Goy Reflects on MCL Data Presented at ASH 2017

Andre Goy, MD

With the excitement of the recent FDA approval of acalabrutinib (Calquence) still moving through the field of mantle cell lymphoma (MCL), there was much anticipation for additional abstracts in the field at the 2017 ASH Annual Meeting.

For example, in addition to the acalabrutinib data, there were data presented on the combination of lenalidomide (Revlimid) plus rituximab (Rituxan), which showed that patients treated with this combination had a high rate of complete response (CR).

OncLive: Can you discuss some of the data in MCL that were presented at this year’s meeting?

In an interview with OncLive during the meeting, Andre Goy, MD, chairman and director, chief of Lymphoma, and director of Clinical and Translational Cancer Research at John Theurer Cancer Center, Hackensack Medical Center, shed light on some of these studies as well as future treatment options for patients with MCL.Goy: At the 2017 ASH Annual Meeting, we have shown the continued progress on the impact of novel therapies, cellular therapies, and immunotherapies. In MCL, we are seeing a continuous shift of novel agents that are changing the landscape as we combine them in the relapse setting, and potentially in the frontline setting.

The long-term follow-up of ibrutinib (Imbruvica) was presented at the 2017 ASH Annual Meeting, which was a report at 3.5 years of several hundred patients receiving the agent in the relapsed/refractory setting. The CR rate was up to 26%, and at 3 years, one-quarter of the patients still had not progressed.

We tried to dive deeper into what could help us predict which patients would do well on ibrutinib. It is interesting, although ibrutinib works in patients regardless of the number of prior therapies…the duration [of response] is clearly affected by the number of prior therapies. Therefore, if you had 1 prior therapy, there was significant difference in outcomes in terms of duration of response and progression-free survival (PFS). These are very powerful data of single-agent ibrutinib in a large group of patients.

During the same ASH session, we had data from the second-generation BTK inhibitor acalabrutinib, which is a more selective inhibitor with probably a better coverage of BTK. What was interesting in this trial was the 80% overall response rate with a 40% CR rate. The criteria of the trial were slightly different than that of the ibrutinib trial, and the safety profile was better—there was no atrial fibrillation in over 100 patients. The rest of the toxicity profile pretty much overlapped with that of ibrutinib.

What we are starting to see are combinations with these biological agents because they are not curative alone in MCL. Although we achieve some CRs with patients eventually progressing, combining these agents might achieve a deeper response. [There was] a pilot study presented at ASH, which was a combination of rituximab (Rituxan), lenalidomide, and ibrutinib, and the response rate was over 85% and the CR rate was 60%. That is very promising for patients who have relapsed or refractory MCL. This is what we are going to see moving forward because achieving a deeper response in MCL clearly affects the outcome. There are ongoing trials trying to develop combinations on nonchemotherapy options, particularly in the frontline setting for elderly patients with MCL who are not candidates for chemotherapy.

I also want to mention updates from the multicenter trial looking at the long-term follow-up of lenalidomide and rituximab. It is a small study but, as a proof-of-concept trial, it was interesting that at 5 years there were still some patients who continued in remission on rituximab or off it.

Finally, there was a presentation on maintenance rituximab, which is part of a large randomized trial of rituximab, fludarabine, and cyclophosphamide versus R-CHOP in the frontline setting in patients who are elderly or ineligible for high-dose therapy and transplant. The results are very impressive, and not surprisingly, the maintenance with rituximab was better tolerated and had better results in terms of PFS and OS.

With all of these new data, what do you predict for the future of MCL?

This was a long-term follow-up—up to 10 years—and it showed a significant advantage both in PFS and OS. Clearly, we have shown across the board that maintenance rituximab impacts outcomes. The question that remains is, “Should everyone get maintenance, or should we identify the patients who need rituximab?” This is in the context of cost and toxicity. The future will be based on minimal residual disease (MRD) studies to potentially decide who needs maintenance therapy, particularly rituximab.It’s interesting; we presented a registry study on many patients with MCL in the real world, and large academic institutions, as well, and looked at the impact of how therapy consolidating influences CR. Therefore, there are these registries that show that we must use intensive therapy, and simultaneously, we are developing these novel regimens that are potentially chemotherapy free. The option will be in the middle—combining novel therapy with some of the chemotherapy agents. There are several trials that have been completed that we are awaiting, such as R-CHOP with bortezomib (Velcade) and also bendamustine and rituximab with or without acalabrutinib. Those studies will likely build upon the backbone of chemotherapy.

The other question would be, “When do we stop treatment?” As I said before with maintenance, the MRD studies will be very critical in terms of achieving early and deep responses in patients with MCL. This is where the field is going to go.

In the relapse setting, we also have venetoclax, which has shown great activity in MCL. There are some ongoing studies combining BTK inhibitors with venetoclax showing impressive results in the relapsed/refractory setting.

What is a significant challenge that the field is still facing?

Also, we are hearing about chimeric antigen receptor (CAR) T-cell therapies. There are ongoing studies, such as ZUMA-2, focusing on a MCL population, with very promising results at this point.One of the big challenges of MCL is that it is truly a disease that has a spectrum. There are about 10% to 15% of indolent MCL, and these patients present with splenomegaly, no lymphadenopathy, high white blood cell counts, and the cytogenetics are not usually complex, making this a much more genetically stable disease. These patients can probably be monitored for quite a while. A very small fraction of those patients will evolve over time and develop 17p deletion and can become more aggressive, but that is kind of a rare event.

We are trying to take advantage of the data published about gene expression profiles looking at the proliferation signature in MCL. We are using Ki-67 as a surrogate marker, and if you have less than 30% versus 30% or more [of Ki-67] that clearly impacts the outcome. The Mantle Cell Lymphoma International Prognostic Index (MIPI) combined with Ki-67 is a factor, but it is not a factor that helps predict the outcome of MCL and customize our treatment. As we dive deeper, patients with p53 mutations or deletions, regardless of the therapy and transplant, their outcomes are worse. These patients should probably receive a different lymphoma therapy. Clearly, chemotherapy is not enough for those patients.

Is there anything else from the meeting that you would like to touch on?

As we further dissect and understand the different subtypes of MCL, we will be able to develop biomarkers. We do not have this yet, because there has been an increased awareness of the biological complexity of MCL. The separation has been a bit difficult. p53 will definitely be a factor, as well as ATM, 11q, and Ki-67 proliferation. This has not yet helped stratify patients.Data were presented from the LyMA trial where, instead of cisplatin, researchers used oxaliplatin, which has not been tested much in MCL before but had been used in relapsed large cell lymphoma. Replacing the cisplatin with oxaliplatin seems very promising, so the group behind LyMA is moving in the direction of using this as a backbone for induction therapy in MCL.

This is not something that we are really using in the United States; we are still using a combination of alternating anthracyclines and cytarabine with or without high-dose therapy and transplant. The paradigm in MCL is building up on novel therapy in the relapse setting, and then combining novel therapy with chemotherapy to try to get deeper responses in the frontline setting, as well as customizing maintenance based on MRD. That is where we are heading.

A lot of the 2017 ASH Annual Meeting has centered around immunotherapy. There are a lot of presentations trying to understand biomarkers to predict response to CAR T cells. This is from the microenvironment, the general inflammation status of the patient, the bulk of the disease. We have an update of the ZUMA-1 trial which showed impressive data. There are definitely some patients who initially relapse, but we also had some partial responses that converted into CRs 1 year later. Once a patient receives a CR over 3 months, very few relapse.

The mechanism of resistance of CAR T cells is something that we are starting to hear. This is the rationale for a trial we are about to start called ZUMA-6, which is ongoing and looking at axicabtagene ciloleucel (axi-cel; Yescarta) plus atezolizumab (Tecentriq). It is a really exciting time to be at the 2017 ASH Annual Meeting.