Ibrutinib Shows High Efficacy as MCL Induction and Maintenance Therapy

Martin Dreyling, MD

According to findings from the phase 3 TRIANGLE study (NCT02858258), adding ibrutinib (Imbruvica) to standard chemoimmunotherapy induction followed by autologous stem cell transplantation (ASCT) and 2 years of maintenance ibrutinib can significantly improve outcomes in comparison with standard chemoimmunotherapy induction and ASCT alone for younger patients with mantle cell lymphoma (MCL).¹

The study results were presented by Martin Dreyling, MD at the 2022 ASH Annual Meeting.

The primary end point of the 3-arm study, conducted by the European MCL Network, was failure-free survival (FFS), with events counted as stable disease following induction, any progression, or death. The 3-year FFS rate was 72% with standard induction and ASCT compared with 88% with ibrutinib added to induction, ASCT, and 2 years of ibrutinib maintenance (HR, 0.52; P = .0008).

Moreover, standard chemoimmunotherapy induction and ASCT failed to show superior FFS compared with ibrutinib plus chemoimmunotherapy as induction and 2-years of ibrutinib maintenance without ASCT, a regimen with far fewer adverse events (AEs). The 3-year FFS rate was 72% for chemoimmunotherapy/ASCT compared with 86% for ibrutinib alone (HR, 1.77; P = .9979). Rituximab (Rituxan) maintenance was permitted across all arms, with approximately half of patients receiving this treatment; however, subgroup analyses found its use did not alter the main results.

“Based on time to failure, autologous transplant plus ibrutinib is significantly superior to autologous transplant, and autologous transplant is not superior to ibrutinib,” said lead author, Dreyling from the Department of Internal Medicine III, LMU University Hospital Munich, in Germany. “Currently, there [are] no decisions about whether autologous stem cell transplant adds to ibrutinib but certainly right now toxicity favors ibrutinib only.”

The open-label study enrolled 870 patients across 3 treatment arms. In the first group, patients received induction therapy with 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone)/R-DHAP (rituximab, dexamethasone, cytarabine,

cisplatin) followed by ASCT (arm A; n = 288). In the second arm, patients received induction ibrutinib added to 3 cycles of R-CHOP/R-DHAP followed by maintenance ibrutinib for 2 years (arm A + I; n = 292). The third arm combined ibrutinib with induction R-CHOP/R-DHAP followed by 2 years of maintenance ibrutinib with no ASCT administered (arm I; n = 290). Rituximab maintenance was administered to 58%, 57%, and 54% of patients in the A, A + I, and I arms, respectively.

Baseline patient characteristics were balanced across arms and consistent with younger patients with MCL, Dreyling noted. The median age of patient in the study was 57 years (range, 27-68) and most were males (76%). Most patients had stage IV MCL (87%), and Mantle Cell Lymphoma International Prognostic Index risk groups were as follows: low (58%), intermediate (27%), and high (15%). Most patients had an ECOG performance status of 0 or 1 (99%).

Following induction therapy, the objective response rate (ORR) was 94% in arm A and the complete response (CR) rate was 36%. In combined findings for patients receiving ibrutinib induction in arm A + I and I (N = 559), the ORR was 98% and the CR rate was 45%. The ORR and CR rates were significantly higher with the combined ibrutinib arms vs the control group, Dreyling noted. Superiority between ibrutinib-containing arms was also assessed, to explore the potential for ASCT, but these findings were still inconclusive.

“Yes, the CR is low, if you compare with other American trials. This is CT-based, it is not PET-CT–based,” Dreyling said. “It is in line with previously published data [using this method] and when we looked at other induction regimens, this is highly comparable.”

Although too early to evaluate statistical significance, Dreyling noted, a trend toward improved overall survival (OS) emerging with the addition of ibrutinib. The 3-year OS rate was 86% with standard chemoimmunotherapy induction followed by ASCT compared with 91% with ibrutinib/chemoimmunotherapy as induction followed by ASCT and ibrutinib maintenance. Those who received ibrutinib/chemoimmunotherapy induction and ibrutinib maintenance without ASCT had a 3-year OS rate of 92%.

Grade 3-5 AEs occurred at a similar frequency between chemoimmunotherapy induction groups following induction therapy. The most common AEs in those receiving chemoimmunotherapy alone vs the addition of ibrutinib for maintenance were thrombocytopenia (59% vs 61%, respectively) neutropenia (47% vs 49%), anemia (22% vs 24%), leukopenia (15% in both), febrile neutropenia (9% vs 12%), infections/infestations (9% vs 12%), and cardiac disorders (2% vs 3%). There were 3 grade 5 events in arm A and 2 in ibrutinib-containing arms.

The AEs associated with ASCT were identical across arms, Dreyling said, with the most common AE being blood and lymphatic disorders in 59% of patients in each arm. In the maintenance phase, there were more AEs observed for those receiving ibrutinib. The most common grade 3-5 AEs for those in arms A + I, A, and I were neutropenia (44%, 17%, 23%, respectively), leukopenia (4%, 2%, 2%), febrile neutropenia (6%, 3%, 3%), infections/infestations (25%, 13%, 19%), and cardiac disorders (3%, 1%, 4%).

There were 39 deaths in arm A, 25 in arm A + I, and 23 in arm I. Lymphoma was a cause of death in 16, 4, and 11 patients across arms, respectively. Dreyling drew attention to concomitant disease and therapy as a cause of death. Of the deaths, 3.8%, 2.4%, and 1.7% were attributed to concomitant disease in arms A, A + I, and I, respectively. Therapy was listed as the cause of death for 1.4% in arm A and for 1.0% and 0% in arms A + I and I, respectively.

Follow up for the study remains ongoing.

_Reference

_{Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized Triangle trial by the European MCL Network. Blood. 2022;140(suppl 1):1-3. doi:10.1182/blood-2022-163018}