¶ Introduction to Evolving MCL Treatment
Welcome to this week's bonus episode of Blood Podcast. Your source for innovative ideas and cutting-edge information. In this episode, Associate Editor Dr. Felipe Armand discusses the review series on mantle cell lymphoma with author Dr. Christine Ryan.
My name is Philippe Armand, and I'm the chief of Billinforma Division at Dana Farba Cancer Institute in Boston, and also have the additional pleasure of being an associate editor for Blood. This is a review series on Mantacell lymphoma, which aims to cover the broad topics that are of relevance both to laboratory searchers and to clinicians.
And the treatment of mentocell infoma, and the way we think about the disease biologically, the way we think about risk stratification, and the way we think about treatment. Is undergoing uh tremendous changes right now. So it seemed like a good time to get experts like Dr. Ryan and others. to guide readers about what those changes are and and how they might impact how we practice and how we think about future research in this disease.
There were four articles, and uh today we're gonna focus our podcast on the the article that Dr. Ryan wrote, which is on the treatment of frontline mantisell lymphoma, which is arguably where most of the, I'd say, momentous changes are taking place in this disease.
In addition, we have a review on the biology of mental cell lymphoma and how it may highlight therapeutic vulnerabilities, a review on the treatment of high-risk mentosell lymphoma, which is also a very complex, rapidly evolving topic. And review on the treatment of relapse refractory med cell information.
My name is Christine Ryan. I'm an attending physician and clinical investigator in the Division of Lymphoma at Dana Farber Cancer Institute. And I had the privilege of writing a review article with Dr. LeCase and Dr. Rahman on the frontline management of mantle cell lymphoma.
In this article, we focus on frontline management of mantle cell lymphoma and we sought to provide a framework for thinking about and assessing the many changes that Dr. Ramon referenced that are going on in this field right now. We identified six key main areas to focus on for the advancement of frontline management and use that as our framework for really discussing the changes in the field right now.
Dr. Ryan, thank you very much for doing the podcast and for authoring the review. My first question to you is there have been an and there are many changes which are happening right now in the frontline treatment of mapstylymphoma. As a starting point, how would you define the, let's call it the old standard of care?
First of all, I'd like to say many thanks for having me and for the opportunity to contribute to this review series. I think i you know, taking a step back and thinking about where our standard of care is right now, for many years now when we think about a newly diagnosed patient with mantle cell lymphoma, it's really been framed by this dichotomy of transplant eligibility. So younger patients eligible for a autologous transplant.
We generally treat with intensive upfront chemoimmunotherapy induction. A mainstay of that has been the inclusion of citerabine in intensive upfront chemoimmunotherapy. followed by a consolidative transplant for those patients in remission, followed by maintenance rituximab. And on the other side of that dichotomy are those patients who are transplant ineligible, so older patients either or ineligible for transplant due to other medical comorbidities.
And these patients we generally treat with upfront chemoimmunotherapy, generally being bendomustine plus rituxamam, and then followed by the option of maintenance rituximam.
¶ Re-evaluating Transplant and Induction Regimens
Let's start perhaps with one of the moving parts now, which is the role of autologous stem cell transplant, which is one of the six. Issues that you brought up in your review. Can you very briefly tell us your your thoughts about the implication of recent research for this?
I think the role of autologous stem cell transplantation and first remission is perhaps of the six areas we identified the one where we're seeing the most tremendous change right now. And that's really because of two pivotal phase three studies that have reported results recently, one actually just in the last several months, even since we finalized the publication of this article.
And those two studies, one was a large randomized study in Europe conducted by the European Mantle Cell and FOMA Network. That was the triangle study. And then in the US, also a large randomized phase three study conducted by the cooperative group, the ECOG Akron EA4151 study.
And both of these studies involved randomization to transplant or no transplant arms. And there are a lot of details within those studies, but I guess just as a high level overview, Both of these studies ask the question about the utility of autologous transplant and both of the results from these studies really call into question that utility. and have demonstrated that there is perhaps no benefit to a tolerus transplant in first line management of this disease.
And if we move back from Otalgous stem cell transplant, which m may be less compelling now, let's say. And think about the induction regimen. What do you think are the major changes that we're seeing in the choice of induction regimen in this disease?
First of all, just to say induction regimens, there's really I'd say a a challenge of a consensus when it comes to induction regimens, especially for younger patients in mantle cell lymphoma. I think that we as a field coalesce around the inclusion of cytarabine, given the results of the randomized phase three mantle cell lymphoma younger study.
But in terms of the chemoimmunotherapy backbone, whether it's RCOP or DHAP, BR, BR, rituximab cyterabine, there's a lot of variability in the options that are used around the world. One change I think that we are seeing is the investigation of inclusion of upfront BTK inhibitor. And this was really heralded by the triangle study. Which included the first generation BTK inhibitor iBrootnib in combination with our CHOP alternating with our DHAP.
And I think that study has led to increased use of BTK inhibition in the front line. But a lot of questions do still remain as we think about adding BTK inhibitor to the frontline, and in particular, especially here in the US where ibrutNib is not available. Also important questions about which BTK inhibitor to add in.
So I think on top of that, you know, as you mentioned, if we take a step back from the transplant question, if sort of longstanding dichotomy of transplant eligible versus ineligible we're sort of putting to the side really raises a question about how we think about a patient that we're seeing with newly diagnosed disease. and perhaps a new dichotomy being established in terms of intensity of chemotherapy induction and really coming down to inclusion or exclusion of cyterapine.
¶ Targeted Therapies for High-Risk MCL
And more provocatively we are seeing greater uptake and a lot of research in chemo free induction regimens. We'll come back maybe if there's time to the P fifty three mutated patients, which are a unique and different category. But considering standard uh let's call them standard risk patients uh for now. Do you think chemo free treatment is a necessary goal in metacell informal?
Indeed a provocative question. I think as clinicians and researchers, we are all very drawn to the concept and the idea of targeted therapy approaches. Um it's very exciting to think about using treatments that are targeted to the disease, to the biology of that disease, I think there is a draw to using targeted therapy approaches and a need to investigate them.
One of the issues with mantle cell lymphoma is that currently it remains largely an incurable disease. As we think about our treatment armamentarium. I think it's important to recognize that we want to use most effectively the agents that we have. And I think that we have a lot of data demonstrating that there are patients for whom upfront chemotherapy can achieve durable remissions. the concept and the rationale of targeted therapies
is very attractive. I think it's important to think about in the context of this disease and the fact that I would say as of right now, we don't know that targeted therapies such as BTK inhibitors have curative potential, that we continue to think about the most effective use of all of our treatments and the role of potentially sequential approaches as well.
That being said, I think for patients who really chemotherapy is not an option or really who we would deem to be quote chemotherapy ineligible or who may not be able to get through many rounds of chemotherapy, then yes, absolutely. a targeted agent approach that is perhaps more tolerable is definitely worth considering for such patients.
And now on to the even more thorny question, which I alluded to earlier. What about those high-risk patients? So Dr. Jane and Dr. Wong wrote a review on the treatment of high-risk patients, which encompasses various definitions, but I think for most of us for practical purposes, uh we use T P fifty three mutation as the easiest way to categorize those patients, though there are many more subtle considerations that are outlined in the review of Chain and Wong.
So let's say limiting it in general to P53 mutated patients, what do we do for them? How has that changed recently?
A very tough and very important question. I think I would say on the one hand, uh very excitingly, we have seen uh data recently published. Looking at a triplet targeted regimen in this disease, that is the Bovin study, which combined the BTK inhibitor Xanobertinib with the BCL2 inhibitor Venetaclax and the anti-CD-20 antibody OBNatousimab.
It was a relatively smaller study, 25 patients published, but really excellent two-year outcomes. And looking at what we have from other chemoimmunotherapy results definitely compares favorably. I just wanna emphasize I think for these patients we are encouragingly seeing potential for improvement.
with the use of targeted therapy. Now, that being said, I think that what we have yet to establish uh in a head-to-head comparison would be that those novel targeted age of its alone versus in combination with chemotherapy
Whether or not it's not a little bit more than a
how those two compare and whether truly a chemo chemo free regimen is superior in that setting. I think we've all
treated patients with very aggressive mantle cell lymphoma where a cytotoxic agent or a debulking agent that quickly can obtain disease control could be desirable as well. And so I think there are still some unanswered questions there. And For me personally one thing that I am very intrigued by is is really how can we target the biology of P fifty three mutated disease, which of course is a holy grail I think in some ways across all of cancer biology and cancer therapeutic.
But I think a better understanding, which thus far has in many ways remained elusive, of what actually drives that malignant biology or aggressive biology of a P fifty three mutated mantle cell. that is perhaps where we'll have the biggest impact in improving outcomes for those patients.
¶ Current Recommendations and Future Research
And then before we talk about upcoming research to conclude this discussion, ask you the next patient who comes into your office and who is Let's say transplant eligible, standard risk patient with manta cell lymphoma. What treatment do you recommend for that patient now?
At our institution we've had a longstanding history of using the chemo immunotherapy backbone of benamustine rituximab followed by rituximab with high dose cyterabine. The rationale for that incorporating cyterabine, which as I've mentioned, you know, we have established data from a phase three study that that improves outcomes of patients.
And then for us drawing from in terms of the chemotherapy backbone of BR, R CHOP, BR, which we also have phase three data showing superiority of BR over RCHOP. So in a sense, kind of drawing from two chemotherapy backbones that we know have high efficacy in this disease. We have us in in in addition to Washington University in St. Louis, have a cohort of patients that now with long term follow-up we've seen very positive and durable responses. And so
For me, that is still my go-to chemoimmunotherapy backbone and a standard of care for this disease. With the publication of the triangle results, there was a lot of discussion and interest in adding BTK inhibitors up front. We didn't quite get into this in terms of the details, but with the inclusion of the BTK inhibitor, both in induction and maintenance.
likely it's the inclusion and maintenance that is pulling the heavy or heavier weight there I should say than just in the upfront induction. And so I think that considering addition of BTK inhibitor to maintenance therapy is a very important option. I think for uh perhaps practicing clinicians who uh
are perhaps more familiar, more used to using the RCHOP or D hat backbone. I definitely think in that situation implementation of a triangle like regimen is very reasonable, obviously with phase three data supporting that. is a very well-founded approach and we know that that inclusion of the BTK inhibitor to that regimen particularly allows the omission of a tolerus transplant, kind of circling back to what we started with.
Now I guess I would say as a last option, you know, there's given that there are still unanswered questions, obviously considering a clinical trial when available is definitely a preferred approach as well.
What about what's coming up? What trials are you excited about? And what this may be a separate question, but what future research directions do you think are important to pursue now?
Yeah, I think there are a lot of ongoing trials in the field, a lot of unanswered questions. Just to say as we you know potentially and likely move away from transplant and frontline, it it really in my mind opens up a huge gap to be filled in terms of what then is our best induction approach and really what is our best maintenance approach as well.
Ongoing studies I think are very promising and exciting to keep an eye on are actually a number of ones that we talk about in the article, but yet to have longer term follow up. in terms of this disease, we know that the long term follow-up is equally important here. And so for example, there is the US Cooperative Group study adding a calibru nib to
the BRRC backbone as well as to BR. I think that will be an important study to see longer term follow up as we continue to investigate the inclusion of cytarabine in frontline. That is a study that will in in some ways answer that question. In addition, you know, there is an ongoing phase three trial of Xanobrutinamp rituximab versus bendamustin rituximab in the frontline setting for older patients.
We saw a version of that trial reported at Ash this past year, the Enriched trial, which used the first generation BTK inhibitor e-brutinim. And I think it will be really exciting to see that study readout with a second generation BTK inhibitor. Then I think as we were discussing for the P53 aberrant patients, ongoing targeted agent approaches there. will be very exciting as we continue to try to improve outcomes for those patients.
And there are also a number of you know earlier phase or phase two trials ongoing now, which look at early escalation studies. So I think that that is an important aspect of thinking about patients who may not have these durable outcomes. How can we best treat them and escalate therapy as needed.
Thank you very much, Luza. Terrific answers and I I hope they make the listeners uh more eager to read your outstanding.
Thank you so much for having me.
would also say in closing, as I mentioned at the beginning, unfortunately we don't have the other authors, but I hope that the listeners are also able to read the other reviews. There's an excellent review led by Clementine Sarkozy on on the biology of medcellymphoma, which summarizes a lot of really exciting
Findings in the field. I already alluded to the review on high-risk mentosell lymphoma from Drs. Jane and Wong, and then finally a review on the treatment of relapsed metricell lymphoma by Dr. Silkenstedt and Dryley.
Thank you for listening to this bonus episode of the Blood Podcast. To read these articles, visit Bloodjournal.org. This episode is copyrighted by the American Society of Hematology.
🎵 Music