Marked survival gains in patients ≤ 65 years with advanced-stage mantle cell lymphoma: a pooled analysis of six randomized phase III trials, 1996-2020

Mantle cell lymphoma (MCL) remains a challenging and generally incurable disease. We aimed to evaluate survival trends in advanced-stage MCL over the past three decades, focusing on the impact of evolving first-line therapies. We pooled six randomized phase III trials of treatment-naïve, advanced-stage MCL patients enrolled between 1996 and 2020. Patients were grouped into four eras by enrollment period. Failure-free survival (FFS) and overall survival (OS) were compared across eras using Kaplan-Meier methods and Cox regression adjusted for the Mantle Cell Lymphoma International Prognostic Index (MIPI) and treatment. Dynamic survival trends were analyzed using penalized splines. Among 2,541 MCL patients, survival outcomes have improved steadily since 1996. In younger and transplant-eligible patients (≤ 65 years), there was a strong increase in median OS from 4.9 years (5-year OS: 49%) in the period 1996-2000 to 13.8 years (73%) in 2004-2014 and was not reached (84%) in 2016-2020. In older and transplant-ineligible patients, median OS improved from 3.8 to 4.8 years (5-year OS: 40-49%) between 1996 and 2014. Dynamic trends revealed a sharp decline in treatment failure and mortality risk between 2000 and 2005, followed by sustained improvements. Patients receiving the same treatment regimens had comparable FFS and OS across eras. Adjusting for treatment eliminated most survival trends, underscoring the impact of rituximab, ASCT, high-dose cytarabine, and ibrutinib on survival improvements. In conclusion, OS in MCL has substantially improved over the past three decades, especially in younger patients, driven largely by improvements in first-line treatment. In older patients, despite significantly improved OS in recent decades, there remains an urgent need for further improvements.