Ibrutinib, lenalidomide, and rituximab in relapsed mantle cell lymphoma: Long-term follow-up of the Nordic Lymphoma Group MCL6 Philemon trial

Relapsed or refractory mantle cell lymphoma (R/R MCL) remains difficult to treat, with outcomes dependent on the treatment regimen and remission duration after first-line therapy. Several non-chemotherapeutic regimens are under evaluation in R/R, but few studies report long-term outcomes. In this study, we present the long-term outcomes of the 50 patients treated with ibrutinib, lenalidomide, and rituximab (IR2) in the Nordic Lymphoma Group MCL6 Philemon phase 2 trial. Survival outcomes were compared with a matched cohort from the Swedish MCLcomplete study. After 5 years, 14 patients (28%) remained relapse-free, including one with a TP53 mutation. The median progression-free survival (PFS) was 17.4 months, with the longest PFS of 8.1 years. Thirty-two patients had died, primarily from MCL (72%). Poorer survival was associated with intermediate or high-risk Mantle Cell Lymphoma International Prognostic Index and impaired health-related quality of life (HRQoL). While TP53 mutations (n = 11) did not significantly impact survival, a trend toward poorer outcomes was observed in multivariable Cox regression analyses (PFS hazard ratio: 2.09, 95% confidence interval: 0.95–4.62, p = 0.068). The IR2 regimen demonstrated superior survival compared to the MCLcomplete cohort both before and after matching. In conclusion, this study highlights the role of non-chemotherapeutic agents in R/R MCL and demonstrates the prognostic impact of HRQoL on overall survival. Although IR2 showed initial activity in TP53-mutated patients, it did not completely overcome their poor prognosis. However, the IR2 regimen may serve as a bridge to allogeneic stem cell transplantation or chimeric antigen receptor T-cell therapy.