We have come to recognize and understand that not all MCL is created equal. That is, we have patients with very indolent, slow-growing disease, patients at the other end of the spectrum with aggressive, high-risk disease, and many patients in between. Dr Leonard and his colleagues at Weill Cornell Medicine have been among the leaders in understanding MCL biology and clinical risk. Risk-adapted therapy is based on both patient and disease risk features, and we must approach each of the MCL patient groups very differently.

The Mantle Cell Lymphoma International Prognostic Index score is incredibly important for assessing the prognostic risk of individual patients. Risk stratification is commonly performed for patients with other lymphomas, such as diffuse large B-cell lymphoma and follicular lymphoma, and it definitely should be done for patients with MCL. As part of the assessment, we also need to look at the patient’s Ki-67 proliferation index. Patients with Ki-67 scores at or above 30% are more concerning than those with lower Ki-67 scores due to the active proliferative nature of their disease. We consider the transcription factor SOX11 in specific cases (eg, more commonly in academic settings than community settings). The positron emission tomography scan is another important tool; it is useful for identifying highly active metabolic lesions and can help us to differentiate patients who may require aggressive treatment from those who can be treated with more conservative and palliative approaches. Lastly, we always want to pay attention to the TP53 findings for the identification of high-risk patients.

I agree with Dr Pagel on the importance of risk stratification and on the importance of TP53. In young patients, for whom you might be considering an intensive-type approach, the data are convincing that the results of this type of approach are disappointing if they are TP53 mutated. Although these mutations may be present in approximately 10% of patients with MCL, we do not have randomized trial data to help guide us on the best approach for this group of patients.

In recent years, minimal residual disease (MRD) has been studied in MCL, and it is now considered one of the more robust prognostic factors (ie, achieving an MRD-negative state is associated with more favorable outcomes). There are different ways to interpret MRD in clinical practice. On the one hand, a patient who achieves a deeper remission and an MRD-negative status may just have disease that is more responsive to therapy. A different, more optimistic interpretation would be that, by achieving an MRD-negative state and a deeper remission, you are hopefully achieving a better outcome for that individual. MRD is becoming more widely used in clinical practice and is already commonly used in clinical trials. Dr Kahl is involved with an ongoing ECOG-ACRIN Cancer Research Group study (EA4151) that illustrates the potential use of MRD in risk-adapted therapy.

One way to consider risk adaptation is to think in terms of personalization. We try to match the intensity of the therapy to the patient’s biologic disease characteristics so that we are neither overtreating nor undertreating patients. And this individualized approach is continually refined as newer therapies are introduced and data from randomized clinical trials become available.

Along those lines, the clinical trial that Dr Leonard mentioned (EA4151) is an investigation for younger patients with MCL for whom one might be considering an autologous stem cell transplantation as a consolidation strategy. We want to determine whether the benefits of stem cell transplantation outweigh the associated toxicities in patients who achieve an initial favorable response to induction chemotherapy, based on MRD status. The protocol allows the local treatment center to provide any reasonable induction regimen they choose (ie, there is no true standard induction regimen for MCL). After induction, the patients who enroll in the trial will have an MRD assessment using the clonoSEQ platform (Adaptive Biotechnologies), a proprietary next-generation sequencing–based approach that can detect up to 1 mantle cell in a background of 1 million cells in the peripheral blood. Patients who achieve MRD negativity in their first remission are then randomized to either stem cell transplantation and maintenance rituximab therapy or maintenance rituximab therapy alone (ie, without the transplantation).