Advancements in the Risk-Adapted Treatment of Mantle Cell Lymphoma
Risk stratification is critical in the approach to mantle cell lymphoma (MCL) treatment. While some patients have indolent, slow-growing disease, others have aggressive, high-risk disease that requires prompt treatment.
How do you approach risk adaptation when treating patients with MCL?
Chief of Hematologic Malignancies
Swedish Cancer Institute
“Risk-adapted therapy is based on both patient and disease risk features, and we must approach each of the MCL patient groups very differently.”
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.
The Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
“In recent years, MRD has been studied in MCL, and it is now considered one of the more robust prognostic factors.”
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.
Professor of Medicine, Division of Oncology
“EA4151 seeks 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.”
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).
Aukema SM, Hoster E, Rosenwald A, et al. Expression of TP53 is associated with the outcome of MCL independent of MIPI and Ki-67 in trials of the European MCL Network. Blood. 2018;131(4):417-420. doi:10.1182/blood-2017-07-797019
ClinicalTrials.gov. Rituximab with or without stem cell transplant in treating patients with minimal residual disease-negative mantle cell lymphoma in first complete remission. Accessed February 22, 2021. https://clinicaltrials.gov/ct2/show/NCT03267433
Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130(17):1903-1910. doi:10.1182/blood-2017-04-779736
Federmann B, Frauenfeld L, Pertsch H, et al. Highly sensitive and specific in situ hybridization assay for quantification of SOX11 mRNA in mantle cell lymphoma reveals association of TP53 mutations with negative and low SOX11 expression. Haematologica. 2020;105(3):754-764. doi:10.3324/haematol.2019.219543
Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle cell lymphoma (MCL): long-term follow-up of the randomized European MCL Elderly trial. J Clin Oncol. 2020;38(3):248-256. doi:10.1200/JCO.19.01294
Ladetto M, Tavarozzi R, Pott C. Minimal residual disease in mantle cell lymphoma: methods and clinical significance. Hematol Oncol Clin North Am. 2020;34(5):887-901. doi:10.1016/j.hoc.2020.06.006
Le Bris Y, Magrangeas F, Moreau A, et al. Whole genome copy number analysis in search of new prognostic biomarkers in first line treatment of mantle cell lymphoma. A study by the LYSA group. Hematol Oncol. 2020;38(4):446-455. doi:10.1002/hon.2750