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NEW ORLEANS -- Results of a large randomized trial support the inclusion of ibrutinib (Imbruvica) to the standard first-line treatment of younger patients with mantle cell lymphoma (MCL), a researcher reported here.

In the aptly named three-arm TRIANGLE trial, failure-free survival (FFS) rates at 3 years were numerically higher in patients receiving ibrutinib either alone (86%) or with autologous stem-cell transplant (ASCT; 88%), as compared with transplant alone (72%), according to Martin Dreyling, MD, PhD, of Ludwig Maximilian University of Munich.

Based on the trial design, the combination of ibrutinib-ASCT met criteria for superiority over transplant alone (HR 0.52, P=0.0008), while ASCT alone failed to demonstrate superiority to treatment with the Bruton's tyrosine kinase (BTK) inhibitor alone (HR 1.77, P=0.9979).

"Autologous transplant is only justified -- because of its higher toxicity -- if there's a significant improvement of FFS," Dreyling explained during a press briefing at the American Society of Hematology annual meeting.

"This hypothesis was rejected," he said, noting that the transplant-alone arm performed similarly to previous trials in . "Essentially, you have a numerical benefit of 14% after 3 years in favor of ibrutinib."

Overall survival (OS) at 3 years was numerically higher in the ibrutinib arms compared with the transplant arm (91-92% vs 86%, respectively), though Dreyling cautioned that it was too early for statistical comparisons.

Current standard of care in MCL includes high-dose cytarabine-containing immunochemotherapy and ASCT, along with rituximab maintenance as determined by national guidelines.

Reached for comment, Catherine Diefenbach, MD, director of the Clinical Lymphoma Program at NYU Langone's Perlmutter Cancer Center in New York City, called the findings practice-informing rather than practice-changing. "The fact that ibrutinib may improve outcomes to the point that you might not need an auto-transplant is very compelling, and it would certainly change practice."

"I'll feel more comfortable saying it's unequivocally practice-changing with longer follow-up," she told 名媛直播, pointing out that the short follow-up of 31 months extends to the period when patients in the study have only just finished taking ibrutinib maintenance.

"I would like to see more mature data to see that these curves stay separate after the patients stop ibrutinib," said Diefenbach. "After 2 more years off ibrutinib, does that benefit persist or do you need to be continually on therapy to have that benefit?"

Dreyling suggested that for the majority of patients, ibrutinib-only will become the new standard of care. While specific subgroups may still benefit from ASCT as well, it may take "3 years from now to have a definite conclusion" for the comparison between the ibrutinib-only and ibrutinib-ASCT arms.

Considering the significant toxicity with autologous transplant, the study favors the ibrutinib-only arm over the combination approach, said Dreyling. While toxicity was largely similar between arms during induction, there were substantially more grade ≥3 adverse events (AEs) with ibrutinib plus ASCT in the maintenance period.

"We autologous transplant 20 years ago and, in my opinion, now the better is the enemy of the good. We have to move on," he said at the end of his presentation.

For a patient not eligible for ASCT, Diefenbach said she could absolutely see BTK inhibition as an option, though she noted that ibrutinib carries significant toxicity, including cardiac risks and bleeding, both of which were observed in TRIANGLE during maintenance. Newer-generation BTK inhibitors, she noted, have more tolerable safety profiles.

"The question is, can you replicate this data with some of the later-generation BTKs?" she said. "In a maintenance setting, this would be quite appealing."

Study Details

From 2016 to 2020, the TRIANGLE trial randomized 870 transplant-eligible MCL patients at centers across 14 countries, primarily in Europe. Following induction therapy, participants received either ASCT alone (control arm), ASCT plus 2 years of ibrutinib maintenance, or 2 years of ibrutinib maintenance alone.

Induction therapy consisted of three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and vincristine) and R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin), with ibrutinib included with R-CHOP as well in the two investigational arms. Overall and complete response rates during induction were slightly higher with the addition of ibrutinib.

Participants were required to have previously untreated MCL, be younger than age 66, and have a good performance status (Eastern Cooperative Oncology Group 0-2).

Median age was 57, while the vast majority had stage IV disease and more than half were considered low risk according to the Mantle Cell Lymphoma International Prognostic Index.

Rituximab maintenance was added during the course of the trial, Dreyling noted, as it became clear the strategy improved progression-free survival (PFS) and OS. Ultimately, 54% to 58% of the three study arms received rituximab in the maintenance setting.

The study's primary endpoint was FFS, and secondary outcomes included response rates, OS, PFS, and safety. Subgroup analyses of the primary endpoint showed that ibrutinib's FFS benefit extended to patients with a high Ki-67 score and high p53 expression.

Following treatment failure, salvage therapy largely consisted of ibrutinib or other BTK inhibitors in the control arm and other therapies in the two investigational arms.

For safety during induction, there were no substantial differences in the occurrence of grade ≥3 AEs with R-CHOP and R-DHAP alone or in combination with ibrutinib, with similar rates of neutropenia, leukopenia, febrile neutropenia, infections, and heart complications. The two ASCT-containing arms had similar rates of grade ≥3 AEs as well.

During maintenance, however, there were substantially more grade ≥3 AEs with ibrutinib and ASCT in combination, including more neutropenia (44% vs 23% with ibrutinib alone or 17% with ASCT alone), leukopenia (4% vs 2% and 2%, respectively), febrile neutropenia (6% vs 3% and 3%), thrombocytopenia (6% vs 3% and 2%), and infections (25% vs 19% and 13%).

More patients on the ibrutinib arms also experienced grade ≥3 cardiac events (3-4%) compared with the ASCT-alone arm (1%) during maintenance.

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