Rituximab, a chimeric anti-CD20 monoclonal antibody, is one of the most important advances in the treatment of patients with B-cell malignancies. Regimens that incorporate rituximab prolong the survival of patients with diffuse large B-cell non-Hodgkin lymphoma (NHL) and follicular lymphoma, and increase the time to treatment failure in patients with other types of NHL.
Nevertheless, patients with follicular lymphoma can all be considered resistant to rituximab therapy as currently given, since none seems to be cured. As a result, several options have been studied in the attempt to improve the efficacy of rituximab. One approach is maintenance therapy: the prolonged administration of rituximab following an induction regimen of single-agent rituximab, chemotherapy or combined chemotherapy and immunotherapy. Hainsworth et al.1 recruited 62 previously untreated patients with follicular or small lymphocytic lymphoma who were treated with 4 weekly infusions of rituximab followed by four additional weekly doses every 6 months until disease progression, or for a maximum of 2 years. Overall and complete response rates increased from 47% and 7% following the initial infusions to 73% and 37%,at the end of maintenance therapy, respectively. Over a median follow-up of 30 months, progression-free survival was an encouraging 34 months.
Unfortunately, randomized trials have failed to support a survival benefit with maintenance rituximab. Ghielmini et al.2 randomly allocated 202 previously treated and untreated patients with follicular lymphoma to four once-weekly rituximab infusions followed by either observation or maintenance therapy—one rituximab dose every 2 months for 8 months. Event-free survival doubled (23 months versus 12 months) in the group given maintenance therapy, but was not associated with an obvious survival advantage. Hochster et al.3 treated patients with indolent lymphoma with cyclophosphamide, vincristine and prednisone followed by rituximab maintenance (four once-weekly doses every 6 months for 2 years). Maintenance therapy prolonged progression-free survival, but not overall survival: relapse was common, but many patients responded to re-treatment with rituximab or other therapies. Forstpointner et al.4 randomly allocated patients with relapse of follicular lymphoma to fludarabine, cyclophosphamide and mitoxantrone with or without rituximab, followed by randomization to maintenance or observation. Response duration was longer with maintenance therapy; however, estimated survival at 3 years was 55% in the group that received maintenance therapy and 57% in those assigned to observation (P = 0.100). Van Oers et al.5 randomly allocated minimally pretreated patients to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus rituximab (R-CHOP), with a secondary randomization to maintenance rituximab or observation. In their initial report, at which time the patients had been followed up for a median of 33 months, maintenance therapy was associated with prolonged survival; however, this advantage disappeared when follow-up was extended to 6 years.6
...randomized trials have failed to support a survival benefit with maintenance rituximab
A meta-analysis of five studies that evaluated maintenance rituximab for patients with follicular NHL concluded that, irrespective of the regimen used, such therapy conferred a survival benefit (hazard ratio [HR] for death 0.58, 95% CI 0.42–0.79) not noted in the untreated population (HR for death 0.68, 95% CI 0.37–1.25).7 Unfortunately, their analysis was flawed. First, they included two versions of the same Eastern Cooperative Oncology Group (ECOG) study, which had different lengths of follow-up and reported markedly different results.3 Second, they included the original Hovon data, which have not withstood the test of time.5, 6 They also seem to have confused event-free with overall survival.2
If progression-free survival or response duration can be prolonged by rituximab maintenance, why should we not embrace it as the standard of care even if survival is not enhanced? First, this therapy is expensive. Second, no established 'standard' regimen exists. The schedule of maintenance has varied considerably among studies: every other month for 8 months;2 four once-weekly infusions every 6 months;1, 3 four once-weekly doses in months 3 and 9 following induction therapy;4 a dose every 3 months;5 or dosing based on blood levels. The duration of maintenance therapy has also varied: 8 months; 2 years; or until progression. An ongoing Swiss study will compare 2 years versus 5 years of maintenance.
Whether maintenance provides an advantage over re-treatment upon relapse is also unclear. Many patients who previously responded to rituximab will respond again to the same therapy, often with longer response duration. Hainsworth et al.8 randomly allocated patients who had relapsed or had refractory disease to maintenance or re-treatment upon relapse. Maintenance led to prolonged progression-free survival, albeit with no survival difference. The completed ECOG RESORT trial, for which results are pending, addressed a similar question in previously untreated patients.
Rituximab maintenance therapy is associated with adverse effects. Patients randomly allocated to rituximab maintenance have an increased incidence of grade 3 and 4 infections,4, 5, 7 with a small risk of potentially fatal, progressive multifocal leukoencephalopathy. Another concern is that prolonged rituximab therapy will result in the development of drug resistance, which could jeopardize the patient's response to subsequent therapies.
Finally, none of the abovementioned studies reflected the current standard of care for patients with follicular lymphoma. About two-thirds of patients treated in the US receive combined chemotherapy and immunotherapy as initial treatment. Yet, in only two of the available trials did maintenance follow such therapy. Both these trials were in relapsed patients, and neither showed a survival advantage.4, 6 In large B-cell lymphoma, rituximab maintenance prolongs the survival of patients treated with CHOP but not those given R-CHOP.9 Whether the same situation will apply to follicular NHL remains to be determined. The PRIMA study successfully accrued more than 1,300 patients who were treated with a chemotherapy and rituximab combination, followed by maintenance or observation. The results of this trial will be critical to define the role of this approach.
One possibility is that subgroups of patients might benefit from maintenance therapy. For example, in the ECOG trial,3 a trend towards prolonged survival was noted in patients who had minimal disease following induction therapy. This suggestion requires confirmation.
Possible alternatives to rituximab maintenance include use of non-cross-resistant agents. Other antibodies in clinical trials include human(ized) anti-CD20 antibodies, galiximab (anti-CD80), and epratuzumab (anti-CD22). The recently published FIT trial10 demonstrated prolonged progression-free survival in patients with follicular NHL who received 90Y-ibritumomab tiuxetan as consolidation therapy after having responded to first-line treatment, although follow-up was too brief to note a survival benefit. Other strategies to consider include the immunomodulatory drug lenalidomide, and small-molecule proapoptotic agents.
Until results from the PRIMA study are available, maintenance rituximab should not be a standard of care for patients with follicular lymphoma. Instead, its use should be limited to clinical trials that address important therapeutic questions.
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