The Shifting MCL Treatment Paradigm Raises Sequencing Questions

Tycel Phillips, MD

As the treatment paradigm for mantle cell lymphoma (MCL) has shifted away from chemoimmunotherapy and moved novel drugs such as BTK inhibitors and CAR T-cell therapy into earlier-line settings, the question of optimal sequencing becomes more pronounced, according to Tycel Phillips, MD.

“Nowadays, we’re talking about patients who survive a decade or more. Historically, we used to discuss patients living only 3 to 5 years,” Phillips said in an interview with OncLive® following an OncLive® State of the Science Summit, which he cochaired. “We’re making a lot of progress, but there is still a way to go. Overall, we are headed in the right direction for those patients.”

Data from studies such as the phase 3 TRIANGLE study (NCT02858258) have shed light on evolving practice patterns. The trial revealed that following therapy with R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) plus R-DHAP [rituximab, dexamethasone, cytarabine, and cisplatin] and then autologous stem cell transplantation (ASCT), the addition of ibrutinib [Imbruvica] resulted in superior efficacy in younger patients with MCL. The 3-year failure-free survival rates were 88% (95% CI, 84%-92%) in patients who also received ibrutinib (n = 292) vs 72% (67%-79%) in patients who received the regimen with no ibrutinib (n= 288; HR, 0.52; one-sided 98.3% CI, 0.0-0.86; one-sided P = .0008).

Investigators noted that the question of whether ASCT adds to the efficacy of an ibrutinib-containing regimen has not yet been answered based on data from the third arm of the trial evaluating R-CHOP plus R-DHAP followed by ibrutinib without ASCT.

In the interview, Phillips, discussed the treatment paradigm for patients with MCL, and in another interview with OncLive following the Summit, detailed advancements in chronic lymphocytic leukemia and non–Hodgkin lymphoma. He is an associate professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, in Duarte, California.

OncLive: How has the MCL treatment armamentarium shifted in recent years?

Phillips: We are slowly but surely moving away from chemoimmunotherapy in patients with MCL. A lot of frontline trials have or are adding novel drugs, which have shown some promise in the relapsed/refractory setting. The biggest takeaway—at least for younger patients—is that we are moving into an era where we [will] likely limit the exposure to ASCT for most patients. We’ll be reserving it for those who may benefit most vs an all-comers situation, which we did historically.

With older patients, we are understanding that it may not be a good idea to combine chemotherapy with [certain] novel treatments; perhaps these patients will benefit from novel treatments and an antibody alone. As such, the consequences [from] using some of our best drugs in a second-line setting [is that it accelerates the shift of] some of these other drugs into early lines of therapy.

[Determining] what to do in the second-line setting and beyond will be a very important discussion point and something we’ll need to figure out because our current paradigm of chemotherapy, BTK inhibitors, and other drugs afterward will be changed as these BTK inhibitors move into the frontline settings. This is because in the second line, it will push up some [of the treatments] such as CAR T-cell therapies, bispecific antibodies, or other treatments, which we reserve for third-line and beyond [settings].

Which agents have played a notable role in the shift in treatments for patients with MCL?

[The shift] has been driven by BTK inhibitors. We historically had 3 covalent drugs: ibrutinib, zanubrutinib [Brukinsa], and acalabrutinib [Calquence]. The ibrutinib molecule was withdrawn from the market based on results from the phase 3 SHINE [NCT01776840] study in elderly patients. Since then, we have 2 second-generation covalent drugs.

We are continuing to push those drugs into the frontline setting vs the second-line [setting] where they had been cemented as standard-of-care [SOC] options. As we move them forward, a question will be whether studies have explored abbreviated treatment. We don’t know how patients will respond when we rechallenge them [with] these drugs after a period of a holiday or whether they will achieve the same duration of response [as] before. Or is it a situation where whether we stop, start, or continue [treatment] indefinitely we will get the same outcome? These are questions that have yet to be answered in this patient population.

What to do when patients [progress] on BTK inhibitors [still needs to be understood] because historically, very few drugs have worked after patients progress on those medications. That does push up [the therapies] we have [used] before, but also limits some of the agents we’ll have in the third-line and beyond settings as we start moving these drugs up.

What additional trials have impacted the treatment space as highlighted at the SOSS event?

We discussed the phase 3 TRIANGLE study, which was a [European] study that looked at 3 experimental arms of SOC R-CHOP plus R-DHAP plus ASCT vs 2 experimental arms. [In the first experimental arm], R-CHOP plus ibrutinib alternated with R-DHAP followed by ASCT and then 2 years of ibrutinib maintenance, and in the second experimental arm, R-CHOP plus ibrutinib alternated with R-DHAP followed by ibrutinib maintenance without ASCT. That has pushed us toward likely eliminating ASCT in most patients.

We talked about the SHINE trial, which led to the removal of ibrutinib from the United States market. We talked about the phase 3 SYMPATICO trial [NCT03112174,] as well, which was a second-line trial looking at ibrutinib plus venetoclax [Venclexta] vs ibrutinib alone in the relapsed/refractory setting. We discussed [data on] the noncovalent BTK inhibitor pirtobrutinib [Jaypirca] from the phase 1/2 BRUIN trial [NCT03740529], which resulted in the drug [receiving] FDA approval as an option for patients who progressed on [2 prior therapies, including a] BTK inhibitor.

There have also been discussions based on the CAR T-cell therapies; brexucabtagene autoleucel [brexu-cel; Tecartus] is approved for patients with MCL and lisocabtagene maraleucel [liso-cel; Breyanzi] is another product recently approved in MCL. These are the main trials that have come to light lately [that have led] to the approval or removal of certain drugs within the clinical space.

What unmet needs remain within the MCL landscape?

We still struggle with how to manage patients with high-risk disease. The definition of that varies to some degree, but for the most part, [many] generally agree that high-risk disease includes patients with p53 mutations or highly proliferative MCL—especially those with a Ki-67 [expression level of] greater than 50%. A lot of those patients tend to have blastoid [and] pleomorphic variants, and we do still struggle to treat those patients.

Even in some of the clinical trials that I mentioned, patients somewhat do not seem to all benefit from the addition of experimental drugs such as BTK inhibitors in the frontline setting, especially patients with highly proliferative [disease]. That’s an area where we need to make improvements because those patients tend to have worse outcomes and a very short survival compared with what we’ve seen for the rest of the field where we’ve exponentially improved survival in patients with MCL.

Reference

1. Dreyling M, Doorduijn J, Giné E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306. doi:10.1016/S0140-6736(24)00184-3