Addition of bortezomib to rituximab in relapsed or refractory follicular lymphoma results in small progression-free survival improvement

by: Nicola Pocock

According to the findings of a Phase III study published early online in the Lancet Oncology, the combination of bortezomib and rituximab is associated with a lower than expected improvement in progression-free survival (PFS) over rituximab monotherapy in the treatment of patients with FL that has relapsed following, or progressed during, previous therapy.

The authors note that follicular lymphoma (FL) is an incurable, indolent, B-cell non-Hodgkin’s lymphoma (NHL). Although median overall survival (OS) has improved in recent years due to the introduction of new treatments, it still typically follows a relapsing course, with patients receiving multiple lines of therapy. Treatment goals in FL are to provide a durable remission and prolonged progression-free survival, with minimum side-effects.

Rituximab is licensed, and is widely used, for the treatment of CD20+ relapsed or refractory FL. Although re-treatment with rituximab (alone or as part of combination therapy) in those with FL initially responsive to rituximab-containing therapy has been shown to be feasible, no randomised studies reporting rates of response and PFS have been published. Rituximab combined with bortezomib in relapsed NHL has been investigated and shown promise in early studies; the current Phase III study evaluated the efficacy and safety of this combination in relapsed or refractory FL.

The study included 676 adults with relapsed grade 1 or 2 FL who were either rituximab-na├»ve or rituximab sensitive (i.e. responded to and progressed ≥6 months after previous rituximab-containing treatment). They were randomised to receive five 35-day cycles of rituximab alone (n=340) or in combination with bortezomib (n=336). Rituximab was administered at a dose of 375mg/m2 on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2—5; bortezomib was given at a dose of 1.6mg/m2 on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. The primary endpoint was PFS, analysed by intention to treat (ITT).

After a median follow-up of 33.9 months, median PFS (assessed by an independent radiology committee) was 11.0 months (95% CI 9.1-12.0) in the rituximab group and 12.8 months (11.5-15.0) in the bortezomib plus rituximab group (hazard ratio 0.82, 95% CI 0.68-0.99; p=0.039). The authors note that the magnitude of clinical benefit seen with the addition of bortezomib was not as large as that anticipated (less than the pre-specified 33% improvement in PFS [HR 0.75] used in the calculation of sample size).

Rates of adverse events of grade 3 or higher were lower in the rituximab monotherapy group (21% vs. 46%), as were serious adverse events (11% vs. 18%). The most common adverse events of grade 3 or higher were neutropenia (4% in the rituximab group and 11% in the bortezomib plus rituximab group), infection (4% and 11%), diarrhoea (0% and 7%), herpes zoster (<1% and 4%), nausea or vomiting (<1% and 3%) and thrombocytopenia (<1% and 3%).

The authors present the results of a number of subgroup analyses and note that the combination of rituximab and bortezomib may result in a greater benefit in some patient subgroups, including those with adverse prognostic factors. They suggest that although the overall clinical benefit of the combination of rituximab and bortezomib was lower than anticipated, it might represent ‘a useful addition to the armamentarium’, particularly for some subgroups of patients.