Both rituximab (Rituxan) and fludarabine (Fludara) have individual antitumor
activity against low-grade lymphoma (LGL). The combination of rituximab plus
fludarabine has been shown to have synergistic activity against resistant
lymphoma cell lines in vitro. We have recently completed a single-institution
clinical trial of rituximab plus fludarabine in 40 patients with either
treatment-naive or previously treated LGL.
Patients received 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 prior to the second, fourth, and sixth cycles of fludarabine.
Patient characteristics were as follows: 50% females, 50% males; 67.5%
treatment-naive, 32.5% relapsed; median age, 53 years (range: 40-77 years).
Histologies were 27.5% International Working Formulation (IWF) A; 57.5% IWF B;
12.5% IWF C; 2.5% IWF D. Of the 40 patients enrolled, 34 completed therapy. Six
patients were taken off study due to prolonged cytopenia (n = 3), progressive
disease secondary to transformed non-Hodgkin’s lymphoma while on therapy (n =
2), and pulmonary hypersensitivity (n = 1).
The response rate in the intent-to-treat group is 90% (82.5% complete
response/unconfirmed complete response [n = 33]; 7.5% partial response [n = 3]);
2 patients who completed therapy were inevaluable for response. Responses were
determined by a modified Cheson criteria (J Clin Oncol 17:1244, 1999) which
permitted monitoring of gallium SPECT imaging in patients. Median duration of
response has not been reached at 15+ months (range: 4+ to 36+ months). Responses
are ongoing in 30 of 36 evaluable patients.
Unique to the rituximab plus fludarabine combination was the observation of
significant cytopenia (primarily neutropenia), requiring treatment
discontinuation in 2 of the first 10 patients. Following discontinuation of
prophylactic trimethoprim and sulfamethoxazole, limiting the use of growth
factors, and allowing a 40% reduction of fludarabine (in patients with prolonged
cytopenia), only 1 of the next 30 patients was unable to complete the planned
therapy. Transient treatment delays were necessary in 10 patients, but
fludarabine dose reduction was necessary in only 3 of these 30 patients. Herpes
simplex/zoster infections were seen in 6 of 40 patients, necessitating the
initiation of prophylactic acyclovir. Otherwise, no opportunistic infections or
an increased number of bacterial infections were observed. Nonhematologic
toxicities were minimal. In general, preservation of mean immunoglobulin levels
and natural killer (NK) cells was observed.
CONCLUSION: Rituximab plus fludarabine is a novel combination therapy
associated with acceptable toxicity and an excellent response rate in patients
with previously treated or untreated LGL.