Too much and not enough: revisiting maintenance rituximab in indolent lymphomas

Despite being slow-growing and chemosensitive diseases, the inevitable outcome of indolent lymphomas is relapse and prevention of relapse has been an important avenue of investigation for decades. The advent of rituximab allowed consideration of a less toxic (compared to chemotherapy) opportunity to maintain remission following induction regimens without the need for prolonged exposure to cytotoxic agents. The common questions have focused on both the schedule and the duration of maintenance therapy, with the goal to improve progressionfree or overall survival; in an ideal world, maintenance strategies might even seek to cure.

Rituximab pharmacokinetics and/or impact on B-cell depletion and subsequent recovery provide sufficient rationale for delivering maintenance rituximab with a variety of approaches: one dose every 8 weeks, one dose every 12 weeks, or four weekly doses every 6 months.^1,2 Although none of these schedules has been directly compared, small retrospective reviews suggest relative equivalence in terms of efficacy and small differences in terms of toxicity.³ In frontline follicular lymphoma, the PRIMA trial established one dose of maintenance rituximab every 8 weeks based on achieving a trough level of 25 mg/mL in the majority of patients, and this has arguably become the most common schedule.⁴ It is important to note that there remains a lack of a survival advantage for maintenance rituximab in frontline follicular lymphoma, but 10-year data show impressive and persistent disease control and validate maintenance rituximab for 2 years as an appropriate option to improve progression- free survival in patients with high-tumor burden follicular lymphoma.

While the schedule of rituximab maintenance can be justified based on pharmacokinetics, the duration of rituximab maintenance is more empirically derived. Given the relatively favorable toxicity profile even with prolonged administration, studies have ranged from several limited doses to 5 years of treatment to indefinite treatment. In the relapsed setting, a meta-analysis from a decade ago suggested improved overall survival for maintenance rituximab in relapsed/refractory follicular lymphoma, although it is critical to acknowledge that the majority of trials included in this study had involved chemotherapy induction and not chemoimmunotherapy induction.⁵

Based on improved progression-free survival and a lure of improved overall survival, is more maintenance better? In this issue of Haematologica,⁶ Rule and colleagues present the final results of the MabCute trial. This prospective, international, randomized phase III trial sought to determine the added benefit of extended rituximab dosing beyond 2 years in responding patients with indolent lymphomas. All patients had relapsed or refractory indolent lymphomas, and could receive any chemoimmunotherapy induction followed by 2 years of rituximab maintenance. Using 2007 response criteria, responding patients at 2 years were randomized to receive either an additional 2 years of maintenance therapy with subcutaneous rituximab or active observation. With a primary endpoint of progression-free survival, 274 patients were randomized and the median follow-up is 28 months. Adverse events were slightly increased in the extended maintenance arm. During the observation period, the number of progression events was quite low in both arms, and the trial is now closed without a clear signal of improved progression- free survival for the extended maintenance arm; no conclusions can be made regarding survival.

The MabCute trial can thus be added to the list of trials showing no advantage from prolonged maintenance with anti-CD20 targeting strategies if disease control, toxicity, and overall survival are considered collectively. As one example, the SAKK 35/03 trial randomized a heterogeneous group of patients with follicular lymphoma to receive either rituximab every other month for four administrations or rituximab every other month for 5 years;⁷ patients in this trial could have had treatment-naïve, relapsed, or refractory disease and all received induction therapy with rituximab monotherapy and not chemoimmunotherapy. While event-free survival was improved, there was more toxicity and no impact on survival in the prolonged treatment arm. Other key trials have shown no benefit from rituximab treatment at relapse compared to a maintenance approach;⁸ specifically, the RESORT trial found no difference in time to next treatment and no improvement in overall survival between maintenance and retreatment in low tumor burden indolent lymphomas. Finally, the induction chemotherapy backbone also influences the risk-benefit profile; for example, the GALLIUM trial observed that patients receiving bendamustinebased induction had more toxicity and even increased mortality, particularly during the maintenance component of therapy.⁹ It is worth noting that the majority of patients in the current trial also received bendamustine-based regimens and no toxicity signal was seen with the extended maintenance, but this may be because of drop-out during the initial maintenance component.

The COVID-19 pandemic has forced us to re-evaluate data with an additional critical lens related to treatment-associated B-cell suppression. Early studies during this pandemic showed that patients on immune suppression or those on chemotherapy suffer more severe complications related to SARS-CoV2, and mortality in patients with hematologic malignancies is high.¹⁰ Since maintenance rituximab has yet to offer cure or improved overall survival after chemoimmunotherapy induction, it seems more appropriate to identify the minimum number of doses rather than trying to expand or extend treatment. Indeed, only a minority of patients with blood cancers mount a sufficient response to vaccines;¹¹ accordingly, recent scientific society (https://www.hematology.org/covid-19/ash-astct-covid-19-andvaccines) and advocacy guidelines¹² highlight that patients receiving B-cell-directed therapies have attenuated or even absent responses to vaccination against SARS-CoV2 and cannot abandon social distancing and masking precautions.

In the end, there is no advantage from prolonged maintenance in indolent lymphomas, and 2 years should remain the standard duration if maintenance rituximab is offered. The MabCute trial thus supports that extended dosing of rituximab is both too much, and also not enough to offer cure or improve overall survival. Future studies should focus on identifying the minimum number of maintenance doses needed to improve outcomes, particularly in light of a pandemic threat.

Footnotes

Correspondence

SONALI M. SMITH - smsmith@medicine.bsd.uchicago.edu

Disclosures

No conflicts of interest to disclose.