Phase II Study of Oral Fludarabine (FAMP) in Combination with Rituximab in Indolent B-Cell Non-Hodgkin Lymphoma (B-NHL)

Abstract

Background and objectives: Although intravenous (IV) FAMP in combination with Rituximab was reported to be effective against indolent B-NHL (JCO 2005; 23:694), IV administration of FAMP for 3 to 5 consecutive days is inconvenient in an outpatient setting. We conducted a multicenter phase 2 study to evaluate the efficacy and safety of oral FAMP with Rituximab for relapsed or refractory indolent B-NHL. Patients and treatment: Eligible patients were: aged 20 to 74 years, with indolent B-NHL, with measurable lesions (the greatest transverse diameter > 1.5 cm by CT), performance status 0 or 1, with no major organ dysfunctions. Mantle cell lymphoma was excluded. Prior chemotherapies were limited to < = 2 regimens, and prior rituximab treatments up to 16 times were allowed. Patients who received nucleoside analogs or stem cell transplant were excluded. Patients who had progressive disease within 6 months of receiving rituximab therapy were also excluded. Based on the results of the preceding phase 2 study (JCO 2006; 24:174), oral FAMP 40 mg/m2 was administered on day 1 to 5, with rituximab 375 mg/m2 on day 1, repeated every 4 weeks, for up to 6 cycles.Results: Forty-one patients were enrolled and received oral FAMP with rituximab. Thirty-eight patients (93%) were follicular lymphoma, two with MALT lymphoma, and one with small lymphocytic lymphoma. Thirty-four patients (83%) received rituximab with or without chemotherapy prior to enrollment. Median treatment cycles were 6 cycles (range: 2 to 6, 66% of patients completed 6 cycles of treatment). Investigator-assessed overall response rate and complete response rate were 83% (34/41; CI: 68 to 93%) and 76% (31/41; CI: 60 to 83%), respectively. Central evaluation is pending. With median follow-up period of 9 months, median progression-free survival was not reached, and 28 patients (68%) were still alive without disease progression. Toxicity was primary hematologic, transient and manageable. Most common grade 4 hematologic toxicities included lymphopenia (98%), neutropenia (66%), and leukopenia (42%). Grade 3 or greater non-hematologic toxicities were observed in 29% of patients including one each of grade 4 stomatitis and hyperuricemia. Dose reduction of oral FAMP (from 40 to 30 mg/m2) was necessary in 44% of patients at some points of treatment courses. One patient died from Pneumocystis jiroveci pneumonia and other 2 from disease progression after the end of the study.Conclusion: Oral FAMP combined with rituximab is highly effective with acceptable toxicities for patients with relapsed or refractory indolent B-NHL who have been mostly pretreated with rituximab, and more convenient than the combination with IV FAMP. Prolonged prophylactic therapy against Pneumocystis jiroveci pneumonia would be recommended.