABL1 MPN Myeloid/lymphoid neoplasms with tyrosine kinase fusions

Key: BM- bone marrow, ICC- international consensus classification, WHO- world health organization, AMC- absolute monocyte count, WBC- white clood cell count, MDS- myelodysplastic syndrome, MPN- myeloproliferative neoplasm, AML- acute myeloid leukemia

^$In CMML promonocytes are considered blast equivlaents and should be included in the blast count.

^*These are considered prerequisite criteria by the WHO for a diagnosis of CMML, while ** are considered supportive criteria for diagnosis of CMML. If the AMC ≥ 1X10⁹/L, all prerequisite criteria and one supportive criterion should be present. If AMC ≥0.5 X 10⁹/L, then all prerequisite criteria and the presence of a clonal marker and BM dysplasia should be present.

For the ICC cases without evidence of clonality, AMC ≥ 1.0 × 10⁹/L and > 10% of the WBC, and increased blasts (including promonocytes), or morphologic dysplasia, or an abnormal immunophenotype consistent with CMML would be required for the diagnosis of CMML.

For cases lacking bone marrow findings of CMML, a diagnosis of CMUS (clonal monocytosis of undetermined significance) could be considered. If cytopenia is present, a diagnosis of CCMUS (clonal cytopenias with monocytosis of undetermined significance) could be entertained. In these diagnostic settings, however, an alternative cause for the observed monocytosis would have to be excluded based on appropriate clinicopathologic correlations.

Myeloid and lymphoid neoplasms with tyrosine kinase fusions include recurrent abnormalities involving the following genes and rearrangements; PDGFRA, PDGFRB, FGFR1, JAK2, FLT3 and ETV6::ABL1.

The median age at CMML diagnosis is ~73-75 years, with a male preponderance (1.5-3:1).^8-10 The exact incidence of CMML remains unknown, but is estimated at 4 cases per 100,000 persons per year.^11,12 Therapy related CMML (t-CMML) cases have been described (~10% of all CMML), and like their MDS counterparts are associated with poor clinical outcomes.^13-15 Patients with t-CMML, in comparison to their de novo counterparts, are more likely to have cytogenetic abnormalities with higher risk karyotypic stratification and a shorter median over-all survival (OS).¹⁵ The presentation of patients with CMML is variable and the clinical heterogeneity is effectively captured by the current categorization into MD-CMML and MP-CMML.^6,16 Those with MD-CMML present with peripheral blood cytopenia(s), effort intolerance, easy bruising, recurrent infections and transfusion dependence.¹⁷ Those with MP-CMML present with leukocytosis, hepatomegaly, splenomegaly and features of myeloproliferation such as; fatigue, night sweats, symptoms from organomegaly, bone pains, weight loss and cachexia.¹⁷ Patients with MP-CMML have a higher frequency of oncogenic RAS pathway mutations (NRAS, KRAS, CBL, PTPN11 and NF1) with a unique transcriptomic and epigenetic profile, largely defined by the RAS-KMT2A-PLK1 axis.^5,6 Approximately 20-30% of CMML patients can present with antecedent or concomitant systemic inflammatory autoimmune diseases (SIAD).^18,19 Rarely, CMML can present with leukemia cutis as an initial manifestation,²⁰ or directly present with blast transformation (CMML-BT).²¹

DIAGNOSIS

General Principles

An approach to patients with monocytosis is shown in Figure 1. It is important to exclude reactive causes of monocytosis before embarking on a workup of CMML. Monocytosis could be attributable to several non-malignant causes – infectious etiologies such as tuberculosis, chronic fungal infections, subacute bacterial endocarditis, viral and protozoal infections (leishmaniosis); connective tissue disorders such as systemic lupus erythematosus and sarcoidosis, and lipid storage disorders. The recovery phase of an acute infection (usually viral) or BM regeneration post chemotherapy is commonly associated with monocytosis.²²

Figure 1:

A schematic approach to the differential diagnosis of sustained peripheral blood monocytosis

*: Peripheral blood abnormalities include unexplained anemia, thrombocytopenia, thrombocytosis, leukocytosis, eosinophilia, granulocytic dysplasia (pseudo Pelger Huët cells), circulating immature myeloid cells such as myelocytes, metamyelocytes and promyelocytes, promonocytes and blasts.

Monocyte repartitioning flow cytometry specifically designed to detect classical (M01; CD14+/CD16−), intermediate (M02, CD14+/CD16+) and nonclassical monocytes (M03; CD14−/CD16+), with CMML cases demonstrating a M01 fraction of >94%.

Peripheral blood NGS (next generation sequencing) can be carried out at times while evaluating cytopenias or cytosis. If myeloid driver mutations commonly seen in CMML are encountered, such as TET2, ASXL1, SRSF2, SETBP1, and oncogenic RAS pathway mutations among others, then further work is recommended.

**: FISH – fluorescence in-situ hybridization, PDGFRA and PDGFRB: Platelet-derived growth factor – A and Platelet-derived growth factor – B, FGFR1- Fibroblast growth factor receptor 1, JAK2- Janus associated kinase 2.

FISH testing for PDGFRA and PDGFRB rearrangements is highly recommended if the peripheral blood monocytosis is associated with concomitant eosinophilia. The ETV6-PDGFRB fusion oncogene can give rise to clonal monocytosis mimicking CMML but is in fact a unique molecularly defined myeloid neoplasm (not to be diagnosed as CMML). Similarly, PDGFRA fusions are commonly associated with eosinophilia, but rarely can have associated monocytosis. Most PDGFRA fusions occur due to the karyotypically occult CHIC2 deletion (not detectable by metaphase cytogenetics) resulting in the FIP1L1-PDGFRA fusion oncogene. The World Health Organization also mandates FISH testing for FGFR1, JAK2, FLT3 and the ETV6::ABL1 rearrangements, however, these abnormalities usually give rise to eosinophilia and are very uncommonly associated with monocytosis. These gene rearrangements are classified as myeloid and lymphoid neoplasms with tyrosine kinase fusions.

*** While estimating peripheral blood blasts in a patient with CMML, the blasts must be summated with promonocytes.

Once these etiologies have been ruled out, molecularly defined clonal hematopoietic disorders need to be considered. First, chronic myeloid leukemia (CML) with the distinctive Philadelphia chromosome and the BCR::ABL1 fusion oncogene must be evaluated and excluded.²³ Rearrangement of the platelet-derived growth factor receptors A (PDGFRA) and B (PDGFRB) should then be evaluated for. PDGFRA (chromosome 4q12) and PDGFRB (chromosome 5q31-q32) are type III receptor tyrosine kinases. Chromosomal translocations involving PDGFRA/B have been associated with myeloid neoplasms characterized by prominent eosinophilia and responsiveness to imatinib.^24,25 At times, PDGFR rearranged myeloid neoplasms can present with monocytosis and BM dysplasia, but given their unique responsiveness to imatinib, these are no longer classified as CMML.²⁶ Patients presenting with a clinical phenotype of CMML with eosinophilia, should be assessed for t(5;12)(q31-q32;p13), giving rise to the ETV6(TEL)-PDGFRB fusion oncogene.²⁶ The association between monocytosis and PDGFRA rearrangements is uncommon.^27,28 Additional molecular markers that should be assessed for, in the context of monocytosis and eosinophilia include FGFR1, JAK2 (e.g. PCM1-JAK2 fusion), FLT3 rearrangements and the ETV6::ABL1 fusion.^1,2,29 Monocytosis can be associated with MPN such as primary myelofibrosis (PMF) and polycythemia vera (PV), where its presence adversely impacts survival.^30,31 The presence of a prior well documented diagnosis of a MPN, or MPN-associated driver mutations such as MPL and CALR, make the diagnosis of CMML less likely.³ Finally, the presence of BM dysplasia in at least one hematopoietic lineage should be established. If myelodysplasia is absent or minimal, a diagnosis of CMML can still be made if clonal cytogenetic or molecular abnormalities are present (Table 1).

Flow cytometry

While the role of conventional flow cytometry for the diagnosis of CMML is limited, since malignant monocytes do not have unique cell surface markers and the fact that monoblasts are usually CD34+ negative, monocyte repartitioning as assessed by flow cytometry has clearly advanced CMML diagnostics. Human monocytes can be divided into three subsets; CD14⁺/CD16⁻ (classical), CD14⁺/CD16⁺ (intermediate) and CD14^low/CD16⁺ (non- classical), with distinct gene expression profiles, chemokine receptor expressions, metabolic dependancies and phagocytic activities.^32,33 The classical monocytes constitute majority of the human monocytes (~85%) in healthy conditions.³³ Compared to healthy donors and patients with reactive monocytosis, CMML patients demonstrate an increase in the fraction of classical monocytes (CD14⁺/CD16⁻) [cut off value 94%] (Figure 2).³² In the abovementioned French study, the associated specificity and sensitivity values were reported at 95.1% and 91.9% respectively.³² Importantly, this repartition was noted to be independent of CMML mutational status and this increment corrected in CMML patients that responded to hypomethylating agents (HMA).³² This technique has also been used to effectively distinguish monocytosis associated with CMML from monocytosis seen in patients with MPN,³⁴ and in identifying MDS patients with monocyte counts <1 x 10⁹/L who eventually develop CMML.³⁵ False negatives with this technique have been encountered in CMML patients with autoimmune diseases where the MO2 fraction increases (false decrease in MO1), and in other myeloid malignancies such as CML and atypical CML.^35,36 Recent studies have shown that slan (6-sulfo LacNac- a carbohydrate modification of P-selectin glycoprotein ligand 1) + non classical monocytes <1.7% can add to the diagnostic accuracy of monocyte repartitioning flow cytometry.³⁷ In addition, we hope that by using monocyte markers such as CCR2, CD36, HLA-DR and CD11c and better assessment techniques such as mass cytometry (cytometry by time of flight–CyTOF), we can improve upon the sensitivity and specificity of this methodology.³⁸ While monocyte repartitioning flow cytometry has been added as a supportive diagnostic criterion for CMML in the 5^th edition of the WHO classification, it has not been included by the ICC^1,2.

Figure 2:

Monocyte repartitioning flow cytometry demonstrating a normal M01 fraction (CD14+, CD16−) in a healthy control (84.95%) patient in the left scatter plot, while the right scatter plot shows an expanded M01 fraction (94.6%) in a patient with an established diagnosis of chronic myelomonocytic leukemia.

Histopathology and Immunohistochemistry

There is no single finding pathognomonic of the diagnosis of CMML. Bone marrow biopsies are often hypercellular with granulocytic hyperplasia and mild to modest dysplasia (Figure 3B-C). Monocytic proliferation can be present, but is often difficult to appreciate and immunohistochemical studies that aid in the identification of monocytes and their precursors are recommended.³⁹ Almost 80% of patients will demonstrate micro-megakaryocytes with abnormal nuclear contours and lobations, and 30% of patients can have an increase in BM reticulin fibrosis (Figure 3C and 4D-E).³⁹ Approximately 30% percent of patients can demonstrate nodules composed of mature plasmacytoid dendritic cells that are clonal [CD123+,lineage negative, CD45+, CD11c-,CD33-, HLA-DR+, BDCA-2+ and BDCA-4+], often have RAS pathway mutations and predict for an inferior AML-free survival (AML-FS) (Figure 3D).⁴⁰ The identification of promonocytes requires expertise and these cells are to be summated with blasts while estimating the blast count (Figure 3A, 3E, 4A-C).⁴¹. Promonocytes are described as monocytic precursors that have a delicately convoluted, folded or grooved nucleus with finely dispersed chromatin, a small indistinct or absent nucleolus, and finely granulated cytoplasm (Figure 4A-C) .^41,42 On immunophenotyping the abnormal BM cells often express myelomonocytic antigens such as, CD13, CD33, with variable expression of CD14, CD68 and CD64. Markers of aberrant expression include CD2, CD15, CD56 (can also be seen in non clonal/reactive causes of monocytosis) or decreased expression of CD14, CD13, HLA-DR, CD64 or CD36. The presence of myeloblasts can often be detected by expression of CD34 (not expressed on monoblasts). The most reliable markers on immunohistochemistry include CD68R and CD163. On cytochemical analysis, monocytes are often positive for non-specific esterases and lysozyme, while the granulocytic precursors are often positive for lysozyme and chloroacetate esterase (Figure 3F). This technique can help differentiate CMML from other MPN such as CML and atypical CML, where BM monocytosis is uncommon.

Figure 3:

Peripheral blood and bone marrow morphology, immunohistochemistry and cytochemical analysis in chronic myelomonocytic leukemia (CMML).

A. Peripheral blood smear of a patient with CMML demonstrating promonocytes (black arrow) along with dysplastic granulocytes (grey arrow). Wright-Giemsa 200 X magnification.

B. Bone marrow aspirate of the same patient with CMML demonstrating minimal/subtle granulocytic dysplasia. Wright-Giemsa 1000 X magnification.

C. Bone marrow core biopsy of a patient with CMML demonstrating a relatively hypercellular marrow (patient aged 81 years) with dysplastic megakaryocytes (black arrow). Hematoxylin and Eosin 100 X magnification.

D. Bone marrow core biopsy of a patient with CMML demonstrating a plasmacytoid dendritic cell nodule (black circle), with an adjacent image at a higher magnification (both hematoxylin and eosin stain) and the same nodule brightly positive for CD123 by immunohistochemistry (1000 X magnification).

E. Peripheral blood smear of a patient with CMML with blast transformation (secondary AML), demonstrating promonocytes (black arrow) and myeloblasts (red arrow). Wright-Giemsa 400 X magnification.

F. Cytochemical analysis on a bone marrow aspirate in a patient with CMML using the dual esterase stain (alpha napthyl butyrate esterase and choloroacetate esterase) demonstrating dysplastic monocytes taking up both colors (blue and brick red). Normal granulocytes stain bright blue, while normal monocytes stain brick red. 400 X magnification.

Figure 4:

Spectrum of monocytes and monocytic precursors that can be encountered in chronic myelomonocytic leukemia (CMML).

A. Peripheral blood smear of a patient with CMML demonstrating mature monocytes with nuclear segmentation, mature clumped chromatin, and pale cytoplasm. Wright-Giemsa stain 1000 X magnification.

B. Peripheral blood smear of a patient with CMML demonstrating promonocytes with less distinct nuclear segmentation, tissue-paper-like nuclear folds, and immature open chromatin. Wright-Giemsa stain 1000 X magnification.

C. Bone marrow aspirate of a patient with CMML demonstrating blasts/ monoblasts devoid of nuclear segmentation, with occasional nuclear folds, and very immature open chromatin with occasional nucleoli. Wright-Giemsa stain 1000 X magnification.

D. Bone marrow core biopsy of a patient with CMML demonstrating extensive reticulin fibrosis (black arrow). Hematoxylin and eosin stain 100 X magnification.

E. Bone marrow core biopsy of a patient with CMML demonstrating extensive reticulin fibrosis (black arrow). Trichrome stain 100 X magnification.

F. Peripheral blood smear of a patient with CMML demonstrating dysplastic bilobed neutrophils (black arrow) with Dohle-like bodies (peripheral light blue cytoplasmic inclusion). Wright Giemsa 1000 X magnification

G. Peripheral blood smear of a patient with CMML demonstrating dysplastic monolobate neutrophils (black arrow) with Dohle-like bodies (peripheral light blue cytoplasmic inclusion). Wright Giemsa 1000 X magnification

H. Peripheral blood smear of a patient with CMML demonstrating dysplastic neutrophils with markedly hypogranular cytoplasm (black arrow) with Dohle-like bodies (peripheral light blue cytoplasmic inclusion). Wright Giemsa 1000 X magnification.

The diagnostic criteria for CMML place a heavy onus on the presence of PB monocytosis. As discussed, monocytosis is associated with a variety of reactive and clonal causes. Persistent reactive monocytosis with bone marrow dysplasia can sometimes wrongly be labelled as CMML. Similarly, CMML patients with progressive dysplasia or splenomegaly might develop PB cytopenias with dysplasia (Figure 4F-H), and despite having monocytosis, fail to meet the diagnostic criteria for CMML. Bone marrow monocytosis can be seen in patients with underlying dysplasia and while these patients may eventually progress to CMML, at this point, BM monocytosis is not incorporated into the diagnostic algorithm.

Cytogenetic abnormalities in CMML

Clonal cytogenetic abnormalities are seen in ~20-30% of CMML patients.^9,43-45 Common alterations include; trisomy 8, - Y, abnormalities of chromosome 7 (monosomy 7 and del7q), trisomy 21, and complex karyotypes.⁴⁴ The Spanish CMML specific cytogenetic risk stratification (CPSS) system categorizes patients in to three groups; high risk (trisomy 8, chromosome 7 abnormalities, or complex karyotype), intermediate risk (all chromosomal abnormalities, except for those in the high and low risk categories), and low risk (normal karyotype or −Y), with 5-year OS of 4%, 26% and 35%, respectively.⁴⁴ Subsequently, in a large international study, 409 patients with CMML were analyzed for cytogenetic and molecular abnormalities.⁴⁶ Thirty percent displayed an abnormal karyotype; with common abnormalities being, +8 (23%), −Y (20%), −7/7q-(14%), 20q- (8%), +21 (8%) and der(3q) (8%).⁴⁶ A step-wise survival analysis resulted in three distinct cytogenetic risk categories: high (complex and monosomal karyotypes), intermediate (all abnormalities not in the high or low risk groups) and low (normal, sole -Y and sole der (3q)) with median survivals of 3 (HR 8.1, 95% CI 4.6-14.2), 21 (HR 1.7, 95% CI 1.2-2.3) and 41 months, respectively (Mayo-French cytogenetic risk stratification system).⁴⁶

Molecular abnormalities in CMML

There has been an exponential discovery of several molecular abnormalities in patients with CMML. On an average, patients with CMML demonstrate ~10-15 somatic variants per kilobase of coding DNA region, similar to patients with AML, but several folds lower than other malignancies such as melanoma and lung cancer.^47,48 These mutations can broadly be divided into the following categories: (a) mutations in epigenetic control of transcription,^49-54 such as histone modification (EZH2, ASXL1, UTX), and DNA methylation (TET2, DNMT3A, IDH1 and IDH2); (b) mutations in the spliceosome machinery (SF3B1, SRSF2, U2AF1, ZRSR2, PRPF8);⁹ (c) mutations in genes that regulate cell signaling (JAK2, KRAS, NRAS, CBL, PTPN11, NF1 and FLT3);^55-59 (d) mutations in transcription factors and nucleosome assembly regulators (RUNX1, GATA2, SETBP1);^56,60,61 and (e) mutations in DNA damage response genes such as TP53 and PHF6.⁶² The relative frequency of these mutations in individuals with CMML is shown in Table 2. Of these, mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%) and the oncogenic RAS pathway (~30%) are most frequent, with only frame-shift and non-sense ASXL1 mutations consistently and independently, adversely impacting OS.^51,63

Table 2:

Relative frequencies of somatic mutations in patients with chronic myelomonocytic leukemia

Major class of genetic mutation		Gene	Frequency of mutation
Epigenetic Control	Histone modification	ASXL1 *	40%
		EZH2	5%
	DNA methylation	TET2	60%
		DNMT3A *	5%
	Dual effect	IDH1	1%
		IDH2	5%
Cell signaling		JAK2V617F	10%
		CBL	15%
		NRAS *	15%
		KRAS	10%
		PTPN11	5%
		NF1	<5%
		FLT3	<5%
Pre-mRNA splicing		SRSF2	50%
		SF3B1	5-10%
		U2AF1	5-10%
		ZRSR2	5%
Transcription and nucleosome assembly		RUNX1 *	15%
		SETBP1 *	15%
		GATA2	5%
DNA damage		TP53 **	<1%
		PHF6	5%

^*Annotates genes that have been shown in various studies to have an independent and adverse prognostic impact on survival outcomes.

^**TP53 mutations are very infrequent In CMML and if present, usually occur in the context of therapy related CMML.

The ASXL1 gene (chromosome 20q11) regulates chromatin by interacting with the polycomb- group repressive complex proteins (PRC1 and PRC2).^49,64 In a seminal paper, Abdel-Wahab et al. demonstrated that ASXL1 mutations resulted in loss of PRC2-mediated H3K27 (histone 3 lysine 27) tri-methylation.⁶⁵ In addition, Balasubramani et al. demonstrated that ASXL1 truncations conferred enhanced activity on the ASXL1-BAP1 (BRCA associated protein 1) complex.⁶⁶ These interactions result in a global erasure of H2AK119Ub and depletion of H327Kme3, promoting dysregulated transcription and oncogenesis. EZH2 mutations (chromosome 7q36.1) occur in <5% of CMML patients, and unlike in epithelial malignancies and lymphoproliferative disorders are loss-of-function mutations.⁶⁷ EZH2 mutations in CMML almost always co-occur with ASXL1 mutations, are frequently associated with a MPN-CMML phenotype, and while they themselves do not impact either OS or LFS, ASXL1/EZH2 co-mutated patients have a shorter OS, in comparison to ASXL1 mutant patients alone.⁶⁷

The TET2 gene located on chromosome 4q24 is a member of the TET family of proteins.⁶⁸ TET2 has a dioxygenase enzymatic activity and converts 5-methyl-cytosine to 5-hydroxymethyl-cytosine (5hmC). 5hmC, represents a new base in genomic DNA, which may have a specific effect on transcription.^69,70 Although TET2 mutations are widely prevalent in CMML (~60%), they have not been shown to independently impact either OS or LFS.^51,71 A recent analysis in a large international cohort of CMML patients has shown that the presence of TET2 mutations in the absence of ASXL1 mutations (ASXL1wt/TET2mt), has a favorable impact on OS.^72,73 The reason for this association remains unclear. In addition, similar to patients with MDS and younger CMML patients (age <65years), this study also validated the positive impact of the presence of TET2 mutations in the absence of ASXL1 mutations on HMA responses (TET2mt/ASXL1wt genotype associated with best HMA responses).^73-75 TET2 mutations in CMML associate with somatic copy number alterations, including copy neutral loss of heterozygosity (CN-LOH) and microdeletions of 4q24 (TET2 locus on the contralateral/unmutated allele).⁷⁶ TET2 somatic copy number alterations should be considered when mutant variant allele fractions are >60%.⁷⁶ Mutations involving TET1, TET3 and ASXL2 are extremely uncommon in CMML.⁷⁷

DNA methylation is mediated by a family of DNA methyltransferase enzymes (DNMT), including DNMT1, DNMT3A (chromosome 2p23), and DNMT3B.⁷⁸ DNMT1 primarily maintains pre-existing DNA methylation patterns, whereas DNMT3A and DNMT3B carry out de novo DNA methylation.⁷⁸ DNMT3A mutations are seen in ~5% of CMML patients and independently and adversely impact both OS and LFS.⁷⁹ Of note, a recurrent Arginine882 (R882) hot spot accounts for 40–60% of DNMT3A mutations, with functional data suggesting loss of methyltransferase activity in in vitro assays.

Spliceosome component mutations (SRSF2, SF3B1, U2AF1, PRPF8 and ZRSR2) affect pre-mRNA splicing.⁹ SRSF2 mutations are common in CMML (~50%) and are associated with increasing age, less pronounced anemia and a diploid karyotype.⁹ Thus far, SRSF2 mutations have not demonstrated an independent prognostic impact on both, OS and LFS.^9,51,80 SF3B1 mutations have a high prevalence (~80%) in patients with MDS and ring sideroblasts (RS)⁸¹ and can also be seen in patients with CMML and RS (~10%).^9,82 While SF3B1 mutations do not influence OS they are associated with a favorable AML-FS.⁸² Similarly, U2AF1 and ZRSR2 mutations are seen in ~10% of CMML patients and have thus far lacked an independent prognostic effect.⁸³

Common signal pathway mutations in CMML include; oncogenic RAS pathway mutations (~30%, NRAS, KRAS, CBL PTPN11 and NF1), and JAK2V617F (~10%).^51,56 RAS pathway mutations are associated with a MPN-like phenotype and play an important role in CMML transformation to AML.⁸⁴ Although univariate analysis studies with RAS mutations have demonstrated inferior outcomes in CMML, these findings have not been substantiated in most multivariable models.^43,51 RAS mutations in CMML drive the MPN-like phenotype via a unique RAS-KMT2A-PLK1 axis.⁶ JAK2V617F in CMML (10%) is associated with MPN-like features, with affected patients demonstrating higher HB/hematocrit levels, higher platelet counts and a higher frequency of TET2 mutations; with no impact on OS, AML-FS and thrombosis free survival.⁸⁵ The CBL gene codes for an E3 ubiquitin ligase involved in degradation of activated receptor tyrosine kinases. RING finger domain (RFD) mutations of CBL are frequently associated with UPD11q (uniparental disomy) and have been reported in 10-20% of patients with CMML.^51,56 RUNX1 is essential for normal hematopoiesis and mutations can be seen in ~10-15% of patients with CMML.^51,56 Although these mutations do not impact OS, they are associated with lower platelet counts and higher rates of AML transformation.^86,87 TP53 mutations are very uncommon in CMML (<3%) and are associated with poor outcomes.⁸⁸

The sequence of genetic events leading to a clinical CMML phenotype remain under investigation. It is thought that the initial driver mutation likely involves TET2, usually at the HSPC level and results in biallelic inactivation of TET2, either due to mutations on each allele, mutation on a single allele and CN-LOH, or mutation on a single allele and microdeletion of 4q24 (TET2 locus) on the contralateral allele (Figure 5).^76,89 Second order mutations usually occur at the myeloid progenitor cell (MPP) and common myeloid progenitor (CMP) cell level and often include additional TET2 and SRSF2 mutations. These events accelerate differentiation along the granulocyte monocyte progenitor axis (GMP), resulting in clonal monocytosis.⁸⁹ The subsequent acquisition of ASXL1, DNMT3A, RUNX1, SETBP1, and SF3B1 mutations usually shape MD-CMML phenotypes.^82,89,90 Similarly, the acquisition of ASXL1, oncogenic RAS pathway mutations and JAK2V617F shape MP-CMML phenotypes.^6,82,89,90 Similar to its pediatric counterpart juvenile myelomonocytic leukemia, there are MP-CMML subtypes where RAS pathway mutations are initial founder/driver mutations, with clonal progenitor cells demonstrating hypersensitivity to GM-CSF.^6,91 Acquisition of RAS pathway mutations, along with somatic copy number alterations play an important role in CMML transformation to AML.⁶

Figure 5:

Schematic representation of patterns of clonal hematopoiesis and clonal evolution in chronic myelomonocytic leukemia (CMML).

Abbreviations: HSPC- hematopoietic stem and progenitor cell, CMP- common myeloid progenitor, SCNA- somatic copy number alterations, dCMML- myelodysplastic CMML, pCMML- myeloproliferative CMML, CN-LOH- copy neutral loss of heterozygosity.

CMML and age-related clonal hematopoiesis (ARCH/CHIP)

Age related clonal hematopoiesis (ARCH) is characterized by an age-dependent increase in somatic mutations in HSPC in hematologically normal adults, resulting in selective fitness and clonal expansion.⁹² ARCH or CHIP (clonal hematopoiesis of indeterminate potential) commonly results from mutations in epigenetic regulator genes; DNMT3A, TET2 and ASXL1 and is associated with an increased incidence of hematological malignancies and all-cause mortality (largely due to cardiovascular disease).^92,93 It is well known that CMML is associated with ageing, with most patients (>70%) having mutations in ⩾2 ARCH related-genes (ASXL1 and TET2 most common), with a higher mutation burden being associated with a shorter OS.⁹⁴ This is suggestive of a cancer model in which the development of CMML occurs due to the accumulation of sufficient number of stochastically acquired age-related mutations that fuel CMML transformation in a myelomonocytic-lineage-biased hematopoietic system.⁹⁴

Clonal Monocytosis of Undetermined Significance (CMUS):

This is a newly defined entity proposed by the ICC, where patients with sustained (>3 months) PB monocytosis (AMC≥0.5 x 109/L, ≥10% of white blood cell count), absence of reactive causes of monocytosis and bona fide hematological neoplasms associated with monocytosis, absence of bone marrow morphological findings consistent with CMML (dysplasia, promonocytes, blasts) are included.¹ These patients usually do not have any MDS-defining cytopenias and if they do, they are more appropriately labelled as CCMUS (clonal cytopenias and monocytosis of undetermined significance. The presence of myeloid related driver mutations with a VAF ≥2% is desired. CMUS and CCMUS are considered precursor conditions for CMML and prospective data validating these entities and better understanding progression rates are much needed.

Systemic inflammatory autoimmune diseases (SIAD) in CMML:

SIAD can be seen in 20-30% of CMML patients and can occur either prior to the diagnosis of CMML, or subsequent to it^18,19. These manifestations include undefined autoimmune syndromes, rheumatoid arthritis including seronegative arthritis, immune mediated thrombocytopenia, leukocytoclastic vasculitis, polymyalgia rheumatica, polychondritis, uveitis, Sweets syndrome, and inflammatory bowel disease, among others⁹⁵. SIAD is thought to occur due to defective innate and adaptive responses in CMML. All patients with SIAD should be screened for somatic UBA1 mutations that define VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic), a recently described entity associated with pervasive inflammation and myeloid neoplasms⁹⁶. In a large series of 404 patients with MDS/CMML, 21% (n=85) were found to have SIAD, with SIAD correlating with the presence of TET2, IDH and SRSF2 mutations⁹⁷. SIAD in CMML can be treated with steroids and steroid sparing agents, however, durable responses have been reported with HMA^18,97. We have also used the JAK2 inhibitor Ruxolitinib, off-label, for SIAD manifestations in CMML patients that don’t meet criteria for treatment with HMA.

Leukemia cutis:

Given the inherent plasticity between monocytes and macrophages, skin lesions can be seen in approximately 10% of patients with CMML^20,98. Cutaneous manifestations can be divided into a) mature myelomonocytic infiltrates, without blasts or blast equivalents, b) mature plasmacytoid dendritic cell infiltrates, c) blastic plasmacytoid dendritic cells, d) blastic indeterminate cellular infiltrates and d) histiocytes or mast cells, due to the frequent cooccurrence of histiocytic and mast cell neoplasms with CMML^20,98-100. Skin biopsies with histopathology and IHC are strongly recommended for establishing an accurate diagnosis. The presence of CD34+ blasts, or frank morphological features of monoblasts/myeloblasts, suggests transformation to AML, necessitating work up for AML transformation and extramedullary disease.

Lysozyme induced nephropathy in CMML (LyN):

Renal abnormalities, including acute kidney injury (AKI) as well as chronic kidney disease (CKD), are seen in a high proportion of patients with CMML and are associated with poor outcomes. A recent study of 395 CMML patients reported an incidence of AKI in 138 patients (34.9%) and CKD in 30 patients (7.6%), higher than expected for age¹⁰¹. In this study, patients with MP-CMML had a significantly higher proportion of AKI (40% vs. 27.8%) as well as CKD (10% vs. 4.2%) in comparison to MD-CMML. Lysozyme, also called ‘muramidase’, is a 15-kDa cationic protein filtered by the glomerulus and reabsorbed in the proximal convoluted tubules, which, in excess, can accumulate in the proximal tubular cells, directly causing tubular injury and leading to LyN.¹⁰² LyN has been shown to be responsible for AKI as well as CKD in CMML, with monocyte counts directly correlating with kidney injury.¹⁰³ LyN should be suspected in CMML patients presenting with kidney injury with subnephrotic proteinuria, with a glomerular injury pattern (hematuria). While serum and urine lysozyme levels can be measured, these tests are not broadly available and cut off values associated with renal injury have not been established. Kidney biopsies with morphology and IHC for lysozyme are helpful to establish diagnosis (Figure 6). Retrospective data suggest that early cytoreduction in LyN (Hydroxyurea or HMA), renal risk factor management and volume resuscitation, can potentially salvage renal function.¹⁰² The differential diagnosis for AKI and CKD in CMML includes LyN, MPN-glomerulopathy, extramedullary hematopoiesis, renal monocytic infiltrates, autoimmune glomerulopathies, obstructive uropathy and urate uropathy, respectively.

Figure 6:

Lysozyme immunohistochemistry of a kidney biopsy specimen demonstrating renal tubular epithelial cells with lysozyme accumulation. Lysozyme IHC 1000 X magnification.

CMML- RISK STRATIFICATION

Numerous prognostic models have been developed for CMML. In this regard, the value of Bournemouth, Lille, International Prognostic Scoring Systems (IPSS) and the revised-IPSSS is limited, as they were designed primarily for patients with MDS, excluding MP-CMML patients.^104,105 The MD Anderson prognostic system (MDAPS) is CMML specific and identified a HB level <12 gm/dl, presence of PB immature myeloid cells (IMC), absolute lymphocyte count (ALC) >2.5 x 10⁹/L and ≥ 10% BM blasts as independent predictors for inferior OS.⁴³ The MDAPS was subsequently applied to 212 CMML patients in the Dusseldorf registry¹⁰⁶; in a univariate analysis circulating IMC had no prognostic impact, while on multivariable analysis, elevated lactate dehydrogenase, BM blast count >10%, male gender, HB <12 gm/dl and ALC >2.5 x 10⁹/L were independently prognostic.¹⁰⁶

The Global MDAPS (2008) was developed for patients with de novo MDS, secondary MDS and CMML (n=1,915).¹⁰⁷ Independent prognostic factors included; older age, poor performance status, thrombocytopenia, anemia, increased BM blasts, leukocytosis (>20 x 10⁹/L), chromosome 7 or complex cytogenetic abnormalities and a prior history of red blood cell transfusions.¹⁰⁷ This model identified 4 prognostic groups with median survivals of 54 (low), 25 (intermediate-1), 14 (intermediate-2) and 6 months (high), respectively.¹⁰⁷ The CMML-specific prognostic scoring system (CPSS) identified 4 variables as being prognostic for both OS and AML-FS; FAB and WHO CMML-subtypes, red blood cell transfusion dependency, and the Spanish cytogenetic risk stratification system. ^10,44 One point was accorded for each variable, with the exception of high risk cytogenetics which earned 2 points, and four risk categories were determined: low (0 points), intermediate-1 (1), intermediate-2 (2-3), and high risk (4-5).¹⁰

The discovery of gene mutations in CMML has resulted in the development of molecular prognostic models. A Mayo Clinic study (n=226) analyzed several parameters, including ASXL1 mutations; on multivariable analysis, risk factors for survival included HB <10 gm/dl, platelet count <100 x 10⁹/L, AMC>10 x 10⁹/L and circulating IMC.¹⁰⁸ ASXL1 mutations did not impact either the OS or the AML-FS. The study resulted in the development of the Mayo prognostic model, with three risk categories, low (0 risk factor), intermediate (1 risk factor) and high (≥2 risk factors), with median survivals of 32, 18.5 and 10 months, respectively.¹⁰⁸ The GFM demonstrated an adverse prognostic effect for ASXL1 mutations in 312 patients with CMML; additional risk factors on multivariable analysis included age >65 years, WBC >15 × 10⁹/L, platelet count <100 × 10⁹/L and HB <10 gm/dl in females and <11 gm/dl in males.⁵¹ The GFM model assigns 3 adverse points for WBC >15 × 10⁹/L and 2 adverse points for each one of the remaining risk factors, resulting in a three-tiered risk stratification; low (0–4 points), intermediate (5–7) and high (8–12), with respective median survivals of 56, 27.4 and 9.2 months.⁵¹ It should be noted that all nucleotide variations (missense, nonsense and frameshift) were regarded as ASXL1 mutations in the Mayo study,¹⁰⁸ whereas only nonsense and frameshift ASXL1 mutations were considered in the French study⁵¹.

To further clarify the prognostic relevance of ASXL1 mutations, an international collaborative cohort of 466 CMML patients was analyzed.⁴⁶ In univariate analysis, survival was adversely affected by truncating ASXL1 (nonsense and frameshift) mutations. In multivariable analysis, ASXL1 mutations, AMC >10 × 10⁹/L, HB <10 gm/dl, platelets <100 × 10⁹/L and circulating IMC were independently predictive of shortened OS. A regression coefficient-based prognostic model based on these five risk factors delineated high (≥3 risk factors; HR 6.2, 95% CI 3.7–10.4) intermediate-2 (2 risk factors; HR 3.4, 95% CI 2.0–5.6) intermediate-1 (one risk factor; HR 1.9, 95% CI 1.1–3.3) and low (no risk factors) risk categories with median survivals of 16, 31, 59 and 97 months, respectively.⁶³ This model is referred to as the Mayo Molecular Model (MMM). Recently the CPSS model was updated to include molecular abnormalities including ASXL1, RUNX1, NRAS and SETBP1 mutations (CPSS-Mol).¹⁰⁹ These mutations, in addition to the prior CPSS cytogenetic scores were used to calculate the CPSS genetic score. One point each was assigned for an intermediate-1 genetic score, WBC ≥ 13 x 10⁹/L, BM blasts≥ 5% and red blood cell transfusion dependency, 2 points for intermediate-2 genetic score and 3 points for a high risk genetic score.¹⁰⁹ The CPSS-Mol stratified CMML patients into four risk categories, low (0 risk factors), intermediate-1(1 risk factor), intermediate-2 (2-3 risk factors) and high (≥4 risk factors) risk, with median OS of not reached, 64, 37 and 18 months; with respective 4-year leukemic transformation rates of 0%,3%, 21% and 48%.¹⁰⁹ Table 3 highlights the CMML specific prognostic models along with their relevant components.

Table 3:

Prognostic scoring systems for chronic myelomonocytic leukemia

Prognostic Score	Year	Number of Patients	External Validation	Variables included in the final model	Median Survival in months				Transformation into AML
					Low risk	Intermed iate-1 risk	Intermed iate-2 risk	High risk
Onida et al (MDAPS)	2002	213	No	1. Hemoglobin <12 gm/dL 2. Circulating immature myeloid cells 3. Absolute lymphocyte count >2.5 x 109/L 4. Bone marrow blasts >10%	24	15	8	5	19% developed AML after a median time of 7 months
Germing et al (Dusseldorf score for CMML)	2004	288	No	1. Bone marrow blasts ≥5% 2. LDH >200 U/L 3. Hemoglobin ≤9 gm/dl 4. Platelets ≤100 x 109/L	93	26		11	8%, 23% and 23% at 5 years, respectively
Such et al (CPSS Model)	2013	578	Yes, in 274 patients	1. CMML FAB type 2. CMML WHO type 3. CMML-specific cytogenetics 4. RBC transfusion dependence	72	31	13	5	Probability of AML evolution at 5 years, 13%, 29%, 60%, and 73%, respectively
Itzykson et al (GFM Model)	2013	312	Yes, 165 patients	1. Age >65 years 2. WBC >15x109/L 3. Anemia 4. Platelets <100 x109/L 5. ASXL1 mutation	Not reached	38.5		14.4	AML-free survival was 56.0, 27.4, and 9.2 months, respectively
Patnaik et al (Mayo Model)	2013	226	Yes, 268 patients	1. Increased absolute monocyte count >10×109/L 2. Presence of circulating blasts 3. Hemoglobin <10 gm/dL 4. Platelet count <100 ×109/L	32	18.5		10	NR
Patnaik et al (Mayo Molecular Model)	2014	466	No	1. Increased absolute monocyte count >10×109/L 2. Presence of circulating blasts 3. Hemoglobin <10 gm/dL 4. Platelet count <100 ×109/L 5. Frameshift and nonsense ASXL1 mutations	97	59	31	16	At a median follow up of 23 months, 75 (16%) leukemic transformations occurred.
Elena et al (CPSS-Mol)	2016	214	260	1. Genetic risk groups as defined by *CPSS cytogenetic risk stratification and gene mutations involving ASXL1, NRAS, SETBP1 and RUNX1. 2. Bone marrow blasts ≥ 5%. 3. WBC count ≥ 13x109/L 4. Red blood cell transfusion dependancy	Not reached	64	37	18	48 months cumulative incidence of AML evolution; 0%, 3%, 21% and 48%, respectively.

Key: MDAPS- MD Anderson Prognostic Scoring System, CPSS- CMML specific prognostic scoring system, CMML- chronic myelomonocytic leukemia, GFM- Groupe Francophone des Myélodysplasies, LDH- lactate dehydrogenase, FAB- French American British, WHO – World Health Organization, WBC- white blood cell count.

The CPSS-Mol used a genetic risk group stratification that assigned a score of 0 for low-risk cytogenetics and absence of ASXL1/NRAS/SETBP1/RUNX1 mutations, a score of 1 for intermediate risk cytogenetics and mutations involving ASXL1/SETBP1 and NRAS, and a score of 2 for high-risk cytogenetics and RUNX1 mutations

Seven clinical prognostic models, not incorporating ASXL1 mutational status (IPSS, R-IPSS, MDAPS, Global MDAPS, Dusseldorf, CPSS and Mayo model) were statistically compared in a large dataset of CMML patients (n=1832).¹⁰⁴ All seven models were found to be valid with comparable performance, but were vulnerable to upstaging.¹⁰⁴ Recently, a post allogeneic stem cell transplant (HSCT) prognostic model has been proposed that accurately predicts for post HSCT survival and non-relapse mortality (NRM).¹¹⁰ This model assigns 4 points for NRAS and/or ASXL1 mutations, 4 points for BM blasts >2% and 1 point for each addition to the HSCT comorbidity index.¹¹⁰

POST CMML-BLAST TRANSORMATION (CMML-BT)

Rates of leukemic transformation (AML) vary among different series of CMML patients, with an approximated incidence of 15-30%.^111-113 Risk factors identified have included high risk karyotype, PB blast %, circulating IMC, AMC >10 x 10(9)/L, ASXL1, RUNX1, NRAS, SETBP1, DNMT3A and NPM1 mutations.^114-116 In a large study of 171 patients with post CMML-BT the median OS was 6 months, with 1-,3-,5-year survival rates of 25%,9% and 6% respectively.¹¹⁷ With the exception of a modest survival benefit from allogenic HCT (5-year survival 21%), all other treatment modalities, including AML-like induction chemotherapy were associated with dismal outcomes (5-year survival <10%).¹¹⁷ Post-BT survival was negatively impacted by PB blast%, prior exposure to HMA, ELN (European Leukemia Net) high risk cytogenetics and a failure to reach a CR/CRi (complete remission/ CR with incomplete recovery of counts) with BT-directed therapies.¹¹⁶ Rare occurrences of CMML BT to blastic plasmacytoid dendritic cell neoplasms (BPDCN) secondary to specific molecular and copy number alterations have been documented, indicative of common clonal origins.¹¹⁸ It is important to note that genetic alterations involving protein coding regions, including copy number gains and losses in driver mutations were only able to explain 44% of CMML cases that transformed to AML, indicating that mechanisms of AML transformation remain to be elucidated.⁶

CMML-SPECIFIC RESPONSE CRITERIA

Traditionally, given the overlap with MDS, responses to drug therapies in CMML were adjudicated using the International Working Group (IWG) MDS criteria.¹¹⁹ However, in 2015, the IWG MDS/MPN working group formulated specific disease response criteria for MDS/MPN overlap syndromes, including CMML.¹²⁰ These response criteria incorporated proliferative aspects of the disease such as monocytosis and splenomegaly and similar to MPN, proposed the development of a total symptom score (TSS) for CMML. These criteria include a clinical benefit category that apart from HB, platelet and neutrophil responses also includes spleen and TSS response scores.¹²⁰ While these criteria await prospective validation in clinical trials, they have been validated retrospectively in CMML-specific HMA response assessment studies.^121,122

RISK ADAPTED THERAPY

After its inclusion as a specific category of myeloid neoplasms in the 2008, WHO classification, treatment options for CMML have evolved. In the late 1990’s, major treatment options consisted of chemotherapy such as etoposide, cytarabine, all-trans retinoic acid,^123-125 topotecan,^126,127 9-nitro-campothecin (topoisomerase inhibitor),¹²⁸ and lonafarnib (farnesyltransferase inhibitor).¹²⁹ Collectively, response rates in these trials were disappointing and therapy was associated with significant toxicities. The first breakthrough in the management of CMML came with the development of DNA methyltransferase inhibitors (DNMTi), also called HMA.

A]. Hypomethylating agents:

HMA such as 5-azacitidine, decitabine and oral decitabine with cedazuridine (cytidine deaminase inhibitor) remain the only US FDA approved agents for the management of CMML, with approval based on the inclusion of small numbers of CMML patients in MDS-predominant clinical trials. The pivotal North American CALGB study (n=191) only included 14 CMML patients; 7 being assigned to the 5-azacitidine arm and 7 to the best supportive care (BSC) arm,¹³⁰ while the European AZA-001 study, only included 11 patients with CMML (all MD-CMML), with 6 being assigned to the 5-azacitidine arm and 5 being assigned to BSC.¹³¹ Ever since, data with regards to HMA efficacy in CMML has been largely retrospective, or from MDS based phase II studies that included CMML patients, with overall response rates (ORR) ranging from 40-50% and true CR rates being <20%.^132-141 A smaller prospective phase II study of decitabine in CMML (n=43) demonstrated a CR rate of 16%, with an ORR of 47%.¹⁴² The lack of efficacy of HMA in MP-CMML subtypes was further highlighted by a prospective randomized phase III clinical trial assessing the efficacy of decitabine versus hydroxyurea in higher risk MP-CMML patients (n=170, decitabine n=84 and hydroxyurea n= 86; DACOTA trial-NCT02214407).¹⁴³ The primary endpoint of the trial was event free survival (EFS), with an event being defined as death or transformation to AML. Higher risk MPN-CMML was defined by the presence of extramedullary disease or ≥2 of the following criteria; BM blasts >5%, ANC≥16 x 10⁹/L, HB <10 gm/dl, platelet count <100,000/ml and spleen size >5 cm below the left costal margin.¹⁴⁴ At last followup (median 17.5 months), the trial demonstrated no significant advantage of decitabine over hydroxyurea in MP-CMML, with a median EFS of 12.1 months in the decitabine arm and 10.3 months in the hydroxyurea arm (HR 0.83, 95% CI 0.59-1.16; p=0.27). Although decitabine significantly reduced the risk of CMML progression to AML (cause specific HR 0.62; 95% CI 0.41 to 0.94; p= .005), it was associated with higher mortality (cause specific HR 1.55; 95% CI 0.82 to 2.9; p= .0 OS), with the median OS being 18.4 months for decitabine versus 23.1 months for hydroxyurea (p=0.72).¹⁴³ A complete list of the studies, including the dose and schedule of the drugs used, toxicities, response rates and survival are shown in Table 4.

Table 4:

Use of hypomethylating agents in chronic myelomonocytic leukemia

Reference	Number of patients	Median Age (years, range)	Phase of Study	Treatment Regimen	Response Rates	Toxicity	Median Survival	Progression to Acute Myeloid Leukemia
Aribi (2007)	19	66 (44-82)	II	Decitabine 100 mg/m2 per course in three different schedules, repeated every 4 weeks	CR: 58% HI: 11%	Myelosuppression associated complications: 8%	19 months	NR
Wijermans (2008)	31	71 (53-81)	II	Decitabine 15 mg/m2 over 4 hours IV three times per day on three consecutive days, with a total dose of 135 mg/m2 per course, every 6 weeks	CR: 10% PR: 16% HI: 19%	Nausea, vomiting, pneumonia, mortality due to sepsis: 3%	15 months	NR
Costa (2010)	38	70 (36-83)	II	Azacitidine 75 mg/m2/day for 7 days or 100 mg/m2/day for 5 days every 4 weeks	CR: 11% PR: 3% HI: 25%	Pneumonia, mortality due to sepsis: 3%	12 months	NR
Garcia-Manero (2011)	41 (4 with CMML)	70 (31-91)	I	1 cycle of subcutaneous azacitidine 75 mg/m2 on the first 7 days of cycle 1, followed by oral azacitidine daily,120 to 600 mg, on the first 7 days of each additional 28-day cycle	ORR: 35% in previously treated patients and 73% in previously untreated patients	diarrhea, nausea, vomiting, febrile neutropenia, fatigue	NR	NR
Braun (2011)	39	71 (54-88)	II	Decitabine 20 mg/m2 per day intravenously for 5 days every 28 days	CR: 10% PR: 20% HI: 8% ORR: 38%	Neutropenia and thrombocytopenia (36%), severe infection (20%)	18 months	NR
Thorpe (2012)	10	66 (41-76)	II	Azacitidine 75 mg/m2 for 7 days or azacitidine 100 mg/m2 for 5 days every 28 days	CR: 20% HI: 40% ORR: 60%	Thrombocytopenia, pneumonia (20%)	29 months	NR
Ades (2013)	76	70 (33-85)	II	Azacitidine 75 mg/m2 for 5-7 days every 28 days	CR: 17% PR: 1% Marrow CR: 8% HI: 17% ORR: 43%	NR	29 months	31% after 1.2 years from azacitidine initiation
Wong (2013)	11	65 (42-80)	II	Azacitidine 75 mg/m2 for 7 days every 28 days	CR: 9% Marrow CR: 27% PR: 9% HI: 9% ORR: 55%	Local skin reactions (55%), nausea (36%), infection (73%)	17 months	18%
Fianchi (2013)	31	69 (53-84)	II	Azacitidine 50-75 mg/m2 for 7 days in 22 patients, and 100 mg flat dose for 5-7 days in 9 patients	CR: 45% PR: 3% HI: 6% ORR: 54%	Grade 4 thrombocytopenia (6%), grade 4 anemia (6%)	37 months	16% after 12.7 months
Santini (2013)	44	71 (42-84)	II	Decitabine 20 mg/m2 for 5 days, every 28 days	CR: 14% PR: 2% Marrow CR: 17% ORR: 33%	Severe infections (17%)	19 months	NR
Pleyer (2014)	48	71 (38-87)	II	Azacitidine 75 mg/m2 for 7 days in 42 patients, and 100 mg flat dose for 5-7 days in 6 patients	CR/marrow CR: 13% HI: 50% ORR: 54%	Grade 3-4 cardiac events (21%)	12.6 months	4% after 9 months
Drummond (2014)	32	70 (57-85)	II	Azacitidine 75 mg/m2 for 7 days, every 28 days	CR: 7% PR: 0 Marrow CR: 7% HI:3% ORR: 17%	NR	16 months	33% after 13 months
Sekeres (2017)	53 with CMML	70 (28-93)	Randomized phase II	Azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); Azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or Azacitidine plus vorinostat (300 mg twice daily on days 3 to 9).	ORR: 38% (68% in the azacitidine and lenalidomide arm)	Azacitidine plus lenalidomide associated with higher incidence of skin rashes, while azacitidine and vorinostat with a higher incidence of Gastrointestinal side effects	Not reached	NR
Santini (2018)	43	71.5 (42-84)	II	Decitabine 20 mg/m2 for 5 days, every 28 days	CR: 16% PR: 2.4% Marrow CR: 19% HI: 9.5% ORR: 47.6%	Thrombocytopenia (64%) Anemia (52%) Gastrointestinal side effects (23.8%)	17 months	57.5%after 51.5 months
Itzykson (2020)	170	73 (68-78)	III	Phase III randomized trial of hydroxyurea versus decitabine 20 mg/m2 for 5 days	Decitabine 6-month ORR-32% [6 CR, 9mCR+HI, 12 SD+HI] Hydroxyurea 6-month ORR-17% [2CR, 4 mCR+HI, 9 SD+HI]	Infections (49%) Hemorrhage (31%)	Median survival for decitabine 18.4 months Median survival for hydroxyurea 23.1 months (p=0.72)	Median AML-free survival for decitabine 13.6 months Median AML-free survival for hydroxyurea 15.8 months (p=0.86)

Abbreviations Used:

CR: complete remission; mCR- marrow CR; PR: partial remission; HI: hematologic improvement; SD: stable disease; ORR: overall response rate; NR: not reported; CMML: chronic myelomonocytic leukemia; AML-acute myeloid leukemia.

Predictors of HMA response remain difficult to identify. In a recent study of 174 HMA treated CMML patients [ORR-52% and CR-17%], ASXL1 mutations predicted a lower ORR, whereas the ASXL1wt/TET2mt genotype was associated with higher CR rates (OR 1.18; p=0.01); with CMML-specific prognostic models having limited predictive ability.¹²¹ In a similar Mayo Clinic study, lower serum LDH levels were associated with HMA responses; with ASXL1/TET2 mutations having no impact.¹²² In this study, the median OS of CMML patients with primary HMA failure was 4 months, with 29% of HMA-treated patients in a CR undergoing BT.¹²² In a pivotal study, serial whole exome sequencing (WES) of HMA-treated CMML patients demonstrated that these agents do not alter the mutational allele burdens, even in responding patients.⁴⁷ The hematological responses obtained are often not durable, and are associated with significant changes in DNA methylation arguing for an epigenetic restoration of normal hematopoiesis, with recent evidence showing that the mutant progenitor cells also contribute to hematopoietic restoration on HMA exposure.^47,145

B]. Novel CMML-directed therapies:

Conventional genetic targets such as IDH1, IDH2 and FLT3 mutations are not frequent In CMML (<5%) and hence formal studies assessing the safety and efficacy of these inhibitors in CMML are not available, with limited evidence being restricted to case reports/series.¹⁴⁶ The addition of the BCL2 inhibitor venetoclax to HMA has significantly improved response rates and survival outcomes in patients with AML and awaits formal prospective assessment in CMML, with preclinical and retrospective data not being encouraging.^147-149 Preclinical data has demonstrated that in CMML, monocytes are resistant to apoptosis largely due to MCL1, with minimal dependency on BCL2. This is further potentiated in an autocrine fashion by the cytokine like protein 1 (CYTL1), which increases ERK signalling through CCR2 (chemokine receptor 2), with in vitro studies with BCL2 inhibitors confirming minimal BCL2 dependancy. ¹⁵⁰ Retrospective data including patients with CMML and CMML-BT have shown modest responses to combination therapy with HMA and venetoclax, with the exception of the ability of this combination to effectively cytoreduce younger patients as a bridge to allogeneic HSCT.^148,149 Targeting MCL1 and CCR2 remain interesting approaches in CMML and are currently undergoing preclinical assessments.

JAK/STAT inhibitors are also being explored in CMML. A recent phase I/II clinical trial (n=50) has demonstrated safety and potential efficacy of ruxolitinib (JAK 1/2 inhibitor) in patients with CMML.^151,152 The ORR as defined by the 2015 IWG MDS/MPN criteria was 38%, with 43% of patients demonstrating a spleen response.¹⁵² The drug was relatively well tolerated with grade 3/4 anemia being seen in 10% and thrombocytopenia in 6% of patients, respectively. Additional JAK/STAT inhibitors being pre-clinically assessed include momelotinib and pacritinib.¹⁵³ Given the inherent, demonstrable, GM-CSF dependent pSTAT5 (phosphorylated Signal Transducer and Activator of Transcription 5) sensitivity in CMML patients, targeted anti-GM-CSF monoclonal antibody therapy (Lenzilumab) has been tested (NCT02546284).^91,154 In a phase 1 clinical trial of 15 patients, the ORR was 33.3% (3 platelet responses, 1 neutrophil response and 1 partial marrow CR).¹⁵⁴ The drug was very well tolerated with minimal side effects. Phase 2 combination studies with HMA are currently underway.

Based on preliminary data demonstrating rationale and preclinical efficacy of PLK1 inhibition in RAS-mutant CMML, the novel, oral, PLK1 inhibitor, Onvansertib, is currently being tested in hydroxyurea and/or HMA relapsed, refractory, or intolerant patients (NCT05549661).⁶ Similarly, given that high dose IV ascorbic acid can enhance unmutant TET2 and TET3 catalytic activity, there is a pilot study assessing high dose IV ascorbic acid with decitabine in newly diagnosed CMML (NCT03418038). Elaborate epigenetic studies have shown that ASXL1 mutant CMML patients have a unique gene expression profile, enriched in leukemia stemness genes like HOXA6–9 and MEIS1 and that these genes are regulated by unique transcription factors and enhancer regions that can be modulated by BRD4 inhibition.⁶⁴ EP31670, is a novel, oral, dual BRD4/p300 inhibitor that is being tested in ASXL1 mutant relapsed/refractory CMML (NCT05488548). Tipifarnib, a farnesyl transferase inhibitor (NCT02807272), SL-401 (Tagraxofusp), a recombinant fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a Met-His linker to IL3.11 (NCT02268253) and Cobimetinib, a MEK inhibitor (NCT04409639), have undergone assessments in CMML, with modest responses. Given the high frequency of spliceosome mutations in CMML (SRSF2), several spliceosome inhibitors are also being explored for biological and disease modulating activity.

C]. Allogeneic Stem Cell Transplantation

Allogeneic HSCT remains the only curative option for patients with CMML. However, due to the advanced median age at diagnosis and existing comorbidities, is an option to a small fraction of patients (approximately 10%).¹⁵⁵ This modality is however fraught with complications including, acute and chronic graft versus host disease (GVHD), non-relapse mortality and post-transplant disease relapse. There unfortunately exists no prospective data analyzing the risks and benefits for HSCT in CMML. The response rates in retrospective studies have ranged from 17% to 50%, with corresponding treatment related mortality rates ranging from 12% to 52% (Table 5).^156-163 The 10-year OS of 85 patients who underwent HCT at Fred Hutchinson Cancer Center was 40%. A multivariable model identified increasing age, higher HCT comorbidity index and poor-risk cytogenetics to be associated with increased mortality and reduced relapse-free survival (RFS).¹⁵⁶ In one of the largest retrospective cohorts involving 513 CMML patients (median age 53 years), the European Group for Blood and Marrow Transplantation reported a 4-year RFS rate of 27% and an OS rate of 33%.¹⁶⁴ Engraftment was successfully documented in 95% of patients, while acute (grade2-4) and chronic GVHD occurred in 33% and 24% of patients, respectively. The achievement of CR at the time of HCT was independently associated with improved RFS and OS. Application of the CPSS model in the HSCT setting was assessed in 209 adult CMML patients from 2001 to 2012, with a median age of 57 years, followed for a median of 51 months.¹¹ On multivariate analysis, CPSS score, Karnofsky performance status and graft source were significant predictors of OS. A recent Mayo Clinic study assessed HCT in 70 CMML patients, including 24 with BT CMML.¹⁶⁵ In this study, the 5-year OS rates were 51% for chronic phase CMML and 19% for BT-CMML, respectively. The cumulative endpoint of graft versus host disease and relapse free survival was only 7 months in the chronic phase CMML cohort, underscoring the morbidity associated with HCT.¹⁶⁵ Recently, a prognostic model predicting for post HSCT survival and relapse has been proposed. In this model the presence of ASXL1 and/or NRAS mutations, BM blasts >2% (assessed as a continuous variable) and HSCT comorbidity index scores were found to be independently prognostic.¹¹⁰ This model awaits prospective validation.

Table 5:

Summary of select allogeneic stem cell transplant studies for chronic myelomonocytic leukemia (CMML)

Reference	N	Age, yrs (median)	Disease Stage	Cytogenetics	Donor Type and Stem Cell Source	Conditioning (Myeloablative, reduced intensity)	Relapse rate and Treatment- related mortality	Outcomes
Kroger (2002)	50	44 (19-61)	CMML-1: 28 CMML-2: 17 Unknown: 5	Diploid: 18 Abnormal: 11 Unknown: 21	MRD: 43 MUD: 7 BM: 40 PBSC: 9	MAC: 50 RIC: 0	RR: 28% TRM: 52%	5-year OS: 21% 5-year DFS: 18%
Mittal (2004)	8	51 (20-64)	NR	Diploid: 3 Abnormal: 4 Unknown: 1	MRD: 6 MUD: 2 BM: 4 PBSC: 4	MAC: 4 RIC: 4	RR: 50% TRM: 12%	18 month OS: 35% 18 month DFS: 31%
Elliott (2006)	17	50 (20-60)	NR	Diploid: 9 Abnormal: 8	MRD:14 MUD:3 BM: 8 PBSC: 7	MAC: 16 RIC: 1	RR: 41% TRM: 41%	3 year OS: 18% 3-year RFS: 18%
Ocheni (2009)	12	56 (38-67)	CMML-1: 7 CMML-2: 3 Unknown: 2	Diploid: 7 Abnormal: 4 Unknown: 1	MUD: 11 MRD: 1 BM: 0 PBSC: 12	MAC: 7 RIC: 6	RR: 17% TRM: 25%	2-year OS: 75% 2-year DFS: 67%
Krishnamurthy (2010)	18	54 (38-66)	CMML-1: 8 CMML-2: 10	Diploid: 7 Abnormal: 11	MRD: 10 MUD: 8 BM: 6 PBSC: 12	MAC: 1 RIC: 17	RR: 44% TRM: 31%	3-year OS: 31% 3-year DFS: 47% (< 5% blasts) 3-year DFS: 20% (>5 % blasts)
Symeonidis (2010)	283	50 (NR)	CMML-MDS:45 CMML-MPN:60 Unknown: 178	NR	MRD: 160 MUD: 85 Unknown: 38 BM: 108 PBSC: 175	MAC: 152 RIC: 87	RR: 25% TRM: 37%	OS: 42% DFS: 38% (time interval not specified)
Eissa (2011)	85	51 (1-69)	CMML-1: 57 CMML-2: 26	Good: 45 Intermediate: 14 Poor: 22	MRD: 38 MUD: 47 BM: 32 PBSC: 53	MAC: 58 RIC: 27	RR (10 yrs): 27% TRM (10 yrs): 35%	10-year OS: 40% 10-year DFS: 40%
Park (2013)	73	53 (27-66)	CMML-1: 40 CMML-2: 29	Good: 48 Intermediate: 13 Poor: 9	MRD: 41 MUD: 32 BM: 27 PBSC: 46	MAC: 30 RIC: 43	RR (3 yrs): 35%	3-year OS: 32% 3-year DFS: 29%
Itonaga (2013)	141	49 (NR)	NR	NR	MRD: 68 MUD: 53 Cord: 10	MAC: 101 RIC: 40	NR	3-year OS: 47%
Duong (2015)	209	57 (23-74)	CPSS low/intermediate-1- 88 (42%) Intermediate-2/high- 79 (38%) Missing- 42	CPSS Cytogenetic groups Low- 50% Intermediate-19% High- 17% Missing- 14%	MRD: 35% MUD: 45% MMUD: 19% BM: 16% PBSC: 84%	MAC: 51% RIC: 41% NMA: 5%	NR	OS at 1, 3 and 5 years for CPSS low /intermediate-1: 61%, 48%, 41%. Intermediate-2/high- 38%, 32%, 19%
Symeonidis (2015)	513	53 (18.5-75.4)	CMML-MDS:73 CMML-MPN: 110 CMML-1: 87 CMML-2: 32 Secondary AML- 95	Normal- 104 Abnormal- 60	MRD: 285 MUD: 228 BM: 119 PBSC: 394	MAC- 249 RIC- 226	RR (4yrs): 32% NRM (4yrs): 41%	4-year OS: 33% 4-year DFS: 27%
Liu HD (2017)	209	57 (23-74)	CMML-1: 140 (67%) CMML-2: 52 (25%) Missing: 17 (8)	NR	MRD: 73 MUD: 95 MMUD: 36	MAC: 105 RIC: 99 Missing: 5	RR (1,3 and 5 yrs.): 46%, 50% and 52% TRM (1,3 and 5 years): 19%, 23% and 28%	OS at 1,3 and 5 years: 50%, 38% and 30%.
Pophali (2020)	70	58 (18-73)	CMML chronic phase- 46 CMML blast transformation- 24	Mayo French Cytogenetic score Low- 279 (73) Intermediate - 74 (19) High- 31 (8)	MRD- 28 (42) MMRD- 1 (2) MUD- 30 (45) MMUD- 3 (4) Umbilical cord blood- 2 (3) Haplo- 3 (4)	MAC- 31 (46) RIC- 37 (54)	RR 27%, chronic phase CMML - 24%, CMML blast transformed 33% TRM- 20%, RIC-%, MAC - 32%	5-year OS- 51% for chronic phase CMML and 19% for blast transformed CMML GVHD-relapse free survival 7 months for chronic phase CMML

Abbreviations Used:

N: total number of patients, yrs: years, CMML-1: chronic myelomonocytic leukemia-1, CMML-2: chronic myelomonocytic leukemia-2, AML- acute myeloid leukemia, CMML-MDS: chronic myelomonocytic leukemia-myelodysplasia type, CMML-MPN: chronic myelomonocytic leukemia- myeloproliferative type, MRD: matched related donor, MMRD: mismatched related donor, MUD: matched unrelated donor, MMUD: mismatched unrelated donor, Haplo: haploidentical donor, BM: bone marrow donor, PBSC: peripheral blood stem cell donor, MAC: myeloablative conditioning, RIC: reduced intensity conditioning, NMA: non myeloablative, RR: relapse rate, TRM: treatment-related mortality, NRM: non relapse mortality, OS: overall survival, DFS: disease-free survival; NR: not reported, CPSS- CMML specific prognostic scoring system.

In general, for younger patients with higher risk disease and an acceptable co-morbidity index, allogeneic HSCT is the preferred treatment modality.⁷⁴ With the advent of reduced intensity conditioning and alternate donor sources (haploidentical HSCT and double umbilical cord blood units), an increasing number of patients have access to HSCT. While reduced intensity conditioning is associated with lower non-relapse mortality, disease relapse rates are higher in comparison to myeloablative regimens.^166,167 Similar to MDS, cytoreductive therapy or HMA are often considered prior to HSCT in patients with increased BM blasts (CMML-2) or prior to a reduced intensity conditioning.¹⁶⁸ While a retrospective study (n=83) did demonstrate that prior therapy with HMA followed by allogeneic HSCT was associated with a lower cumulative incidence of relapse (22% versus 35%; p=0.03), without a significant increase in the one-year transplant related mortality, these findings await prospective validation.¹⁶⁹ The pre-HSCT use of HMA can be a double edged sword, with HMA sometimes contributing to worsening cytopenias and increased transfusion dependance, with consequent alloimmunization. Figure 7 highlights our treatment approach for patients with CMML, with risk stratification being conducted using the Mayo Molecular Model.

Figure 7:

How we diagnose and treat CMML. CMML risk stratification was conducted using the Mayo Molecular Model.

Abbreviations: CMML- chronic myelomonocytic leukemia, HSCT- hematopoietic stem cell transplant, MP- myeloproliferative CMML, MD- myelodysplastic CMML, DNMTi- DNA methyltransferase inhibitors, ESA- erythropoiesis stimulating agent therapy, MMF- mycophenolate mofetil.

Recommendations:

Hydroxyurea remains the cornerstone of therapy for patients with myeloproliferative features. Guidelines for supportive care measures such as the use of erythropoietin analogs for the treatment of anemia, prophylactic antibiotics for isolated neutropenia and iron chelation therapy for patients with a heavy transfusion burden are in general like guidelines for patients with MDS, and data for their use specifically in patients with CMML do not exist. Hypomethylating agents remain the only approved drugs for the management of CMML and are associated with ORR of 40-50% and true CR rates of <20%. While HMA epigenetically restore hematopoiesis in a subset of responding patients, mutational allele burdens remain unaffected and disease progression remains inevitable. Predictors of response to HMA remain challenging, with some suggestions that the ASXL1^WT/TET2^MT genotype might be most predictive. Thus, allogenic HSCT, a procedure applicable only to a minority of affected patients remains the only curative option but is fraught with morbidity and mortality. Given the dismal outcomes of CMML-BT, standard induction chemotherapy followed by allogeneic HCT should be considered for all eligible patients. The development of CMML-specific response criteria is a major step forward and given the poor responses to currently available therapies, enrollment in CMML-specific clinical trials should be strongly encouraged.

CONCLUSION

CMML, a myeloid neoplasm with features of MDS and MPN, often presents with PB monocytosis and has an inherent risk for transformation to AML. Clonal cytogenetic changes are seen in ~30% of patients, while gene mutations are seen in >95% of patients, with common abnormalities involving; epigenetic regulators (TET2~60% and ASXL1~40%), spliceosome components (SRSF2~50%) and cell signaling (oncogenic RAS~30%). Of these, only frameshift and nonsense ASXL1 mutations have universally been shown to negatively impact OS and have been included in molecularly integrated prognostic models like the Mayo Molecular Model, GFM model and the CPSS-Mol. Lower risk CMML patients that present with MPN-like features are effectively managed with hydroxyurea. Hypomethylating agents are associated with overall response rates of ~ 40-50%, with complete remission rates of <20%. These responses are generally not sustained, do not alter mutational allele burdens, and survival after loss of response is often dismal (<6 months). Allogeneic HSCT remains the treatment of choice for younger patients with higher risk disease. Complications of HSCT including non-relapse mortality, acute and chronic graft versus host disease, limit generalized applicability of this treatment strategy. The development of CMML-specific disease response criteria and clinical trials exploiting genetic and epigenetic vulnerabilities are important future directions to look forward to.¹²⁰