Combined fludarabine and rituximab for low grade lymphoproliferative disorders

Background: As both fludarabine and rituximab are active against low grade CD20+ lymphoproliferative disorders, it is logical to test the efficacy of these drugs in combination. Protocol & patients: This is a phase I-II trial of combined fludarabine and rituximab therapy: fludarabine 30 mg/m² on days 1-4 and escalating doses of rituximab 125-375 mg/m² on day 5. The regimen is given every 4 wks to a maximum of 8 cycles until complete remission (CR), relapse, or patient intolerance. Fifteen patients have enrolled ( 10 men, 5 women, age 26-80 yrs, median 56 yrs). Of 5 patients treated for chronic lymphocytic leukemia (CLL), all had Rai stages 1I-IV. Of 10 patients treated for low grade lymphoma (follicular, 5, small lymphocytic, 2, Waldenstrom's, 2, mantle cell, 1), all had Ann Arbor stage IV disease. Chemotherapy had previously been administered to 6 patients, of whom 3 had received at least 2 regimens. Results: Rituximab has been administered at a dose of 125 mg/m² to 3 patients, 250 mg/m² to 4 patients, and 375 mg/m² to 8. A total of 79 cycles of treatment have been given. Fludarabine doses have been reduced or delayed in 6 instances. Two patients received only 1 treatment. A 59 year old man with advanced CLL and a prior episode of near-fatal pneumonia developed fever, pulmonary infiltrates, and septic shock and died one day after completing his first cycle; this was the sole infectious complication in the overall series. One patient with follicular lymphoma suffered anaphylaxis after the first 5 minutes of her first rituximab infusion. Non-hematopoietic toxicity has not exceeded grade I-II in any other patient. Grade II-III leukopenia has been noted in 2 patients and immune hemolytic anemia in a third. Of 11 évaluable patients, 6 have had a CR (median duration 3+ mos, range 2-10+ mos), one has had a partial response (PR) of 2 mos, one stable disease for 3 mos, and 2 showed progressive disease. Of the 6 patients with CR's, 3 were treated for CLL and 2 for follicular lymphoma. One patient with mantle cell lymphoma had a PR after 4 cycles of treatment, but then developed Burkitt's lymphoma. Responses have been seen at all dose levels of rituximab. Conclusions: Our preliminary data suggest that combined fludarabine/ rituximab therapy has excellent activity with acceptable toxicity in patients with low grade CD20+ lymphoproliferative disorders. We will continue to study this novel combination regimen.