MCL Experts Give Overview of Expected Trends in the Field

"In the last few years, we’ve seen a substantial advancement in the treatment of patients with new drugs, new strategies that come in different families of treatments, new inhibitors, receptors, anti-apoptotic tracks targeting the apoptotic pathways, and ongoing therapeutic strategies together with classical treatments. This results in substantial advancements in the improvement of the outcome of patients with longer survival rates."

In May 2023, hematologic oncology experts convened for the Mantle Cell Lymphoma Scientific Consortium and Workshop hosted by the Lymphoma Research Foundation. During the meeting, various presentations occurred focusing on clinical trials, the tumor biology of mantle cell lymphoma (MCL), and how the disease should be approached over the next 20 years.

In conjunction with the consortium, ONCOLOGY® published the findings and outcomes in the February 2024 issue. This high-level overview provided key takeaways from each discussion and may offer clinicians insights into the optimal way to determine the best course of treatment.

Several leading clinicians who were a part of the consortium met with ONCOLOGY to discuss their biggest takeaways, and how they hope to see the field evolve in the coming years. These clinicians included Julie M. Vose, MD, MBA, Neumann M. and Mildred E. Harris Professor in the Division Chief, Division of Hematology and Oncology, at the University of Nebraska Medical Center, and Coeditor in chief of ONCOLOGY; Michael Wang, MD, professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center; Elías Campo, MD, PhD, research director and professor of Anatomic Pathology at the Hospital Clinic of the University of Barcelona, Spain; and Martin Dreyling, MD, PhD, professor of medicine in the Department of Medicine and head of the Medical Clinic III at the University of Munich-Grosshadern in Germany.

What topic do you think was most prevalent that was discussed during the consortium?

Campo: In the last few years, we’ve seen a substantial advancement in the treatment of patients with new drugs, new strategies that come in different families of treatments, new inhibitors, receptors, anti-apoptotic tracks targeting the apoptotic pathways, and ongoing therapeutic strategies together with classical treatments. This results in substantial advancements in the improvement of the outcome of patients with longer survival rates. These new treatments also [come] with new challenges because we see how the biology of the tumor advances with these new treatments. Some of them are resistant to these new therapies. Some of these tumors are resistant from the beginning. We started to see, on one side, how good novel therapies were and our strategies [to incorporate them into treatment]. On the other hand, [we looked at] how these tumors are resistant to treatment. If we understand the mechanism of refractoriness and resistance, we might be able to design new therapies that take into consideration these methods.

Until now, we have been concentrating on the biology of the tumor cells, and that has been important to understand how the cells evolved. There were several presentations that reflect the interests of the community. In addition to the tumor cells, [other topics discussed included] the host cells, the immune system, the tumor microenvironment, where each one of these cells is growing, and how the cells that are surrounding the tumor cells are interacting with the tumor. These are new perspectives that may help us to understand biology, but also there are a lot of mechanisms of resistance to the tumor cells.

The third point is that we started to see evidence that not all patients with MCL need the same therapeutic approach. Based on the biology of the tumor, we have patients who need intravenous control for long periods with nonchemotherapy protocols. For patients with not very aggressive disease, we can control the disease without introducing very harmful or infectious regiments. New treatments and new mechanisms of resistance and being refractory emphasize the tumor microenvironment and different strategies for different types of patients based on the biology of tumors.

Wang: I’m mainly a clinician and clinical researcher, and I do some translational research as well. The most important is our advances in therapeutics because this directly [benefits] our patients. One of the major advances in 2023 is that the consortium and the many investigators in the consortium participated in this international clinical trial with pirtobrutinib [Jaypirca] in relapsed/ refractory [MCL] because the result [from the phase 1/2 BRUIN trial (NCT03740529)] is so good. The response rate was 50%, and the complete response rate was 13%. Because of the efficacy [and the tolerability] of pirtobrutinib, the FDA approved this drug for relapsed/refractory MCL in the United States in January 2023. Therefore, we have added another oral treatment for our patients…because this is a very well-tolerated pill and is highly effective.¹

Vose: There’s a number of topics discussed; the first day is more focused on basic research, and the second day is more on clinical research. The things that are an important part of this consortium [are] to bring the basic and clinical scientists together, to try to come up with new therapies and translate that from basic research into clinical trials into treatments for patients eventually. That’s how a lot of the new treatments that we have for MCL, and other types of lymphomas have come about in this collaboration. This is a type of symposium that... we should [have] for other types of diseases as well as to bring researchers and clinical scientists together to collaborate and improve outcomes for patients and to develop new therapies. That’s the [goal] of this consortium, to try to improve outcomes for these specific types of patients.

Dreyling: It depends on what your priorities are. There are very interesting data on the molecular makeup, of MCL. When it comes to clinical application or therapeutical application, I think it’s mainstreamed to consider BTKi plus [an additional treatment]. The other strong impact is the future role of immunotherapy. Now we know that chimeric antigen receptors [CAR] T cells are registered for relapsed MCL, essentially for BTKi failures, but the field is moving on. There are already some studies completed with patients who are BTKi-naive. It might well be that at a certain point, we think that some patients may be treated with immunotherapy and others may be treated only with targeted treatment.

What was the rationale for putting this consortium together?

Wang: MCL is a rare disease. [It’s important] to have the combined wisdom, exchange ideas of how to cure this disease, exchange clinical practice knowledge, share, and promote the progress of clinical research, and further promote basic research and the connection between clinical research and basic research. The overall goal is to cure MCL. We have been united under the MCL Consortium for many decades, and the consortium will continue to grow. In 2023, we reached a new peak of activity [in the field]; therefore, we summarized this activity in terms of basic research, translational research, and clinical research for this article. We are very happy to share this in a publication so everybody in the world can read it.

Vose: This consortium has been going on for a number of years, now sponsored by the Lymphoma Research Foundation, and brings together researchers specifically in MCL, which is a rare type of lymphoma where we don’t have a lot of great treatments. [This consortium] brings scientists as well as physicians together to try to brainstorm new ideas, and new clinical trials, to collaborate and work together on research for MCL to improve the outcome for patients and develop new therapies. Over the years, this has been helpful because there’s researchers from around the world [who] have attended and collaborated, there have been publications out of each of the consortiums, and it has been helpful to the field...to work together to improve the outcomes for patients with MCL. We want to continue to do that and to improve our treatments for patients with this rare lymphoma.

Where should future research efforts be focused in the MCL field?

CAMPO: Many of these tumors are complex in terms of biology. We need to accomplish different aspects, so it’s difficult to [name] just one focus. All of them are interactive. The tumor is biologically heterogeneous, so we don’t completely understand what the drivers of these different biologies are, why we are seeing some patients have stable disease for so many years, and why some patients develop the disease quickly and others slowly. We still need to understand that better. [In addition, another focus should be on] the opposite side of the disease. Why do some patients have very difficult-to-treat, aggressive diseases up front? Understanding this biology better will lead us to key aspects to target it more aggressively. That biology is important to try to design drugs and therapies that might control or even cure the disease without harming the patient. Lastly, understanding how the tumor cells and the host interact is also an area of increasing interest.

Dreyling: The major theme is to challenge chemotherapy overall in the first line, so we have established a combination of chemotherapy plus BTKI. Namely, the phase 3 TRIANGLE trial [NCT02858258] where we have established the significant benefit of ibrutinib as the first-generation BTKi, and my understanding is that this was also implemented in the US guidelines, and then been mentioned that you could also apply second-generation BTK is.² Although we don’t have the data [yet], I think it’s obvious that with a similar efficacy and with a better tolerability that that makes sense. On the other hand, the next wave, I would say of studies is moving a non-cytostatic approach into first-line [therapy]. Some of these data are already available. We do have data from MD Anderson, and we do have data from Barcelona, in patients with low risk [disease], using a clear-cut randomized comparison of chemotherapy vs a non-chemotherapy approach.

References

1. FDA grants accelerated approval to pirtobrutinib for relapsed or refractory mantle cell lymphoma. FDA. January 27, 2023. Accessed January 5, 2024. https://bit. ly/47qhzyQ
2. Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized Triangle trial by the European MCL Network. Blood. 2022;140(suppl 1):1-3. doi:10.1182/blood-2022-163018