For many younger patients with mantle cell lymphoma (MCL), an important treatment standard has been cytarabine-based induction therapy, autologous stem cell transplantation (ASCT), and long-term rituximab maintenance therapy. Observational data suggest that de-escalated approaches might be feasible without sacrificing survival, and clinical trials exploring these questions are ongoing.

The field is in a bit of a state of flux. The role of ASCT and the need for high-dose cytarabine are up in the air right now. What is not up in the air, however, is the role of maintenance rituximab. We have a prospective European clinical trial that showed an advantage in overall survival (OS) with maintenance rituximab following ASCT for younger patients. An analysis of older patients in the Flatiron Health database found that those who received bendamustine plus rituximab (BR) induction therapy followed by maintenance rituximab derived huge benefits in progression-free survival and OS. So, the role of maintenance rituximab in MCL is well established in both younger and older individuals.

The lingering questions are about the intensity of induction and the necessity of transplantation. The most commonly used induction strategy in younger patients with MCL incorporates 6 months of high-dose cytarabine, which is a moderately difficult chemotherapy to go through. And most patients go on to receive consolidation therapy with ASCT. That is a difficult procedure to go through because it means spending a long time in the hospital, and it takes patients months and months to recover. Thus, the first year of treatment is very difficult for younger patients with MCL. After consolidation therapy, patients typically receive maintenance therapy, which is relatively easy to tolerate.

In light of this, investigators are studying whether the first year of treatment can be de-intensified so that the therapy is more tolerable but patients get the same outcomes. A retrospective study using a historical control from the BC Cancer-Vancouver Centre for Lymphoid Cancer found that BR induction prior to ASCT appeared as efficacious as a high-dose cytarabine–containing regimen. And so, there is some suggestion that you might be able to dial down the intensity of the induction. Another piece of supporting data comes from the previously mentioned analysis of real-world data in the Flatiron Health database. Younger patients who received BR induction did just as well as patients who received high-dose cytarabine induction in terms of the time to next treatment. These were not head-to-head clinical trials, so they do not provide the strongest level of evidence, but they do provide some suggestion that we may be able to dial down induction therapy. This possibility justifies examination in definitive studies, some of which are already underway.

In addition to induction, various investigators have studied the necessity of ASCT. In the same Flatiron Health database study, only approximately 1 in 4 transplant-eligible patients under age 65 years received a transplant. ASCT was associated with only a slight improvement in patient time to next treatment, and OS did not improve. So, stem cell transplant consolidation may lengthen that first remission without patients actually living longer. If that is true, I think that ASCT is optional, and that is the way that I describe it to my patients. I tell them that they will need to spend 1 month at the hospital, and it will take them 3 to 6 months after the transplant to feel good again. But if they do it, they may stay in remission longer. I also make it clear that they are not more likely to be alive 5 or 10 years from now, and some patients opt out based on that information.

There is a really interesting ongoing study called EA4151 that is randomizing patients with MCL who achieve minimal residual disease–negative status after induction therapy to receive ASCT or no transplant. All patients are going on to receive 3 years of maintenance rituximab. This study may help us understand whether we can safely subtract ASCT in patients who achieve a high-quality remission from induction therapy.