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Rituximab/Fludarabine for Low-Grade NHL

Rituximab/Fludarabine for Low-Grade NHL

SAN FRANCISCO—Interim results of a trial of the combination of rituximab (Rituxan) and fludarabine (Fludara), a novel approach for the treatment of low-grade or follicular B-cell lymphoma, suggest excellent antitumor activity. Rituximab, an anti-CD20 monoclonal antibody, is the only approved monoclonal antibody therapy for refractory or relapsed low-grade or follicular non-Hodgkin’s lymphoma (NHL).

Both rituximab and fludarabine monotherapy have demonstrated good antitumor activity in patients with indolent lymphoma, said Myron Czuczman, MD, assistant professor of medicine and head of the Lymphoma Service, Roswell Park Cancer Institute.

Durable Remissions

Furthermore, prior experience with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy has demonstrated very durable remissions in this patient population, Dr. Czuczman said at the 42nd Annual Meeting of the American Society of Hematology (ASH).

In a recently updated analysis, median duration of response has not been reached after 50.4+ months of observation, and time to progression has not been reached after 52.1 months.

"We were looking at other combinations that potentially are as beneficial, and we realized that fludarabine as a single agent has excellent activity in CLL [chronic lymphocytic leukemia] and in previously treated or untreated lymphomas," Dr. Czuczman said.

Fludarabine is a fluorinated nucleotide analogue of ara-A (cytarabine) that inhibits DNA synthesis in sensitive cells. He noted that French investigators have reported a 65% response rate in 49 assessable previously untreated patients with 37% complete responses and 28% partial responses after a median of seven cycles of fludarabine.

In addition, in vitro data demonstrate synergistic activity against resistant cell lines when rituximab and fludarabine are combined. Importantly, rituximab and fludarabine have non-cross-resistant mechanisms of action and no apparent overlapping toxicities.

Dr. Czuczman and his colleagues, therefore, conducted a phase II single-institution trial of rituximab plus flu-darabine for both treatment-naïve and previously treated patients with advanced-stage indolent B-cell NHL.

Thirty-nine of 40 planned patients have been enrolled and are receiving 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 are given at the beginning and end of therapy, and single infusions of rituximab are given prior to the second, fourth, and sixth cycles of fludarabine.

Evaluable patients (n=30, median age 55.5 years, 47% male) include 60% who are treatment-naïve and 40% relapsed. Twenty-seven percent had small B-cell lymphocytic lymphomas.

The protocol was modified after the first 10 patients, Dr. Czuczman explained, when three patients were withdrawn from therapy, two for cytopenia and one for pulmonary hypersensitivity reaction. The investigators discontinued the use of prophylactic Bactrim (trimethoprim-sulfamethoxazole), limited the use of growth factors, and, when needed because of prolonged cytopenia, reduced fludarabine doses by 40%.

Study Results

In the initial 10 patients, complete response was reported in 6 of 7 patients who completed therapy and partial response in 1. Seven of the initial 10 patients had growth factor support. Limited herpes zoster infections occurred in 2 patients.

With the next 20 patients, complete response was reported in 16 of 17 patients completing therapy. Partial response was reported in 1. Of the 3 discontinuations, 1 was for cytopenia and 2 were secondary to transformed NHL. Three patients developed limited herpes zoster infections, and no serious or opportunistic infections occurred.

In an interview with ONI, Dr. Czuczman said that about halfway through planned therapy, about 90% of patients have demonstrated significant responses. "We saw an elimination of bcl-2 cells from blood and marrow in the majority of patients," he said.

Toxicity

Dr. Czuczman noted that nonhema-tologic toxicities have been minimal. While flow cytometry has shown significant decreases in T cells (CD3) and depletion of B cells (CD19, CD20), mean quantitative immunoglobulin levels and natural killer cells were preserved in the majority of patients.

"That explains why we are not seeing opportunistic infections," Dr. Czuczman said. Avoiding steroids, he added, which increase opportunistic infection risk with fludarabine, also helps.

He commented that the 17% (5 of 30) incidence of herpes zoster has led to initiation of prophylactic oral acyclovir therapy. The most common adverse events attributed to rituximab were fever and chills, seen primarily with the first infusion, he added.

Dr. Czuczman concluded: "Rituxi-mab and fludarabine chemoimmuno-therapy is associated with excellent antitumor activity in patients with low-grade or follicular B-cell lymphoma. Long-term follow-up will determine the durability of this promising combination for this population."

Subsequent investigations might evaluate even fewer days (3 rather than 5) of fludarabine to determine whether similar responses with reduced hematologic toxicity can be achieved. Also, larger trials in a cooperative group setting might compare rituximab/fludarabine with rituximab/CHOP, Dr. Czuczman commented.

 
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