What is the initial treatment approach for patients with Chronic Myelomonocytic Leukemia (CMML)?

Initial Treatment Approach for Chronic Myelomonocytic Leukemia (CMML)

The initial treatment for Chronic Myelomonocytic Leukemia (CMML) should be based on disease classification as either predominantly myelodysplastic (MD-CMML) or myeloproliferative (MP-CMML), using hydroxyurea for proliferative cases and hypomethylating agents for dysplastic cases, while considering allogeneic stem cell transplantation for eligible patients. 1

Disease Classification and Risk Assessment

Before initiating treatment, proper classification and risk assessment are essential:

1. Disease phenotype determination:

   • MD-CMML: White blood cell count <13 × 10^9/L
   • MP-CMML: White blood cell count ≥13 × 10^9/L 2, 1

2. Blast percentage evaluation:

   • Low blast count: <10% in bone marrow, <5% in peripheral blood
   • High blast count: ≥10% in bone marrow, ≥5% in peripheral blood 2

3. Risk stratification:

   • Use CMML-specific scoring systems (CPSS-Mol, Mayo Molecular, or GFM) 3
   • Consider genetic and molecular factors (mutations in ASXL1, EZH2, RAS) 1

Treatment Algorithm

For MD-CMML (Myelodysplastic Type):

1. Low blast count (<10% in BM):

   • Supportive care focused on correcting cytopenias 2
   • For severe anemia (Hb ≤10 g/dL with serum erythropoietin ≤500 mU/dL): Erythropoiesis-stimulating agents 2
   • Myeloid growth factors only for patients with febrile severe neutropenia 2

2. High blast count (≥10% in BM or ≥5% in blood):

   • Hypomethylating agents (5-azacytidine or decitabine) 2, 1
   • Evaluate response after at least 6 cycles 1
   • Consider allogeneic stem cell transplantation for eligible patients 2

For MP-CMML (Myeloproliferative Type):

1. Low blast count:

   • Hydroxyurea as the drug of choice 2
   • Initial dose: 1000 mg/day orally 1
   • Goal: Control proliferative myelomonocytic cells and reduce organomegaly 2

2. High blast count:

   • Blastolytic therapy with polychemotherapy 2
   • Follow with allogeneic stem cell transplantation when possible 2
   • If transplant is not an option, inform patients that chemotherapy is recommended for quality of life maintenance 2

Special Considerations

• Allogeneic stem cell transplantation: The only potentially curative option, but rarely feasible due to advanced age of most patients 2, 4

• Treatment initiation timing: Treatment should be started when disease is symptomatic or progressive, including anemia, high blast percentage, low platelets, high WBC count, immature granulocytes, extramedullary disease, or symptomatic splenomegaly 1

• Pre-treatment evaluation: Patients starting therapy more than three months after diagnosis should have a pre-treatment re-evaluation including bone marrow aspiration, biopsy, and cytogenetic analysis 2

Second-Line Treatment Options

For patients who are resistant or intolerant to first-line therapy:

1. MD-CMML with high blast count:

   • Supportive therapy
   • Consider experimental therapeutic studies 2

2. MP-CMML resistant to hydroxyurea:

   • Without high blasts: VP16, low-dose ARA-C, or thioguanine as single agents 2
   • With high blast count: Consider new and experimental therapies 2

Common Pitfalls to Avoid

• Misdiagnosis: Do not confuse CMML with chronic myeloid leukemia (CML), which is characterized by the Philadelphia chromosome and treated with tyrosine kinase inhibitors 1

• Inadequate response evaluation: For MD-CMML, absence of hematologic improvement after at least 6 cycles of hypomethylating agents without disease progression defines resistance 1

• Insufficient monitoring: Follow-up should include complete blood counts and focused clinical examinations, with frequency depending on disease subtype 1

• Premature treatment discontinuation: Hypomethylating agents require multiple cycles before response can be properly evaluated 1