Results of topotecan single-agent therapy in patients with myelodysplasticsyndromes and chronic myelomonocytic leukemia

The activity of topotecan was evaluated in patients with myelodysplastic sy ndrome (MDS) and chronic myelomonocytic leukemia (CMML). Sixty patients wit h a diagnosis of MDS (n=30) or CMML (n=30) were treated. Their median age w as 66 years, with 50 patients (83 %) being over 60 years of age at time of study entry. Chromosomal abnormalities were present in 50 % of patients and thrombocytopenia of less than 50 x 10(9)/L in 50 %. Topotecan was administ ered as 2 mg/m(2) by continuous infusion over 24 hours daily for five days (10 mg/m2 per course) every 4 to 6 weeks for two courses, then at maximum t olerated dose level (1-2 mg/m(2) by continuous infusion over 24 hours daily for five days) once every 4-8 weeks for a maximum of 12 courses. Evaluatio n of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leuke mia. Nineteen patients (31 %) achieved a complete response (CR). A CR was a chieved in 11 of 30 patients with MDS (37 %) and in eight of 30 with CMML ( 27 %). A CR was achieved in 10 of 23 patients with previously untreated MDS (43 %). Eight of 11 patients who presented with cytogenetic abnormalities (five of which involved chromosome 5 and/or 7 abnormalities) and achieved C R, were evaluated cytogenetically in CR: all were cytogenetically normal in CR. Characteristics associated with a higher CR rate were lack of previous chemotherapy, absence of ras oncogene mutations, and presence of less than 10% monocytes in either peripheral blood or bone marrow. In contrast, CR r ates were similar by different agent groups, by different karyotype abnorma lities, and by other pre-therapy peripheral blood counts. Non-myelosuppress ive side effects were mucositis in 67 % of patients (severe [grade 3-4] 23 %), diarrhea in 38 % (severe 17 %), and nausea and vomiting in 28 % (severe 5 %). Febrile episodes during neutropenia occurred in 85 % of patients and documented infections in 47 %. Mortality in the first four weeks was 20 %. With a median follow-up duration of 31 months, the 12 month survival rate was 38 %, median survival time 10.5 months, and median remission duration 7 .5 months. In summary, topotecan has significant single-agent activity in M DS and CMML. Complete responses associated with topotecan therapy often inv olve the disappearance of abnormal, poor-prognosis karyotypes, which is par ticularly encouraging. Future strategies to optimize topotecan's role inclu de combination regimens with topoisomerase II: reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).