Topotecan in Treating Patients With Myelodysplastic Syndrome

OBJECTIVES: I. Estimate complete or partial remission, hematologic improvement, and
cytogenic response rate when oral topotecan is given twice a day for 5 days versus once a
day for 10 days to patients with myelodysplastic syndromes. II. Evaluate the safety and
toxicity of oral topotecan in these patients. III. Evaluate whether there are morphologic
and/or cytogenetic subsets of the myelodysplastic syndromes that will respond optimally to
this regimen. IV. Evaluate the change in the percentage of bone marrow blast cells in these
patients during treatment. V. Evaluate the time to transformation to acute myeloid leukemia
(AML) or death in this patient population.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to FAB
subtype: 1. Refractory anemia with excess blasts 2. Refractory anemia with excess blasts in
transformation 3. Chronic myelomonocytic leukemia 4. Refractory anemia, refractory anemia
with ringed sideroblasts, and refractory cytopenia with multilineage dysplasia Patients are
randomized to receive oral topotecan either twice daily for 5 days or once daily for 10
days. Courses are repeated every 21 days. Patients are evaluated for hematologic response
after the initial 2 courses, and then every 4 courses. If a partial response or hematologic
improvement is observed, treatment continues until disease progression to acute myeloid
leukemia, relapse, death, or irreversible toxicity. Patients who achieve a complete response
receive an additional 2 courses of therapy before discontinuation of protocol treatment.
Patients are followed every 3 months for 2 years, then every year for an additional 3 years,
and at time of progression.

PROJECTED ACCRUAL: A total of 90 patients (45 per arm) will be accrued for this study within
13 months.

DISEASE CHARACTERISTICS: Primary or therapy-related myelodysplastic syndrome: Refractory
anemia with excess blasts Refractory anemia with excess blasts in transformation Chronic
myelomonocytic leukemia Refractory anemia, refractory anemia with ringed sideroblasts, or
refractory cytopenia with multilineage dysplasia These patients must also have one of the
following criteria: Greater than 4 units of RBCs transfused within the past 3 months OR
Platelet count less than 50,000/mm3 OR Neutrophil count less than 1,000/mm3 AND a recent
infection requiring antibiotics

PATIENT CHARACTERISTICS: Age: Over 15 Performance status: 0-2 Life expectancy: Not
specified Hematopoietic: See Disease Characteristics Hepatic: Bilirubin no greater than
1.5 mg/dL SGOT no greater than 2 times upper limit of normal Renal: Creatinine no greater
than 1.5 mg/dL Other: Not pregnant or nursing Fertile patients must use effective
contraception Free of any evidence of prior cancer for at least 12 months

PRIOR CONCURRENT THERAPY: Biologic therapy: At least 1 month since prior interferon No
prior hematopoietic growth factors or cytokines except epoetin alfa No concurrent epoetin
alfa Chemotherapy: No prior topotecan No prior chemotherapy for this disease At least 12
months since prior chemotherapy for another disease No other concurrent chemotherapy
Endocrine therapy: At least 1 month since prior corticosteroids No concurrent hormonal
therapy for disease-related conditions Concurrent steroids for adrenal failure allowed No
concurrent dexamethasone and other steroidal antiemetics Radiotherapy: No prior
radiotherapy for this disease At least 12 months since prior radiotherapy for another
disease Surgery: Not specified Other: No prior cytotoxic therapy (including low-dose
antimetabolites) for this disease At least 1 month since prior retinoids