Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

PRIMARY OBJECTIVES:

I. Determine the toxicity profile, dose-limiting toxicity, and maximum tolerated dose of
flavopiridol (alvocidib) as consolidation chemotherapy after cytoreduction chemotherapy in
patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics and cellular pharmacodynamics of flavopiridol in these
patients.

II. Determine the complete response (CR) and overall response rate (CR and partial response)
of patients treated with flavopiridol.

OUTLINE: This is a dose-escalation study. Patients receive alvocidib intravenously (IV) over
30 minutes (loading dose), followed by alvocidib IV over 4 hours on days 1, 8, and 15.

Treatment repeats every 5 weeks for up to 2 courses in the absence of disease progression or
unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of flavopiridol
until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A total
of 12 patients are treated at the MTD (i.e., recommended phase II dose). Patients undergo
blood collection at baseline and periodically during study for pharmacokinetic and cytokine
studies (levels of tumor necrosis factor-alpha, interleukin [IL]-6, -11, and -16) by
enzyme-linked immunosorbent assay (ELISA). Interphase cytogenetics, p53 mutational status,
p53/ATM function, V_H mutational status, zeta-chain-associated protein kinase 70 (ZAP-70)
overexpression, and single nucleotide polymorphisms are also examined.

After completion of study treatment, patients are followed at 2 months and then every 3
months for 5 years.

Inclusion Criteria:

- Diagnosis of 1 of the following:

- B-cell chronic lymphocytic leukemia (CLL)

- Small lymphocytic lymphoma (SLL)

- Must have received 1-3 prior therapies for CLL

- Completed therapy 2-12 months ago

- Prior therapy must have led to a partial response or greater

- No evidence of progressive disease

- ECOG performance status 0-2

- Absolute neutrophil count ≥ 1,000/mm³

- WBC ≤ 5,000/mm³

- Platelet count ≥ 50,000/mm³

- Cytopenia allowed

- Creatinine < 2.0 mg/dL

- Bilirubin ≤ 1.5 times normal (unless due to Gilbert's disease or hemolysis)

- AST ≤ 2 times normal (unless due to hemolysis)

- No secondary malignancy or other disease that would limit survival to < 2 years

- No history of inflammatory bowel disease unless inactive for > 2 years

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- See Disease Characteristics

- No other concurrent chemotherapy

- No concurrent radiotherapy

- No concurrent dexamethasone or other corticosteroid-based antiemetics

- No concurrent chronic corticosteroid therapy

- No other concurrent hormonal therapy except for the following:

- Steroids for new adrenal failure

- Hormones for nondisease-related conditions (e.g., insulin for diabetes)