Refining Treatment Approaches Remains a Priority in High-Risk MCL

Andre Goy, MD

Although the relapsed/refractory mantle cell lymphoma (MCL) treatment paradigm has undergone several practice-changing shifts in recent years, standard therapies are often inadequate for patients with high-risk disease features, such as high Ki-67 proliferation, TP53 mutations, and blastoid morphology, according to Andre Goy, MD. 

“It’s important to think diagnostically, not just in MCL [but in all] cancer models, to identify how we [should] treat patients [with high-risk disease] differently,” Goy said in an interview with OncLive^® during the 41st Annual CFS^®.

In the interview, Goy discussed the agents that are currently available for the treatment of patients with relapsed/refractory MCL, explained the prevalence of high-risk features in this patient population, and emphasized the importance of enrolling patients with these features into clinical trials to expand the MCL treatment arena.

Goy is physician in chief at Hackensack Meridian Health Oncology Care Transformation Services, as well as the chairman, chief physician officer, and chief of the Lymphoma Division at John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

OncLive: What treatment evolutions have taken place in the MCL treatment armamentarium over the past few years, and what needs remain for this patient population?

Goy: We are undergoing a changing landscape in MCL, and it’s exciting for patients. The standard of care [SOC] has been established by doing more intensive therapy, transplant consolidation, and maintenance therapy in [both] younger and older patients, bringing the [median] progression-free survival from, in the R-CHOP [rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone] setting, [from] 14 to 16 months, to over 8 to 10 years after high-dose therapy and maintenance. This is exciting.

However, regardless of [these developments], we see a pattern of relapse over time in both younger and older patients with longer follow-up. There’s still an opportunity [for improved treatments], and that’s what has fueled the field of clinical research. We now have several drugs approved, [including] CAR T-cell therapy and BTK inhibitor–based combinations, that provide durable responses in the relapsed/refractory setting and potentially some long, favorable outcomes, even in [patients with] relapsed/refractory disease, a subset [of whom might be] cured post–CAR T-cell therapy.

All this is reshuffling the deck as we understand [it]. [However], despite all this progress, in the real world, the median overall survival [OS] is approximately 5 years, and for patients with high-risk features, particularly blastoid morphology, high Ki-67 proliferation, and p53 complex karyotypes, the median OS is less than half [of that], approximately 18 to 24 months at most. This is the unmet need. Thanks to these novel therapies that benefit patients with high-risk disease in the relapsed setting, we are changing the field by improving the outcome of patients with high-risk disease and changing the way we consider induction therapy in medicine.

Could you expand on the CAR T-cell therapy and BTK inhibitors that are available for patients with MCL?

Brexucabtagene autoleucel [brexu-cel; Tecartus] is approved for relapsed/refractory MCL after [3 lines] of therapy in the United States and after 2 lines of therapy, including a BTK inhibitor, in Europe. This has changed the field, because [prior to this agent], patients who progressed after BTK inhibitors had a short median OS in the relapsed/refractory setting [of only] a few months. Multiple studies documented this. [Brexu-cel elicited] an overall response rate of 91% and a complete response rate of 68%. [Four-year] follow-up study that will be [presented at the 2023 ASH Annual Meeting],

[Brexu-cel] is meaningful, even in [patients with] high-risk disease. A subset of patients [in the phase 2 ZUMA-2 trial (NCT02601313) has been] cured [with brexu-cel], with 3 relapses [occurring] after 24 months. The question with CAR T-cell therapy will be: How can we do better? There’s a pipeline of other cell therapies. Can we identify the patients who are on the long-term curve? We don’t yet have good biomarkers to [answer that question, but research] is ongoing.

We have 4 BTK inhibitors approved. We have the covalent [BTK inhibitors] ibrutinib [Imbruvica], acalabrutinib [Calquence], and zanubrutinib [Brukinsa] approved after 1 line of therapy. It’s difficult to compare these agents because their clinical trials did not enroll the same populations.

An ongoing trial [is investigating] pirtobrutinib [Jaypirca], the first noncovalent BTK inhibitor approved in the third-line setting after progression on a [covalent] BTK inhibitor, which was remarkable. This is the [phase 3] BRUIN-MCL-321 trial [NCT04662255] evaluating pirtobrutinib vs another BTK inhibitor of choice in BTK-naive patients [with relapsed MCL]. [That trial] might help us. However, at this point, choosing [between BTK inhibitors] is not necessarily easy based on efficacy. However, regarding toxicity profiles, ibrutinib [is associated with] more off-target effects vs acalabrutinib and zanubrutinib, which, because of their kinome inhibition, [are associated with fewer] off-target effects, which explains why we see fewer class effects such as hypertension, arrhythmia, bleeding, etc., with [these] BTK inhibitors.

[BTK inhibitors are] populating the field of relapsed/refractory [MCL] as single agents or often in combination with rituximab, lenalidomide [Revlimid], or venetoclax [Venclexta], and [they] are providing responses in the relapsed/refractory setting. For the first time, [we have] proof of concept that some patients, particularly after venetoclax, [can] stop therapy because they are minimal residual disease [MRD] negative. Achieving MRD negativity in the relapsed/refractory setting is unheard of, [and these patients] remain in remission off therapy. BTK inhibitors and CAR T-cell therapies are changing the paradigm, and we have a lot of other compounds in the pipeline as well.

How might the presence of high-risk disease features influence treatment decisions for patients with MCL?

Besides the progress in the SOC, [which includes] the novel therapies that are changing the treatment options in the frontline setting [and beyond], what is important to understand is how we define the high-risk population. [High-risk disease is defined by characteristics] such as MCL International Prognostic Index score, Ki-67 proliferation, or [disease progression after 24 months (POD24)]. [These criteria] either help decide [treatments at] baseline or after the fact, [in the case of] POD24 and MRD negativity. MRD negativity is becoming a new end point in MCL. It’s not yet in the standard routine, but that’s where we’re heading.

However, none of these [high-risk criteria] help us identify how to treat these patients differently. Because next-generation sequencing [NGS] is now easily accessible and you can look at the entire signature, not surprisingly, when we do NGS, like we did in early days in acute myeloid leukemia in elderly patients above 60 or 65 [years of age, we find that these patients] have much more complex genetics. When we do NGS in MCL, we find that approximately 25% to 30% of patients have high-risk features, very often TP53 mutations, 17p deletions, or more frequently, complex karyotype, a typical feature of MCL that is genetically unstable, even without being blastoid variant. I have presented multiple cases [of patients] with standard [MCL] presentation [whose] genetics were complicated on NGS.

[Early] understanding and identification of this [high-risk] population that we know will do poorly, even with high-dose therapy and transplant, [is important]. Long-term data from Europe in patients with TP53 abnormalities [showed a] median OS of 1.8 years vs 12.7 years [in those without] those features.

What is your main message for colleagues regarding developments in the MCL armamentarium?

It’s important that for a rare disease [such as] MCL, we can show that [by] working with the community, our patients, and our colleagues, we have been able to move the needle relatively fast over the past 2 decades and improve outcomes for our patients. It’s important to think of clinical trials, particularly in patients with unmet needs and high-risk features that you need to identify. You need to [evaluate patients for potential high-risk features] and then refer them to a place that has a clinical trial. That’s the best option for our patients.

Reference

Goy AH. MCL: one size does not fit all any longer.Presented at: 41st Annual CFS^®; November 8-10, 2023; New York, NY.