In recent years, clinical trials have begun to challenge the frontline treatment paradigm, including the role of autologous stem cell transplant (ASCT), in mantle cell lymphoma (MCL). Although this may be considered the era of chemoimmunotherapy, some data suggest that we could enter a new era of chemoimmunotherapy in combination with BTK inhibitors.

Historically, we have treated patients with MCL based on their transplant eligibility. Transplant-eligible patients would receive cytarabine-based chemoimmunotherapy and, if they responded, would then receive high-dose consolidation therapy and ASCT. There are data supporting rituximab maintenance post transplant. Obviously, there are toxicities with chemoimmunotherapy, ASCT, and rituximab maintenance, but, generally, patients get through it and can be in remission for many years. More recently, results from the TRIANGLE study suggest that we may be able to spare ASCT in some patients and add a BTK inhibitor to upfront chemoimmunotherapy. That has generally been our approach at Memorial Sloan Kettering Cancer Center for transplant-eligible patients who are younger than 65 years of age and without comorbidities with TP53 wild-type disease.

For transplant-ineligible patients, we have historically thought about chemotherapy approaches such as bendamustine and rituximab or nonchemotherapy approaches such as rituximab plus lenalidomide, which has proven efficacy. Recent data support chemotherapy-sparing approaches using targeted therapies with high activity in relapsed/refractory MCL, and they are being moved to the upfront setting. We have worked with other centers on a study called BOVen, which examines zanubrutinib, obinutuzumab, and venetoclax for (a) transplant-ineligible patients and (b) patients with TP53-mutated MCL. So, for individuals with TP53-mutated MCL, we prioritize enrollment in that study. Off-study, bendamustine plus rituximab and lenalidomide with rituximab are quite active. In the BOVen trial, we were encouraged by the data because patients with TP53 mutations do not benefit from an intensive approach with ASCT. Thus, my center and other centers are looking at chemotherapy-free approaches for these patients.

I echo a lot of what Dr Epstein-Peterson has said, and I will add that centers in the United States have adopted the results of the TRIANGLE study for transplant-eligible patients in different ways. It is not standard practice to combine a BTK inhibitor with chemoimmunotherapy for the frontline treatment of MCL. In fact, a randomized study of this combination showed only a modest benefit from adding a BTK inhibitor. It really begs the following question: If you put all your eggs in the frontline basket, what happens in terms of treatment options and response at subsequent relapses?

The TRIANGLE study demonstrated a lack of benefit of ASCT when patients are treated with a BTK inhibitor and chemoimmunotherapy followed by maintenance with anti-CD20 therapy and a BTK inhibitor. However, chemoimmunotherapy plus a BTK inhibitor is not currently our standard of care at the Dana-Farber Cancer Institute, and we have not been as quick to adopt it as our approach as other centers have been. However, we still question the benefit of ASCT for the transplant-eligible population and so are putting our frontline, transplant-eligible patients on the ECOG-ACRIN Cancer Research Group EA4151 trial. This is a large, multicenter, phase 3 trial that is randomizing patients who are measurable residual disease negative after frontline chemoimmunotherapy to either rituximab maintenance or to ASCT before rituximab maintenance. This study will answer the question of the benefit of ASCT for patients in the era of chemoimmunotherapy for frontline MCL, since chemoimmunotherapy plus BTK inhibitor therapy is not currently our standard.

With MCL, it is really important to look at patient age and comorbidities, as well as which treatments you think they are able to tolerate. We stage patients very thoroughly and determine whether they have a TP53 mutation, because treatment choice may differ based on that. For young patients who are TP53 negative, I would probably still plan to transplant them at first remission. There are various induction options for these patients, and we do 6 cycles of either a moderate treatment option, which may contain higher-dose regimens, or bendamustine with rituximab, and we may even try the TRIANGLE regimen. Then, at the time of remission, we discuss transplantation with them if they are interested, with the potential for rituximab maintenance post transplant. The TRIANGLE data are still a little unclear, and longer follow-up is necessary to determine the outcome of using BTK inhibitors earlier in the course of MCL. I would say that we are still up in the air about the best use of BTK inhibitors in frontline therapy.

For older patients, bendamustine with rituximab is usually our first-line choice, and we also discuss rituximab maintenance post induction. Again, unless a patient is in a clinical trial, BTK inhibitors are typically part of the relapse treatment strategy for older adults. MCL with a TP53 abnormality is certainly more difficult to treat, and we would want to use a BTK inhibitor as part of their induction therapy. Sometimes the BOVen treatment regimen may be a good option. Venetoclax, a BTK inhibitor, and obinutuzumab or another anti-CD20 antibody might be a good option for patients with TP53 mutations. BTK inhibitors would definitely be something to look at in the frontline treatment for those patients. I think that the category of older patients with a TP53 abnormality is where we could really use some improvements.