What is the treatment approach for a patient with myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) who also has chronic myelomonocytic leukemia (CMML)?

Treatment Approach for CMML

Treatment of CMML must be stratified by disease phenotype (myelodysplastic vs. myeloproliferative) and bone marrow blast percentage, with this two-step classification determining all therapeutic decisions. 1

Initial Classification Framework

The first critical decision point is determining whether the patient has:

• Myelodysplastic-type (MD-CMML): WBC count <13 × 10⁹/L
• Myeloproliferative-type (MP-CMML): WBC count ≥13 × 10⁹/L 1

The second decision point is bone marrow blast percentage:

• Low blast count: <10% blasts in bone marrow
• High blast count: ≥10% blasts in bone marrow (or ≥5% in peripheral blood) 1

Treatment Algorithm by Phenotype

MD-CMML with Low Blasts (<10%)

Manage with supportive therapy alone aimed at correcting cytopenias. 1

• For severe anemia (Hb ≤10 g/dL) with serum erythropoietin ≤500 mU/dL, treat with erythropoietic stimulating agents 1
• Myeloid growth factors should be reserved only for patients with febrile severe neutropenia 1
• Monitor with complete blood count monthly for first 3 months, then every 3 months 1

MD-CMML with High Blasts (≥10%)

Integrate supportive therapy with hypomethylating agents, specifically 5-azacytidine or decitabine. 1

• 5-azacytidine is the preferred hypomethylating agent based on consensus recommendations 1
• Decitabine is FDA-approved for CMML as part of the MDS spectrum 2
• Response should be assessed using IWG 2006 criteria for MDS 1
• Resistance is defined as absence of hematologic improvement after at least 6 cycles of 5-azacytidine without disease progression 1
• Consider allogeneic stem cell transplantation in selected patients within clinical trials 1

MP-CMML with Low Blasts (<10%)

Treat with cytoreductive therapy using hydroxyurea as the drug of choice. 1

• Hydroxyurea controls proliferative myelomonocytic cells and reduces organomegaly 1
• Standard dosing is at least 2 g/day for 3 months to assess response 1
• Resistance/intolerance to hydroxyurea is defined by: failure to reduce massive splenomegaly by >50% after 3 months, uncontrolled myeloproliferation (platelets >400 × 10⁹/L and WBC >10 × 10⁹/L) after 3 months, cytopenias at lowest effective dose, or unacceptable toxicities including leg ulcers 1
• Response should be assessed using IWG 2009 criteria for myelofibrosis 1

MP-CMML with High Blasts (≥10%)

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

• If allogeneic stem cell transplantation is not possible, chemotherapy is still recommended to maintain quality of life, though it is not curative 1
• This represents the most aggressive CMML phenotype with highest transformation risk to acute myeloid leukemia 3, 4

Second-Line Treatment Options

For MD-CMML with High Blasts

• Patients resistant or intolerant to 5-azacytidine who are not transplant eligible should receive supportive therapy and enrollment in experimental therapeutic studies 1

For MP-CMML Resistant to Hydroxyurea

• Without blasts (<10%): Use cytolytic therapy with VP16, low-dose cytarabine, or thioguanine as single agents 1
• Hypomethylating agents should only be used in the context of clinical trials for this population 1
• With high blast count: Treat with new and experimental therapies, as topoisomerase I inhibitors, farnesyl-transferase inhibitors, and bendamustine have shown little effect as single agents 1

Allogeneic Stem Cell Transplantation Considerations

Allogeneic stem cell transplantation is the only curative strategy but is feasible in only a minority of patients due to advanced median age (65-75 years). 1, 3, 4

• Should be offered within clinical trials in selected patients for both MD-CMML and MP-CMML 1
• HLA typing is recommended for all patients aged under 65 years 1
• Reduced intensity conditioning has improved non-relapse mortality compared to myeloablative conditioning 1

Critical Monitoring Requirements

• Patients starting therapy >3 months from diagnosis require pre-treatment re-evaluation including bone marrow aspiration, biopsy, and cytogenetic analysis 1
• Serum erythropoietin should be determined in all patients with severe anemia (Hb ≤10 g/dL) 1
• In patients not candidates for transplantation, bone marrow examination for blast count and cytogenetics should be performed annually and with any relevant hematologic changes 1

Common Pitfalls to Avoid

• Do not use the same treatment approach for MD-CMML and MP-CMML—the WBC count threshold of 13 × 10⁹/L fundamentally changes management 1
• Do not continue hydroxyurea beyond 3 months if clear resistance criteria are met, as this delays potentially more effective therapies 1
• Do not expect hypomethylating agents to alter mutational allele burdens—they epigenetically restore hematopoiesis in responders but progression remains inevitable 4
• Hypomethylating agents are particularly ineffective in proliferative CMML subtypes with RAS mutations 4