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EDITORIALS
Too much and not enough: revisiting maintenance rituximab in indolent lymphomas
Sonali M. Smith
Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA E-mail: SONALI M. SMITH - smsmith@medicine.bsd.uchicago.edu
doi:10.3324/haematol.2021.279101
Despite being slow-growing and chemosensitive dis- eases, the inevitable outcome of indolent lym- phomas 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 remis- sion following induction regimens without the need for pro- longed exposure to cytotoxic agents. The common ques- tions have focused on both the schedule and the duration of maintenance therapy, with the goal to improve progression- free or overall survival; in an ideal world, maintenance strate- gies might even seek to cure.
Rituximab pharmacokinetics and/or impact on B-cell depletion and subsequent recovery provide sufficient ration- ale 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 front- line 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 ritux- imab for 2 years as an appropriate option to improve pro- gression-free survival in patients with high-tumor burden follicular lymphoma.
While the schedule of rituximab maintenance can be justi- fied based on pharmacokinetics, the duration of rituximab maintenance is more empirically derived. Given the relative- ly favorable toxicity profile even with prolonged administra- tion, 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 criti- cal 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, interna- tional, 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 main- tenance 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 progres- sion-free survival for the extended maintenance arm; no con- clusions 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 mainte- nance and retreatment in low tumor burden indolent lym- phomas. Finally, the induction chemotherapy backbone also influences the risk-benefit profile; for example, the GALLI- UM trial observed that patients receiving bendamustine- based induction had more toxicity and even increased mor- tality, 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 mainte- nance, 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-associat- ed 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 chemoim- munotherapy induction, it seems more appropriate to identi- fy 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-and- vaccines) and advocacy guidelines12 highlight that patients receiving B-cell-directed therapies have attenuated or even
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