Phase II study of fludarabine and alpha-interferon in patients with low-grade non-Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: Low-grade non-Hodgkin's lymphoma (NHL) remains incurable with standard dose chemotherapy. Nucleoside analogs such as fludarabine are effective, but even when used as initial therapy, the median duration of remission ranges from only 16 to 24 months. Interferon (IFN) is also active and has been investigated both by incorporating it into the chemotherapy regimen and/or as maintenance therapy, where it may prolong remission. We designed a phase II trial of alternating fludarabine and IFNalpha2a to determine response rate, time to progression and toxicity of this regimen in patients with advanced stage low-grade NHL or mantle cell lymphoma.

DESIGN AND METHODS: Patients had received 0-2 prior regimens that did not include nucleoside analogs or IFN and had adequate organ function. Fludarabine was administered intravenously at 25 mg/m2/day for 5 days once every 6 weeks with IFN in weeks 4 and 5 at 3x10(6) U/m2 subcutaneously three times weekly for 6 doses. Treatment continued in responders for 2 cycles past maximal response (minimum 6 cycles). No maintenance was given.

RESULTS: Between 1994 and 1999, 31 patients were accrued and were evaluable for toxicity, with 29 eligible for evaluation of response. Toxicity was primarily myelosuppression, with grade 3 neutropenia in 12 patients and grade 4 thrombocytopenia in one patient. The overall response rate was 51.7% (15/29), including 6 complete and 9 partial responses. With a median follow-up of 35.6 months, the median overall survival was 60.8 months, and the median time to disease progression (TTP) was 12.6 months. Of the 15 responding patients, treatment-naive patients had a median response duration of 39.6 months with a median TTP of 42.1 months, while the median response duration was 5.2 months with a median TTP of 14.5 months in patients who had received prior treatment (p=0.0065 and 0.0374, respectively).

INTERPRETATION AND CONCLUSIONS: This schedule of alternating fludarabine with IFN does not seem to increase response rate appreciably, but there are some prolonged responses, particularly in previously untreated patients. Given the non-overlapping toxicities of IFN with those of chemotherapy and antibody-based therapeutics, there may be a role for combination therapies, especially if the biological basis of response to IFN can be elucidated.