Myelodysplastic syndromes (MDS) and
chronic myelomonocytic leukemia (CMML) are heterogeneous disorders for which there exist few active
therapies and where the standard of care is still considered supportive. Identification of new effective
therapies in MDS and CMML is a high priority for hematologic oncologists. We have evaluated the efficacy of single-agent
topotecan, a
topoisomerase I inhibitor, in patients with MDS (
refractory anemia with excess blasts [
RAEB] and
refractory anemia with excess blasts in transformation [
RAEB-T]) and CMML. Sixty patients (MDS = 30; CMML = 30) with a median age of 66 years were treated.
Chromosomal abnormalities were present in half of the patients, as was
thrombocytopenia.
Topotecan was administered at 2 mg/m2 by continuous
intravenous infusion over 24 hours daily for 5 days every 4 to 6 weeks until remission, followed by one course every 4 to 8 weeks for a maximum of 10 courses. Nineteen patients (32%) achieved a complete response (CR); seven had hematologic improvement. CRs were observed in 11 of 30 patients with MDS (37%) and eight of 30 patients with CMML (27%). Conversion to diploid karyotype was observed in eight patients with karyotypic abnormalities at diagnosis who later achieved a CR. History of prior
chemotherapy and monocytosis was associated with poor prognosis. Mutation of the RAS oncogene was found in six CMML patients (20%), and none responded to
topotecan therapy. The estimated 12-month survival rate was 33%, the median survival time was 9.3 months, and the median remission duration was 7 months. The most significant toxicities were gastrointestinal, including
mucositis (67%; severe 23%) and
diarrhea (38%; severe 17%). Febrile episodes were noted in 85% of the patients, while documented
infection occurred in 47%.
Topotecan has demonstrated significant single-agent activity in MDS and CMML with generally manageable side effects. Future studies will evaluate
topotecan-based combination
therapies with
topoisomerase II reactive agents,
cytarabine,
alkylating agents, and hypomethylating agents.