What are the treatment options for Chronic Myelomonocytic Leukemia (CMML)?

Treatment Options for Chronic Myelomonocytic Leukemia (CMML)

Treatment for CMML should be tailored according to the disease phenotype (myelodysplastic or myeloproliferative) and blast percentage in bone marrow, with allogeneic stem cell transplantation being the only potentially curative option. 1

Disease Classification and Initial Assessment

• CMML is classified by the WHO as a clonal hematopoietic malignancy with features of both myelodysplastic syndrome and myeloproliferative neoplasm 1
• Initial evaluation should include bone marrow aspiration and biopsy with cytogenetic analysis, peripheral blood evaluation, and molecular testing 2
• CMML is categorized into two main phenotypes:
  • Myelodysplastic CMML (MD-CMML): characterized by cytopenias 1
  • Myeloproliferative CMML (MP-CMML): characterized by leukocytosis and organomegaly 1
• Blast percentage in bone marrow is a critical factor for treatment decisions (low: <10% or high: ≥10%) 1

First-Line Treatment Options

For Myelodysplastic CMML (MD-CMML):

• With low blast count (<10% in bone marrow):

  • Supportive therapy aimed at correcting cytopenias 1
  • Erythropoietic stimulating agents for severe anemia (Hb ≤10 g/dL) with serum erythropoietin ≤500 mU/dL 1
  • Myeloid growth factors only for patients with febrile severe neutropenia 1

• With high blast count (≥10% in bone marrow, ≥5% in blood):

  • Hypomethylating agents (5-azacytidine or decitabine) combined with supportive care 1
  • FDA-approved hypomethylating agents have shown response rates of 15-17% in clinical trials 3, 4

For Myeloproliferative CMML (MP-CMML):

• With low blast count (<10%):

  • Cytoreductive therapy with hydroxyurea as the drug of choice to control proliferative myelomonocytic cells and reduce organomegaly 1

• With high blast count (≥10%):

  • Blastolytic therapy with polychemotherapy followed by allogeneic stem cell transplantation when possible 1
  • If transplantation is not an option, patients should be informed that chemotherapy, while not curative, is recommended to maintain quality of life 1

Second-Line Treatment Options

• For MD-CMML with high blast count resistant to hypomethylating agents:

  • Supportive therapy and enrollment in experimental therapeutic studies 1

• For MP-CMML resistant to hydroxyurea with low blast count:

  • Cytolytic therapy with VP16, low-dose ARA-C, or thioguanine as single agents 1
  • Hypomethylating agents may be considered in clinical trials 1

• For MP-CMML with high blast count resistant to conventional therapy:

  • New and experimental therapies 1
  • Topoisomerase I inhibitors, farnesyl-transferase inhibitors, or bendamustine have shown limited efficacy as single agents 1

Allogeneic Stem Cell Transplantation

• Only potentially curative option for CMML 1, 5, 6
• Limited by patient age and comorbidities (median age at diagnosis ~72 years) 7, 8
• Recommended for fit patients under 60 years with high-risk CMML requiring treatment 1
• Reduced intensity conditioning (RIC) transplant has shown improved outcomes compared to myeloablative conditioning 1
• For MP-CMML with high blast count, transplant should be preceded by polychemotherapy 1
• For MD-CMML, 5-azacytidine may be considered before transplant 1

Monitoring and Follow-up

• Patients not receiving treatment should have full blood count one month after diagnosis, then every three months 1
• For patients on treatment, response assessment should follow modified International Working Group response criteria 1
• Bone marrow examination should be performed yearly and with any significant hematologic changes 1

Common Pitfalls to Avoid

• Delaying treatment in symptomatic patients or those with high blast counts 5, 7
• Using intensive chemotherapy in elderly patients or those with significant comorbidities 9
• Neglecting supportive care alongside disease-modifying therapy 9
• Failing to recognize disease progression from MD-CMML to MP-CMML, which requires treatment strategy adjustment 1

Despite current therapeutic options improving patients' quality of life, they barely modify disease evolution. Allogeneic stem cell transplantation remains the only potentially curative option, but its application is limited by patient age and comorbidities 10, 6, 8.