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 withindolent lymphoma. In vitro data demonstrate synergistic activity againstresistant cell lines when rituximab and fludarabine are combined. Rituximab andfludarabine have non-cross-resistant mechanisms of action and no apparentoverlapping toxicities.

We conducted a phase II single-institution trial of rituximabplus fludarabine for both naive and previously treated patients withadvanced-stage indolent B-cell non-Hodgkin’s lymphoma (NHL). Of 40 plannedpatients, 39 have been enrolled. Patients receive seven doses of rituximab (375mg/m²/dose) in combination with six cycles of fludarabine (25 mg/m²/d × 5 daysevery 28 days). Two infusions of rituximab were given at the beginning and endof 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 to77 years); histologies: International Working Formulation (IWF) A 26%, IWF B59%, IWF C 13%,IWF D 3%. A total of 24 patients are evaluable for response to date. Fivepatients were taken off study due to prolonged cytopenia (n = 2), progressivedisease 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 24patients), with 67% complete responses and 25% partial responses. Medianduration of response is 15+ months (range: 7 to 25+ months).

The most common adverse events attributed to rituximab werefever and chills observed primarily with the first infusion. Unique to therituximab/fludarabine combination was the observation of significant neutropeniain the first 10 patients treated, which led to discontinuation of prophylacticBactrim, limited use of growth factors, and if needed, a 40% reduction offludarabine in patients with prolonged cytopenia. Of the next 14 treatedpatients, only 2 required transient growth factor support. Four patientsdeveloped limited herpes zoster infections. No serious or opportunisticinfections have been seen to date. Nonhematologic toxicities have been minimal.In general, lymphocyte subset analysis by flow cytometry demonstrates B- andT-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/fludarabinecombination therapy demonstrates excellent antitumor activity with acceptabletoxicity, and is a novel approach for the treatment of indolent NHL.

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