As reported in The Lancet by Martin Dreyling, MD, PhD, of Ludwig Maximilian University Hospital Munich, and colleagues, results in the European Mantle Cell Lymphoma Network phase III TRIANGLE trial indicate that the addition of ibrutinib to immunochemotherapy and autologous stem cell transplantation (ASCT) significantly improved failure-free survival in first-line treatment of patients with mantle cell lymphoma aged 65 or younger.¹ No significant benefit of immunochemotherapy plus ASCT was observed over ibrutinib and immunochemotherapy without ASCT.

Martin Dreyling, MD, PhD

Study Details

In the open-label trial, 870 patients from sites in 14 countries were randomly assigned on a 1:1:1 basis between July 2016 and December 2020 to receive immunochemotherapy and ASCT (group A, n = 288), ibrutinib and immunochemotherapy and ASCT (group A + I, n = 292), or ibrutinib and immunochemotherapy without ASCT (group I, n = 290). All groups received induction immunochemotherapy with six alternating cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin; some patients in the R-DHAP group received oxaliplatin rather than cisplatin). Group A + I and group I received ibrutinib at 560 mg daily on days 1 through 19 of R-CHOP cycles and as daily maintenance for 2 years. The primary outcome measure was failure-free survival in the intention-to-treat population.

Failure-Free Survival

The median follow-up was 31 months. Failure-free survival at 3 years was superior in group A + I (88%, 95% confidence interval [CI] = 84%–92%) vs group A (72%, 95% CI = 67%–79%), with a hazard ratio (HR) of 0.52 (one-sided 98.3% CI = 0–0.86, P = .0008). Superiority of group A over group I was not shown, with a 3-year failure-free survival rate of 72% (95% CI = 67%–79%) vs 86% (95% CI = 82%–91%) and a hazard ratio of 1.77 (one-sided 98.3% CI = 0–3.76, P = .9979). The comparison of group A + I vs group I is ongoing.

In group A + I vs group A, hazard ratios for failure-free survival in Mantle Cell Lymphoma International Prognostic Index (MIPI) risk groups were 0.49 (one-sided 98.3% CI = 0–0.99) for low risk, 0.35 (one-sided 98.3% CI = 0–0.77) for intermediate risk, and 0.58 (one-sided 98.3% CI = 0–1.32) for high risk. In group A vs group I, hazard ratios for MIPI risk groups were 1.49 (one-sided 98.3% CI = 0–2.83) for low risk, 4.01 (one-sided 98.3% CI = 0–9.98) for intermediate risk, and 1.86 (one-sided 98.3% CI = 0–4.25) for high risk.

Among 805 patients with a partial or complete response at the end of induction therapy, remission persisted at 3 years in 76% of group A (HR = 1.80, P < .99 vs group I), 88% of group A + I (HR = 0.52, P = .0021 vs group A), and 87% of group I. The cumulative incidence of salvage treatment at 3 years was 18.2% in group A, 5.8% in group A + I, and 10.1% in group I. Progression-free survival rates at 3 years were 73% (95% CI = 67%–79%) for group A, 88% (95% CI = 84%–93%) for group A + I, and 87% (95% CI = 83%–92%) for group I. Uncorrected hazard ratios were 0.46 (one-sided 98.3% CI = 0–0.72, P = .00012) for group A + I vs group A and 2.10 (one-sided 98.3% CI = 0–3.28, P > .99) for group A vs group I.  Overall survival rates at 3 years were 86% (95% CI = 82%–91%) in group A, 91% (95% CI = 88%–95%) in group A + I, and 92% (95% CI = 88%–95%) in group I.

Adverse Events

No marked differences in grade ≥ 3 adverse events were observed during induction therapy or ASCT between group A and group A + I. The most common grade ≥ 3 adverse events were blood and lymphatic system disorders, occurring in 71% to 76% of patients. During maintenance or follow-up, grade ≥ 3 hematologic adverse events (50%) and infections (25%) were more common in group A + I compared with group I (28% and 19%) and group A (21% and 13%).

Infections were the most common fatal adverse events during ASCT, occurring in four patients (2%) in group A and five patients (2%) in group A + I. Infections were also the most common fatal events during maintenance or follow-up, occurring in three patients (1%) in group A, two patients (1%) in group A + I, and two patients (1%) in group I.

Secondary hematologic malignancies were observed in two patients in group A (acute myeloid leukemia and myelodysplastic syndrome) and one patient in group I (multiple myeloma). Secondary nonhematologic malignancies occurred in 14 patients (5%) in group A + I, 10 patients (3%) in group I, and 5 patients (2%) in group A; the 3-year cumulative incidence rates were 5.5%, 3.5%, and 2.0%, respectively.

The investigators concluded: “Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined.” 

DISCLOSURE: The study was funded by Janssen and Leukemia & Lymphoma Society. Dr. Dreyling has received research grants from AbbVie, Bayer, Bristol Myers Squibb/Celgene, Gilead/Kite, Janssen, and Roche; speakers’ honoraria from AstraZeneca, BeiGene, Gilead/Kite, Janssen, Lilly, Novartis, and Roche; travel support from Janssen and Roche; and has participated on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb/Celgene, Gilead/Kite, Janssen, Lilly/Loxo Oncology, Novartis, and Roche.

REFERENCE

1. Dreyling M, Doorduijn J, Giné E, et al: Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): A three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet 403:2293-2306, 2024.