When a patient with MCL begins to relapse after chemoimmunotherapy, we start thinking about the BTK inhibitors as a second-line option. Ibrutinib has been commonly used, since it was the first US Food and Drug Administration (FDA)–approved BTK inhibitor in this setting, but now we have both acalabrutinib and zanubrutinib as other FDA-approved options for this patient population. Based on the profiles of these agents, if I had a patient with MCL and atrial fibrillation or an increased risk of bleeding, I typically would not use ibrutinib, particularly if the patient were on warfarin. I would consider using acalabrutinib or, possibly, zanubrutinib. Zanubrutinib is the most recently FDA-approved agent in this setting and we do not completely understand its effects on atrial fibrillation and bleeding risk, but the hope is that it, too, would be more targeted and have less risk than ibrutinib. Further, bortezomib and lenalidomide have some activity in MCL, and, although these agents are currently used less commonly for MCL, it is important to remember that they can be used in later lines of therapy. 

It is difficult to say what the expected overall survival is today for a patient with MCL because it keeps improving. Additional improvements are expected, given the advent of newer therapies and others on the horizon. I think that the survival of patients with relapsed/refractory MCL will likely improve significantly in the coming years. Patients with relapsed MCL may also be good candidates for clinical trials, and there is interest in various combination strategies in the investigational setting. For example, BTK inhibition combined with BCL2 inhibition is something that is being explored. BCL2 inhibition after BTK inhibition also seems to have activity and might be considered in relapsed patients who are TP53  mutated or 17p deleted. Although we now have a number of different treatment options, relatively little is known regarding an ideal or optimized approach to the sequencing of available therapies in the relapsed setting. Right now, there is much agreement on chemoimmunotherapy in the frontline setting and BTK inhibitor–based therapy in the relapsed setting, for most patients, but there is little agreement on the optimal therapy after a BTK inhibitor. With newer approaches such as chimeric antigen receptor T-cell therapy potentially being approved by the FDA, we may experience a disruption of the status quo; however, I suspect that, if these therapies are approved, they would occupy the space after BTK inhibitor–based therapy. Finally, it should be noted that allogeneic stem cell transplantation may be an option in the second-line setting for selected individuals who are eligible for this treatment.