Fludarabine/Carboplatin/Topotecan w/Thalidomide for Relapsed/Refractory AML, CML and MDS

OBJECTIVES:

• Determine the response rate of patients with relapsed/refractory or high-risk acute myeloid leukemia, chronic myelogenous leukemia, or advanced myelodysplastic syndromes treated with fludarabine, carboplatin, topotecan, and thalidomide.
• Determine the non-hematologic toxicity profile and time to hematopoietic recovery in patients treated with this regimen.
• Determine the effects of this regimen on changes in biologic parameters that may predict response in these patients.
• Correlate bone marrow microvascular density before and after treatment with response in these patients.
• Determine the prognostic value of pretreatment plasma and serum levels of vascular endothelial growth factor (VEGF) and/or the modulation of serum levels of VEGF during treatment in predicting response in these patients.

OUTLINE: Patients are stratified according to diagnosis (previously untreated acute leukemia vs other).

Patients receive fludarabine IV over 5-10 minutes and carboplatin IV over 24 hours on days 1-5 followed by topotecan IV continuously over 72 hours. Patients receive oral thalidomide daily beginning within days 1-3 and continuing in the absence of disease progression or unacceptable toxicity.

Patients with residual disease on day 16-18 may receive a second course of chemotherapy as above. Patients who achieve remission may receive a third course of chemotherapy as above as consolidation beginning 4-8 weeks after completion of prior chemotherapy.

Patients are followed monthly for 6 months.

PROJECTED ACCRUAL: A total of 40 patients (20 per stratum) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

• Acute myeloid leukemia meeting 1 of the following criteria:

• Previously untreated and not a candidate for anthracycline-based chemotherapy
• In first or second relapse or refractory
• Secondary to chemotherapy or an antecedent hematologic disorder and treated with no more than 1 prior intensive induction regimen
• Chronic myelogenous leukemia in blast crisis at diagnosis or after prior imatinib mesylate
• Myelodysplastic syndromes (MDS)

• Refractory anemia with excess blasts (RAEB) or RAEB in transformation
• Must meet at least 1 of the following criteria:

• Absolute neutrophil count no greater than 500/mm^3
• Platelet or red cell transfusion-dependent after no more than 1 prior intensive induction chemotherapy
• Acute promyelocytic leukemia

• t(15, 17)
• Failed prior treatment with tretinoin and arsenic
• Relapsed disease at least 3 months after prior autologous stem cell transplantation
• No active CNS leukemia

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-3

Life expectancy

• At least 8 weeks

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin no greater than 2.0 mg/dL
• AST and ALT less than 3 times upper limit of normal

Renal

• Creatinine clearance at least 50 mL/min

Cardiovascular

• Ejection fraction at least 40%
• No poorly controlled cardiac disease

Pulmonary

• No poorly controlled pulmonary disease

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile female patients must use 1 highly effective and 1 additional method of contraception for 4 weeks before, during, and for at least 4 weeks after study
• Male patients must use effective contraception during and for 4 weeks after study
• Willing and able to comply with the System for Thalidomide Education and Prescribing Safety (STEPS) program
• HIV negative
• No poorly controlled infection
• No other active malignancy
• No severe peripheral neuropathy

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• Prior thalidomide allowed for MDS
• At least 5 days since prior hematopoietic growth factors
• At least 2 weeks since prior biologic therapy
• No prior allogeneic bone marrow transplantation

Chemotherapy

• See Disease Characteristics
• At least 24 hours since prior hydroxyurea

Endocrine therapy

• At least 24 hours since prior corticosteroids

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• At least 2 weeks since prior cytotoxic anticancer therapy
• Prior amifostine allowed for MDS