CMML

 Reference: CMML How I treat

Reference: Teferri American Journal of Hematology 2024

CMML is relatively homogeneous, demonstrating approximately 10-12 somatic variants per kilobase of coding region, with most pathogenic variants involving TET2 (60%), ASXL1 (40%), SRSF2 (50%) and RAS pathway (30%) genes. Broadly, CMML can be classified into dys-plastic CMML (dCMML), presenting with cytopenias and clinical signs and symptoms related to the same (fatigue, bruising and transfusion dependence) and proliferative CMML (pCMML), presenting with significant myeloproliferation, extramedullary hematopoiesis and associated constitutional symptoms :fever, weight loss, night sweats, anorexia, pruritus, bone pain and cachexia.

CMML inherent risk to transform to acute myeloid leukemia (AML; 15%–20% over 3–5 years

Pearls:

1. Unlike in MDS, MPN or AML, TP53 mutations are extremely infrequent in CMML (<1%), and are only really encountered at the time of CMML to AML transformation, or in the context of therapy-related CMML

2. In the absence of dysplasia, a diagnosis of CMML can be made if the monocytosis has persisted for ≥3 months, reactive causes have been excluded, or somatic cytogenetic or molecular markers frequent in CMML (e.g., ASXL1, TET2, SRSF2 and SETBP1) can be documented.

3. 2022: Threshold for monocytosis now >0.5 not 1.0- the ICC and WHO criteria are different. Peripheral monocytosis > 10%.  ICC needs cytopenia, WHO 2022 needs bone marrow dysplasia in one or more myeloid lineages > 10%.

4. Chromosomal translocations/rearrangements involving PDGFRA and PDGFRB can give rise to myeloid neoplasms, often characterized by prominent eosinophilia and responsiveness to imatinib. Among these, PDGFRB-rearranged myeloid neoplasms can be associated with absolute monocytosis (<1% of all cases morphologically diagnosed as CMML), usually with concomitant eosinophilia, and given their unique responsiveness to imatinib are best classified as molecularly defined neoplasms and not as CMML.

5. Causes of monoctyosis: Reactive monocytosis is very common in practice and while viral infections and recovering bone marrow (from injury, drugs or chemotherapy) are frequent causes, sustained reactive monocytosis is more common in chronic infections such as subacute bacterial endocarditis, tuberculosis, brucellosis, leishmaniasis and leprosy and in autoimmune/inflammatory disorders such as systemic lupus erythematosus, sarcoidosis and mixed connective tissue disorder. Reactive monocytosis can also be seen in the context of metastatic visceral neoplasms, either due to enhanced mobilization of monocytes from the bone marrow, or due to increased monopoiesis.

6. CMML is the most frequent hematologic neoplasm associated with SM. Always assess CMML for coexistent mastocytosis with tryptase level and aberrant expression of CD2 and CD25 on mast cells.

7. Oligoclonal CMML usually evolves ( greater than 0.5 ). Now this is considered CMML.

8. monocyte repartitioning by flow: useful tool to differentiate between JAK 2 associated CMML versus MPN with monocytosis.

9. Prognosis: MD Anderson CMML model and Mayo CMML prognostic models

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 versus 18.4 months, respectively, despite response rates being higher for decitabine (56% vs. 31%).

In other words, in proliferative CMML HMA are only as good as hydroxyurea.

 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 and 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.

Unique Disease Associations

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