Frontline Lenalidomide/Rituximab Combo Warrants Further Investigation in MCL

Jia Ruan, MD, PhD,

Jia Ruan, MD, PhD

Investigators have determined that the combination of lenalidomide (Revlimid) plus rituximab (Rituxan) can achieve a high rate of complete response (CR) and minimal residual disease (MRD) negativity when used as an initial treatment for patients with mantle cell lymphoma (MCL).

The 5-year follow-up analysis of a phase II multicenter study of lenalidomide plus rituximab as first-line treatment for patients with MCL presented at the 2017 ASH Annual Meeting showed durable remission and MRD negativity beyond 4 years.

Previous results have shown that this combination induces an overall response rate of 92% and a CR rate of 64%, warranting further investigation in a phase III trial, according to lead investigator Jia Ruan, MD, PhD.

“It is a very exciting time for clinicians and scientists working in the field of MCL, but even more importantly, it is very exciting for the patients,” said Ruan, an associate professor of clinical medicine at Weill Cornell Medicine/NewYork-Presbyterian Hospital.

OncLive: Can you provide some background on this study?

In an interview with OncLive during the meeting, Ruan discussed the pivotal analysis of this combination, as well as the next steps for this regimen in the field of MCL.Ruan: At the 2017 ASH Annual Meeting, we reported the long-term outcome of a phase II multicenter pilot study with the combination of lenalidomide plus rituximab as initial treatment for patients with MCL. We started this study in 2011 because we wanted to explore the combination of novel agents that are free of chemotherapy, which could provide an option that is not only effective but also convenient and can be used in an outpatient setting. We know that lenalidomide has activity in MCL, as does rituximab maintenance. In fact, they both extend survival for patients who have MCL, so it makes sense to combine those 2 agents.

Our study design includes both induction and maintenance phases. The induction phase uses those 2 agents—lenalidomide 3 weeks on, 1 week off—and rituximab once weekly for the first cycle and then every other cycle. That goes on for 12 treatments, and subsequently patients who have a response will go on to receive maintenance therapy with both agents. Patients can stay on treatment chronically, but they have the option to stop treatment in 3 years.

We have reported the efficacy of this combination in a previous paper that was published in the New England Journal of Medicine in 2015. In that study, we showed that this combination has very high response rates. The overall response rate was over 90% and the CR rate was over 60%. In the long-term follow-up presented [at the 2017 ASH Annual Meeting], we reported long-term survival outcomes, which showed that the duration of response is very impressive.

At 4 years, 70% of patients remained in remission and 83% are alive and have good quality of life. In addition, we report the MRD assessment, which will essentially allow us to see what depth of treatment responses those patients can potentially achieve. In 10 patients who had over 3 years of treatment, we saw that 80% of them can achieve MRD-negative CRs, which is very promising. This not only reflects on how promising the combination is, but also allows us to ask further questions. Can we, at some time, stop treatment or use a response-adaptive approach to provide chronic therapy?

Finally, we looked at the side effect profile with chronic maintenance treatment, and we did not see any unexpected signals. The majority of patients can be managed in an outpatient setting, and their side effects can be adjusted using dose modifications. We are very excited to report the long-term outcomes of this very effective combination of lenalidomide and rituximab.

Are there any next steps with this study?

Again, because this is a phase II pilot study, we are hoping that with the long-term outcomes we can inspire more interest and momentum to conduct larger studies, either with this combination alone in comparison with other active regimens or building on this combination by adding additional novel agents. All of these would contribute to better outcomes for patients with MCL.We are hoping that there will be additional large studies that evaluate this combination with a larger patient population. We would also hope that we could conduct a randomized study using this combination with other potentially active novel agents, or low-intensity chemotherapy that can be easily provided in the outpatient setting.

What would be the take-home message from this study?

Finally, we are hoping to continue to build this doublet by adding novel therapies to make it even more effective, but not adding toxicities. In all settings, we are hoping to measure biomarkers for disease and MRD status, which would allow us to adjust our treatment intensity and duration. With this combination with novel biological agents, considering our long-term data, we can now say with some confidence that it not only appears to be active, but also safe in the long term. In our update, we have shown that 70% of patients can be progression free at 4 years and 83% of patients are alive and doing well. It is clearly very well tolerated.

What are some of the challenges that persist in the treatment of patients with MCL?

Are there any other studies in MCL that you are excited about?

The typical population of patients with MCL tends to be elderly and with comorbidities. This provides an option they could have for getting treatment in the outpatient setting and not being removed from their daily life; they continue to maintain quality of life while receiving effective treatment. Obviously, this is under the supervision of experienced physicians. This combination is patient-friendly and, at the same time, it is potentially very effective, as well.We must find out what type of treatment might be better tailored to certain subsets of patients with MCL. Therefore, we need biomarkers that can predict risk or responsiveness to agents or combination of agents. Those require additional and concerted efforts, and it will be better conducted in prospective clinical trials where we would collect those clinical, pathological, and biomarker data in advance and subsequently correlate to specific treatment regimens, as well as their response and duration data.There are certainly many good novel agents that are coming into the market and they all contribute to more options for patients. There are very effective agents with manageable side effects, such as the second-generation BTK inhibitor acalabrutinib (Calquence), the highlights of which were presented at the 2017 ASH Annual Meeting. There was a very high response rate, including CR rate.

This is an oral agent that is taken twice daily and can be easily administered in the outpatient community setting. That is an additional option to our previous BTK inhibitor ibrutinib (Imbruvica). Certainly, we need to have follow-up and better experience to compare and contrast the effectiveness and side effects, in order to determine which group of patients would be best served by each of those agents.

Is there anything else that you would like to highlight?

The other aspect is that MCL has traditionally been treated by chemotherapy, and generally tailored to young and fit patients. At the 2017 ASH Annual Meeting, there is discussion about maintenance rituximab following autologous stem cell transplant. That certainly extends previous research in terms of intensive regimens for young and fit patients. We know what additional approaches and options that we can continue to provide for those patients who prefer to have high-intensity treatment with a finite course of time.We hope that, with the activity and the safety data that are coming out of this study, there will be more interest and momentum generated to look further at this combination in the frontline setting to make it more effective, safer, and potentially response-adapted. This would be very welcoming for our patients.

We hope to work together with investigators and patients to continue to find novel strategies to manage MCL. It takes a team, but more and more we are hoping that, with this particular novel therapy approach, we could bring very effective treatment to our patients who can potentially achieve very deep durations of response and hopefully making cure a tangible reality. Again, this requires additional studies that are larger and randomized.

Ruan J, Martin P, Christos P, et al. Initial treatment with lenalidomide plus rituximab for mantle cell lymphoma: 5-year follow-up and correlative analysis from a multi-center phase II study. In: Proceedings from the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 154.