Long-Term Follow-up of Bendamustine/Rituximab – Rituximab/Cytarabine (BR/RC) Induction Therapy for Previously Untreated Transplant-Eligible Patients with Mantle Cell Lymphoma (MCL)

Introduction: Durability of first remission in younger patients with MCL is key to long-term favorable outcomes. Given the established benefit of high-dose cytarabine in induction and the superiority of bendamustine/rituximab (BR) over R-CHOP, we hypothesized that combining BR with rituximab/cytarabine (RC) would be a highly effective induction regimen in previously untreated transplant-eligible patients with MCL. We previously conducted a pooled analysis of 2 single-institution phase 2 studies as well as an off-trial cohort treated with BR/RC induction (Merryman et al., 2020). Here we report long-term follow-up results.

Methods: DFCI and WUSTL led independent phase 2 trials investigating frontline BR/RC in transplant-eligible patients with MCL (NCT01661881; NCT02728531). Patients received 3 cycles of BR (B, 90 mg/m² [days 1 & 2] and R, 375 mg/m² [day 1] every 4 weeks) and 3 cycles of RC (R, 375 mg/m² [day 1] and C, 2-3 g/m² every 12 hours for 4 doses [days 1 & 2] every 3 weeks, with specified dose reductions for age, renal dysfunction, or neurotoxicity). At DFCI, BR and RC cycles were given sequentially; at WUSTL, BR and RC cycles were alternated. Off-trial DFCI patients were identified retrospectively and included if they had a confirmed diagnosis of MCL, initiated BR/RC therapy, and had an end-of-induction PET/CT available. For off-trial patients, cytarabine dose was per treating physician decision. Data cutoff was July 1, 2024.

Results: 88 patients were included for analysis with ranges of treatment initiation as follows: n=23 DFCI trial (2012-2014), n=18 WUSTL trial (2016-2018), n=47 DFCI off-trial (2014-2018). Patient characteristics were: 73% male, median age 58 years (range, 30-72), 19% with high-MIPI score, 24% with Ki67 >30% and 12% with blastoid/pleomorphic morphology. 75 patients (85%) underwent consolidative autologous stem cell transplantation (ASCT), of whom 31 (41%) received maintenance rituximab (MR). The median follow-up for survivors was 8.04 years.

For the entire cohort, the median progression-free survival (PFS) was 9.9 years (95% CI: 8.7-not reached [NR]) and the median overall survival (OS) was NR; 8-year PFS was 63% (95% CI: 51.4-72.4) and 8-year OS was 71% (95% CI: 59.8-79.7). In the 75 patients who underwent ASCT, median PFS was NR; the 8-year PFS was 68% [95% CI: 55.2-77.3] and the 8-year OS was 76% [95% CI: 64.3-84.5]). The 8-year PFS in patients who did and did not receive MR following ASCT was 72% (95% CI: 50.7-85.0) and 65% (95% CI: 48.8-77.3), respectively (p=0.37). In the 22 patients with high-MIPI score disease and/or blastoid/pleomorphic morphology, the median PFS was 5.1 years (95% CI: 1.1-NR) and the median OS was NR; 8-year PFS was 39% (95% CI: 18.1-58.8) and 8-year OS was 54% (95% CI: 31.6-72.2).

There have been 24 deaths: 11 progressive MCL and 13 non-relapse mortality (n=8 infection [including 2 fatal respiratory syncytial virus infections 13 and 56 days post-ASCT]), n=2 metastatic cancer [colorectal, prostate], n=1 amyotrophic lateral sclerosis, n=2 unknown). 11 patients (13%) developed a second malignancy following treatment initiation (n=3 myelodysplastic syndrome/acute myeloid leukemia, n=1 each: breast, colorectal, melanoma, pancreatic, prostate, pharyngeal squamous cell carcinoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma). Safety was as previously described without new significant toxicity otherwise observed.

Conclusion: These long-term follow-up results of BR/RC induction in transplant-eligible previously untreated patients with MCL demonstrate excellent efficacy (median PFS nearly 10 years), which compares favorably with long-term results of other induction approaches (e.g., Nordic MCL2: median PFS 8.5 years [Eskelund et al., 2016]; MCL Younger cytarabine-containing arm: median time-to-treatment-failure 8.4 years [Hermine et al., 2023]). Notably fewer than half of patients in our cohort received post-ASCT MR as it was not standard-of-care at the time, and addition of maintenance therapy may further lengthen PFS with this induction approach. BR/RC is the backbone of the ongoing ECOG-ACRIN EA4181 study that investigates the addition of acalabrutinib to chemoimmunotherapy induction, and our long-term follow-up results provide a foundation for further investigation of BR/RC induction in combination with BTKi or other novel agents, particularly as the field moves toward omission of ASCT in first remission.