Bispecific antibodies that target CD20 on B cells and CD3 on T cells represent an exciting emerging treatment approach in relapsed/refractory (R/R) MCL. Bispecific antibodies have demonstrated excellent efficacy in other subtypes of B-cell non-Hodgkin lymphoma, such as follicular lymphoma and diffuse large B-cell lymphoma (DLBCL). Patients with MCL who participated in the early studies of bispecific antibodies have experienced promising responses, but we await more robust data specifically in MCL. This is a very exciting area, and we are all looking forward to understanding the efficacy of bispecific antibodies in MCL. 

Another approach that may be of interest is combination strategies with Bruton tyrosine kinase (BTK) inhibitors. There is evidence of therapeutic synergy when BTK inhibitors are combined with BCL-2 inhibitors, such as venetoclax. We have been looking at BTK inhibitors used in combination with phosphoinositide 3-kinase (PI3K) inhibitors. Although these are not randomized studies, they seem to indicate that BTK inhibitors used in combination with novel therapies may have higher complete response rates vs single-agent BTK inhibitors. 

An ADC that appears very encouraging is polatuzumab vedotin, which has shown promising activity in patients with DLBCL. Further, some interesting work combining lenalidomide with venetoclax and rituximab in the frontline setting has also been reported. I think that there will be a number of different combinations with lenalidomide that might be of interest, as this agent has activity in MCL in both frontline and R/R settings. 

MCL has a great deal of clinical and biological heterogeneity. We have seen patients with MCL with very slow-moving disease who have been observed for more than a decade, and then there are those with extraordinarily aggressive disease with blastoid morphology and high proliferation rates. It is very unlikely that we will ever have a one-size-fits-all approach to the treatment of MCL. We need a greater understanding of how to sequence these drugs and utilize the information that we have about molecular profiling and disease biology to make rational selections about different treatments over time. Hopefully, the field will move toward this direction in the future.

There is an expectation that the first bispecific anti-CD3/anti-CD20 antibody will be US Food and Drug Administration (FDA) approved in the follicular lymphoma space within the next few months, and eventually could be of use in MCL, while several other bispecific agents are currently being tested in patients with several lymphoma types. Loncastuximab tesirine is a CD19-directed ADC that is currently approved for patients with DLBCL. The question then becomes: Does using such drugs prior to chimeric antigen receptor (CAR) T-cell therapy compromise CAR T-cell efficacy? There are favorable data on using loncastuximab tesirine after CAR T-cell therapy in patients with DLBCL. Parsaclisib is a PI3K inhibitor that has shown activity in MCL. There are 4 PI3K inhibitors (ie, idelalisib, duvelisib, umbralisib, and copanlisib) that are FDA approved for follicular, marginal zone, and other lymphomas—but not yet for MCL.

An important question regarding the bispecific antibodies is: Will we get the same efficacy as we get with CAR T cells? The basic concept of bispecific antibodies is similar to that of CAR T cells (ie, to redirect a patient’s normal T cells to kill the B-cell lymphomas). CAR T cells are individualized, whereas the bispecifics are designed to direct the natural activity of T cells without individualization or ex vivo manipulation. If we are able to have the same activity from bispecific antibodies as we do from CAR T cells, which are comparatively more toxic and expensive, would we still use CAR T cells? We are currently looking at combinations of BTK inhibitors and other agents with CAR T cells in an attempt to enhance immunity, reduce T-cell exhaustion, and make the CAR T cells more effective.

By the time patients with MCL are candidates for novel therapies, they are usually heavily pretreated. With respect to CAR T cells, there are currently studies examining the use of BTK inhibitors in combination with CAR T cells. Since the BTK inhibitors work fairly well in patients with MCL, we are looking forward to further information on these combinations. The bispecific antibodies are mostly being studied in patients with other B-cell lymphomas, but the early results are favorable and we hope to extend these studies to more patients with MCL.

Another area of interest would be the noncovalent BTK inhibitors. Several covalent BTK inhibitors, which include ibrutinib, acalabrutinib, and zanubrutinib, have been tested in clinical trials and have been FDA approved for the treatment of B-cell malignancies, but patients do experience resistance. Noncovalent BTK inhibitors target alternative sites within BTK that are distinct from the sites targeted by the currently approved covalent BTK inhibitors. These agents are currently in development for MCL and other B-cell malignancies. Preliminary data on noncovalent BTK inhibitors look promising in patients who have failed other BTK inhibitors.

The noncovalent BTK inhibitor LOXO-305 has been studied in the phase 1/2 BRUIN study, which included 61 patients with R/R MCL, including 57 (93%) with prior treatment with a covalent BTK inhibitor. While there are currently no FDA-approved ADCs for MCL, there is interest based on the experience with other B-cell non-Hodgkin lymphomas such as DLBCL, for which loncastuximab tesirine was recently approved.

ROR1 is also a target of interest. Preliminary results from a first-in-human phase 1 study demonstrate single agent activity in R/R MCL for the ROR1-targeted ADC VLS-101. Among 15 patients with previously treated MCL in a phase 1 study, VLS-101 had an overall response rate of 47%, including a 13% complete response rate. Reported toxicities of VLS-101 included grade 3 diarrhea in 9% and grade 2 or higher neuropathy in 35% of patients.

In recent years, 3 ADCs (ie, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine) have been approved and are already establishing their place in lymphoma treatment. Anti-CD19–directed ADCs are showing promising efficacy in MCL, particularly when used in combination with BTK inhibitors. So, we are awaiting further data on these treatments as well. While there are no PI3K inhibitors that are currently approved by the FDA for the treatment of MCL, multiple drugs within this class have demonstrated activity in MCL, and this class of agents remains of clinical interest for the treatment of relapsed disease.