MCL Landscape Shifting With Combo Regimens on Horizon

Andre Goy, MD

Investigators have been working on novel approaches to improve outcomes in both the frontline and relapsed/refractory settings of mantle cell lymphoma (MCL) with the use of current FDA-approved agents in combination. New clinical endpoints are also beginning to take priority in MCL research, such as minimal residual disease (MRD) negativity.

Such explorative regimens can be seen in findings from a phase II study presented at the 2016 ASH Annual Meeting. With the goal of reducing the hematologic toxicities associated with cytarabine, researchers treated patients with rituximab (Rituxan) at 375 mg/m², bendamustine at 70 mg/m², and cytarabine at a 500-mg/m² dose (RBAC500). Prior trial results showed that the 800-mg/m² dose of cytarabine was too difficult to tolerate.

Results showed that the treatment was, indeed, less toxic as frontline therapy for elderly patients with MCL and has the potential to be a new standard of care in this setting.

“The future of MCL is really broader than we think,” explains Andre Goy, MD. “We have a lot of novel options, particularly in the patients who are high risk and don’t benefit, such as those with p53 or 17p deletions. The concept of MRD negativity in MCL is going to be something really critical to achieving an early response, complete response (CR), and molecular CR, as it has a clear impact on progression-free survival (PFS) and overall survival (OS).”

In an interview with OncLive, Goy, chairman and director, chief of Lymphoma, and director of Clinical and Translational Cancer Research at John Theurer Cancer Center, Hackensack Medical Center, highlights what researchers can expect next in the field of MCL in both the frontline and relapsed/refractory settings given the recent pivotal data from clinical trials.

OncLive: What changes are you seeing in the frontline setting of MCL?

Goy: In the frontline setting of MCL, the consensus is that the patients who are fit can actually benefit with a dose-intensive regimen—a cytarabine-containing regimen—with or without stem cell transplant consolidation. This is because it gives a PFS in excess of 5 to 7 years, so that became sort of the standard after a large randomized trial that confirmed a benefit with cytarabine.

The reason is that you achieve a deeper, early CR and molecular CR in those patients. In MCL, MRD status is really becoming something very important.

Where do we go to improve on this? MRD is being looked at; we are trying to see if we can develop maintenance strategies. This has been looked at in the LyMa trial, which was 4 cycles of R-DHAP, instead of R-CHOP, followed by high-dose therapy and transplant. The data were presented at the 2016 ASH Annual Meeting with a benefit in PFS and OS by 3 years of maintenance with rituximab versus observation. The benefit of maintenance has been proven both in the elderly and younger patients.

That is where the field is, and we are looking at additional ways to improve this maintenance. There are trials looking at “R-squared”—rituximab plus lenalidomide (Revlimid)—as maintenance versus rituximab alone to see if we can get better control of the disease. The goal of the trial is to attain a more durable response, because the problem in MCL is that it becomes chemotherapy resistant.

The high-dose therapy or dose-intensive strategies are not easily feasible in patients who are elderly, and the median age of diagnosis is in the mid-to-late 60s, so there are opportunities to improve on the default standard of R-CHOP, which is definitely not sufficient. By 2 years, 75% of patients progress.

What are some interesting ongoing clinical trials exploring novel approaches?

There were trials looking at R-CHOP combined with bortezomib (Velcade). The activity with single-agent bortezomib in the relapse setting is a 33% response rate and 8% CR rate. It is quite durable for refractory patients.

This trial randomized patients to the combination of bortezomib plus R-CHOP versus R-CHOP alone. The results showed a dramatic improvement—close to 60% improvement in PFS at 14 to 27 months and a significant improvement in CR rate in the experimental arm. That became one of the new standards in the frontline setting, and the first newly approved standard of combining our chemotherapy with a novel agent.

Bendamustine and rituximab (BR) has been used a lot in the elderly MCL population because it is easier to tolerate and it is noninferior to R-CHOP, as seen from the StiL trial. Now, this is being looked at in combination with bortezomib with a CR rate in excess of 50%. It is promising enough to develop a randomized trial that is ongoing, with BR plus or minus bortezomib followed by a second randomization of rituximab versus R-squared as maintenance. The results are obviously not out; the trial is not completed yet. This is really trying to build up and bring a novel agent into the frontline setting.

Bendamustine and cytarabine is a chemotherapy option that is not as toxic as the dose-intensive strategies. It has also been looked at in this population, but the 800-mg/m² dose of cytarabine was still very difficult to administer in the real world, so the 500-mg/m² dose presented at the 2016 ASH Annual Meeting appears very promising. We need more follow-up, but the CR rate was very impressive and potentially could also become a new standard in this part of the population.

What investigation is being done in the relapsed/refractory setting?

In the relapsed/refractory setting, there are a number of novel therapies that have been approved. We have ibrutinib (Imbruvica), lenalidomide, and bortezomib; in addition, temsirolimus (Torisel) is approved in Europe. Ibrutinib has dramatic activity with a 68% response rate, a 21% CR rate, and a median duration of response of over 17 months.

Now, it’s being combined in the frontline setting in a number of different studies. Particularly, one phase II study presented at the 2016 ASH Annual Meeting looked at ibrutinib plus rituximab for 2 to 4 cycles—with a very impressive CR rate in the frontline setting—followed by a shorter course of hyper-CVAD for 4 cycles.

These high-risk patients are more prominent and we perhaps underestimated them. We [used to] just look at 17p deletion, and when you look at next-generation sequencing, we found that 18% to 22% of patients have p53 mutations at baseline. These patients do very poorly, even with high-dose therapy and transplant. It is very important that we have strategies for those patients.

Researchers also combined ibrutinib with BR in a large, randomized trial for non—transplant eligible patients and the results are still pending.

Lenalidomide is also approved in MCL. The activity is similar: 33% response rates, an 8% CR rate, and a duration of response also at 16 to 17 months in a very heavily pretreated population—half of them were refractory to chemotherapy. Therefore, the R-squared data in the relapsed/refractory setting is also impressive and has a little bit more myeloid toxicity.

However, in the frontline setting of R-squared as treatment for MCL, it took a while for patients in that trial to achieve a CR—up to 1 year—but the CR was very impressive, even in a high-risk patient. That, potentially, could be a new frontline therapy in MCL. We still need more follow-up. Once we treat them with biological therapy where we see an accelerated disease, it might be more difficult to salvage those patients.

Finally, venetoclax is also really impressive in MCL. There are studies ongoing in combination with other biological agents or chemotherapy for MCL.

The next steps in MCL are to continue excellent work over the years of pushing clinical trials. [Previous ones] have led to 4 drugs approved in this rare disease. We need to try to stratify patients better from the get-go.

Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine and cytarabine (RBAC500) as induction therapy in elderly patients with mantle cell lymphoma: final results of a phase 2 study from the Fondazione Italiana Linfomi. In: Proceedings from the 58th Annual ASH Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 472.