Mantle cell lymphoma (MCL) is a rare, incurable form of non-Hodgkin lymphoma that has a heterogenous clinical presentation and course. The introduction of targeted agents such as covalent Bruton tyrosine kinase inhibitors (cBTKis) has, in relative terms, made an enormous impact on those with relapsed/refractory (R/R) disease, though not quite to the degree seen in those with chronic lymphocytic leukemia.1-3 Given the safety and efficacy of these agents, numerous attempts have been made to move these drugs into the frontline space. Most trials have combined cBTKis with chemoimmunotherapy.4,5 To date, TRIANGLE is the only randomized phase 3 study that has investigated this combination in “medically fit” patients aged 18 to 65.
Conducted by Martin Dreyling, MD, PhD, and colleagues, the TRIANGLE trial by the European Mantle Cell Lymphoma Network randomized 870 patients into three groups to investigate the effectiveness of ibrutinib as an adjunct to standard-of-care (SOC) chemoimmunotherapy, both with and without autologous stem cell transplantation (ASCT). The control group received the SOC treatment of six alternating cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and either R-DHAP (rituximab plus dexamethasone, cytarabine, and cisplatin) or R-DHAOx (rituximab plus dexamethasone, cytarabine, and oxaliplatin), followed by ASCT. The first experimental group received the addition of ibrutinib during the first 19 days of the cycles of R-CHOP, with R-DHAP or R-DHAOx administered as in the SOC arm, followed by ASCT and two subsequent years of ibrutinib maintenance, while the second experimental group received the same treatment as the first, but without ASCT. Rituximab maintenance was added to about half of all enrolled patients after publication of the LYMA trial.6
After 31 months of follow-up, the study reported a three-year failure-free survival (FFS) benefit of 88% and 86%, respectively, for the first and second experimental groups, compared with 72% for the SOC group. The study reported overall and complete response rates of 98% and 45%, respectively, for the two experimental groups, compared with 94% and 36%, respectively, for the SOC group. Overall survival (OS) at three years was 86% (95% CI 82-91) in the SOC group; 91% (95% CI 88-95) in the first experimental group; and 92% (95% CI 88-95) in the second experimental group.
Lymphoma was the cause of death in 6% of those in the SOC arm, 1% in the first experimental group, and 4% in the second experimental group. The three-year cumulative incidence of treatment failure was higher in the SOC group (21.9%) compared with the first and second experimental groups (6% and 10.8%, respectively). While understanding the limitations of subset analysis, it is important to note that the hazard ratio (HR) for those with suspected p53 mutations (high immunohistochemistry [IHC] expression) was 0.14 one-sided (98.3% CI 0-0.57), compared with 0.57 one-sided for those with wild-type p53 (98.3% CI 0-0.1.14). With the addition of rituximab maintenance in some patients, it was noted that duration of remission was improved when added to ibrutinib. While overall toxicity was equivalent during induction therapy, higher rates of grade 3 and above adverse events were noted during maintenance in the first experimental group, as were more adverse events when rituximab was combined with ibrutinib in the same group.
In Brief
Based on the study findings, the authors concluded that adding ibrutinib to SOC induction and maintenance therapy should become the standard practice for transplant-eligible patients with MCL who are below age 65. However, while acknowledging these promising early results, it also should be noted that the study findings are immature compared to those of other practice-changing trials.7-10 In patients with a p53 mutation (high IHC expression), the addition of ibrutinib would be expected to bolster the historically poor efficacy of chemoimmunotherapy.11-13 So, it is not such a leap of faith to assume that the significant benefits associated with the treatments used in the experimental groups will continue.
In the study, patients with high p53 expression had an HR of 0.14, with early and wide separation of FFS curves. In those with wild-type p53, the experimental groups had a modest FFS compared with SOC treatment, with most of the separation occurring after completion of induction. Given that those with wild-type p53 would be expected to benefit from chemoimmunotherapy, one can only ponder if the fact that approximately half of these patients in the SOC arm received no maintenance therapy while all the patients in the experimental arms received maintenance therapy (either ibrutinib alone or ibrutinib plus rituximab) has any impact on the results. Longer follow-up will be needed in this group to clearly demonstrate the superiority of the experimental groups over SOC. This last point takes on extra meaning given that the FFS is approximately 85% at three years in the pivotal LYMA R maintenance trial vs. approximately 68% in the observation arm.6 Over the last year, we have seen a slow but growing trend toward adoption of the second experimental group of the trial, fueled in small part by the slow gravitation of the field to reduce or eliminate ASCT consolidation in MCL patients in first-remission MCL due to long-term toxicity concerns and lack of OS benefit.
While a pending analysis between the two experimental groups is ongoing, it should be noted that the trial was never truly designed to compare these arms. So, while elimination of ASCT from induction based on this study in general can in some ways be debatable, the early move to eliminate ASCT based on the currently reported data is truly a leap of faith. Finally, how will this study’s findings impact later lines of therapy? The cBTKi in TRIANGLE is not given until progression, so retreatment can be considered. What we cannot answer right now is how effective retreatment with a cBTKi will be in this setting. TRIANGLE is one of two studies14 to have explored cBTKi maintenance in first remission in MCL; to date, neither study has reported on retreatment after recurrence. All of this sets up a dilemma that we must address when deciding on a treatment plan for transplant-eligible MCL patients. Do we take the safe route with ASCT, while waiting to see what lies below the cliff? Or do we take the proverbial leap of faith and push forward without ASCT while this study matures? Only time will tell us the best approach and what we can truly take from this exciting study and its ultimate overall impact on first-line transplant-eligible SOC therapy.
Competing Interests
Dr. Phillips indicated no relevant conflicts of interest.
