Ibrutinib could become new standard for first-line treatment of mantle cell lymphoma
NEW ORLEANS — Patients with newly diagnosed mantle cell lymphoma who received ibrutinib with a standard-of-care regimen had higher failure-free survival rates than those who received standard-of-care treatment alone.
Data from the randomized phase 3 TRIANGLE study, presented at ASH Annual Meeting and Exposition, also showed nonsuperior outcomes with standard-of-care therapy vs. ibrutinib (Imbruvica, Janssen) without a hematopoietic stem cell transplant, suggesting ibrutinib may have a role in the first-line treatment of mantle cell lymphoma in patients aged younger than 65 years.
“We established autologous stem cell transplant as the standard more than 25 years ago and, in my opinion, we now have to move on,” Martin Dreyling, MD, professor of medicine and head of the lymphoma program at Ludwig Maximilians University in Munich, said during a press conference.
Background
Mantle cell lymphoma can be challenging to treat because it can manifest as either an indolent disease — known as “classical” mantle cell lymphoma — or it can develop an aggressive course based on biological risk factors, according to Dreyling.
The only randomized trial to confirm the OS benefit of HSCT as first-line therapy for mantle cell lymphoma was conducted 25 years ago, he added.
“Meanwhile, we have since improved our first-line treatment [options],” he said during a presentation. “Patients who have [received] salvage therapy with ibrutinib have achieved significantly better overall survival, so that was the starting point of our study implementing this approach into first-line treatment.”
Methodology
TRIANGLE is an investigator-initiated, open-label, randomized phase 3 trial conducted by the European MCL Network at one of 13 centers throughout Europe and Israel. The trial aimed to determine the role of ibrutinib, a Bruton tyrosine kinase inhibitor, to improve outcomes — with or without consolidation autologous HSCT — as front-line therapy for those aged younger than 65 years with newly diagnosed mantle cell lymphoma.
Between July 2016 and December 2020, the investigators randomly assigned 870 patients (median age, 57 years; range, 27-68; 76% male) in 1:1:1 ratio to one of three treatment arms, including ibrutinib plus standard-of-care treatment (n = 292), standard-of-care treatment alone (n = 288) and ibrutinib without allogeneic HSCT (n = 290).
Eighty-seven percent of patients enrolled in the study had stage IV disease.
The study included patients with previously untreated, advanced stage II to stage IV mantle cell lymphoma aged 65 years or younger who were eligible for treatment with high-dose cytarabine and allogeneic HSCT.
Study treatment comprised standard-of-care therapy with three cycles of R-CHOP/R-DHAP (rituximab, dexamethasone, cytarabine and cisplatin ) alone or with ibrutinib added to R-CHOP cycles and 2 years of rituximab (Rituxan, Genentech) maintenance therapy given according to national guidelines to all responding patients irrespective of treatment group. Patients who responded to standard care alone or in combination with ibrutinib were eligible for consolidation therapy with autologous HSCT.
Failure-free survival (FFS), stable disease at the end of induction therapy, and disease progression or death served as the study’s primary outcome measures. Secondary outcomes included overall and complete response rates, OS and safety.
Median follow-up was 31 months.
Key findings
Pooled data from the ibrutinib monotherapy and ibrutinib plus standard-of-care therapy groups showed higher overall (98% vs 94%) and complete response rates (45% vs 36%) compared with standard-of-care therapy alone.
Investigators noted nonsuperior estimated 3-year FFS for standard-of-care therapy compared with ibrutinib monotherapy (72% vs 86%, HR = 1.77).
Standard of care plus ibrutinib demonstrated superior 3-year FFS compared with standard-of-care therapy alone (88% vs 72%; HR = 0.52).
Subgroup analysis using the intent to apply rituximab as maintenance therapy did not alter the main findings that standard-of-care therapy conferred noninferior results compared with ibrutinib monotherapy or that standard of care plus ibrutinib produced superior outcomes than standard-of-care treatment alone, the researchers noted.
Researchers reported estimated 3-year OS rates of 86% for the standard-of-care group, 91% for standard of care plus ibrutinib and 92% for ibrutinib alone.
Similar rates of grade 3 or higher treatment-related adverse events occurred during the induction portion of regimen, with or without ibrutinib. Likewise, grade 3 or higher treatment-related adverse events occurred at a similar rate among patients in both groups containing HSCT consolidation therapy.
Investigators noted “substantially” increased rates of grade 3 or higher treatment-related adverse events during the maintenance therapy period among patients who received standard of care plus ibrutinib compared with those who received standard of care or ibrutinib alone. Adverse events of note during the maintenance period among patients who receive standard of care plus ibrutinib included neutropenia (44%), infections (25%) and cardiac disorders (3%).
Clinical implications
Ibrutinib monotherapy is poised to become the new standard of care for adults with mantle cell lymphoma based on the increased toxicity seen in the HSCT arm of the study, Dreyling said.
“It might well be that certain patients may still benefit from autologous transplant, but that will still take [a few] years from now before there is a definite conclusion,” he said.
Perspective
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These data directly challenge the current treatment paradigm that all fit patients undergo upfront transplant for mantle cell lymphoma. Early incorporation of BTK inhibitors as part of front-line and maintenance therapy demonstrates a clear benefit compared with standard-of-care therapy. Whether autologous transplant in addition to ibrutinib has any added benefit remains unclear. However, considering recently published data demonstrating functional “cures” for patients with mantle cell lymphoma who received cytarabine-based therapy and autologous transplant — with a 10-year PFS rate of 46% — longer follow-up of patients in the two ibrutinib-containing arms is indicated to see if there is an increase in late relapse among patients not receiving autologous HSCT. Assuming front-line approval of BTK inhibitors in mantle cell lymphoma, these results support the use of ibrutinib during induction and maintenance therapy for younger adults with mantle cell lymphoma and question whether autologous HSCT — with its associated risks — is indicated for every patient as an upfront consolidation procedure.
Reference:
Hermine O, et al. J Clin Oncol. 2022;doi:10.1200/JCO.22.01780.
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Dreyling M, et al. Abstract 1. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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