Page 165 - 2022_02-Haematologica-web

Prolonged maintenance with rituximab in indolent NHL
cy in this setting too.23,24,31,32 The findings prompt the ques- tion of whether further and prolonged maintenance ther- apy (beyond 2 years) would benefit patients with R/R indolent NHL who have maintained their response to treatment.
The overall tumor response rate after induction (~85%) in MabCute was consistent with rates observed in previ- ous studies in R/R indolent NHL (75-95%).22-24,31,32 These trials showed significant improvements in response dura- tion and median PFS when rituximab maintenance thera- py was given for up to 2 years compared with observation alone, and are supported by a meta-analysis of 2,586 patients participating in nine randomized trials which showed a significant improvement of median OS with rit- uximab maintenance therapy versus observation only in patients with R/R FL (HR 0.72, 95% CI: 0.57–0.91).28 Maintenance with rituximab for 2 years following the end of Induction in the current study was associated with a rate of partial response to complete response conversion similar to that observed in previous studies.21
Although an OS benefit has been observed following rituximab maintenance in the R/R setting, it has not been demonstrated in the frontline setting. A 10-year follow- up of the PRIMA study in 1,018 patients with high tumor burden, previously untreated FL showed a significant long-term PFS benefit of rituximab maintenance over observation for 2 years after response to induction with rituximab and chemotherapy.27 Although there was no sig- nificant OS benefit, the authors noted that over half of patients in the rituximab arm had not had disease progres- sion over the 10 years, and had not required new anti- lymphoma treatment. Similar findings (significant PFS improvement but no significant effect on OS) were report- ed by the ECOG-ACRIN group after a median 11.5 years of follow-up of 387 patients who attained at least stable disease after CVP induction.33 In addition, a prior study by the German STIL group confirmed the benefit of ritux- imab maintenance in R/R indolent NHL after a bendamus- tine or fludarabine salvage therapy.34
The key benefits of SC rituximab, with its short admin- istration time, are linked to reductions in healthcare resource utilization18,35 and patients’ preference15,36 relative to the intravenous formulation, particularly for long-term therapy.
Unfortunately, MabCute was unable to address its pri- mary endpoint of investigator-assessed PFS in the ran- domized population. This was due to a much lower than anticipated number of PFSrand events, representing only a third of the required events to have a power of 80% with a hazard ratio of 0.605. The reason for the low rate of PFSrand events was not clear, but may have been related to the effectiveness of supportive care and treatment delivery under the study protocol.
There were 18 deaths in total, ten in the rituximab arm and eight in the observation arm (not including the patient with a retrospective record of death). This study was not powered to evaluate survival, and follow-up was relative- ly short at the time of the analysis.
The exploratory analysis of PFSreg and OSreg from enroll- ment to end of Maintenance I (i.e. the non-randomized part of the study) showed 3-year PFSreg and OSreg rates of 63% and 83%, respectively in patients treated with ben- damustine, 58% and 70%, respectively, in those treated with CHOP, and 59% and 82%, respectively, in those treated with CVP. It should be noted that there was a bias
in patients’ selection; the investigator could decide what regimens to give to which patients – most patients were treated with bendamustine in the Induction period, and the size of the subgroups is very different. Therefore, a direct comparison between treatment regimens is not appropriate. In MabCute, approximately 60% of patients received bendamustine at Induction, and this proportion of patients was maintained out to the Maintenance II phase. There are few data available on the use of ben- damustine in R/R NHL. A study by Sakai et al. recently reported 3-year PFS and OS rates of 71% and 89%, respec- tively, in a population of patients with R/R FL,37 while the STIL group reported a 1-year PFS of 76% and median OS of 109.7 months in patients with R/R indolent NHL or mantle cell lymphoma.34 However, comparison between these trials is difficult; the PFSreg survival data from the cur- rent study were censored after Maintenance I, and are therefore not comparable with general PFS data.
No unexpected toxicities were reported during Maintenance II, and good tolerability and safety were maintained throughout follow-up. The proportion of patients who experienced adverse events during long- term maintenance was slightly greater in the rituximab arm than in the observation arm. These observations were as expected, given the known profile of rituximab SC.12 Rituximab is always given by intravenous infusion for the first cycle, when the risk of infusion-related reactions is greatest, to allow slowing or stopping of the infusion (as a preventative measure). The incidence of infusion-related reactions decreases with subsequent infusions. The over- all safety profile of rituximab SC is similar to that of the intravenous formulation, but with a greater incidence of mostly mild-to-moderate infusion/administration-related reactions, primarily injection-site reactions, which decrease in frequency over time.14,15,17,38 This pattern was observed in the current study (i.e. from 47.7% of patients during Induction to 15.2% during Maintenance I and 10.1% of rituximab patients in Maintenance II). Interestingly, in line with prior publications on frontline therapy of FL, a bendamustine-based induction resulted in more frequent pyrexia and neutropenia (Online Supplementary Table S5).
In conclusion, the MabCute study was unable to address the question of whether prolonged (beyond 2 years) maintenance therapy with rituximab adds any clear benefit compared with observation only in patients with R/R indolent NHL (who have responded to induction ther- apy with rituximab plus chemotherapy), due to a low number of PFS events. Extension of treatment was not associated with any important additional toxicity (in par- ticular no additional neutropenia or infection), and no new safety signals were observed. Two years of maintenance with rituximab after response to initial induction therapy therefore remains the standard of care in these patients.
Disclosures
SR declares a consultation or advisory role for Janssen, AstraZeneca, F. Hoffmann-La Roche Ltd, Sunesis, Pharmacyclics, Celgene, Celltrion, Kite; speakers bureau for Janssen; and research funding from Janssen. WGB declares no conflict of interest. JB declares honoraria from F. Hoffmann-La Roche Ltd, Takeda, Celgene, Novartis, and Gilead; consultation or advisory role for Takeda, Janssen, Celgene, and Gilead; research funding from F. Hoffmann-La Roche Ltd; and travel and/or accommodation expenses from F. Hoffmann La-Roche
haematologica | 2022; 107(2)
507