Frontline Mantle Cell Lymphoma Treatment Must Involve Personalized Approach

Peter Martin, MD

First-line therapy for patients with mantle cell lymphoma (MCL) must be administered in an individualized approach based on patient and disease characteristics, according to Peter Martin, MD.

Peer discussions held during the PER Medical Crossfire: Hematologic Malignancies meeting show several controversies in frontline management, including the difference in therapies that should be used in patients who are younger or older. Physicians do agree, however, that younger patients respond better to intensive therapy than older patients and that BTK inhibition should be used as a second-line therapy.

Recent research is also exploring ways to further improve responses with BTK inhibitors. For example, a phase I dose-finding study of ibrutinib (Imbruvica) in combination with the CDK4/6 inhibitor palbociclib (Ibrance) showed that the regimen is active in patients with previously treated MCL. In this trial, the maximum-tolerated doses were ibrutinib 560 mg daily and palbociclib 100 mg given on day 1 to 21. In the trial, patients showed an overall response rate of 67% and a complete response rate of 37%. The progression-free survival (PFS) rate at 2 years was 59.4%.

A phase II study (AFT-32) is underway to gather more data about the combination of ibrutinib and palbociclib in patients with MCL (NCT03478514).

In an interview with OncLive, Martin, an assistant professor of medicine, Division of Hematology/Oncology, Weill Cornell Medicine, recounts physician crossfire discussions related to frontline MCL treatment and provides his own expert opinion on the subject.

OncLive: What is most important thing for oncologists to know about frontline therapies for MCL in today's landscape?

Martin: There's no standard for anyone and treatment needs to be individualized. As oncologists, we need to keep all of the disease characteristics in mind, including morphology, cytology, Ki-67, p53 status, patient comorbid conditions, and age. Then, we need to carefully consider what the patient's goals are and merge that with available treatments.

Are there any areas of controversy amongst oncologists regarding the frontline therapy for MCL?

It was interesting to hear the discussion regarding frontline therapy. In general, I think there's a consensus that young patients can do well with more intensive approaches, at least in terms of PFS. I think most [physicians] were open to the idea of high-dose cytarabine-based induction therapy for younger people who were interested in intensive therapy. But, interestingly, there was a difference in opinions on the role of the platinum agent [regarding its importance], and there's an uncertainty regarding the requirement of autologous stem cell transplantation after cytarabine induction. What we end up with is a general agreement that younger people can do well with intensive therapy, at least in terms of PFS. But, maybe, a range of opinions on how best to deliver that therapy and what kind of consolidation and maintenance should be given.

Regarding older patients, there was a general agreement regarding the approach but some discordance regarding some of the nuances of therapy. In general, there's an agreement that older patients can probably be managed less intensively. Many people suggested that bendamustine (Treanda) was the primary modality of chemotherapy for frontline treatment of older patients, but that was not universally true. R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) and VR-CAP (bortezomib [Velcade], rituximab, cyclophosphamide, doxorubicin, and prednisone) backbones are still reasonable for older patients and have a lot of good data supporting them.

There's still some discordance regarding the role of cytarabine in older patients. It's active in younger patients. [The question is] should we be withholding it from older patients purely based on their age? It was interesting to learn that in France, they still try to give it when they can. It's a little less common in the United States.

Are there also controversies amongst oncologists regarding maintenance and subsequent therapies for patients with MCL?

Another question is regarding rituximab maintenance following a bendamustine backbone, particularly in older patients. The majority of [physicians] were against it, although others, like me, think that there may be a role for it. It is the same thing amongst older patients where we have to take into account a lot of factors and try to come up with a regimen that is going to accomplish our goal, which is to help people live better lives without a lot of issues related to the lymphoma. That's challenging in MCL, maybe more so than in almost any other lymphoma.

Almost across the board, everyone agrees that the best second-line therapy should begin with a BTK inhibitor-based treatment. And that is true in North America and Europe. In Europe, they don't have access to acalabrutinib (Calquence) yet in the second-line setting, whereas in the United States we do. In North America, ibrutinib and acalabrutinib are probably viewed similarly in the second-line setting of MCL.

Can you explain the emerging differences between the subgroups of MCL and how these patients should be treated differently?

MCL is clearly a heterogeneous disease, it may be more so than was recognized 10 years ago. Biologically speaking, it's now widely recognized and is in the World Health Organization classification of lymphoid neoplasms that MCL has a leukemic non-nodal presentation. Those MCL cells tend to evolve from a cell that passes through the germinal center reaction. They tend to be SOX11 negative, IGHV mutated, and they tend to have a more indolent clinical behavior. Some of those patients may go on to develop TP53 mutations and blastoid transformation.

Separately from that, there are the more classic MCLs, which are the typical nodal patients. These are derived from MCL cells that have not passed through the germinal center. They are SOX11 positive and IGHV unmutated, for the most part. On average, they [usually] have a worse prognosis than the leukemic non-nodal patients. Although, about 20% of them or more can be observed for some significant period of time.[Simon Rule, MD, recently presented data suggesting that many of them could do well for a couple of years without any therapy. So, biologically, there are differences there.

Additionally, the blastoid morphology that comes with a more proliferative state tends to do a little bit worse. Those patients with TP53 mutations or high p53 protein expression tend to do worse. Oftentimes, Ki-67, blastoid morphology, and p53 go hand-in-hand, but that's not universally true. Those patients should probably be managed differently. Specifically, the patients with p53 mutations who are not blastoid, could be managed with non-chemotherapy approaches. Those patients with blastoid morphology and p53 mutations should probably be offered allogenic stem cell transplant early on in therapy or be considered for clinical trials with CAR T cells.

You recently conducted a phase I dose-finding study for the combination of ibrutinib and palbociclib in MCL. How is this combination being considered to improve responses for patients with MCL?

Ibrutinib is a good drug for MCL, as all BTK inhibitors are good for MCL. But they leave a lot of room for improvement. About 30% of people don't response and of the responders, the majority of them usually relapse within a year. It's clearly different than the scenario with CLL where people can be stable on a single-agent BTK inhibitor for years, or now, maybe even decades.

[At Weill Cornell Medicine] we sought to find ways to improve on BTK inhibitors and we started by looking at cells derived from patients who were resistant to ibrutinib and found that some of the pathways that were active were bypassing the BTK blockade. We looked at exposing those ibrutinib-resistant cells to palbociclib (a CDK4 inhibitor), which interestingly, does not have a lot of single-agent activity.

But we found that cells that had a growth cycle arrest due to palbociclib were subsequently sensitized to killing by ibrutinib. So, we could re-sensitize ibrutinib-resistant cells to ibrutinib following exposure to palbociclib. So, we conducted a phase I trial and we found the combination was well tolerated overall; there was some myelosuppression, which is expected with palbociclib, which is currently approved in breast cancer. We also found a hint that there might be some immunological affects so we had some people with rash, and that may hint at why the combination may be more effective.

We also found that about the same 30% of people were not responsive, in other words, those patients that were likely to be primarily refractory to ibrutinib were still primarily refractory to the combination of ibrutinib plus palbociclib. But the patients that were sensitive to ibrutinib seemed to have a rapid and deep response that appeared to be more durable than what we might expect from ibrutinib by itself.

Of course, it's a phase I trial and we can't draw major conclusions from it. But we are now conducting a phase II trial AFT-32, [in which we plan to] refine some our scientific hypotheses that will allow us to select the patients that are most likely to benefit from that combination. So, the trial is underway and going relatively well. Hopefully, in a couple of years we will see some interesting data there.

Martin L, Bartlett NL, Blum KA, et al. A phase I trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma. Blood. 2019;133(11):1201-1204. doi: 10.1182/blood-2018-11-886457.