Outcomes of Sequenced Therapy in Mantle Cell Lymphoma in Patients Treated with First-Line Autologous Stem Cell Transplantation and Second-Line BTK Inhibitor
Authors: McLane Michael , Nachar Victoria , Carty Shannon A. , Kaminski Mark S , Phillips Tycel J. , Sano Dahlia , Weiss Jonathan , Wilcox Ryan A. , Ahmed Iman , Karimi Yasmin H. 
Published: December 2024

Introduction. Mantle cell lymphoma (MCL) is an incurable disease for which induction chemoimmunotherapy (CIT) followed by autologous stem cell transplantation (ASCT) has long been the standard of care for young patients with adequate performance status. Median progression free survival (PFS) after first-line cytarabine-containing CIT and ASCT has been reported at 9.1 years and allows many young patients significant time off therapy (Hermine O, et al. Lancet. 2016). Bruton's tyrosine kinase inhibitors (BTKi) are commonly used in the second line setting with median PFS of around 20 months. Several recent studies have evaluated the role of combination CIT and BTKi in frontline treatment. The TRIANGLE study compared outcomes for patients with MCL receiving CIT induction followed by ASCT (group A), to those receiving first line ibrutinib either with (group A+I) or without (group I) ASCT (Dreyling M, et al. Lancet. 2024). The authors reported an improvement in failure-free survival in group A+I (88%) compared to group A (72%), but with increased toxicity and no difference in overall survival (OS).
Because of the incurable nature of MCL, balancing treatment-free intervals with treatment toxicity is paramount. The aim of this analysis was to compare outcomes for patients treated with sequenced therapy (upfront ASCT followed by BTKi at time of first relapse) with those who received upfront combination therapy (ASCT + BTKi) in the A+I arm of the TRIANGLE study.
Methods. In this single center, retrospective analysis, we reviewed clinical outcomes of 20 patients diagnosed with MCL between 1/1/2004 and 1/1/2019 who underwent induction CIT and ASCT as first-line systemic therapy, followed by treatment with BTKi at first relapse. Clinical endpoints included OS, PFS after ASCT, and combined PFS, defined as the time from initiation of induction CIT to second relapse (after ASCT and second-line BTKi) or death.
Results. 90% (18/20) of patients were white, 5% (1/20) were black and 5% (1/20) were American Indian or Alaskan native. At diagnosis, median age was 55 years (range 57-80), and median MIPI score was 5.5 (low risk n = 9, intermediate risk n = 5, high risk n = 1). Median Ki67 was 30% (6 patients with Ki67 &lt;30%, 4 patients with Ki67 &gt;30%). TP53 molecular testing results were available for 6 patients with 2 patients being positive for TP53 mutation (33%). 80% (16/20) of patients received a cytarabine-containing induction CIT regimen and the remaining four received either R-EPOCH (1) or R-CHOP (3; one of which was also treated with R-ICE prior to ASCT). 30% (6/20) received maintenance rituximab after ASCT (all but one patient who received ASCT after 2017 were treated with maintenance rituximab). BTKi received as second line therapy included ibrutinib (n = 12), zanubrutinib (n = 6), and acalabrutinib (n = 2). The 3-year PFS after ASCT in our cohort was 60% (95% CI 36-78%) compared to 73% (67-79%) in group A in the TRIANGLE study. The median time from first relapse to start of BTKi was 31 days (range 0-1,622 days). The combined PFS in our cohort at 3 years was 75% (50-89%) and was similar to the TRIANGLE study which reported 3-year PFS of 88% (84-93%) for group A+I. OS was also similar in our cohort at 84.2% (59-95%) at 3 years, compared to 91% (88-95%) for TRIANGLE group A+I and 86% (82-91%) for group A.
Conclusions. Our analysis showed no difference in PFS or OS for patients treated with sequential therapy compared to those who received upfront combination therapy in the A+I arm of the TRIANGLE study. Given the added toxicity of combination therapy for patients with an incurable malignancy treated with palliative-intent therapy, further analysis with larger datasets is warranted to understand the true benefit of upfront combination therapy in MCL.