The activity of
topotecan was evaluated in patients with
myelodysplastic syndrome (MDS) and
chronic myelomonocytic leukemia (CMML). Sixty patients with a diagnosis of MDS (
n = 30) or CMML (
n = 30) were treated. Their median age was 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 administered
as 2 mg/m2 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 tolerated dose level (1-2 mg/m2 by continuous infusion over 24 hours daily for five days) once every 4-8 weeks for a maximum of 12 courses. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute
leukemia. Nineteen patients (31%) achieved a complete response (CR). A CR was achieved 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 CR, 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 rates were similar by different agent groups, by different karyotype abnormalities, and by other pre-
therapy peripheral blood counts. Non-myelosuppressive 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 MDS and CMML. Complete responses associated with
topotecan therapy often involve the disappearance of abnormal, poor-prognosis karyotypes, which is particularly encouraging. Future strategies to optimize
topotecan's role include combination regimens with
topoisomerase II reactive agents,
cytarabine, or hypomethylating agents (
azacytidine and
decitabine).