Phase II Study of Rituximab Plus Fludarabine in Patients With Low-Grade Lymphoma: Final Report

March 1, 2002

Both rituximab (Rituxan) and fludarabine (Fludara) have individual antitumor activity against low-grade lymphoma (LGL). The combination of rituximab plus fludarabine has been shown to have synergistic activity against resistant lymphoma cell lines in vitro. We have recently completed a single-institution clinical trial of rituximab plus fludarabine in 40 patients with either treatment-naive or previously treated LGL.

Both rituximab (Rituxan) and fludarabine (Fludara) have individual antitumoractivity against low-grade lymphoma (LGL). The combination of rituximab plusfludarabine has been shown to have synergistic activity against resistantlymphoma cell lines in vitro. We have recently completed a single-institutionclinical trial of rituximab plus fludarabine in 40 patients with eithertreatment-naive or previously treated LGL.

Patients received seven doses of rituximab (375 mg/m²/dose) in combinationwith six cycles of fludarabine (25 mg/m²/d × 5 days, every 28 days). Twoinfusions of rituximab were given at the beginning and end of therapy, andsingle infusions prior to the second, fourth, and sixth cycles of fludarabine.Patient characteristics were as follows: 50% females, 50% males; 67.5%treatment-naive, 32.5% relapsed; median age, 53 years (range: 40-77 years).Histologies were 27.5% International Working Formulation (IWF) A; 57.5% IWF B;12.5% IWF C; 2.5% IWF D. Of the 40 patients enrolled, 34 completed therapy. Sixpatients were taken off study due to prolonged cytopenia (n = 3), progressivedisease secondary to transformed non-Hodgkin’s lymphoma while on therapy (n =2), and pulmonary hypersensitivity (n = 1).

The response rate in the intent-to-treat group is 90% (82.5% completeresponse/unconfirmed complete response [n = 33]; 7.5% partial response [n = 3]);2 patients who completed therapy were inevaluable for response. Responses weredetermined by a modified Cheson criteria (J Clin Oncol 17:1244, 1999) whichpermitted monitoring of gallium SPECT imaging in patients. Median duration ofresponse has not been reached at 15+ months (range: 4+ to 36+ months). Responsesare ongoing in 30 of 36 evaluable patients.

Unique to the rituximab plus fludarabine combination was the observation ofsignificant cytopenia (primarily neutropenia), requiring treatmentdiscontinuation in 2 of the first 10 patients. Following discontinuation ofprophylactic trimethoprim and sulfamethoxazole, limiting the use of growthfactors, and allowing a 40% reduction of fludarabine (in patients with prolongedcytopenia), only 1 of the next 30 patients was unable to complete the plannedtherapy. Transient treatment delays were necessary in 10 patients, butfludarabine dose reduction was necessary in only 3 of these 30 patients. Herpessimplex/zoster infections were seen in 6 of 40 patients, necessitating theinitiation of prophylactic acyclovir. Otherwise, no opportunistic infections oran increased number of bacterial infections were observed. Nonhematologictoxicities were minimal. In general, preservation of mean immunoglobulin levelsand natural killer (NK) cells was observed.

CONCLUSION: Rituximab plus fludarabine is a novel combination therapyassociated with acceptable toxicity and an excellent response rate in patientswith previously treated or untreated LGL.

Click here to read Dr. Bruce Cheson's commentary on this abstract.