Frontline Therapies for Patients With Untreated and Relapsed Mantle Cell Lymphoma

Tycel Phillips, MD, University of Michigan, Ann Arbor, reviews standard therapies utilized for patients with mantle cell lymphoma (MCL), including nonaggressive regimens and BTK inhibitor therapies.

Dr Phillips presented on this topic in a session at the 2022 Great Debates and Updates in Hematologic Malignancies in New York, NY.

Transcript

Hi, my name is Dr Tycel Phillips. I'm an associate professor of medicine at the University of Michigan in Ann Arbor, Michigan. So today we discussed mantle cell lymphoma. It's a bit of a heterogeneous non-Hodgkins lymphoma in the simple fact that there's a lot of interpatient variability as far as presentation, outcomes to treatment. So today we reviewed some of the standard frontline therapies that are utilized in our patients of sort of non-aggressive regimens, such as R-CHOP followed by maintenance rituximab, bendamustine-rituximab plus or minus maintenance rituximab, lenalidomide-rituximab, the R-squared regimen, the WINDOW study as well from Dr Michael Wayne, all of which typically we'll treat with chemotherapy without the utilization of autologous stem cell transplantation.

All of the ones I mentioned prior, except for the WINDOW study targeted an older transplant ineligible patient population. The WINDOW study was for all comers, and it, in the short term, has indicated a very good treatment response indicating maybe some potential for rituximab and ibrutinib in an upfront setting with the chemotherapy consolidation.

Now, for those patients who are younger and fitter, we typically will consider autologous stem cell transplantation. And in that, again, you have a multitude of regimens that have been utilized. The Nordic regimen, which is R-maxi-CHOP and R-hyper-CVAD. What we typically refer to is a French regimen, which is R-DHAX followed by R-CHOP if needed. And also you have R-hyper-CVAD, which is the regimen of choice at MD Anderson Institution. So of the three regimens, I mentioned the first two, the French and the Nordic are the ones that use consolidation with stem cell transplantation. And from what we can see from the data is that with autologous stem cell transplantation, we get a prolongation of the progression for survival, any the time interval before the cancer comes back without any substantial benefits so far that we can see an overall survival.

So, I mean, all in all, I think for induction therapy, the bigger questions that we're trying to answer now is the role of autologous stem cell transplantation. Is it needed in everyone, but also there's some exploration of some sort considered non cytotropic chemotherapy regimens, which hopefully in the next couple years, we'll have more data on those.

Now flipping the script to relapse refractory mantle cell lymphoma. I think with the advent of the BTK inhibitors and a publication from Simon Rule, those drugs have become entrenched in a second line setting. That's currently we have three FDA approved options, ibrutinib, acalabrutinib, zanubrutinib, ibrutinib being the first generation acalabrutinib, zanubrutinib being second generation molecules, which these molecules are a little bit more selective, meaning they have a little bit more selectivity to the BTK versus some of the other kinases that may be illustrated in the kinal map. With that, we see a little bit better safety profile, at least in the early term studies. We'll wait to see how those mature out. Future directions for BTK inhibitors is in a second line setting will probably be in combination with some other drugs, such as Venetoclax, potentially with CAR T. And we do have a non-covalent BTK inhibitor, which is into the market, pirtobrutinib.

And that is being explored in the phase three study against the three covalent drugs that I mentioned before in the second line setting. Now post BTK inhibitor exposure, again, is in at need area, as we discussed today, and the patient outcomes have been very poor. And with some of the options we have such as Vel K for the chemotherapy, lenalidomide, Venetoclax and even the PI3 kinase inhibitor. So the first major breakthrough I would say was Brexicaptogene Aruso which is the CAR T product from Kite, which demonstrated in very impressive overall outcome CR rate. And so far has a pretty decent duration of response, even though that data is still maturing. The biggest downside to CAR T is it's limited ability in all patients, if they have to be at transplant centers, it's not something that can be readily given in the community. And also there's a high percentage of neurotoxicity that we've noted with that medication.

So again, with further time, we'll see how that plays out. Thereafter, a lot of the other agents are really still in clinical trials. So there's pirtobrutinib, as we mentioned before, was also explored in a post covalent BTK setting. That medication did indicate it did have some efficacy in its post BTK, covalent BTK setting. But as of right now, that data is very immature. And also given that the MCO sort of resistance to the BTK inhibitors, isn't really clear, unlike COL, how Pirtobrutinib actually produces sort of efficacy is something that's still up for debate.

Thereafter, we have the bispecific antibodies, which again, function to sort of harness the patient's T cells. These are all in clinical trials and there are several agents being explored. And then lastly, there is an ROR1 inhibitor, which is a drug antibody conjugate connected to the antibody against ROR1 with methomonal oral E, or MMAE. So again, those agents will be something we'll be looking forward to as we get more mature data, bigger data in a more MCO specific subset. And hopefully that will be further sort of improvements along the line as we continue to try to improve outcomes and overall survivor for our MCO patients, hopefully one day we can say these patients will be cured, but as of right now, I think if we can ensure that these patients die with their cancer and not from their cancer, we would've accomplished a lot.