Expert Highlights Novel Combos, Potential of Immunotherapy in MCL

Stephen M. Ansell, MD, PhD

Emerging regimens are being tested in several ongoing trials in mantle cell lymphoma (MCL), according to Stephen M. Ansell, MD, PhD.

A triplet currently in development is ibrutinib (Imbruvica), rituximab (Rituxan), and lenalidomide (Revlimid). In the phase II PHILEMON study, an estimated 50 patients with relapsed/refractory disease will receive the 3 drugs in an induction phase (NCT02460276). Patients who achieve complete response, partial response, or stable disease will then enter a maintenance phase and receive treatment with ibrutinib and rituximab until disease progression.

A separate phase Ib dose-escalation trial is seeking to determine the maximum-tolerated dose and safety profile for the combination of ibrutinib at 560 mg daily plus lenalidomide dose-escalated at 10, 15, 20, or 25 mg orally on days 1 to 21, and rituximab at 375 mg/m2 intravenously on day 1 for patients with relapsed/refractory MCL (NCT02446236).

Additionally, ibrutinib plus rituximab is being combined with 2 different intensive chemotherapy regimens in a phase II study (NCT02427620). In part 1 of the trial, patients will receive ibrutinib at 560 mg orally daily on days 1 to 28 of a 28-day cycle and rituximab at 375 mg/mg2 intravenously weekly during the first cycle, then day 1 of cycles 3 to 12 of a 28-day cycle. Depending on response in this first part, patients will then receive 2 alternating chemotherapy combinations for 2 to 8 cycles in part 2.

The regimens being alternated will be rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and rituximab plus high-dose methotrexate and cytarabine. Researchers will evaluate overall response rate and adverse events for the primary endpoints.

OncLive: What are some the most exciting recent advancements in MCL, and what can we expect coming soon?

In an interview with OncLive, Ansell, professor of medicine at Mayo Clinic, discusses emerging combinations being investigated in patients with MCL, the possible role of immunotherapy, and challenges oncologists are still struggling with in this population.Ansell: MCL is a disease that is moving and changing rapidly. Some of the things that we have used that have been our past dogma are now being challenged by new and exciting combinations and therapies. In the past, we really kind of took the view that there were patients who were young and healthy, and older patients who were not. We could move into an approach that was highly aggressive in the younger patients—considering transplantation and the like—and more palliative and less aggressive in elderly patients.

Can you expand on some of those combinations being studied?

Could we see immunotherapy making headway in this field?

However, new agents—many of them targeted therapies, such as lenalidomide and ibrutinib—in combination with antibodies have really resulted in excellent results. As we look to the future, we are going to see some of these new combinations being tested against some of the standard therapies. In the future, our approach to MCL will change entirely with a much more sophisticated and nuanced treatment, rather than a very aggressive, [nonpersonalized] approach.There have been a number of trials, particularly looking at lenalidomide and rituximab used in frontline therapy for patients with MCL. The exciting part has been that the response rates have been very high in patients with this disease. This has challenged a little bit of our thinking with needing to be very aggressive, when you can get results that are very promising with far less aggressive therapy. That is where the future lies, to compare some of these combination approaches with what we have done in the past.We could. The challenge right now is that we have very little data on exactly how well immune checkpoint therapies work in MCL. The trials right in the beginning had very few patients with MCL and there has not really been an MCL-focused trial—to the best of my knowledge—to date. There are lots of trials ongoing, and so I am sure that data will come. But, at this point, we don’t know for a fact whether it is an effective therapy.

All of these therapeutic advancements aside, what obstacles are researchers still facing in the MCL landscape?

However, MCL has surprised us in the past with how well patients have responded, and ibrutinib is a good example of that. We need to watch the space and see what comes. There are a few things that are hard. There is a variant of MCL called blastoid MCL. It is not a very common variant, but it is a very stubborn one and one that is very difficult to treat. Not a lot of the therapies we have work well for those patients. Clearly, we need new agents that will really make a difference in those patients.

The second area where there are some challenges is that there are some patients who do really well. Therefore, how do we best pick them out, so we can really give them far less therapy? Or, are those the ones in whom we may just have to watch and wait [if the disease [progresses]? We really need to be able to differentiate between the people we need to treat and be more aggressive with versus the people we may need to do far less therapy in. We need good tools to be able to differentiate those groups.