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
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.