Front-line treatment of chronic lymphocytic leukemia (CLL) with single-agent fludarabine (Fludara) achieves complete remission in 35% of patients. The addition of an alkylating agent, cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), increases the complete remission rate to 43% and the median time to progression is increased by more than a year. Rituximab(Drug information on rituximab) (Rituxan), a humanized mouse monoclonal antibody against CD20, has a different mechanism of action than these cytotoxic agents and dose-related activity in treating CLL. To further improve on the complete remission rate, rituximab has been combined with fludarabine/cyclophosphamide.
A regimen of six cycles of FCR (fludarabine at 25 mg/m²/d and cyclophosphamide at 250 mg/m²/d on days 2-4 of cycle 1 and on days 1-3 of cycles 2-6, and rituximab at 375 mg/m² on day 1 of cycle 1 and 500 mg/m² on day 1 of cycles 2-6) was evaluated as front-line treatment for CLL. Enrollment began in July 1999. To date, 79 enrolled patients (54 males, 25 females) can be evaluated for response by National Cancer Institute Working Group criteria. The median patient age is 57 years (range: 36-86 years); white blood 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 162,000 cells/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 patients were Rai stage III or IV at enrollment.
Treatment was well tolerated, with 60 of 79 (76%) patients completing six cycles and only 2 of 79 (2.5%) completing fewer than three cycles. Complete remission was demonstrated in 52 of 79 patients (66%), nodular partial remission in 11 (14%), partial remission in 12 (15%), no response in 3 (4%), and early death in 1 (1%) patient. Fever and chills were experienced by nearly half of the patients with the first rituximab infusion and a minority of patients experienced hypotension (18%), nausea (18%), and dyspnea (10%). Toxicity related to 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 soft tissue 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%) complete responders tested. Of 79 patients, 74 are surviving, with a median follow-up time of 24 months. All responders except two remain in complete remission or nodular partial remission. Eleven of the patients in complete remission were evaluated by PCR 6 to 12 months after treatment, and eight remain PCR negative in complete remission.
CONCLUSION: Fludarabine/cyclophosphamide/rituximab is well tolerated and produces the highest complete remission rate in front-line treatment of CLL of any other regimen tested thus far. Furthermore, molecular remissions are demonstrated in a significant number of complete responders.
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