Ibrutinib Makes Its Case for First-Line Treatment in Mantle Cell Lymphoma

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 younger MCL. “Essentially, you have a numerical benefit of 14% after 3 years in favor of ibrutinib.”

Overall survival (OS) at 3 years was numerically 5% higher in the ibrutinib arms compared with the transplant arm, 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.

But the results of the European MCL Network trial “suggest that patients with mantle cell lymphoma may be able to skip stem-cell transplantation altogether,” said press briefing moderator Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine.

Dreyling said 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.”

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.

“We established 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.

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.

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, there were substantially more grade ≥3 AEs with the combination approach, including more neutropenia, leukopenia, febrile neutropenia, and infections.