LILLE, France—As front-line treatment for chronic lymphocytic leukemia (CLL), the combination of fludarabine (Fludara) and cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) administered orally "could be a good compromise with a good efficacy and an acceptable tolerance," reported Bruno Cazin, MD, of the Hôpital Claude Huriez in Lille, France, and his colleagues at the French Cooperative Group for CLL. An intermediate analysis of 59 of 76 patients that were enrolled in a multicenter phase II trial supports this claim, producing an overall response rate of 78% and mostly manageable toxicities.
Studies showing that the efficacy of oral fludarabine does not differ from the intravenous formulation served as one basis for the study. Interest in the oral formulation of fludarabine centers on (1) its potential to offer a better quality of life for patients undergoing treatment, and (2) lower cost, as it can be administered on an outpatient basis. In addition, fludarabine and cyclophosphamide have demonstrated a synergistic effect in vitro and in vivo, and oral cyclophosphamide has been effective as currently used in the 5-day CHOP regimen (cyclophosphamide, doxorubicin(Drug information on doxorubicin) HCl, vincristine [Oncovin], prednisone(Drug information on prednisone)), Dr. Cazin said.
In the study, fludarabine is given at a dose of 30 mg/m²/d and cyclophosphamide at 200 mg/m²/d on days 1 to 5, repeated every 28 days for six courses. Herpes-zoster and Pneumocystis carinii pneumonia (PCP) prophylaxis is recommended.
Enrollment closed with 76 patients in February 2001, with follow-up planned to continue to 2006, Dr. Cazin noted. The third intermediate analysis included 59 patients, all with no previous treatment. The median age was 54 (range: 37-66); 48 were male, 11 female; 48 had Binet stage B disease and 11 had stage C. A mean for cycles of treatment administered was 5.3, and response was assessed 2 months after the last treatment.
Of the 58 patients evaluable for response, 27 (46.5%) achieved complete remission, 18 (31%) achieved partial remission, 7 (12%) had stable disease, 4 (6.8%) failed treatment, and 2 (3.4%) died in therapy (1 after cycle 1 of unexplained causes, and 1 after cycle 5, probably due to infection) (see Figure 1).
"It is important to note," Dr. Cazin said, "that some patients are registered as having stable disease because of cytopenia, but they had good resolution of disease."
Safety data were evaluated on days 15, 21, and 28 for 313 cycles in the 58 patients. Toxicities were mostly hematologic, with National Cancer Institute (NCI) grade 3 to 4 lymphopenia in 79% of cycles, neutropenia in 50%, thrombocytopenia in 5%, and anemia in 4%. "Except for lymphopenia," Dr. Cazin noted, "hematologic toxicity was short, with a very low rate of toxicity at day 28."
Autoimmune hemolytic anemia occurred in seven patients (12%), five during therapy, and treatment was stopped in these patients. "All responded to steroids," Dr. Cazin said, "but three cases associated with immune thrombocytopenic purpura needed a splenectomy to definitively resolve complications."
Gastrointestinal toxicities were mostly mild, with 75% of patients experiencing grade 1 to 2 nausea and 6% grade 3 to 4; 38% had grade 1 to 2 vomiting and 2% grade 3 to 4. "Compliance to treatment was good, with only one patient with stable disease after five cycles stopping treatment because of gastrointestinal toxicity," reported Dr. Cazin.
"Despite the higher rate of neutropenia, the rate of infection remained low," Dr. Cazin said, "with 15% of cycles complicated by grade 1 or 2 infection and only three cases of grade 3 to 4 infection." There was one case of PCP, which occurred 4 months after the end of treatment and prophylaxis.
In addition to the 78% overall response rate, Dr. Cazin reported that 80% achieved immunologic response and 70% achieved molecular response. "Collection of peripheral stem cells after this treatment seems very difficult and should be performed only with granulocyte colony-stimulating factor (G-CSF [Neupogen])," he concluded.