Until relatively recently, we have had very limited non-chemoimmunotherapeutic options for patients with MCL, particularly those with relapsed MCL. We understand that MCL can be a particularly challenging malignancy to manage when it relapses. Even among patients who have had relatively durable long-term remissions with first-line therapy, the disease biology at relapse is often more aggressive. The duration of remission may become quite limited, even with the use of treatments that are nominally different from the earlier-line regimens. Thus, for all of these reasons, looking to the novel agents, with their distinct mechanisms of action, is critically important. Many of these patients are older, are frail, or have treatment-limiting comorbidities. That is where having a BTK inhibitor for the first relapse has been a major change for us, as these agents provide a targeted option that is distinct from that of cytotoxic chemotherapy.

The 3 BTK inhibitors that are currently approved by the US Food and Drug Administration for use in relapsed/refractory MCL are ibrutinib, acalabrutinib, and zanubrutinib. These therapies have outstanding single-agent efficacy, with overall response rates of up to 84% and complete response rates of approximately 20% to 60%. Remissions can be quite meaningful, with progression-free survivals for many patients of approximately 1.5 years. And the BTK inhibitors are extremely well tolerated. Acalabrutinib and zanubrutinib are second-generation BTK inhibitors that were designed to have fewer off-target toxicities such as atrial fibrillation or bleeding.

While most patients would be eligible for BTK inhibitor therapy, some may not benefit much—or at all—from this type of treatment, or they may only benefit for a very short period of time. Approximately one-third of patients display primary resistance to BTK inhibitors, and nearly all patients eventually progress. Recognizing such individuals early is critical in planning for alternative or subsequent treatment for if and when they do progress. Patients to watch include those who have had very short remissions in the frontline setting and those with genetic aberrations involving the TP53 tumor suppressor gene. We need to test for TP53 aberrations, and we need to understand that these patients will have to be watched much more closely. While BTK inhibitors may be helpful for these individuals in the short-term, they should be considered as a bridge to another treatment, such as a cellular therapy and, particularly, chimeric antigen receptor T-cell treatment.

To come full circle, the BTK inhibitors really have been a game changer in relapsed MCL. They have tremendous tolerability and they have provided significant benefits to the majority of patients with relapsed disease.