In high-risk MCL, we are taking a lesson from our experience in chronic lymphocytic leukemia (CLL), where we know that chemotherapy is insufficient and inactive for many patients with high-risk disease. Biologically targeted combinations, such as a Bruton tyrosine kinase (BTK) inhibitor plus venetoclax, may enable a chemotherapy-free or reduced-intensity approach for certain patients with MCL, which is a really exciting step forward. In CLL, the triplet combination of CD20 monoclonal antibodies with a BTK inhibitor and venetoclax has been studied. We are starting to see studies of this combination for high-risk MCL in the front line, and it will be interesting to learn where they lead.

MCL appears to have a cure rate with allogeneic stem cell transplantation, which makes immunologic therapy particularly exciting. Chimeric antigen receptor T-cell therapy is a cellular immunotherapy that has really improved outcomes significantly for patients with relapsed MCL. For many patients, it has extended survival beyond what was historically possible. Bispecific antibodies may have potential in MCL, although, thus far, data in patients with MCL are quite limited; hopefully, successes that have been observed in some of the other B-cell malignancies will translate to MCL.

Technologies for evaluating minimal residual disease (MRD) in MCL will be helpful. In addition to predicting response durability, MRD technologies could also potentially help to uncover the biology of residual and recurrent disease. We might be able to rescue live residual disease cells to test them for mutational profiles that could be associated with persistence. Thus, emerging technologies may assist us in the development of biologically targeted therapies for MCL at a much faster rate than in the past.

There is evidence of synergy between BTK and BCL2 inhibition in patients with TP53-aberrant MCL. In the OASIS study, the combination of obinutuzumab, ibrutinib, and venetoclax demonstrated efficacy and was well tolerated among patients with newly diagnosed MCL and those with relapsed or refractory MCL.

Building on OASIS, researchers at Memorial Sloan Kettering Cancer Center designed a study of zanubrutinib, a second-generation BTK inhibitor, combined with obinutuzumab and venetoclax in patients with TP53-mutant MCL, a population for whom chemoimmunotherapy really fails. This combination was previously studied in CLL. Preliminary results from the BOVen study in MCL presented at the 63rd American Society of Hematology Annual Meeting and Exposition in 2021 showed significant efficacy, and the combination was well tolerated. It was very rewarding to see that high-risk patients with blastic disease, highly proliferative disease, or a very high burden of disease responded well to the initial combination of obinutuzumab and zanubrutinib for 2 cycles followed by a venetoclax ramp-up beginning in the third cycle.

A larger phase 3 study comparing zanubrutinib plus rituximab with bendamustine plus rituximab in transplant-ineligible, untreated MCL is currently underway and has the potential to be practice changing. It may be possible to envision a future in which we utilize chemotherapy-free combinations specifically for patient subsets with high-risk biology, and then also potentially for patients who are transplant ineligible. It will be more difficult to tease out the risks and benefits of alternative upfront treatments in younger, fit patients without TP53 aberrancy. These patients require disease control over a much longer period of time and can achieve very long remission durations with upfront intensive chemoimmunotherapy.

Finally, MRD is an important biomarker in MCL, although it remains to be seen how it will be incorporated clinically. In the IMCL-2015 study of indolent MCL, investigators used MRD data to guide the early cessation of therapy. Many patients who discontinued treatment early continued in remission. There really is a lot of exciting work in progress that will help us to determine how MRD can be used to guide treatment.

Regarding how best to combine these agents, much is still unknown, including whether a particular BTK inhibitor is better than another in combination with a monoclonal antibody. In my view, the currently available BTK inhibitors are all essentially the same from an efficacy standpoint. The challenge lies in trying to marry the anticipated toxicities to a specific patient. For example, we may see more atrial fibrillation with ibrutinib than with the other 2 BTKs, while zanubrutinib may cause more cytopenias and acalabrutinib may result in more myalgias and headaches. So, with the BTK inhibitors, the focus is more on differential toxicity management and less on differential efficacy.

In the ASPEN trial, which compared zanubrutinib with ibrutinib in patients with Waldenström macroglobulinemia, the efficacy rates were similar but the discontinuation rates were lower for zanubrutinib. For the most part, we start BTK inhibitors with the intent of continuing them indefinitely, so tolerability is important. And we do not want patients to discontinue because of toxicity, since that will undermine the benefit. 

I agree that tools such as MRD analysis and next-generation sequencing are important in MCL. MRD is dependent on the time point and on the type of therapy, such that a one-size-fits-all approach to MRD analysis does not work and the response kinetics of whichever therapy you are using need to be considered. With MRD, we are essentially trying to assess how effective the treatment was at clearing the disease quickly, and then we are trying to use that to predict what will happen next.

Next-generation sequencing at the time of diagnosis is another critical tool. We do not want to wait until relapse to prove that the disease was chemotherapy resistant. And, although TP53 status is clearly important, there are a host of other mutations that inform prognosis and may even predict sensitivity to different therapies. Thus, we really want to use a broad panel that encompasses some of these other high-risk features (eg, BIRC3, TRAF2, NOTCH1, NOTCH2, and TNFAIP3). 

In conclusion, MCL is wildly heterogeneous, and we really need to shy away from the conventional thinking that patients under age 60 should receive cytarabine-based therapy plus transplant, while patients over age 60 should receive bendamustine plus rituximab. I am a proponent of one-size-fits-all approaches—but only if they work.