Ibrutinib (Imbruvica) plus chemoimmunotherapy in the first-line setting plus ibrutinib maintenance enhanced overall survival (OS) outcomes among patients with TP53-mutated mantle cell lymphoma and appeared to reduce the adverse prognostic impact of other high-risk genetic lesions among patients with TP53-mutated mantle cell lymphoma (MCL), according to findings from an analysis of the MCL TRIANGLE trial (NCT02858258) presented at the European Hematology Association (EHA) 2026 Congress.1
Specifically, a clinically significant differential effect was observed with TP53 mutations on OS (P = 0.048). Moreover, similar effects were noted among other high-risk MCL genetic alterations, including NOTCH1/2 mutations, MYC amplification, CCND1 3’UTR mutations/deletions, CDKN2A/B loss, and SMARCA4 mutations/deletions.
Moreover, the investigators noted that the impact of the addition of autologous stem cell transplantation (ASCT) to ibrutinib was not conclusive at the time of the study analysis. Further validation is being conducted among patients treated with or without ASCT, with 300 pending new sequenced cases and clinical analysis underway.
“Fifty five percent of TP53-mutated MCL show p53 protein overexpression. Distribution and type of TP53 mutations was similar in cases with and without p53 overexpression,” Marta Grau, of Fundació Recerca Clínic Barcelona Institut d’Investigacions Biomèdiques August Pi i Sunyer in Barcelona, Spain, and Centro de Investigación Biomédica en Red de Cáncer in Madrid, Spain, stated in the presentation. “The addition of ibrutinib at first line and at maintenance appeared to partially abrogate the poor outcome of [patients with] TP53-mutated disease.”
Investigators in the MCL Triangle trial enrolled patients with previously untreated stage II to IV MCL. Patients were required to have been 65 years or younger, be suitable for ASCT, and have an ECOG performance status of 0 to 2. Those enrolled were randomly assigned 1:1:1 to receive ASCT alone (Arm A), ibrutinib plus ASCT (Arm A + I), or ibrutinib alone (Arm I).
Across all cohorts, patients initially received 3 cycles of rituximab (Rituxan) with either cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) with or without ibrutinib. In the A and A + I arms, patients were subsequently treated with ASCT. In the A + I and I arms, ibrutinib maintenance followed initial chemoimmunotherapy or ASCT, if administered.
The primary outcome of the TRIANGLE MCL trial was investigator-assessed failure-free survival (FFS).2 Secondary end points included OS, progression-free survival, duration of remission, overall remission rate, complete remission rate, and partial to complete remission conversion following induction therapy. Adverse effects were reported using CTCAE v4.03 criteria.
In the study, across all patients enrolled, the HR for FFS between arms A and A + I was 0.63 (98.33% CI, 0.00-0.89; P = .0026) in favor of arm A + I. Between arms A and I, it was 1.45 (98.33% CI, 0.00-2.02) favoring arm I. However, between arms I and A + I, the HR for FFS was 0.86 (98.33% CI, 0.00-1.27), numerically supporting A + I, but not reaching significance (P = 0.21).
The relationship between the clinical impact of TP53 mutations and overexpression on FFS outcomes was clinically significant in arm A (P < .001) but did not reach significance in arm A + I (P = .053) or arm I (P = .119).
Regarding the relationship between TP53 mutations and p53 overexpression, 89% of tumors in the study (n = 32/36) with a p53 expression of greater than 50% had TP53 mutations. In contrast, 55% (n = 32/58) of TP53-mutated tumors showed p53 overexpression. Additionally, the distribution and type of TP53 mutation was comparable among tumors with and without p53 overexpression. The most common type of TP53 variant in p53 low MCL was missense (54%) followed by truncating (38%).
References
- Grau M, Nadeu F, Montaner A, et al. Genomic predictors of outcome in mantle cell lymphoma: TP53 and additional alterations in the TRIANGLE trial by the Multiply Consortium. Presented at: European Hematology Association 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S233.
- Dreyling M, Doordujin J, Giné E, et al. Addition of autologous stem-cell transplantation to an ibrutinib-containing first-line treatment in patients aged 18–65 years with mantle cell lymphoma (TRIANGLE): 4·5-year follow-up of a three-arm, randomised, open-label, phase 3 superiority trial of the European MCL Network. Lancet. 2026;407(10542):P1953-1967. doi:10.1016/S0140-6736(26)00362-4
