Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicity and maximum-tolerated dose of treatment with
cyclophosphamide, alvocidib, and rituximab in patients with high-risk B-cell chronic
lymphocytic leukemia or small lymphocytic lymphoma.

II. To determine the feasibility of administering this regimen as an outpatient regimen in
these patients.

SECONDARY OBJECTIVES:

I. To determine the complete response rate, partial response rate, and minimal-residual
disease-negative response rate in patients treated with this regimen.

II. To determine the pharmacokinetics of alvocidib and dexamethasone as part of this
regimen.

III. To determine the immunologic effects of this regimen as measured by serial T-cell and
NK-cell number, T-cell function, and immunoglobulin levels.

OUTLINE: This is a dose-escalation study of alvocidib.

Patients receive rituximab IV over 4 hours on days 1 (days 1-3 in course 1),
cyclophosphamide IV over 30-60 minutes on days 1-3, and alvocidib IV over 4.5 hours on days
1 and 8 (day 8 only in course 1). Treatment repeats every 21 days for 6 courses in the
absence of disease progression or unacceptable toxicity. Blood samples are collected
periodically for pharmacokinetic and pharmacodynamic studies.

After completion of study treatment, patients are followed up for up to 5 years.

Inclusion Criteria:

- Histologically confirmed chronic lymphocytic leukemia (CLL) or B-cell prolymphocytic
leukemia* (PLL) arising from CLL

- Patients must have documented B-cell lymphocytosis > 5 x 10^9/L at some point
since initial diagnosis of CLL

- Patients must have B-cells that co-express CD5 with CD19 or CD20

- Patients who do not have dim sIg or CD23 expression on their leukemia cells
should be examined for cyclin D1 over-expression or t(11;14) to rule out mantle
cell lymphoma

- To be considered high risk, patients must meet the following criteria:

- At least 1 of the following:

- 17p deletion

- 11q deletion

- Un-mutated IgV_H (≥ 98% homology)

- Age > 70 years

- B_2M > 4

- AND at least 1 of the following:

- Progressive or marked splenomegaly and/or lymphadenopathy

- Anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets <
100,000/mm^3)

- Weight loss exceeding 10% of body weight over preceding 6 months

- NCI grade 2 or 3 fatigue

- Fevers > 100.5° F or night sweats for > 2 weeks without evidence of
infection

- Progressive lymphocytosis, with an increase exceeding 50% over a 2-month
period or a doubling time of < 6 months

- No other concurrent hormones, chemotherapy, or radiotherapy except for steroids for
new adrenal failure or hormones for nondisease-related conditions (e.g., insulin for
diabetes)

- No requirement for chronic corticosteroids

- ECOG performance status 0-2

- Creatinine ≤ 2.0 mg/dL

- Bilirubin ≤ 1.5 times normal unless due to Gilbert disease, hemolysis, or disease
infiltration of the liver

- AST ≤ 2 times normal unless due to hemolysis or disease infiltration of the liver

- Negative pregnancy test

- Not pregnant or nursing

- Fertile patients must use effective contraception

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

- No uncontrolled concurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situations that would limit compliance with study
requirements

- No uncompensated HIV without adequate CD4 (> 200/mm^3) and requiring HIV medication

- No active hepatitis B infection

- No known G6PD deficiency

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to alvocidib, cyclophosphamide, rituximab, or other agents used
in this study

- No prior alvocidib

- No prior purine analog therapy

- No more than 1 prior treatment with a biologic or alkylating agent

- No other concurrent investigational agents