Efficacy of Decitabine in the Treatment of Patients with Chronic Myelomonocytic Leukemia (CMML).

CMML is a preleukemia that results in cytopenias, dysplastic morphology of bone marrow and peripheral blood cells, produces large numbers of ineffective monocytes, and is notoriously hard to treat. The recent revision of the WHO classification excludes CMML from the myelodysplastic syndromes (MDS), and reclassifies it as a myelodysplastic/myeloproliferative disease. Decitabine (Dacogen™) is a cytosine analog that reverses aberrant DNA hypermethylation, leading to re-expression of silenced tumor suppressor genes. The reclassification of CMML has led to a review of CMML patients treated with decitabine. Overall response rates (ORR) (complete response [CR] + partial response [PR]) from one pivotal phase 3 trial (D-0007) and two phase 2 trials (PCH 95-11, PCH 97-19) in the subset of patients with CMML receiving decitabine were reviewed. The two phase 2 trials were open-label and single-arm, with a recommended minimum of 4 treatment cycles and a maximum of 8 cycles. The phase 3 trial used a 1:1 randomized comparison of decitabine plus supportive care (SC) vs SC alone with a maximum of 10 cycles of therapy. The phase 3 trial study design dictated that patients be removed from therapy following 8 cycles of decitabine if CR was not achieved, and following 6 cycles in the absence of PR. Patients who maintained a CR for 2 cycles were removed from therapy. For consistency across trials, all decitabine-treated patients were evaluated using the phase 2 response criteria (CR was defined by normocellular bone marrow with <5% blasts, and normal Hgb, WBC, and platelet counts, and PR required 50% decrease in blast count, increases in Hgb by >1.5 mmol/L, WBC count by >1000, and platelet count by >50,000). A total of 28 patients diagnosed with CMML are included in this review. Similar demographics and disease characteristics were observed in all 3 studies, with an average age of 70.2 years and 71% of patients male. A baseline WBC of >20,000 was observed in 8/28 (29%) patients and baseline bone marrow blasts >5% were observed in 11/28 (39%) patients. All clinical responses were centrally reviewed. The ORR was 25% (14% CR + 11% PR). Hematologic improvement was observed in 11% of patients and stable disease in 39% of patients. The decitabine adverse event profile seen in CMML patients was similar to observations in other hematologic patient populations, with myelosuppression and related infectious complications. These data demonstrate encouraging activity for decitabine in CMML, and suggest that studies in other myeloproliferative diseases may be warranted.