Initial treatment of chronic lymphocytic leukemia (CLL) with
fludarabine (Fludara) or fludarabine/cyclophosphamide (Cytoxan, Neosar) resulted
in complete remission (CR) rates of 28% and 35%, respectively. Recently,
rituximab (Rituxan) has been shown to have significant dose-related efficacy in
CLL and to sensitize lymphoid cells to chemotherapy. Based on these data, 68
patients with previously untreated CLL who have progressive or advanced-stage
disease (National Cancer Institute Working Group Criteria) have been entered on
a fludarabine/cyclophosphamide/rituximab protocol (fludarabine at 25 mg/m2,
cyclophosphamide at 250 mg/m2) daily for 3 days for six courses every 4 weeks.
Rituximab is given at 375 mg/m2 on day 1 of course 1 and 500 mg/m2 on day 1 of
courses 2 through 6.
Thirty-five patients are evaluable after six courses and 21
patients are evaluable after three courses. The patients were younger than usual
(median age: 58 years; range: 36 to 83 years) and 40% were Rai stage III/IV with
a median white blood cell count of 111 × 103/mL. The results by course number
are as follows:
Toxicities associated with the first infusion of rituximab were
mainly fever and chills or changes in blood pressure. Toxicity grade was I/II in
61% and grade III/IV in 14%. Reactions to rituximab in courses 2 through 6 were
uncommon. Toxicities associated with fludarabine/cyclophosphamide were nausea in
21% of courses associated with vomiting in 7%. Alopecia was noted in one
patient. Major (pneumonia 1.1%, septicemia 1.9%) and minor infections (fever of
unknown cause 4.2%, herpes infection 1.5%, soft tissue infection 4.2%) occurred
in 13% of courses. Opportunistic infections were not noted. Neutropenia was the
most common hematologic toxicity leading to dose reduction of
fludarabine/cyclophosphamide in 21% of patients. No hemolytic anemia has been
noted. Chemical (3 patients) and clinical (2 patients) tumor lysis was noted
before allopurinol prophylaxis was initiated. One patient died of pneumonia
after the second course.
As shown above, a high response rate is noted after three
courses. After six courses, all responders except two PRs had < 5% CD5- and
CD19-coexpressing lymphocytes (median: 0.8%) in the marrow. Four of 10 CR
patients studied became polymerase chain reaction (PCR)-negative for
immunoglobulin heavy-chain rearrangement.
CONCLUSION: Fludarabine/cyclophosphamide/rituximab is the most
active regimen explored by our group in previously untreated CLL. The toxicity
profile is similar to that seen with fludarabine/cyclophosphamide alone.