What is the management strategy for a patient with Chronic Myelomonocytic Leukemia (CMML) as part of a myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndrome with a TET2 (Ten-Eleven Translocation 2) mutation?

Management of CMML with TET2 Mutation

The presence of a TET2 mutation in CMML does not fundamentally alter the treatment approach, as management should be stratified primarily by disease phenotype (myelodysplastic vs. myeloproliferative) and blast percentage, with TET2 mutations being present in ~60% of CMML patients and actually associated with favorable prognosis when present without concurrent ASXL1 mutations. 1, 2, 3

Risk Stratification and Prognostic Implications

• TET2 mutations occur in approximately 60% of CMML patients and are among the most common molecular alterations in this disease. 4, 5, 3

• The absence of TET2 mutations (combined with presence of ASXL1 mutations) negatively impacts overall survival, while the ASXL1WT/TET2MT genotype is considered favorable. 3, 6

• Risk stratification should utilize molecularly-integrated prognostic models such as the Mayo Molecular Model (MMM), CMML-specific prognostic scoring system (CPSS-Mol), or Groupe Français des Myélodysplasies (GFM) model, which incorporate molecular information beyond just TET2 status. 7, 8, 3

• The MMM stratifies patients into four risk groups based on: truncating ASXL1 mutations, absolute monocyte count >10 × 10⁹/L, hemoglobin <10 g/dL, platelet count <100 × 10⁹/L, and circulating immature myeloid cells—with median survivals of 16,31,59, and 97 months for high, intermediate-2, intermediate-1, and low risk, respectively. 3, 6

Treatment Algorithm Based on Disease Phenotype

Myelodysplastic CMML (MD-CMML, WBC <13 × 10⁹/L)

For MD-CMML with low blast count:

• Initiate supportive therapy aimed at correcting cytopenias, focusing on symptom reduction and quality of life improvement. 1, 2
• Use erythropoietic-stimulating agents for severe anemia (hemoglobin <10 g/dL) after measuring serum erythropoietin levels. 1, 2

For MD-CMML with high blast count (CMML-2):

• Integrate supportive therapy with hypomethylating agents (azacitidine or decitabine) to reduce blast counts and improve survival. 1, 2
• Azacitidine and decitabine achieve overall response rates of 40-50% with complete remission rates of <20%, though they do not impact mutational allele burdens. 5, 3
• Define resistance as absence of hematologic improvement after at least six cycles of azacitidine without disease progression. 7

Myeloproliferative CMML (MP-CMML, WBC ≥13 × 10⁹/L)

For MP-CMML with low blast count:

• Initiate cytoreductive therapy with hydroxyurea to control proliferative myelomonocytic cells and reduce organomegaly. 1, 2
• A recent phase-3 study (DACOTA) comparing hydroxyurea versus decitabine in high-risk MP-CMML showed similar overall survival (23.1 vs. 18.4 months), despite higher response rates with decitabine (56% vs. 31%). 3

For MP-CMML with high blast count:

• Administer blastolytic therapy with polychemotherapy followed by allogeneic stem cell transplantation when feasible. 1, 2

Indications to Initiate Treatment

Therapy should be started when one of these criteria is met: 7

• Severe anemia (hemoglobin <10 g/dL)
• Peripheral blood blasts >5% (including myeloblasts, monoblasts, and promonocytes)
• Platelet count ≤50 × 10⁹/L
• WBC count ≥30 × 10⁹/L
• Immature granulocytes ≥10% in peripheral blood
• Extramedullary manifestations (cutaneous or lymph nodal involvement)
• Symptomatic splenomegaly

Allogeneic Stem Cell Transplantation

• Allogeneic HSCT remains the only potentially curative treatment option and should be considered for intermediate to high-risk patients who are eligible. 1, 2, 8

• Reduced-intensity conditioning (RIC) transplant has demonstrated improved outcomes compared to myeloablative conditioning, particularly relevant for the typical CMML patient presenting in the 7th decade of life. 7, 1, 2

• ASCT is appropriate for MMM high/intermediate-2 risk disease and should be considered earlier rather than later in eligible patients. 3

Monitoring and Response Assessment

For patients not receiving treatment:

• Obtain full blood count one month after diagnosis to assess hematologic stability. 7, 1
• For MD-CMML: monitor with full blood count and clinical examination every three months. 7
• For MP-CMML: monitor monthly for the first three months to exclude rapid WBC rise, then every three months. 7
• Perform bone marrow examination for blast count and cytogenetics once yearly and with any relevant hematologic changes. 7

For patients on treatment:

• Apply IWG 2006 response criteria for MDS in MD-CMML patients. 7
• Apply IWG 2009 response criteria for myelofibrosis in MP-CMML patients. 7
• Responses must last at least 4 weeks to be considered true treatment responses. 2

Critical Pitfalls to Avoid

• Do not delay treatment in symptomatic patients or those with high blast counts, as median overall survival for CMML is <36 months with inevitable progression to AML in most cases. 2, 5

• Do not use intensive chemotherapy in elderly patients or those with significant comorbidities without considering transplant eligibility, given that most CMML patients present in the 7th decade with high comorbidity burden. 2

• Do not fail to recognize disease evolution from MD-CMML to MP-CMML, which requires hematologic and cytogenetic re-evaluation and treatment strategy adjustment. 7, 2

• Do not neglect supportive care alongside disease-modifying therapy, including management of cytopenias, splenomegaly, and associated inflammatory/autoimmune conditions present in up to 20% of patients. 1, 8

• Do not overlook monitoring for lysozyme-induced nephropathy during leukocytosis, which requires close renal function monitoring and is a potential indication for cytoreductive therapy. 3