JCO Article Insights: Long Term Follow Up of the RESORT (E4402) and LYSA Study

In this JCO Article Insights episode, Alexandra Rojek provides a summary on two long term follow studies: "Long-Term Follow-Up of Rituximab Maintenance in Young Patients With Mantle-Cell Lymphoma Included in the LYMA Trial: A LYSA Study" by Sarkozy, et al published on December 18th, 2023 and "Long Term Follow Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma," by Kahl, et al, published January 9, 2024.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing two clinical trial updates published in the March 1st issue of JCO, focusing on the long-term outcomes of rituximab therapy for patients with lymphoma. The first paper discusses the use of maintenance rituximab for mantle cell lymphoma patients in the LYMA trial, and the second paper addresses rituximab dosing strategies for low tumor burden follicular lymphoma in the RESORT study.

The first article by Sarkozy et al. for the LYSA group is titled "Long-Term Follow-Up of Rituximab Maintenance in Young Patients with Mantle Cell Lymphoma Included in the LYMA Trial: A LYSA Study." The LYMA trial was designed to answer whether the addition of the CD20-targeting monoclonal antibody rituximab provided additional benefit for patients with mantle cell lymphoma who achieved a response to induction chemoimmunotherapy, followed by consolidative autologous stem cell transplant in randomized patients, maintenance rituximab for three years versus observation alone. The primary analysis of the LYMA trial was published in 2017 and showed that the primary endpoint of four-year event-free survival or EFS was met at 79% in the maintenance rituximab arm compared to 61% in the observation alone arm. Additionally, there was a four-year overall survival or OS benefit of 89% versus 80% in favor of maintenance rituximab. Thus, on the basis of the LYMA trial primary analysis, the use of maintenance rituximab after consolidative autologous stem cell transplantation has become the standard of care in the field for these patients. 

The long-term safety and efficacy data presented in this clinical trial update for the LYMA study continue to demonstrate ongoing EFS and OS benefit for patients randomized to maintenance rituximab. Patients were initially enrolled between 2008 and 2012, and 240 patients were randomized to either arm. EFS in this study was defined as absence of disease progression, relapse, or death, severe infection, or allergy to rituximab. The data cutoff for this updated analysis was April 2019, with a median follow-up from randomization of seven years for living patients with a note that this is prior to the COVID-19 pandemic. For those in the maintenance rituximab arm, the seven-year EFS was 76% compared to 46% for those under observation. For those on the rituximab arm, the majority of relapses occurred within three years of randomization and thus while on maintenance rituximab, which the authors suggest does not show an increase in incidence of relapse after the end of maintenance therapy. The seven-year overall survival was 83% for those on the rituximab arm compared to 72% for those on the observation, with a log-rank p-value of 0.08. There was no difference in causes of death between the treatment arms noted. 

Notably, the patients who received maintenance rituximab after induction and transplant experienced a shorter second OS after relapse therapy, with a median OS2 of 1.1 years compared to 4.6 years favoring those on the observation arm, without impact of the type of salvage therapy received. Although this study was conducted before BTK inhibitors were approved in France and thus used at a low rate for patients who relapsed after initial therapy. This suggests that those who relapse after maintenance rituximab were those with the most aggressive disease biology. The authors also identified a group of patients who experienced progression of disease within 24 months of initial therapy or POD24 and showed that a Ki-67 score greater than 30% and high MIPI score were prognostic of POD24 events. For those who experienced POD24 within the rituximab arm, they also experienced a shorter OS2 compared to those on observation, again suggesting that those whose disease relapses after maintenance rituximab tend to have more aggressive and difficult-to-treat. 

While the interpretation of post-relapse outcomes and therapies needs to be interpreted in the light of a different era of available therapeutic options in more recent years, particularly the newest generation of BTK inhibitors, this updated follow-up of the LYMA study provides additional strength to the standard of care established through the trial's primary analysis of the benefit of maintenance rituximab after induction therapy and consolidative autologous stem cell transplantation for patients with mantle cell lymphoma. Although the extended follow-up was conducted prior to the COVID-19 pandemic, during which increased risk of infection was shown for those undergoing B-cell depletion with agents such as rituximab, this extended follow-up of the LYMA study continues to show that the optimal therapy for mantle cell lymphoma should include maintenance rituximab after transplant. Studies since the design of the LYMA trial have sought to address whether consolidative transplants are necessary when BTK inhibitors are added to induction therapy, and ongoing studies in this era of newer treatment agents will continue to challenge and potentially redefine this now well-established standard of care.

The second article by Kahl et al. is titled "Long-Term Follow-Up of the RESORT Study: E4402, a Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma." The RESORT study, conducted by the Eastern Cooperative Oncology Group, was designed to address whether rituximab-responsive low tumor burden follicular lymphoma patients benefit from maintenance rituximab until progression versus a rituximab retreatment approach at the time of progression. The primary analysis of the RESORT study, published in 2014, did not show a difference in the primary endpoint, which was defined as time to treatment failure. The five-year risk of treatment failure for those on a maintenance strategy was 53% compared to 50% for those on a retreatment dosing strategy. At the time of the primary analysis, letters were sent to participants and providers, and thus the data was locked for further primary endpoint analysis in late 2011. The data lock for long-term follow-up presented in this paper was continued through 2021. 

The authors looked at several endpoints in this long-term follow-up. They found that freedom from first cytotoxic therapy, at a median follow-up of almost nine years, favored the maintenance group over the retreatment group, with 83% versus 63% of patients free from chemotherapy or radiation at year seven. When looking at response duration, the analysis also favored a maintenance over retreatment approach, of 66% versus 30% for 10-year response duration, with a median follow-up of 12 years. However, when looking at overall survival at 10 years, there was no difference between rituximab dosing strategies, with a 10 -year overall survival of 83% for those receiving maintenance versus 84% for those receiving retreatment. While this extended follow-up of the RESORT study was not able to assess the long-term follow-up of the primary endpoint, the secondary endpoints suggest that while a maintenance dosing strategy was superior for prolonging time to first cytotoxic therapy and response duration, this again did not translate to an overall survival benefit. The authors conclude that they continue to recommend a rituximab retreatment strategy for these patients instead of a maintenance strategy, in the absence of a survival benefit, particularly with the high response rates observed with next-line treatment strategies for follicular lymphoma patients. 

Similarly to the LYMA study discussed in the first paper, the treatment arms of the RESORT study were completed prior to the COVID-19 pandemic. B-cell depletion, such as with prolonged rituximab therapy, is known to negatively impact the ability to combat viral infections such as SARS-CoV-2. Thus, the authors conclude that, in light of current and future infectious concerns, the extended follow-up of the RESORT study does not support the use of maintenance rituximab for patients with low tumor burden follicular lymphoma. Other studies have also evaluated modified and abbreviated maintenance rituximab dosing strategies for this same population and have also not shown a survival benefit, thus further strengthening this recommendation of favoring a retreatment approach over maintenance therapy.

Together, the extended follow-ups of the LYMA and RESORT studies, while addressing different questions regarding the use of maintenance rituximab in mantle cell lymphoma and follicular lymphoma, support the primary endpoints of each respective study. There is a clear role for the use of maintenance rituximab therapy to promote improved event-free and overall survival, as the LYMA study has shown for mantle cell lymphoma patients. However, this does not extend to low tumor burden follicular lymphoma patients in the RESORT study. The updated analyses of these two studies provide additional strength to the nuanced and targeted application of this stalwart of lymphoma therapy that is rituximab, in the modern treatment era. While ongoing studies will aim to address how we optimize therapies with new agents for each subtype of lymphoma patients, the LYMA and RESORT studies continue to guide best practice and standards of care. 

This is Alexandra Rojek, thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. 

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