We know from experience that, even with optimal cell manufacturing processes, which result in a 3- to 4-week turnaround time, patients with high-risk MCL can progress to an extent that will preclude them from receiving CAR T-cell therapy. So, we do often need bridging therapy; however, the optimal approach to bridging therapy and the impact of bridging therapy on clinical outcomes are unclear. Conceptually, there have been discussions of immune recovery or immune reconstitution being important leading up to apheresis and CAR T-cell therapy. Salvage or bridging therapy is, by nature, needed immediately. Thus, the ideal path forward would keep the MCL at bay almost immediately while not compromising a patient's outcomes with CAR T-cell therapy.

There is an inherent selection bias because patients with high-risk disease typically need bridging therapy and require more intensive bridging therapy. Moreover, the literature guiding the choice of therapy is largely observational, and so, prospective studies are needed.

For a patient whose progression is more moderate, we can control the disease with treatment options that are somewhat less toxic. But if we see significant progression, we might have to choose a treatment that is potentially a bit more toxic if it results in better disease control. There have been hints in the literature that seem to support the use of the Bruton tyrosine kinase inhibitor ibrutinib, either alone or in combination with venetoclax, prior to cellular immunotherapy, since it allows for immune reconstitution. However, the immune reconstitution is predicated upon achieving disease control. So, I think that our primary goal is to keep the disease controlled. There may be reasons to believe that Bruton tyrosine kinase inhibitors are a better option for bridging than conventional chemotherapy, but we still do not understand their effects on the CAR T-cell response. It is considered positive if we can avoid the toxicities of chemotherapy, which kills some immune effector cells. I think that the data on ibrutinib for reconstitution were interesting and tantalizing, but by no means definitive.