Rituximab (Rituxan) is approved for use in patients with relapsed and refractory follicular lymphoma. Considering the immune modulating effect of interferon alfa-2a (IFN [Roferon-A]) and its efficacy as a single agent in follicular lymphoma, a multicenter randomized phase II study with rituximab and IFN as "priming" was started in September 1998. Patients with symptomatic previously untreated or first-relapse (less than 6 months of chlorambucil [Leukeran] and/or local radiotherapy) CD20-positive low-grade lymphoma were included.
Treatment consisted of a first cycle of rituximab at 375 mg/m2 every week × 4 (IV infusion). Patients in complete remission at week 14 were observed with no further treatment until symptomatic relapse, while patients with stable or progressive disease went off-study. Patients with partial response (PR) or minor response (MR) were randomized to receive either a second cycle of rituximab at 375 mg/m2 every week × 4 or IFN at 3 million IU/d sc (week 1), 4.5 million IU/d (weeks 2-5) in combination with rituximab at 375 mg/m2 every week (weeks 3-6). Accrual was stopped in November 1999. Two patients did not fulfill the inclusion criteria and were excluded.
A total of 69 male and 56 female patients were included, with a median age of 54 years (range: 26 to 75 years). Lymphoma type was as follows: 92 follicular lymphoma grade I/II, 10 lymphoplasmacytoid, 5 mantle cell, 5 marginal zone, and 13 unspecified low grade. Eighty patients (64%) were previously untreated, while 45 (36%) had received chlorambucil and/or local radiotherapy. Of 125 patients, 110 (88%) had advanced disease (stage III/IV) and all were symptomatic.
At the time of follow-up (July 2000), 123/125 patients were evaluable for response to the first rituximab cycle (week 14); 15 showed CR (12%), 55 PR (45 %), and 13 MR (11%). Both patients with low- and high-intensity CD20 expression on the tumor cells responded. Of the 68 patients with PR or MR, 66 were randomized to the second cycle: rituximab (n = 32) or rituximab plus IFN (n = 34). Response data after cycle 2 were available for 51 patients; 19/25 patients (76%) receiving rituximab responded with CR or PR, compared to the 6/26 patients (100%) receiving rituximab plus IFN (P < .05). Moreover, the CR rate was higher with the combination: 14 patients (54%) compared to 4 patients (11%) (P < .05).
Toxicity was mild and mostly related to the first infusion in both cycles. Twenty serious adverse events were reported, 11 of them unrelated to the drug and none with World Health Organization (WHO) grade 4 toxicity. Reversible thrombocytopenia and leukopenia (WHO grade 3) were seen in 1 and 6 patients, respectively, all in the rituximab plus IFN group.
CONCLUSION: This study shows that two cycles of rituximab is an efficient and well-tolerated treatment for patients with symptomatic previously untreated or first-relapse low-grade lymphoma. The effect of rituximab seems to be augmented when combined with IFN, but final conclusions must await complete analysis and a longer follow-up.