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

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

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.

Patients received seven doses of rituximab (375 mg/m²/dose) in combination with six cycles of fludarabine (25 mg/m²/d × 5 days, every 28 days). Two infusions of rituximab were given at the beginning and end of therapy, and single 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. Six patients were taken off study due to prolonged cytopenia (n = 3), progressive disease 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% complete response/unconfirmed complete response [n = 33]; 7.5% partial response [n = 3]); 2 patients who completed therapy were inevaluable for response. Responses were determined by a modified Cheson criteria (J Clin Oncol 17:1244, 1999) which permitted monitoring of gallium SPECT imaging in patients. Median duration of response has not been reached at 15+ months (range: 4+ to 36+ months). Responses are ongoing in 30 of 36 evaluable patients.

Unique to the rituximab plus fludarabine combination was the observation of significant cytopenia (primarily neutropenia), requiring treatment discontinuation in 2 of the first 10 patients. Following discontinuation of prophylactic trimethoprim and sulfamethoxazole, limiting the use of growth factors, and allowing a 40% reduction of fludarabine (in patients with prolonged cytopenia), only 1 of the next 30 patients was unable to complete the planned therapy. Transient treatment delays were necessary in 10 patients, but fludarabine dose reduction was necessary in only 3 of these 30 patients. Herpes simplex/zoster infections were seen in 6 of 40 patients, necessitating the initiation of prophylactic acyclovir. Otherwise, no opportunistic infections or an increased number of bacterial infections were observed. Nonhematologic toxicities were minimal. In general, preservation of mean immunoglobulin levels and natural killer (NK) cells was observed.

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

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

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