Investigator Commentary on the MAINTAIN study by Dr. Mathias Rummel

At the 2017 ASH Annual Meeting, New Evidence spoke with Dr. Mathias Rummel, Head of the Department of Hematology at the Clinic for Hematology and Medical Oncology at the Justus-Liebig University Hospital, Giessen, Germany, about the results of the MAINTAIN study assessing rituximab maintenance after induction with bendamustine and rituximab (BR).

New Evidence: Please describe the design of the MAINTAIN study. What was the rationale for the two versus four years of rituximab maintenance?

Dr. Rummel: The MAINTAIN study aimed to assess the value of maintenance with rituximab following induction treatment with BR.1 In 2008, when the study was started, there were no data available on whether BR followed by maintenance would benefit patients with indolent lymphomas. At the same time, the medical community had expectations that maintenance would improve progression-free survival (PFS) in these patients. The hope was that with rituximab maintenance, we could achieve high efficacy and maybe go as far as cure the disease.

After a long debate among participating physicians, we decided to investigate the outcomes of two years versus four years of rituximab maintenance following induction with BR. Patients were randomized after BR induction and two years of rituximab maintenance to two more years of maintenance (four-year arm) or no more treatment (two-year arm).

New Evidence: Please summarize and comment on the efficacy results of the MAINTAIN study.

Dr. Rummel: The primary objective of the MAINTAIN study was the comparison of PFS between two and four years of rituximab maintenance in patients with follicular lymphoma (FL). The results presented at ASH 2017 demonstrated benefit with four-year maintenance; however, with a hazard ratio of 0.73 (one-sided; p = 0.01), this difference was not statistically significant which was likely due to a smaller number of observed events than was originally planned.

The other objective of the study was to compare the results historically to the StiL NHL 1 trial. For this comparison we included all patients from the MAINTAIN study, even those who had not responded and those who had stopped early in the maintenance phase due to toxicities or progression. In order to compare only patients who had received two years of maintenance, we censored the patients from the four-year maintenance arm at the time of randomization. The results were clearly in favour of maintenance after induction with BR. This time the difference was statistically significant (p = 0.007). Even when considering the limitations of a cross-study comparison, it was clear that maintenance after BR prolongs PFS.

New Evidence: What is the most important endpoint in this patient population?

Dr. Rummel: There is always a debate on what is the most important endpoint for these patients. Many of my colleagues believe that maintenance is very beneficial following BR, leading to improved PFS. On the other hand, other physicians interpret the results as showing no benefit with maintenance, since the overall survival (OS) was not improved. Therefore, the answer clearly depends on the interpretation of each physician, with some choosing PFS and some choosing OS as their most important endpoint.

New Evidence: Please comment on the safety results with rituximab maintenance for two versus four years.

Dr. Rummel: Importantly, as reported during the presentation, the toxicity of rituximab maintenance was not as high as some physicians had originally speculated. In my opinion, the lower-than-expected toxicity observed in MAINTAIN was due to a very meaningful clinical management of the patients. More specifically, all patients who were likely to not tolerate maintenance well (for example, due to neutropenia, severe infections, or progression) were excluded earlier in the study, before randomization to an additional two years of maintenance or observation. Given that patients were not yet randomized during the first two years of rituximab maintenance, physicians felt a high degree of freedom to stop treatment early, which is good practice as they are able to prevent potentially severe complications from occurring. Interestingly, patient decision also played a big part in patients dropping out of the study, with those who felt fatigued withdrawing their informed consent (15% of the 261 patients who were not randomized).

In general, it is a good idea to start maintenance for all patients. Most of my real-world patients feel strong enough, experience no side effects, and prefer to continue with maintenance because they believe that it provides them with added benefit. However, for those patients who experience adverse events as well as a decline in quality of life, or are not motivated to continue maintenance, there is no risk in stopping maintenance early to prevent severe complications.

New Evidence: How do the results from this subgroup analysis of FL patients compare to the previously reported results of patients with mantle cell lymphoma (MCL) in the MAINTAIN study?

Dr. Rummel: The trial presented at ASCO 2016 was a phase II comparison between two years maintenance versus no maintenance in patients with MCL.2 It is difficult to compare the results from these two subgroup analyses of MCL patients and FL patients in the StiL NHL 7-2008 MAINTAIN trial. Firstly, the aim of the trial presented at ASCO for patients with MCL was to compare two years of rituximab maintenance versus no maintenance in patients with MCL, whereas the trial presented at ASH for patients with FL directly compared BR plus two years versus four years of rituximab maintenance. Secondly, as the incidence of MCL is lower than FL, we usually enroll fewer patients in these trials which decreases the statistical power. This was the case for this phase II subanalysis of the MCL patients. Lastly, MCL and FL are different diseases and as a result we cannot extrapolate that maintenance with rituximab is good for all indolent lymphomas.

New Evidence: Do you think the superior PFS with four-year rituximab maintenance warrants a change in the standard of care for patients in this setting?

Dr. Rummel:  Absolutely not. There was a clear trend of benefit with four years of maintenance, but the difference was not statistically significant. In my opinion, if a patient can tolerate two years of maintenance, then it is good enough. Alternatively, some patients and some physicians believe that if they continue maintenance for longer than two years they may achieve better results. Ultimately, it is good to see that the PFS curves for both two-year and four-year maintenance ran very well.

New Evidence: Where do you see the treatment of FL heading in the future? What key unmet needs remain for the management of these patients?

Dr. Rummel: One of the main unmet needs is to identify the patients with FL who will not respond well to treatment with chemoimmunotherapy. Ideally, we would like to have a method of identifying these patients before starting treatment. Analyzing the progression of disease after 24 months and recognizing that a patient has an early relapse is not very helpful, as physicians know that these patients will not have a good prognosis and outcome in the future.

Our group has started to implement next-generation sequencing, liquid biopsies, and cell-free tumour DNA analysis into our practice. Through these advanced methods, we can hopefully identify high-risk populations which will not benefit from BR. Otherwise, BR, with or without maintenance, is still an excellent treatment with a good long-term outcome. This is likely to remain the treatment of choice in the next few years. While there is space for improvement, none of the new compounds that are currently being tested in MCL, chronic lymphocytic leukemia, and so on (i.e., ibrutinib and venetoclax) are showing convincing activity in FL. Furthermore, other studies presented at ASH 2017 demonstrated that the addition of compounds like bortezomib and lenalidomide to BR led to increased toxicities, but not improved efficacy, once again outlining BR alone as an excellent treatment for patients with FL.

New Evidence: In which patients would you recommend rituximab maintenance following induction with bendamustine and rituximab?

Dr. Rummel: When I do not have a protocol for patients with lymphoma, I feel absolutely confident to put patients on BR, possibly without maintenance. Patients have excellent outcomes with BR alone and if they relapse, they can be retreated. The PRIMA study demonstrated that while patients undergoing maintenance with rituximab after R-CHOP have better disease control, overall survival was not improved.3 From the perspective of a patient, who wants to live as long as possible and with a good quality of life, I do not believe that they would need the maintenance, because excellent salvage regimens are available. However, if a patient wants to have good disease control and the longest treatment-free interval, and they understand the data behind it, then maintenance with rituximab is a good option. Otherwise, BR alone is a good enough regimen with excellent outcomes..

References: 1. Rummel M, Buske C, Hertenstein B, et al. Four versus two years of rituximab maintenance following bendamustine plus rituximab in patients with previously untreated follicular lymphoma: results of the prospective, randomized, multicenter phase 3 study StiL NHL 7-2008 MAINTAIN trial. ASH Annual Meeting Abstracts 2017:483. 2. Rummel M, Knauf W, Goerner M, et al. Two years rituximab maintenance vs. observation after first-line treatment with bendamustine plus rituximab in patients with mantle cell lymphoma: first results of a prospective, randomized, multicenter phase II study (a subgroup study of the StiL NHL7-2008 MAINTAIN trial). J Clin Oncol (ASCO Annual Meeting) 2016;34(Suppl):abstr 7503. 3. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011;377(9759):42–51.