Although longer follow-up is needed, the results of the three-arm randomized TRIANGLE study suggest that the tyrosine kinase inhibitor ibrutinib may replace autologous stem cell transplantation (ASCT) after chemoimmunotherapy in younger patients with previously untreated mantle cell lymphoma (MCL). The study also found that when ibrutinib was added to ASCT, the 3-year failure-free survival was significantly superior to ASCT alone. Furthermore, at the 3-year mark, no difference in failure-free survival was observed when ibrutinib was added to ASCT or given instead of ASCT. This study appears to usher in a new standard of care for some patients with MCL. These results were reported at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

Martin Dreyling, MD

“Based on our findings, standard chemotherapy plus ibrutinib (with or without autologous stem cell transplantation) is the new standard of care for first-line treatment of patients with MCL,” said Martin Dreyling, MD, of Ludwig Maximilian University Hospital Munich. “We have to wait for the full results; so far, we don’t see any difference between these two ibrutinib curves for progression-free and overall survival, but already now both curves are numerically superior to the old standard, autologous transplant alone.”

“I think clinicians will interpret these results as suggesting you may essentially substitute autologous transplant with ibrutinib to avoid its well-known long-term toxicities,” Dr. Dreyling added. “In my opinion, we have to move on.”

“This is one of the abstracts that challenge the standard of care and suggest it is possible to give less therapy to patients, reducing the burden of care and improving quality of life. This study suggests that some patients with mantle cell lymphoma may be able to skip stem cell transplantation altogether thanks to the targeted drug ibrutinib,” stated ASH Committee on Communications Chair ­Mikkael Sekeres, MD, Chief of Hematology and Professor of Medicine at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine.

Mikkael Sekeres, MD

Mantle cell lymphoma is a heterogeneous disease that can have indolent cells or a rather aggressive course, based on biological factors. Mantle cell lymphoma is often diagnosed at a later stage, so many patients have a relatively poor prognosis. For about 25 years, ASCT has been the backbone of therapy for
previously untreated MCL. One common treatment approach is high-dose cytarabine-containing chemoimmunotherapy followed by ASCT with rituximab maintenance. The TRIANGLE results are poised to upend this option.

Study Details

The TRIANGLE study was conducted in 14 countries, primarily in Europe. The three-arm study randomly assigned 870 previously untreated patients to one of three treatment arms: the control arm: standard-of-care induction chemoimmunotherapy (high-dose cytarabine-containing chemoimmunotherapy followed by ASCT and rituximab maintenance); induction chemoimmunotherapy plus ibrutinib and ASCT followed by 2 years of ibrutinib maintenance; or induction chemoimmunotherapy with ibrutinib followed by 2 years of ibrutinib maintenance.

The study was modified to include rituximab maintenance in all study arms, when it “became obvious that maintenance does improve failure-free survival,” Dr. Dreyling noted.

Patients enrolled in TRIANGLE had stage II to IV MCL and were aged 65 or younger (median age, 57 years). The primary endpoint of the study was failure-free survival, defined as survival without stable disease or disease progression at the end of the initial course of treatment.

Key Results

At a median follow-up of 31 months, the addition of ibrutinib therapy to ASCT led to superior failure-free survival vs ASCT. The 3-year failure-free survival rate was 88% with ibrutinib vs 72% without ibrutinib, for a 48% reduction favoring ibrutinib that was statistically significant (P = .008). Median failure-free survival was not reached in either arm.

“The absolute improvement of disease freedom at 3 years is 16%, and this is highly significant,” Dr. Dreyling emphasized.

The head-to-head comparison of ibrutinib vs ASCT demonstrated numerically higher 3-year failure-free survival rates with ibrutinib (86% vs 72% on the ASCT arm) and was found to be noninferior to the current standard of ASCT after chemoimmunotherapy.

“We can only justify ASCT if there is a significant improvement in efficacy. This comparison showed the superiority of the ibrutinib arms, with a numerical benefit of 14% in the 3-year failure-free survival,” he said.

For the third arm of the study, no difference was evident in the comparison between ibrutinib with ASCT and ibrutinib substituted for ASCT, but longer follow-up is needed, Dr. Dreyling noted.

In terms of safety, ASCT is known to cause substantial toxicity and is difficult for patients to tolerate. The TRIANGLE study found there was no major difference between the two ASCT-containing arms in the incidence of grade 3 to 5 adverse events, with neutropenia, febrile neutropenia, leukopenia, and infections being the most common. In the comparison between ibrutinib plus ASCT vs ibrutinib as a substitute for ASCT, more grade 3 or higher adverse events were observed during maintenance with the combination of ASCT and ibrutinib.

In the maintenance phase of treatment, the standard of care plus ibrutinib led to higher rates of adverse events compared with either the standard of care or ibrutinib alone. This suggests ibrutinib may have optimal use as a replacement for, rather than an addition to, ASCT. “From the perspective of toxicity, the ideal regimen is a combination of conventional chemotherapy plus ibrutinib,” said Dr. Dreyling.

Overall, adding ibrutinib to induction treatment and as maintenance therapy with or without ASCT was feasible and active. Also, the current standard high-dose regimen is not superior to the ibrutinib-containing regimen without ASCT, the researchers found, but they said longer follow-up is needed. 

DISCLOSURE: The study was supported by Janssen. Dr. Dreyling has served as a consultant and/or received honoraria or research funding from Lilly/Loxo, AstraZeneca, Novartis, Roche, Janssen, Gilead Sciences/Kite, Amgen, BMS/Celgene, Bayer, AbbVie, and BeiGene. Dr. Sekeres has served on boards of directors or advisory committees for Novartis, Takeda/Millennium, and BMS.

REFERENCE

1. 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. 2022 ASH Annual Meeting and Exposition. Abstract 1. Presented December 11, 2022.