Mantle Cell Lymphoma
Developments in the Molecular Risk Stratification of Mantle Cell Lymphoma
Recent developments in mantle cell lymphoma (MCL) molecular profiling have identified proliferative gene signatures and individual genetic mutations that provide a potential framework for tailoring management approaches to individual patients.
The Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
“Alterations and deletions in TP53 have been associated with less favorable outcomes in patients with MCL, particularly those receiving chemotherapy-based treatment.”
In addition to clinical risk stratification with the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, the Ki-67 proliferation score is useful for the molecular risk stratification of patients with MCL. In a 2016 study, the modified combination of the Ki-67 index and the MIPI, which incorporated a dichotomized Ki-67 proliferation index with a 30% cutoff level, differentiated survival outcomes into 4 risk groups, with 5-year overall survival ranging between 17% and 85%.
One of the newer approaches to the risk stratification of patients with MCL is the detection of alterations or deletions in the TP53 tumor suppressor gene. Alterations and deletions in TP53 have been associated with less favorable outcomes in patients with MCL, particularly those receiving chemotherapy-based treatment. In the Nordic MCL2 and MCL3 studies, mutations of TP53 (11%) and NOTCH1 (4%) and deletions of TP53 (16%) and CDKN2A (20%) were linked to unfavorable outcomes. In the randomized European MCL Younger study, simultaneous deletions of CDKN2A and TP53 were associated with dismal outcomes. An analysis of pooled data from 3 ibrutinib MCL studies found that the high-risk simplified MIPI score, bulky disease, and blastoid histology were adversely associated with overall survival and progression-free survival.
The MIPI score and TP53 frequently go hand in hand, with high-risk MIPI scores often being accompanied by TP53 mutations or deletions. The presence of simultaneous negative findings in both parameters predicts a poor prognosis.
Minimal residual disease (MRD) in MCL is another area of potential advancement. Molecular remission according to MRD status after induction treatment was highly predictive of response duration and disease progression in multiple studies of intensive treatment protocols that incorporated high-dose cytarabine and consolidative autologous stem cell transplantation, including the Nordic MCL2 and MCL3 studies and the European MCL Younger study. MRD may be one of the more robust profiling tools that will probably have more clinical use in the future.
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
Hermine O, Hoster E, Walewski J, et al; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388(10044):565-575. doi:10.1016/S0140-6736(16)00739-X
Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34(12):1386-1394. doi:10.1200/JCO.2015.63.8387
Jain P, Dreyling M, Seymour JF, Wang M. High-risk mantle cell lymphoma: definition, current challenges, and management. J Clin Oncol. 2020;38(36):4302-4316. doi:10.1200/JCO.20.02287
Jerkeman M, Eskelund CW, Hutchings M, et al. Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Lancet Haematol. 2018;5(3):e109-e116. doi:10.1016/S2352-3026(18)30018-8
Lokhande L, Kuci Emruli V, Kolstad A, et al. Immune-related protein signature in serum stratify relapsed mantle cell lymphoma patients based on risk. BMC Cancer. 2020;20(1):1202. doi:10.1186/s12885-020-07678-4
Ruan J. Molecular profiling and management of mantle cell lymphoma. Hematology Am Soc Hematol Educ Program. 2019;2019(1):30-40. doi:10.1182/hematology.2019000011
Rule S, Dreyling M, Goy A, et al. Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies. Br J Haematol. 2017;179(3):430-438. doi:10.1111/bjh.14870