Mantle cell lymphoma (MCL) is a unique lymphoma that is in the intermediate spectrum of indolent and aggressive non-Hodgkin lymphomas. Patients can be observed until symptomatic, but when requiring treatment, intensive chemoimmunotherapy is often utilized. In addition, fit patients are offered autologous stem cell transplantation (ASCT) as consolidation therapy. Treatment with intensive chemoimmunotherapy upfront plus ASCT has been shown to provide a progression-free survival (PFS) benefit but has not influenced overall survival. Several novel therapies, including ibrutinib, have been recently approved for MCL. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, has shown encouraging efficacy in relapsed MCL and as frontline therapy in older patients.
Dr. Martin Dreyling and colleagues from the European MCL Network asked the important question of whether incorporating ibrutinib into front-line therapy in young patients with advanced MCL improves outcomes. They presented their impressive work at the #ASH22 Plenary Scientific Session.
Through a remarkable cooperative group effort, 870 patients with previously untreated, stage II-IV MCL were randomized to three groups: A, A+I, or I (A for ASCT and I for ibrutinib). Study treatment consisted of three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-DHAP (rituximab, dexamethasone, high-dose ara-C, and cisplatin) without (arm A) or with ibrutinib added to R-CHOP cycles and two years of maintenance (arms A+I, I). ASCT was planned for responding patients of arms A and A+I. Rituximab maintenance could be applied according to national guidelines in all responding patients, irrespective of the trial arm. The patients in the A and A+I groups received ASCT consolidation if the lymphoma responded to chemotherapy. The primary endpoint was failure-free survival (FFS), with stable disease at the end of induction, progression, and death constituting qualifying events.
Ibrutinib alone without ASCT (I arm) and the ASCT-only arm (A arm) demonstrated similar FFS at three years (86% vs. 72%). Addition of ibrutinib to ASCT (A+I arm) showed superior FFS compared to ASCT alone (A arm; 88% vs. 72%). The statistical monitoring of the A+I versus I arms is ongoing. The three-year overall survival rates were 86 percent, 91 percent, and 92 percent in the A, A+I, and I arms, respectively. Rituximab maintenance was given in 50 to 60 percent of patients and was well balanced throughout the study arms. Notably, there was no differential efficacy of ibrutinib by rituximab maintenance. The addition of ibrutinib to induction therapy was safe with no significant differences in grade 3 to 5 adverse events. However, there was a higher incidence of grade 3 to 5 adverse events, including neutropenia and infections, in the A+I arm compared to A and I arms during maintenance therapy.
In conclusion, the addition of ibrutinib to autologous transplantation yielded superior FFS, and the autologous transplant arm was not superior to the ibrutinib alone arm. We eagerly await the longer-term follow-up results of the A+I versus I arm to determine whether the addition of ASCT to ibrutinib provides benefit. The authors commend the European MCL Network for dismantling and reMANTLing the upfront treatment of MCL.
Readers who are interested in use of other targeted therapies in MCL should also review the oral abstract session Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological I, which took place on Saturday, December 10.
Dr. Kumar and Dr. Jeong indicated no relevant conflicts of interest.
