Ibrutinib (Imbruvica) may allow patients with newly diagnosed mantle-cell lymphoma (MCL) to forego autologous stem-cell transplantation (ASCT), according to results of the 3-arm randomized TRIANGLE clinical trial presented at the 64th American Society of Hematology Annual Meeting and Exposition. The addition of ibrutinib to ASCT improved failure-free survival (FFS) by 16% compared with ASCT alone. In addition, no difference in FFS was observed at the 3-year time point when ibrutinib was added to ASCT or given as a substitute for ASCT. These data are poised to be practice-changing, but longer follow-up is needed.
“Based on our findings, standard chemotherapy plus ibrutinib [with or without ASCT] is the new standard of care for first-line MCL patients,” said Martin Dreyling, MD, Professor of Medicine, and Head of the Lymphoma Program, Medical Clinic III, Groβhadern Clinic, Ludwig-Maximilians-Universität, Munich, Germany. “We have to wait for the full results; so far, we don’t see any difference between these two ibrutinib curves for progression-free survival and overall survival, but already both curves are numerically superior to the old standard, autologous transplant only.”
“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.”
MCL is a heterogeneous hematologic malignancy that can be indolent or aggressive. It is frequently diagnosed at a later stage, conferring a poor prognosis. For more than 2 decades, ASCT has been the cornerstone of therapy for previously untreated MCL. In the United States, the current standard of care is high-dose cytarabine-containing chemoimmunotherapy followed by ASCT with rituximab (Rituxan) maintenance.
The TRIANGLE study randomized 870 previously untreated patients with MCL to 1 of 3 treatment arms:
- 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 amended to include rituximab maintenance in all 3 arms.
Patients enrolled in the trial had stage II to IV MCL and were aged ≤65 years. Median age was 57 years.
At a median follow-up of 31 months, the addition of ibrutinib to ASCT led to superior FFS versus ASCT (primary end point of the trial). Three-year FFS was 88% in the ibrutinib-containing arm versus 72% without ibrutinib, reflecting a statistically significant 48% reduction favoring ibrutinib (P = .008). Median FFS was not reached in either arm.
“The absolute of disease freedom at 3 years is 16% and highly significant,” Dr Dreyling noted.
The head-to-head comparison of ibrutinib versus ASCT demonstrated numerically higher 3-year FFS for ibrutinib: 86% versus 72% for ASCT. Ibrutinib was 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 ibrutinib, with a numerical benefit of 14% in three-year failure-free survival,” he said.
In the third comparison, no difference was seen between ibrutinib with ASCT and ibrutinib substituted for ASCT, but longer follow-up is needed, Dr Dreyling noted.
There was no major difference between the 2 ASCT-containing arms in the incidence of grade 3 to 5 adverse events (AEs), with the most common events being neutropenia, febrile neutropenia, leukopenia, and infection. In the comparison between ibrutinib plus ASCT versus ibrutinib as a substitute for ASCT, more grade ≥3 AEs were observed during maintenance with the combination of ASCT and ibrutinib.
In the maintenance phase of treatment, higher rates of AEs were observed with standard of care plus ibrutinib compared with either standard of care or ibrutinib alone.
“This suggests that ibrutinib may have optimal use as a replacement for, rather than an addition to, ASCT. Even from the perspective of toxicity, the ideal regimen is a combination of conventional chemotherapy plus ibrutinib,” stated Dr Dreyling.
At a press conference during the meeting, moderator Mikkael A. Sekeres, MD, MS, Chief and Professor, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL, said, “This is one of the abstracts that challenge standard of care and suggest that 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.”