In a large, randomised, phase III TRIANGLE study of the European Mantle Cell Lymphoma Network, the pre-trial standard of immunochemotherapy followed by autologous stem-cell transplantation (ASCT) in younger patients with mantle cell lymphoma was challenged by ibrutinib, either in combination or instead of ASCT. Both ibrutinib-containing groups showed a relevant improvement in response rates as well as failure-free survival. In line with previous reports on immunochemotherapy-only based regimens, especially in the biological high-risk subset with p53 overexpression, the addition of ibrutinib led to a major improvement in efficacy.
Whether ASCT, with additional toxicity, still adds benefit to ibrutinib-based treatment in subsets of patients is not yet determined. The findings are published by Prof. Martin Dreyling of the Department of Medicine III, LMU University Hospital in Munich, Germany, and colleagues on 2 May 2024 in The Lancet.
The authors wrote in the background that during the last decade, in addition to the clinical mantle cell lymphoma international prognostic index (MIPI), blastoid morphology, high Ki-67, and TP53 alterations have been identified as the most important high-risk biological features. In young (aged ≤65 years), medically fit patients, dose-intensification by adding cytarabine or ASCT has led to improved long-term clinical and survival outcomes versus standard immunochemotherapy, although this has mostly been in low-risk patients. In addition, rituximab maintenance has resulted in improved survival rates compared with observation. In relapsed mantle cell lymphoma, monotherapies with Bruton’s tyrosine kinase (BTK) inhibitors have become the preferred salvage treatments, based on superior efficacy compared with conventional chemotherapy or other targeted therapies. In the front-line setting, the addition of the BTK inhibitor ibrutinib to bendamustine–rituximab has resulted in superior progression-free survival.
TRIANGLE is an investigator-sponsored, multicentre, randomised, open-label, three-arm parallel-group, confirmatory superiority study in which ibrutinib has been added during induction and as maintenance to one of the current immunochemotherapy standards, both in addition to ASCT and instead of ASCT. The study team aimed to investigate whether the addition of ibrutinib to immunochemotherapy and ASCT results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing immunochemotherapy without ASCT. Furthermore, considering the short-term and long-term toxicity of high-dose treatment, the TRIANGLE investigators aimed to investigate whether standard treatment with ASCT is still superior to a treatment adding ibrutinib to induction and maintenance without ASCT.
Patients were recruited from 165 secondary or tertiary university, community, or private hospitals and private clinical centres in Germany, Italy, the Netherlands, Spain, Sweden, Poland, Denmark, Switzerland, Norway, Czech Republic, Belgium, Israel, Portugal, and Finland. Patients with previously untreated, stage II–IV mantle cell lymphoma, aged 18–65 years and suitable for ASCT were randomly assigned 1:1:1, stratified by study group and MIPI risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP and R-DHAP or R-DHAOx, followed by ASCT. In group A plus I, ibrutinib 560 mg orally each day was added on days 1–19 of R-CHOP cycles and as fixed-duration maintenance 560 mg orally each day for 2 years after ASCT. In group I, ibrutinib was given the same way as in group A plus I, but ASCT was omitted.
Between 29 July 2016 and 28 December 2020, 288 patients were randomly assigned to group A, 292 patients to group A plus I, and 290 patients to group I. After 31 months median follow-up, group A plus I was superior to group A with 3-year failure-free survival of 88% (95% confidence interval [CI] 84–92) versus 72% (67–79; hazard ratio [HR] 0.52, one-sided 98.3% CI 0–0.86; one-sided p = 0.0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67–79) versus 86% (82–91; HR 1.77, one-sided 98.3% CI 0–3.76; one-sided p = 0.9979). The comparison of group A plus I versus group I is ongoing.
There were no relevant differences in grade 3–5 adverse events (AEs) during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3–5 haematological AEs and infections were reported after ASCT plus ibrutinib (group A plus I; haematological 50%, infections 25%, fatal infections 1%) compared with ibrutinib only (group I; haematological 28%, infections 19%, fatal infections 1%) or after ASCT (group A; haematological 21%, infections 13%, fatal infections 1%).
The authors commented that recently, ibrutinib has been withdrawn from the US market for relapsed mantle cell lymphoma, but two additional second generation BTK inhibitors are still registered for relapsed mantle cell lymphoma. Although these compounds seem to have quite comparable efficacy, no phase III data on combinations with chemotherapy are currently available.
Based on this potentially new standard of an ibrutinib-containing regimen, salvage treatment in patients might be more challenging. Historically, patients progressing under ibrutinib showed a poor outcome independent of conventional salvage treatment. Therefore, it is important to emphasise that the ibrutinib maintenance in the current study was applied for a fixed duration of 2 years, and the majority of patients were still in remission after completion of maintenance. Thus, re-exposure with BTK inhibitors might be worthwhile, but only scarce data on salvage after a time-limited ibrutinib treatment are currently available in mantle cell lymphoma. In addition, immunological approaches including CAR T cells and bispecific antibodies as well as BTK protein degraders or non-covalent BTK inhibitors might at least partially overcome the poor outcome of relapses after covalent BTK inhibitors.
The authors wrote that limitations of their study include the still limited follow-up, and the outstanding comparison of the two experimental groups and overall survival. No patient-reported outcomes were collected in this complex academic trial.
In an accompanied comment, Drs. Peter Martin and Kami Maddocks of the Meyer Cancer Center, Weill Cornell Medicine in New York, NY, US wrote that despite clear benefit associated with ibrutinib in this study, there are numerous questions beyond the role of ASCT. In April, 2023, approval for ibrutinib’s indication for the treatment of mantle cell lymphoma was voluntarily withdrawn from the market in the US, losing its accelerated approval status due to suboptimal benefit seen in confirmatory trials. Fortunately, the safety profiles of the remaining covalent BTK inhibitors, acalabrutinib and zanubrutinib, are superior to ibrutinib with fewer adverse events and, at least in other B-cell lymphomas, they appear to be more efficacious. However, replacing ibrutinib with the other agents would require another randomised controlled trial, an unfortunate use of resources when there are other pressing questions.
Although substitution of a BTK inhibitor for ASCT might make mantle cell lymphoma therapy available for people who cannot access ASCT, the expense of prolonged courses of BTK inhibitors might introduce new financial challenges for patients or health care systems. Additionally, this study does not address the management of older patients, who comprise most of the population with mantle cell lymphoma. Fortunately, the success of TRIANGLE establishes a clear role for inhibitors in the front-line treatment setting, providing a less toxic and more effective therapy than ASCT. The findings from TRIANGLE might also help to encourage the ongoing development of novel front-line mantle cell lymphoma regimens, including regimens entirely free of chemotherapy.
The study was funded by Janssen Pharmaceutical Companies and Leukemia & Lymphoma Society. The following study groups supported the trial by providing resources and by project administration and supervision (in alphabetical order): Czech Lymphoma Study Group (CLSG), Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON), Fondazione Italiana Linfomi (FIL), Grupo Español de Linfoma/Trasplante Autólogo de Médula Ósea (GELTAMO), Instituto Português de Oncologia (IPO), Israeli Lymphoma Group (ILG), Nordic Lymphoma Group (NLG), Polish Lymphoma Research Group (PLRG), and Swiss Group for Clinical Cancer Research (SAKK).
References
- Martin Dreyling, Jeanette Doorduijn, Eva Giné, 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. The Lancet; Published Online 2 May 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00184-3
- Martin P, Maddocks K. Does TRIANGLE take down transplantation in mantle cell lymphoma? The Lancet; Published online 2 May 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00301-5