The typical patient with MCL starts out somewhat vulnerable because the median age at onset is approximately 68 years. Age-associated comorbidities come into play, some of which may be treatment limiting. For example, a patient may have coronary artery disease and atrial fibrillation and may require anticoagulation therapy. But there is a whole spectrum of comorbidities that, I think, makes it more challenging to treat the patient aggressively, like how we might treat a 45-year-old patient, for instance. 

For older individuals who are not candidates for intensive therapy, there have been several developments in recent years that have improved the outlook. There is no question that Bruton tyrosine kinase (BTK) inhibitors have been a powerful tool in relapse. Further, we have seen a more widespread use of rituximab maintenance and, in some cases, more prolonged courses of rituximab maintenance. Having these options for maintenance and in relapse has really helped to extend remissions and improve survival. Chimeric antigen receptor T-cell trials also took off relatively recently. While it may be too early for us to know if this will be curative for some patients, chimeric antigen receptor T-cell therapy certainly has been a powerful tool as well. 

In the front line, lenalidomide plus rituximab is an established lower-intensity alternative. The WINDOW and the IMCL-2015 studies have evaluated frontline BTK inhibitor combination therapy, so there is movement away from chemotherapy. We are starting to have good alternatives to the more intensive, more toxic protocols for patients who would benefit from a different approach.

Older patients with significant comorbidity are clearly a vulnerable group, I agree, and this can limit their eligibility for various treatments. Dr Shah mentioned several key developments that have helped to move the needle for vulnerable patients with MCL, including the increased use of novel therapies. The current standard-of-care chemoimmunotherapy regimen, bendamustine plus rituximab, also remains an efficacious and well-tolerated option for many older transplant-ineligible patients. I agree that BTK inhibitors in relapse have also been a significant step forward. Recent work using data from the Surveillance, Epidemiology, and End Results Program shows a survival benefit paralleling the widespread adoption of BTK inhibitor therapy, which was unsurprising and consistent with our experience in relapsed and refractory MCL.

We can also think of vulnerability in terms of biology and high-risk disease features. For patients with TP53 aberrancy, blastic or pleomorphic disease, and high proliferative rates, standard treatments are not very effective. This is an area of unmet need for which there are ongoing studies of targeted agents and immunotherapies. Barriers and lack of access to the latest treatments can also confer vulnerability. We have seen in several “real-world” studies that the rates of upfront autologous stem cell transplantation and the use of cellular therapy in MCL are unexpectedly low, even in younger age groups. This highlights the fact that treatment patterns in the community do not always align with treatment patterns at a specialized tertiary care center. 

To overcome such barriers, a number of initiatives here at Memorial Sloan Kettering Cancer Center aim to bridge the gaps and improve access to clinical trials and cutting-edge therapeutics for community-based patients. I serve as a medical director at such a site in Basking Ridge, New Jersey. We are also trying to expand the therapeutic arms of clinical trials to include more patients and community-based oncologists who can administer emerging novel therapeutics safely in the community setting. For cellular therapy and stem cell transplantation, patients in New Jersey still need to travel to Manhattan, which can prove to be a significant barrier. However, I find that, once you have developed a relationship with clinicians and patients in the community, it is easier to collectively overcome some of those barriers as a team.

My colleagues have nicely identified vulnerable groups in MCL, noting disease features, comorbid features, and demographic/access features. I would only add that MCL remains largely incurable, and perhaps the most vulnerable patients in MCL are those who have cycled through all of the available therapies and are now without any established treatments. So, we still need to do better.

Regarding the Surveillance, Epidemiology, and End Results data in the BTK inhibitor era, I am glad that these types of analyses are being done, and perhaps some of these data can be used to replace older and outdated survival statistics that newly diagnosed patients with MCL might come across. Improving the first line of therapy has had an important impact on survival. For standard frontline MCL therapy, the median progression-free and event-free survivals could be as long as 6 to 10 years—and that is just the median. Then add to that the survival benefit of improved and improving treatments for relapsed disease.

Clinical trials are so important, and there are a number of clinical trials right now that are looking at improving frontline therapy for some of the more vulnerable populations that we are talking about—those with high-risk disease with a TP53 mutation, complex cytogenetics, or blastoid or pleomorphic morphology. Hopefully, these clinical trials will improve outcomes for this group of patients as they have for more standard-risk patients to date.

When it comes to access and outreach, I think of access to these therapies in relation to concentric proximity rings around the major centers. In the immediate community, or the first ring, expanding the network reach helps to recruit/educate patients and build relationships with those referring providers. We are doing better with that first ring, but I think that there is still more to be done for minority communities within that ring and beyond, and for more remote/rural populations in the outer rings.