Rituximab Plus Fludarabine Shows Excellent Antitumor Activity in Low-Grade Lymphoma

BUFFALO, New York—Final data from a phase II study of rituximab (Rituxan) plus fludarabine (Fludara) in low-grade lymphoma show that this combination is associated with excellent antitumor activity, clears bcl-2-positive cells from blood and/or bone marrow in most patients, and is well tolerated, according to Myron S. Czuczman, MD. Dr. Czuczman, who is chief of the Division of Lymphoma at Roswell Park Cancer Institute in Buffalo, New York, presented this single-institution study in a poster session at the 43rd Annual Meeting of the American Society of Hematology.

Single-Institution Study Design

The trial included 40 patients who were either chemotherapy-naive (n = 27) or had previously treated but relapsed low-grade lymphoma (n = 13). Patients’ median age was 53 years (range: 40-77 years). Histologies included 27.5% International Working Formulation (IWF) A, 57.5% IWF B, 12.5% IWF C, and 2.5% IWF D. Fourteen patients (35%) had stage III disease, and 26 (65%) had stage IV disease. Thirty-four of the 40 patients completed therapy.

The treatment regimen included 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 were given prior to the second, fourth, and sixth cycles of fludarabine. Because of hematologic toxicities requiring treatment discontinuation in two of the first ten patients treated, the protocol was modified by discontinuing prophylactic trimethoprim-sulfamethoxazole, reducing the fludarabine dose by 40% for patients who had grade 4 cytopenia for more than 14 days without growth factors, and limiting the use of growth factor support. Transient treatment delays were necessary in 10 of the next 30 patients, but fludarabine dose reduction was necessary in only 3 of these patients.

Six patients were taken off study. Three had prolonged cytopenia, two had progressive disease secondary to transformed non-Hodgkin’s lymphoma while on therapy, and one had pulmonary hypersensitivity.

Intent-to-Treat Analysis

According to intent-to-treat analysis, the response rate was 90%, including 80% complete response/unconfirmed complete response (n = 32) and 10% partial response (n = 4). Two patients who completed therapy were not evaluable for response.

Median duration of response had not been reached at 15+ months (range: 4+ to 36+ months). Responses are ongoing in 29 of 36 evaluable patients (81%). Cells with bcl-2 (t[144:18]) rearrangements were cleared from the peripheral blood in 93% of patients and from the bone marrow in 87%. Serum immunoglobulins either improved or remained unchanged in the majority of cases, and the median percentage of natural killer cells was preserved in most patients.

Herpes simplex/zoster infections were seen in 6 of 40 patients, necessitating the initiation of prophylactic acyclovir, but no other opportunistic infections or increased bacterial infections were observed.

Novel Combination

"Rituximab plus fludarabine is a novel combination therapy associated with acceptable toxicity and an excellent response rate in patients with either previously treated or untreated low-grade lymphoma," Dr. Czuczman concluded. "In view of significant responses seen midtreatment, a trial of reduced fludarabine dosing (ie, 3 instead of 5 days) is warranted and should preserve rituximab/fludarabine responsiveness with less hematologic toxicity."