Fludarabine, Cyclophosphamide, and Rituximab in Treating Patients Who Have Chronic Lymphocytic Leukemia

OBJECTIVES:

- Determine the response rate in patients with chronic lymphocytic leukemia treated with
sequential fludarabine, high dose cyclophosphamide, and rituximab.

- Survival up to 5 years

- Utilize flow cytometry and polymerase chain reaction as sensitive measures of minimal
residual disease in these patients.

OUTLINE: This is an open label study.

Patients receive fludarabine IV once daily for 5 days. Treatment is repeated every 4 weeks
for 3 or 6 courses.

Three weeks later, cyclophosphamide is administered intravenously every 2-3 weeks for 3
courses. Filgrastim (G-CSF) is administered on days 2-10. Beginning 4 weeks after the last
dose of cyclophosphamide, patients receive rituximab by intravenous infusion once weekly for
4 weeks.

Patient are followed every 3 months until death.

PROJECTED ACCRUAL: This study will accrue 30 patients within 3 years.

Inclusion criteria:

- Patients must have either intermediate or high-risk chronic lymphocytic leukemia as
defined by the three-stage Rai system (see section 2.2 page 2). Patients with Rai
intermediate risk disease should meet the criteria for active disease as outlined by
the NCI Working Group guidelines (including weight loss, fatigue, fevers, evidence of
progressive marrow failure, splenomegaly, progressive lymphadenopathy, or progressive
lymphocytosis with a rapid doubling time).

- Patients must be previously untreated (with cytoreductive agents) for their CLL.

- The patient must have an absolute lymphocytosis in the blood of at least 5,000
lymphocytes/μl, or bone marrow lymphocytosis greater than or equal to 30% of all
nucleated cells. These lymphocytes must have an appropriate immunophenotype for CLL
including expression of CD5 and CD20.

- Karnofsky performance status equal to or greater than 60% (see Appendix B).

- Eligible patients should have a reasonable life-expectancy greater than four weeks.

- Age ≥ 18 years and ≤ 75 years.

- Total bilirubin ≤ 2.0 mg per deciliter. Total creatinine ≤ 2.0 mg/ dl.

- Platelet count ≥ 50,000/ ul.

- Signed informed consent, which indicates the investigational nature of this, is
required.

- No patient may be entered onto the study without consultation with the principal
investigator.

EXCLUSION CRITERIA:

- Patients with Rai intermediate risk disease who meet the criteria of Montserrat
"smouldering leukemia" will not be eligible for treatment on this protocol.

- Patients with significant autoimmune hemolytic anemia or autoimmune thrombocytopenia
shall not be eligible for treatment on this protocol as there is some evidence that
fludarabine can worsen these conditions.

- Patients with active infections requiring systemic antibiotics.

- Prior cytotoxic treatment of their CLL.

- Pregnant or lactating women. Women and men of childbearing age should use effective
contraception.

- Patients with a serious cardiac condition.

- Concomitant chemotherapy or radiotherapy while on protocol.

- Concomitant prednisone therapy will not be permitted as the combination of fludarabine
and prednisone is known to increase the risk of opportunistic infections. Patients may
receive intravenous immunoglobulin (IVIG) and other supportive care measures as
clinically appropriate while on protocol.