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Phase II Study of Rituximab in Combination With Fludarabine in Patients With Low-Grade or Follicular B-Cell Lymphoma

Phase II Study of Rituximab in Combination With Fludarabine in Patients With Low-Grade or Follicular B-Cell Lymphoma

Both rituximab (Rituximab) and fludarabine (Fludara) monotherapies have demonstrated good antitumor activity in patients with indolent lymphoma. In vitro data demonstrate synergistic activity against resistant cell lines when rituximab and fludarabine are combined. Rituximab and fludarabine have non-cross-resistant mechanisms of action and no apparent overlapping toxicities.

We conducted a phase II single-institution trial of rituximab plus fludarabine for both naive and previously treated patients with advanced-stage indolent B-cell non-Hodgkin’s lymphoma (NHL). Of 40 planned patients, 39 have been enrolled. Patients receive 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 of rituximab were given prior to the second, fourth, and sixth cycles of fludarabine.

Characteristics of enrolled patients are as follows: 49% female, 51% male; 33% relapsed, 67% treatment-naive; median age: 53 years (range: 40 to 77 years); histologies: International Working Formulation (IWF) A 26%, IWF B 59%, IWF C 13%, IWF D 3%. A total of 24 patients are evaluable for response to date. Five patients were taken off study due to prolonged cytopenia (n = 2), progressive disease associated with transformed NHL (n = 2), and pulmonary hypersensitivity (n = 1). The current response rate in the intent-to-treat group is 92% (22 of 24 patients), with 67% complete responses and 25% partial responses. Median duration of response is 15+ months (range: 7 to 25+ months).

The most common adverse events attributed to rituximab were fever and chills observed primarily with the first infusion. Unique to the rituximab/fludarabine combination was the observation of significant neutropenia in the first 10 patients treated, which led to discontinuation of prophylactic Bactrim, limited use of growth factors, and if needed, a 40% reduction of fludarabine in patients with prolonged cytopenia. Of the next 14 treated patients, only 2 required transient growth factor support. Four patients developed limited herpes zoster infections. No serious or opportunistic infections have been seen to date. Nonhematologic toxicities have been minimal. In general, lymphocyte subset analysis by flow cytometry demonstrates B- and T-lymphocyte depletion, but preservation of natural killer (NK) cells. Overall, mean immunoglobulin levels are maintained on rituximab plus fludarabine.

CONCLUSION: Interim results show that rituximab/fludarabine combination therapy demonstrates excellent antitumor activity with acceptable toxicity, and is a novel approach for the treatment of indolent NHL.

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

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