To establish the role of fludarabine (Fludara) in previously untreated patients with low-grade malignant non-Hodgkins lymphoma (NHL), 381 patients were enrolled by 60 centers in nine countries between April 1993 and January 1997. Patients older than 18 years with NHL Working Formulation class A (chronic lymphocytic leukemia [CLL] excluded), B, and C were eligible. They were randomized, either immediately after diagnosis or after a wait-and-see period, to either eight courses of fludarabine (25 mg/m² intravenously [IV] daily for 5 days every 4 weeks) or eight courses of onventional CVP chemotherapy (cyclophosphamide, 750 mg/m² IV on day 1; vin-cristine, 1.4 mg/m² IV on day 1; and prednisone(Drug information on prednisone), 40 mg/m² PO on days 1-5 every 4 weeks). At entry and after the last course of treatment, complete (re)staging was performed, including computed tomographic (CT) scans and a bone marrow biopsy. From the 381 patients randomized, 72 (19%) were declared ineligible, mainly because of inadequate histology (CLL, mantle cell lymphoma) on central pathology review.
Response rates and survival times are presented according to intent-to-treat analysis. The overall response rate was 69% (39% complete response [CR], 30% partial response [PR]) in the fludarabine group and 53% (17% CR, 36% PR) in the CVP group (P = .001). In both treatment arms, these response rates were not significantly different between the subgroups of patients treated immediately after diagnosis or those treated after a wait-and-see period.
With a median follow-up of 570 days since randomization, the time to progression was 494 and 396 days for the fludarabine- and CVP-treated groups, respectively. With the limited number of deaths that have occurred so far, it is not possible to accurately assess any influence on overall survival at this time.
Toxicity > 2 (according to the World Health Organization [WHO] scale) was observed more frequently in the fludarabine arm for granulocytopenia and thrombocytopenia (P = .001). Significant hair loss occurred in the CVP group only. There were no significant differences in the frequency of severe infections between the two groups (2%). So far, 50 patients have died, 24 from NHL, 2 from a secondary malignancy, 3 from complications of treatment, 4 from intercurrent disease, and 17 from a variety of other causes (including missing data).
CONCLUSION: From the present study it can be concluded that fludarabine monotherapy is established as up-front treatment of patients with extensive low-grade malignant NHL, given the significant response rate (two times higher CR rate) and response duration without enhanced life-threatening toxicities. Apparently, it is too early to judge about possible differences in overall survival time. Fludarabine adds another important ingredient to the treatment strategy of patients with low-grade malignant NHL.