Less toxic induction was explored in a phase 2 study, where 3 cycles of BR followed by 3 cycles of rituximab and cytarabine demonstrated high incidence of MRD negativity prior to ASCT.4 To address the risk for relapse after ASCT, maintenance rituximab therapy has been examined and has shown improved PFS and OS. In an extension of the MCL2 study, rituximab treatment was able to convert patients with molecular relapse back to MRD negativity.5
Although effective, induction with high-dose cytarabine followed by ASCT can lead to toxicities that must be considered, especially as trial dropout rates can reach 30%. “Given the association between MRD status at end-of-induction (EOI) [and] PFS, using EOI MRD status to de-escalate therapy is an attractive option,” the researchers wrote; this strategy is being assessed in the ECOG EA4151 intergroup trial (ClinicalTrials.gov Identifier: NCT03267433).
Of note, ASCT and its associated toxicities may be supplanted by the integration into front-line treatment of novel agents such as ibrutinib, venetoclax, and lenalidomide that have shown efficacy in patients who experience relapse. Ideally, effective novel agents would be used to attain high rates of MRD negativity upfront, and an MRD-driven maintenance strategy would be employed as follow-up.
Though a clear definition “remains elusive,” high-risk MCL is characterized by blastoid or pleomorphic morphology, which is seen in 13% to 19% of MCL cases and is known to be associated with inferior outcomes. There are not enough prospective data to inform management of patients with high-risk MCL, though a large retrospective analysis suggested that ASCT consolidation may provide increased PFS and OS.
Mutations in TP53 are a robust marker of poor prognosis, but optimal management of these patients is also undefined. Large trials have demonstrated inadequate disease control with standard intensified induction and ASCT consolidation, and no prospective data exist to support allogeneic SCT in the frontline setting. Nonetheless, novel agents have shown promising results; in a small phase 2 study of heavily pretreated young patients with MCL, combination therapy with ibrutinib and venetoclax led to 50% of TP53-mutated patients achieving complete remission.
Though it has demonstrated promise, high-intensity induction followed by ASCT cannot be used in a significant proportion of patients with MCL — in particular, elderly and nontransplant-eligible patients. In these patients, R-CHOP and BR are both well validated induction regimens, with the StiL and the BRIGHT trials reporting superior PFS (though not OS), as well as a more favorable toxicity profile, for BR compared with R-CHOP and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP).6,7 Thus, BR has become a standard induction regimen in older patients with MCL.
Attempts to further modify R-CHOP and BR to improve efficacy have not been successful in managing the associated toxicities, as demonstrated in phase 2/3 studies of rituximab, bendamustine, and cytarabine (R-BAC) or bortezomib plus CHOP (VR-CAP).8,9 Alternative approaches may include examining agents with single-agent activity in relapsed or refractory MCL, such as ibrutinib or acalabrutinib, in a regimen with a BR backbone. Rituximab maintenance is another potential strategy for delaying relapse; this treatment achieved 4-year PFS and OS rates of 57% and 87%, respectively, when combined with R-CHOP induction.10
For frail, elderly patients unable to tolerate standard induction chemotherapy, options for frontline management have been limited, but the development of novel agents may change this. The chemotherapy-free regimen of lenalidomide and rituximab given during both induction and maintenance until disease progression has yielded an overall response rate of 92% with durable remission, a 5-year PFS rate of 64%, and a 5-year OS rate of 77%.11 The efficacy of induction with rituximab and ibrutinib is currently being assessed in the phase 2 ENRICH trial (ClinicalTrials.gov Identifier: NCT01880567).
The evolution of treatment options for MCL over the past decade has led to major improvements in patient outcomes, and the development of novel therapeutic agents has challenged the existing treatment paradigm of anthracycline- and cytarabine-based chemoimmunotherapy followed by ASCT consolidation. Biomarker and serial MRD testing may aid the personalization of therapy and reduce drug costs due to the administration of novel agents until disease progression. Furthermore, potential chemotherapy-free therapeutic approaches should undergo further evaluation.
“Translational studies are needed to better inform decision-making, to drive consolidation or maintenance therapy and the need for intensified or novel therapy, and to determine mechanisms of disease resistance,” the reviewers concluded.
- Tang C, Kuruvilla J. Optimal frontline management of mantle cell lymphoma: can we agree? Expert Rev Hematol. 2018;11(12):911-914. doi:10.1080/17474086.2018.1537778
- Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105(7):2677-2684. doi:10.1182/blood-2004-10-3883
- Hermine O, Hoster E, Walewski J, et al. 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
- Armand P, Redd R, Bsat J, et al. A phase 2 study of Rituximab-Bendamustine and Rituximab-Cytarabine for transplant-eligible patients with mantle cell lymphoma. Br J Haematol. 2016;173(1):89-95. doi:10.1111/bjh.13929
- Kolstad A, Pedersen LB, Eskelund CW, et al. Molecular monitoring after autologous stem cell transplantation and preemptive rituximab treatment of molecular relapse; results from the Nordic mantle cell lymphoma studies (MCL2 and MCL3) with median follow-up of 8.5 years. Biol Blood Marrow Transplant. 2017;23(3):428-435. doi:10.1016/j.bbmt.2016.12.634
- Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2
- Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123(19):2944-2952. doi:10.1182/blood-2013-11-531327
- Visco C, Chiappella A, Nassi L, et al. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017;4(1):e15-e23. doi:10.1016/S2352-3026(16)30185-5
- Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018;19(11):1449-1458. doi:10.1016/S1470-2045(18)30685-5
- Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367(6):520-531. doi:10.1056/NEJMoa1200920
- Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018;132(19):2016-2025. doi:10.1182/blood-2018-07-859769