Rituximab (R) in Combination with Interferon-a2a (IFN) Versus Single R in Patients with Follicular or Other CD20+ Low-Grade (indolent) Lymphoma. Final Results From a Randomized Phase III Study From the Nordic Lymphoma Group

The optimal treatment schedule and best order of therapies are not well established for patients (pts) with indolent lymphoma. The aim of this trial was to evaluate the effect of adding interferon-alpha (IFN) to first-line rituximab (R) monotherapy, with extended dosing, in pts with CD20+indolent lymphoma and to define pts with no need of initial chemotherapy.

Pts with symptomatic, advanced indolent lymphoma (previously untreated or at first relapse after a short course of chlorambucil) were randomized to R (Mabthera^R) 375 mg/m2 once-weekly for 4 consecutive weeks or R with 5 weeks IFN (Roferon-A^R) as priming. Patients achieving either a complete response (CR), partial response (PR) or a minor response (MR) at evaluation 6 weeks after last R in this first cycle, were planned to receive a second cycle with four infusions of R alone or combined with IFN, according to the initial randomization. Primary endpoint was time to treatment failure (TTF), defined as the time period from randomization to one of the following events: progressive disease during treatment, death of any cause or initiation of new therapy.

In total, 313 patients were randomized. The median age was 59 years, 51% were females, 90% Ann Arbor stage III or IV and 31% showed elevated LDH. The clinical characteristics were well-balanced between the treatment groups. Pathology review showed 127 follicular lymphoma (FL) grade I, 110 grade II and 9 grade IIIA. In total, 4 pts in each arm did not fulfill inclusion criteria: 5 DLBCL/ transformed, 2 MCL and one Hodgkin. Most patients were previously untreated, but 10 pts in the R group and 13 with R+IFN had had a previous response to chlorambucil and 18 and 9 had had local radiotherapy. respectively. After cycle 1, response rates among all 313 randomized pts were 8.6 % CR/CRu, 47.9 % PR, 22.4 % MR and 16.9 % of pts were considered resistant (SD/PD). In total 244 pts were qualified for cycle 2. Overall response rates after cycle 2 were 82% and 74%, in the R+IFN- and the R-group, respectively (n.s), but the CR/CRu rates were higher with the combination (41% vs 22.4%, p< 0.01). Also pts with FLIPI 3–5 (45% of all pts) showed a deeper response with R+IFN (CR/Cru 38.0% compared to 23.1%). More patients in the combination arm improved their responses from PR/MR in cycle 1, to CR after cycle 2. In the intention–to treat (ITT) population (n=313), median time to TTF was 21 and 28 months in the R and R+IFN group, respectively. Most events consisted of initiation of new therapy including chlorambucil, COP or CHOP, but in 7 patients in the R group, relapse treatment was single R (in one case with the addition of IFN) and in the R+IFN group 10 pts had R (3 with IFN). Two pts in the R-group and 12 pts in the R+IFN group had late relapses treated with local irradiation. After a median follow-up time of 60.7 months, for surviving pts, 35 % of the ITT patients were still event-free with 90% survivors, but with no difference between the treatment groups. Patients with FL grade II and IIIA showed a longer TTF than pts with grade I (p=0,05).

This randomized phase III trial demonstrates that extended rituximab therapy is safe and effective as first-line therapy in patients with symptomatic low-grade B-cell lymphoma, with improved responses and a delayed time to early failure if combined with IFN. The long term FU suggests that more than 1/3 of this patient population does not need initial chemotherapy, but predictive markers for response to R and new biological combinations are needed.

Kimby:Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.