Combined Fludarabine, Cyclophosphamide, and Rituximab Achieves a High Complete Remission Rate as Initial Treatment for Chronic Lymphocytic Leukemia

Front-line treatment of chronic lymphocytic leukemia (CLL) with single-agentfludarabine (Fludara) achieves complete remission in 35% of patients. Theaddition of an alkylating agent, cyclophosphamide (Cytoxan, Neosar), increasesthe complete remission rate to 43% and the median time to progression isincreased by more than a year. Rituximab (Rituxan), a humanized mouse monoclonalantibody against CD20, has a different mechanism of action than these cytotoxicagents and dose-related activity in treating CLL. To further improve on thecomplete remission rate, rituximab has been combined withfludarabine/cyclophosphamide.

A regimen of six cycles of FCR (fludarabine at 25 mg/m²/d andcyclophosphamide at 250 mg/m²/d on days 2-4 of cycle 1 and on days 1-3 ofcycles 2-6, and rituximab at 375 mg/m² on day 1 of cycle 1 and500 mg/m² on day 1 of cycles 2-6) was evaluated as front-line treatment forCLL. Enrollment began in July 1999. To date, 79 enrolled patients (54 males, 25females) can be evaluated for response by National Cancer Institute WorkingGroup criteria. The median patient age is 57 years (range: 36-86 years); whiteblood cell count is 94,600 cells/µL (range: 5,400-620,000 cells/µL);hemoglobin is 12.2 g/dL (range: 6.9-18.7 g/dL); platelet count is 162,000cells/µL (range: 25,000-367,000 cells/µL); median beta-2-microglobulin is 4 mg/L (range: 1.9-16.4 mg/L); and 31/79 (39%) of patientswere Rai stage III or IV at enrollment.

Treatment was well tolerated, with 60 of 79 (76%) patients completing sixcycles and only 2 of 79 (2.5%) completing fewer than three cycles. Completeremission was demonstrated in 52 of 79 patients (66%), nodular partial remissionin 11 (14%), partial remission in 12 (15%), no response in 3 (4%), and earlydeath in 1 (1%) patient. Fever and chills were experienced by nearly half of thepatients with the first rituximab infusion and a minority of patientsexperienced hypotension (18%), nausea (18%), and dyspnea (10%). Toxicity relatedto rituximab infusion was very uncommon with cycles 2 through 6. Neutropenia(absolute neutrophil count below 500 cells/µL) was observed in 87 of 429 (20%)cycles administered, and grade 3 or 4 thrombocytopenia was seen in 18 of 429(4%). Major infection (sepsis 1% or pneumonia 2%) was associated with 13 of 429(3%) cycles and minor infection (fever of unknown origin 5%, herpes 2%, or softtissue 6%) was associated with 59 of 429 (14%) cycles.

Molecular remission, demonstrated by polymerase chain reaction (PCR)negativity for immunoglobulin H, was documented in 22 of 37 (59%) completeresponders tested. Of 79 patients, 74 are surviving, with a median follow-uptime of 24 months. All responders except two remain in complete remission ornodular partial remission. Eleven of the patients in complete remission wereevaluated by PCR 6 to 12 months after treatment, and eight remain PCR negativein complete remission.

CONCLUSION: Fludarabine/cyclophosphamide/rituximab is well tolerated andproduces the highest complete remission rate in front-line treatment of CLL ofany other regimen tested thus far. Furthermore, molecular remissions aredemonstrated in a significant number of complete responders.