It is becoming increasingly clear that there are subsets of patients with MCL who have markedly inferior outcomes with standard chemoimmunotherapy. There are multiple ways to categorize high-risk MCL. These include the prognostic Mantle Cell Lymphoma International Prognostic Index score, which has been widely used to predict survival in patients with MCL, and other biologic features, such as TP53 mutations and an elevated proliferation index as estimated by Ki-67. A number of additional high-risk genetic lesions have been described, such as the KMT2D mutation, NOTCH1 and NOTCH2 mutations, and loss of the CDKN2A tumor suppressor gene. By morphology, patients with blastic or pleomorphic MCL subtypes tend to do worse than those with conventional MCL. 

With regard to biologically targeted therapies, BTK inhibitors have changed our approach to relapsed/refractory (R/R) MCL. To my knowledge, the overall response rates with BTK inhibitor use in patients with R/R MCL range from 60% to 80%, while the complete response rates are low (around 20%), so there is still room for improvement in the depth and durability of response. Combinations of BTK inhibitors and BCL-2 inhibitors are showing promise in patients with R/R MCL. The AIM study looked at ibrutinib and venetoclax in patients with R/R MCL and showed efficacy among those with TP53 mutations. This study also looked at dynamic molecular monitoring using circulating tumor DNA analysis to describe emerging mechanisms of resistance and how the baseline genomic profile might predict responsiveness to the treatment. Hopefully, in the future we can learn more about which subsets of patients with MCL are likely to respond to BTK inhibitor and BCL-2 inhibitor combinations, as well as other biologically targeted combinations. 

These findings support the development of additional combination approaches that will be of interest in patients with high-risk MCL. For example, the OASIS study examined the combination of obinutuzumab, ibrutinib, and venetoclax in patients with relapsed MCL and in treatment-naive patients with MCL. The investigators reported promising progression-free survival rates and high rates of clinical and molecular remissions in those with high-risk features such as the TP53 mutation and blastic histology. In the future, combinations of biologically targeted agents (vs chemoimmunotherapy) may become the new standard for the frontline treatment of high-risk MCL, particularly in patients with TP53 mutation. 

How do we define high-risk MCL? From the clinical perspective, patients with MCL who are refractory to first-line and subsequent lines of therapy and those who relapse quickly are known to have poor outcomes. Up to approximately 20% of MCLs have more indolent behavior, approximately 60% to 70% have a classic aggressive pattern, and approximately 10% to 20% have particularly high-risk features, such as blastoid morphology, TP53 alterations, and/or complex karyotype. Chemoimmunotherapy options have generally been associated with poor outcomes in patients with high-risk MCL, so we look toward the newer therapies to improve outcomes in these individuals. 

Treatment toxicity is a major concern because many of the patients are physiologically older at presentation and are unable to tolerate some of the more aggressive treatment options. We have looked at a variety of novel agents, including BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib; BCL-2 inhibitors such as venetoclax; proteasome inhibitors such as bortezomib and ixazomib; immunomodulatory agents such as lenalidomide; phosphoinositide 3-kinase inhibitors; and anti-CD20 monoclonal antibodies. Generally speaking, these options do not work as well in patients with high-risk MCL as they do in those with lower-risk MCL. The previously mentioned AIM study, which included a simultaneous inhibition of BTK and BCL-2 with venetoclax in patients with high-risk MCL, demonstrated a complete response rate of 42% at week 16, which was significantly greater than the 9% rate that was reported in historical controls. The complete response rate as assessed by positron emission tomography was 62% at week 16 and 71% overall. Because the signature abnormality of MCL, t(11;14), involves the cyclin D1 gene, there have been attempts to use cyclin-dependent kinase inhibitors, which are US Food and Drug Administration approved for use in other indications such as breast cancer, in patients with high-risk MCL. 

I think that the more promising agents are immunotherapies such as chimeric antigen receptor (CAR) T cells. While we look forward to chemo-free regimens, survival in MCL still requires significant improvement, and we should use all treatment modalities in trying to improve the outlook in this lymphoma. There needs to be a continuous process of exploration and refinement to understand the genetic and epigenetic features of MCL. We know that MCL is very heterogeneous, and many of us believe that the solutions are going to be individualized, based not only on the clinical profile but also on the specific molecular profile of MCL in the individual patient. 

Patients with MCL in community settings are not always tested for genetic abnormalities, and I think that this is a disservice. We want to be sure that all patients with MCL are tested for the TP53 mutation at a minimum, and hopefully some of the other high-risk lesions as well. And, of course, patients should be tested for the blastic variant, which is more easily detected.

We know that standard chemoimmunotherapy does not work well in patients with these high-risk markers. For these individuals, we often seek out clinical trials in which 2 or 3 of these molecularly associated pathway-type agents are either added to, or used in place of, chemoimmunotherapy. I think that immunotherapy would probably be helpful in some of the combinations that we have discussed. Patients with MCL and the TP53 mutation are refractory to chemotherapy, so we would try not to incorporate that approach in these high-risk patients.

For patients with the blastoid variant, we usually recommend very aggressive therapy, such as hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), and we consider early transplantation. These patients may be appropriate candidates for novel combination therapies. Moreover, we may be seeing early CAR T-cell therapy used as second-line treatment in these individuals. Patients may achieve good partial or complete responses with some of the novel agents, but the responses may not be durable. Early CAR T-cell therapy may be considered a consolidation-type treatment in the near future.