Page 26 - Haematologica Vol. 110 - January 2025

EDITORIAL
Help or hindrance? Rituximab maintenance and COVID
Ariela Noy
Memorial Sloan Kettering Cancer Center and Weil Cornell Medical College, New York, NY, USA
In this retrospective study across six Spanish centers, Serna et al.1 explore the impact of rituximab maintenance during the SARS-CoV-2 (COVID) pandemic. Immunocompromised people had, and still have, a higher risk of complications with COVID infection. Not surprisingly, hematologic malignancy patients treated with B-cell depleting therapies suffered disproportionately due to the lack of antibody response, particularly at the height of the pandemic before vaccines were available. It is expected that the depth of immuno- suppression and the duration of suppression contribute to increased risk.
To explore this further, Serna et al. analyzed 215 patients, 178 (83%) with follicular lymphoma (FL) and 37 (17%) with man- tle cell lymphoma (MCL) who began maintenance rituximab after induction chemoimmunotherapy with rituximab-ben- damustine or RCHOP/RCVP. The maintenance had to be received from March 2000 to March 2022, during the height of the COVID pandemic, although they could have started maintenance prior to March 2020. Of note, few patients re- ceived bendamustine-based induction (see Table 11). In the FL group, only 14 (7%) were treated with BR induction, while 164 (76%) received cyclophosphamide-containing regimens. The MCL cohort included only 6 (3%) patients treated with bendamustine and 31 (14%) patients with cyclophosphamide regimens. Those receiving RCVP due to cardiac co-morbid- ities totaled 6 FL and 2 MCL.
The study had a number of interesting findings relating to COVID in the setting of B-cell depleting antibodies, includ- ing the expected low seroconversion rate to COVID vaccine (22%), 44% maintenance interruption, and 22% mainte- nance discontinuation. The most notable finding, however, was the impact of the induction chemotherapy itself on the outcomes during the maintenance phase. The authors analyzed this directly (see Figure 1B1) and by an inverse probability of treatment weighting (IPTW) ATE analysis per- formed according to the type of first-line treatment (ben- damustine- or cyclophosphamide-containing regimens) to adjust for potential imbalances in other prognostic variables between both groups in SARS-CoV-2 survival (see Figure
2B1). The results were the same in both analyses. Patients previously exposed to bendamustine had a far higher rate of COVID-related infection, hospitalization, Intensive Care Unit admission and death. Given the prolonged T-cell sup- pression of bendamustine and the need for T-cell response during the later phases of viral clearing, this is not an entirely unexpected result. However, we should note a comparison with those not receiving maintenance was not performed. How should this study be put into context? The authors mention several other indolent front-line studies all per- formed far before COVID. The two randomized trials, Stil2 and Bright,3 showed non-inferiority for R-bendamustine compared to R-CHOP/R-CVP and, in fact, had improved and clinically meaningful progression-free survival (PFS), albeit without overall survival benefit, fewer infections, and better tolerability with respect to factors such as alopecia and neuropathy. In contrast, the Gallium trial4 did suggest more infections for bendamustine compared to CHOP irre- spective of rituximab or obinutuzumab. Real-world analysis5 also suggested more infections with benadmustine-based induction. Thus, overall, it is likely the overall benefit still favors R-bendamustine, though the Spanish centers clearly prefer RCHOP for their patients.
Moreover, as Serna et al. note,1 they did not compare their results to those receiving induction chemoimmunotherapy without maintenance rituximab. After first-line induction, the benefit of rituximab maintenance for FL has no impact on OS, and the PFS benefit must be weighed carefully in a disease we are treating for control and palliation.6 The Serna study adds indirect evidence that rituximab maintenance may be harmful during a pandemic and with continued circulation of the COVID virus, as it adds ongoing immuno- suppression during a time when B-cell recovery is expected 6-12 months after the last dose of induction rituximab. With an expanding list of potent treatment options beyond first line, maintenance rituximab is of decreasing value.
Mantle cell lymphoma is a different disease, and the cal- culus is different for those with the virulent form of MCL. Specifically, while maintenance rituximab did not improve
Haematologica | 110 January 2025
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Correspondence: A. Noy noya@mskcc.org
Received: Accepted: Early view:
July 22, 2024. September 5, 2024. September 12, 2024.
https://doi.org/10.3324/haematol.2024.286142
©2025 Ferrata Storti Foundation Published under a CC BY-NC license