Combinations Are Showing Promise in MCL

By using current combinations, investigators are working on novel approaches for the frontline and relapsed/refractory settings to treat patients with mantle cell lymphoma (MCL). Also, additional newer clinical endpoints are moving into the space for MCL research, including minimal residual disease (MRD) negativity.

Such explorative regimens can be seen in findings from a phase 2 study presented at the 2016 ASH Annual Meeting. With the goal of reducing the hematologic toxicities associated with cytarabine, researchers treated patients with Rituxan (rituximab) 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, M.D. “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).”

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

In an interview with CURE, 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.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 five to seven 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 four 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 three years of maintenance with Rituxan 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” — Rituxan plus Revlimid (lenalidomide) — 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.

What are some interesting ongoing clinical trials exploring novel approaches?

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 two years, 75 percent of patients progress.There were trials looking at R-CHOP combined with Velcade (bortezomib). The activity with single-agent Velcade in the relapse setting is a 33 percent response rate and 8 percent CR rate. It is quite durable for refractory patients.

This trial randomized patients to the combination of Velcade plus R-CHOP versus R-CHOP alone. The results showed a dramatic improvement—close to 60 percent 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 Velcade with a CR rate in excess of 50 percent. It is promising enough to develop a randomized trial that is ongoing, with BR plus or minus Velcade 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.

What investigation is being done in the relapsed/refractory 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. In the relapsed/refractory setting, there are a number of novel therapies that have been approved. We have Imbruvica (ibrutinib), Revlimid and Velcade; in addition, Torisel (temsirolimus) is approved in Europe. Imbruvica has dramatic activity with a 68 percent response rate, a 21 percent 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 2 study presented at the 2016 ASH Annual Meeting looked at Imbruvica plus rituximab for two to four cycles — with a very impressive CR rate in the frontline setting — followed by a shorter course of hyper-CVAD for four 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 percent to 22 percent 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 Imbruvica with BR in a large, randomized trial for non—transplant eligible patients and the results are still pending.

Revlimid is also approved in MCL. The activity is similar: 33 percent response rates, an 8 percent 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 one 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 four drugs approved in this rare disease. We need to try to stratify patients better from the get-go.