Follicular lymphoma: chemotherapy and/or antibodies?

Comment on van Oers et al, page 3295

Administering 2-year maintenance with rituximab (1 infusion every 3 months) prolongs the progression-free survival of follicular lymphoma patients even when rituximab was previously given as part of the induction therapy.

Because follicular lymphoma (FL) is usually not curable, FL patients in remission have been candidates for maintenance trials with alkylating agents first and with interferon later. Alkylators were too toxic and interferon, despite prolonging remission, failed to demonstrate a survival advantage in the meta-analysis and never entered general use because of the negative impact on quality of life.

The advent of rituximab, an agent with little toxicity and good single-agent activity in FL, reopened the maintenance issue. Several studies proved that rituximab maintenance can consistently prolong a remission obtained with single-agent rituximab or with chemotherapy.^1-3  The question was still open if rituximab maintenance could be effective when the antibody had been previously administered in combination with induction chemotherapy. In this issue of Blood, an intergroup study presented by van Oers and colleagues provides a positive answer: rituximab maintenance after rituximab-CHOP (R-CHOP) induction produces the same benefit that it does after CHOP only. The antitumor effect of rituximab is therefore not exhausted during induction but continues with further treatment. A German trial confirms the data on a smaller sample size.⁴  The authors also find a survival advantage in favor of maintenance, a very encouraging observation that will need substantiation by longer follow-up and data from other maintenance trials.

Although the route to rituximab maintenance is nicely paved, some unanswered questions remain. Do these data obtained in relapse also apply to first-line patients? Which of the so-far published maintenance schedules is the optimal one (weekly × 4 every 6 months or 1 single infusion every 2-3 months)? Would a longer maintenance be even more effective? Ongoing trials will answer some of these questions. As to the issue of long-term maintenance, the potential harm of prolonged B-cell depletion after long-term exposure to rituximab must be solved: although a 2-year maintenance appears to be devoid of relevant subjective toxicity and causes an infection rate just slightly higher than controls, an even longer exposure to rituximab could cause further yet unknown complications.

The van Oers et al paper is finally a chance to sum up some evidence on the differential efficacy of aggressive chemotherapy and single-agent antibodies in indolent lymphoma: in this trial CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) obtains remissions of approximately 1-year duration, whereas the adjunction of rituximab (with and after chemotherapy) adds 3 further years. In another trial in relapsed indolent lymphoma, single-agent rituximab followed by 2-year maintenance demonstrated a median progression-free survival (PFS) of almost 3 years.¹  Finally, preliminary data from a small randomized trial in first-line indolent lymphoma patients, where single-agent rituximab was compared with CNOP (cyclophosphamide, vincristine, mitoxantrone, prednisone) or R-CNOP, suggest no difference in response rate or in 2-year PFS for the 3 arms, whereas the only significant difference was a higher toxicity for the chemotherapy-containing treatments.⁵  In this era of highly effective antibodies, do all FL patients deserve the burden of aggressive chemotherapy? ▪