Our ability to identify patients with biologically defined disease has improved. Advancements in supportive care have also occurred and are not often recognized for their contributions to improvements in overall survival (OS). These include growth factor support in the setting of intensive therapy, antibiotic prophylaxis, and other supportive treatments that allow for the use of more intensive therapies in the upfront setting, as well as modern antifungal treatments. 

By and large, the greatest contributors to survival improvements in patients with MCL have been the newer treatments such as the Bruton tyrosine kinase (BTK) inhibitors, maintenance rituximab therapy after stem cell transplantation, and other therapies that allow patients with relapsed/refractory MCL, who previously had limited options, to have meaningful survival benefits. With respect to BTK inhibition, we now have a second generation. The first-generation BTK inhibitor ibrutinib has proven to be highly effective, but it also has several off-target effects by inhibiting other tyrosine kinases (eg, epidermal growth factor receptor). Second-generation BTK inhibitors have fewer off-target effects; the goal in their design was to improve efficacy and reduce toxicity. 

It is encouraging to see these data from our respective individual centers, and we are all in agreement that OS in MCL is improving. However, our patients are somewhat selected, owing to referral patterns. Therefore, I look to MCL patterns across the country and the world, and it is good to see that larger clinical studies and population-based analyses also suggest that people are living longer with MCL. Now, if we go back 2 decades, some patients with MCL who tended to do better were actually misdiagnosed as having chronic lymphocytic leukemia and are now more accurately diagnosed with MCL; so, improved diagnosis might, in some small part, account for observed survival trends, depending on the analysis and the time frame. Thus, a number of factors are likely involved, but I think that the main driver of improved OS in MCL is the introduction of newer therapies. Newer agents, such as the BTK inhibitors, are definitely improving outcomes in patients with MCL. And I am hopeful that chimeric antigen receptor (CAR) T cells and other new therapies on the horizon will improve outcomes even further.

I agree on the factors being discussed and their importance in improving survival in MCL. I would add that the introduction of bendamustine and rituximab as an effective chemoimmunotherapy platform for older patients with indolent MCL has also been an advance, and improved efficacy and better tolerability when compared with R-CHOP have been reported. In patients with relapsed/refractory MCL, for whom there is no standard of care, increased access to clinical trials is an important contributor to improvement in survival. Indeed, increasing patient engagement and enrollment in clinical trials likely have had a positive impact on survival in patients with MCL due to earlier access to novel therapies and novel drug combinations; these include novel targeted small molecules, immunomodulators, and emerging immunotherapies such as CAR T-cell therapy and bispecific antibody therapy.

There is significant controversy about whether high-dose therapy and autologous stem cell transplantation in the first complete remission are associated with an OS benefit in MCL. When examined retrospectively, the data suggest that this approach certainly seems to be linked to a prolonged progression-free survival benefit for younger, fit patients. We also see evidence of survival benefit for allogeneic stem cell transplantation in very high–risk patients with relapsed/refractory MCL; so, although allogeneic stem cell transplantation is associated with significant toxicity, it may contribute to improvements in survival in some select patients. In the future, novel immunotherapies, such as CAR T-cell therapy, may decrease the use of allogeneic stem cell transplantation in patients with relapsed/refractory MCL.