Treatment Approaches for Patients With Untreated and Relapsed MCL

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. Today we discussed mantle cell lymphoma. It's a heterogeneous non-Hodgkin lymphoma, and there's a lot of inter-patient variability as far as presentation, outcomes and treatments.

Today we reviewed some of the standard frontline therapies that are utilized in our patients, of nonaggressive regimens such as R-CHOP followed by maintenance rituximab, bendamustine rituximab plus or minus maintenance rituximab, lenalidomide rituximab, the R2 regimen, the WINDOW study, as well, from Dr. Michael Wang, 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, 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 a chemotherapy consolidation.

Now, for those patients who are younger and fitter, we typically will consider autologous stem cell transplantation. And in there, 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 as the 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 Summit Institutions.

Of the 3 regimens I mentioned, the first, the French and Nordic, are ones that use consolidation with stem cell transplantation. And for what we can see from the data is that with autologous stem cell transplantation, we get a prolongation of the progression-free survival, meaning the time interval before the cancer comes back, without any substantial benefits so far that we can see in overall survival. For induction therapy, the bigger question that we're trying to answer is the role of autologous stem cell transplantation. Is it needed in everyone? But also there's some exploration of some what we consider non-cytotoxic chemotherapy regimens, which hopefully in the next couple of years we'll have more data on those.

Now, flipping the script to relapsed/refractory mantle cell lymphoma, I think with the advent of the BTK inhibitors, in a publication from Simon Rule, those drugs have become entrenched in a second-line setting. Currently, we have 3 FDA-approved options: ibrutinib, acalabrutinib, zanubrutinib. Ibrutinib being the first generation, acalabrutinib and zanubrutinib being second-generation molecules. 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 kinome 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 used in a second-line setting will probably be in combination with some other drugs such as venetoclax, potentially with CAR T.

We have a non-covalent BTK inhibitor, which is pirtobrutinib. That is being explored in a phase 3 study against the 3 covalent drugs that I mentioned before, in the second-line setting. Now, post BTK inhibitor exposure, again as in at-need area as we discussed today, and the patient outcomes have been very poor with some of the options we have such as Velcade for the chemotherapy, lenalidomide, venetoclax, and even the PI3 kinase inhibitors. The first major breakthrough I would say was brexucabtagene autoleucel, which is the CAR T-cell product from Kite, which demonstrated a 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 its limitability [to] 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. With further time, we'll see how that plays out. Thereafter, a lot of the other agents are really still in clinical trials. There's pirtobrutinib, as we mentioned before, was also explored in a post-covalent BTK setting. That medication did indicate that it did have some efficacy in this post BTK, covalent BTK setting. But as of right now, that data is very immature. And also given that the MCL sort of resistance to the BTK inhibitors isn't really clear, unlike CLL, how pirtobrutinib may actually produce this sort of efficacy is something that is 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 monomethyl auristatin E or MMAE. Those agents will be something we'll be looking forward to.

We will get more mature data, and bigger data, and a more MCL-specific subset, and hopefully there will be further improvements along the line as we continue to try to improve outcomes and overall survival for our MCL 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.

Source:

Tycel Phillips, MD. 2022 Great Debates and Updates in Hematologic Malignancies. New York, NY