It can be challenging to know exactly what we mean by less intensive, given the various treatment paradigms in MCL right now. The established approach has been to stratify patients in terms of transplant eligibility. For example, younger fit patients may be eligible for intensive cytarabine-containing induction followed by high-dose therapy and autologous stem cell transplantation, whereas older transplant-ineligible patients would typically be considered for less-toxic chemoimmunotherapy regimens.

The rituximab-plus-lenalidomide regimen was the first chemotherapy-free regimen for newly diagnosed older patients with MCL, and this was a significant step forward. We are hopeful that the field will continue to advance and go beyond the older-vs-younger or the transplant-eligible–vs–transplant-ineligible treatment paradigm, incorporating an evolving understanding of MCL biology—an understanding that reflects biomarkers, molecular data, and the clinical factors that are associated with indolent-vs-aggressive disease.

How do we incorporate our understanding of the clinical and biologic heterogeneity of MCL into a more nuanced or individualized approach? Response-adapted therapy is an exciting emerging area that may have an important role. Assessing minimal residual disease (MRD) at a very sensitive level to accurately measure the depth of the remission may potentially inform whether we use a more-intensive treatment strategy or, potentially, deescalate therapy. We do not currently do this in routine clinical practice, but a number of studies suggest movement in that direction. 

The phase 2 IMCL-2015 study was an MRD-driven study with rituximab plus ibrutinib in patients with treatment-naive, indolent MCL. Eligible patients were asymptomatic with nonblastoid variants and with a low Ki-67 proliferative index (ie, <30%) and no significant tumor bulk. MRD status guided the treatment duration, allowing many patients to stop treatment after 2 years of therapy. Overall, the treatment combination in this favorable subset of MCL was highly efficacious and was associated with high response rates (overall response rate, 84%; complete response rate, 80%) and high rates of MRD undetectability (87%). Longer-term follow-up is needed, but this study is compelling because it used less-intensive treatment in patients with indolent MCL that was defined by clinical and biological characteristics. 

The phase 2 WINDOW studies are also response adapted. In the WINDOW-1 study, younger patients with MCL received ibrutinib with rituximab, followed by a variable number of cycles of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine (the R-hyper-CVAD/MTX-ara-C regimen). Patients who achieved a complete response after ibrutinib and rituximab were able to receive fewer cycles of R-hyper-CVAD (ie, 4 vs the standard 8 cycles). The WINDOW-2 study explored the addition of venetoclax followed by risk- and response-stratified consolidative therapy, ranging from observation to 2 or 4 cycles of R-hyper-CVAD/MTX-ara-C. One of the aims of WINDOW-2 was to use the triplet chemotherapy-free induction regimen to reduce chemotherapy exposure.

Another study applying response adaptation is the Eastern Cooperative Oncology Group study EA4151, in which younger transplant-eligible patients with MCL who achieve a positron emission tomography–negative complete response and are MRD undetectable after induction chemotherapy are then randomized to high-dose therapy and autologous stem cell transplantation followed by rituximab maintenance vs rituximab maintenance alone. This study will help to determine whether high-dose therapy/autologous stem cell transplantation consolidation can be safely omitted in patients who achieve a deep response after induction chemotherapy. 

In the BOVen study, very high-risk patients with TP53-mutant MCL received a chemotherapy-free regimen of zanubrutinib, obinutuzumab, and venetoclax. Given that chemoimmunotherapy is ineffective in patients with MCL who harbor a TP53 mutation, this study offers a highly active and synergistic triple drug, targeted therapy combination as an alternative to standard regimens. This study also uses MRD and response indicators to determine treatment duration. After 2 years of therapy, if patients achieve a complete response and are MRD undetectable, treatment can be discontinued. It has been exciting to be involved in this study and to see the promising preliminary efficacy results and that the combination has been well tolerated. 

In conclusion, a number of less-intensive chemotherapy-free options are in development. In the future, I believe that we will be offering novel biologically targeted therapies or immunotherapies such as chimeric antigen receptor T cells to patients with high-risk disease biology, as chemoimmunotherapy has proven to be inadequate for them.