Barbara Dreta, Haematologist from UHC Zagreb, Croatia, comments on a recent publication published in The Lancet.
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
Dreyling, Martin et al. The Lancet, Volume 403, Issue 10441, 2293 – 2306
Mantle cell lymphoma is a non-Hodgkin lymphoma with multiple clinical subtypes, ranging from indolent disease with no need for treatment to highly aggressive disease prone to multiple relapses. Several therapeutic approaches exist and new therapeutical options, ranging from conventional chemotherapy followed with autologous stem cell transplant, targeted therapy with e.g. BTK inhibitors, cellular therapy with CAR-T cells and bispecific antibodies, are being rapidly developed. Today there are multiple clinical trials incorporating new therapeutic options in treatment of MCL in earlier lines.
One subgroup of special concern are young fit patients that are currently treated with dose-dense chemotherapy containing high-dose cytarabine followed by autologous stem cell transplant and rituximab maintenance. This approach led to improved long-term survival outcomes compared to standard immunochemotherapy. BTK inhibitor monotherapy is the preferred salvage treatment in relapsed MCL, showing superior efficacy and good tolerability compared to conventional chemotherapy regimens.
TRIANGLE is a clinical trial performed by the European Mantle Cell Lymphoma Network that incorporated ibrutinib with standard-dose chemotherapy in front line treatment of young and fit patients. This is a multicenter, randomized, open-label, three arm, superiority trial including previously untreated MCL patients aged 18-65 years suitable for ASCT. Patients were randomized in one of three treatment arms: immunochemotherapy (alternating R-CHOP/R-DHAP for a total of six cycles), followed by ASCT (group A); same immunochemotherapy as in group A with the addition of ibrutinib during R-CHOP cycles, followed by ASCT (group A+I); and the same induction treatment as in group A+I but without ASCT (group I). Ibrutinib maintenance was continued for 2 years in groups A+I and I. Patients received rituximab maintenance as per national guidelines.
870 patients were enrolled in the study, 56% of them received rituximab maintenance.
After a median follow-up of 31 months failure-free-survival (FFS) was superior in group A+I compared to group A (88% vs 72%, hazard ratio 0.52). Group A was not superior to group I (72% vs 86%, hazard ratio 1.77); and group A+I was not superior to group I. The results were consistent across different prognostic subgroups, including those defined by MIPI, cytology, Ki-67 and use of rituximab maintenance. Rituximab maintenance improved outcome in all three treatment arms. Three-years overall survival was 86% in group A, 91% in group A+I, and 92% in group I. Progression free survival at 3 years was 73% for group A, 88% for group A+I and 87% for group I.
Most common side-effects grade 3-5 were hematological: thrombocytopenia (R-CHOP/R-DHAP 59% vs IR-CHOP/R-DHAP 61%), and neutropenia (R-CHOP/R-DHAP 47% vs IR-CHOP/R-DHAP 50%). The incidence of febrile neutropenia during induction was similar in patients treated with and without ibrutinib (9% vs 12%). The number of hematological and infectious AEs during ibrutinib maintenance was significantly higher in the A+I group in comparison to patients treated with ibrutinib but without ASCT.
These results show that the addition of ibrutinib to frontline treatment of MCL results in improved efficacy and abrogates the need for consolidating response with ASCT. The benefit of addition of ibrutinib is especially prominent in patients with biologically high-risk disease with p53 overexpression.
This phase three clinical trial led to a new standard of care for front-line treatment of young, medically fit patients.