Dr. Med. Prof. Martin Dreyling, PhD, Department of Medicine III, LMU Hospital speaks about ASH 2021 Abstract – 383 R-High Dose Cytarabine/Dexamethasone (R-HAD) Plus Bortezomib Is Superior to R-HAD Only in Relapsed Mantle Cell Lymphoma: A Randomized Phase 3 Trial of the European MCL Network.
Link to Abstract:
https://ash.confex.com/ash/2021/webprogram/Paper148585.html
Background:
Relapsed mantle cell lymphoma (MCL) has an aggressive clinical history and only achieves a short-term remission after immunochemotherapy. The addition of high-dose cytarabine to a CHOP-like regimen resulted in significantly longer time to treatment failure (TTF) in younger patients (Hermine et al, Lancet 2016), whereas the addition of bortezomib to a CHOP-like regimen resulted in superior PFS and overall survival (OR) rates after a long follow-up in older patients (Hermine et al, Lancet 2016). (Robak, Lancet Oncology 2018). We assessed the efficacy and safety of adding bortezomib to an R-HAD regimen previously studied in older individuals in the recently completed R-HAD study (Weigert, Leukemia Lymphoma 2009).
Methods:
This open-label, randomized phase 3 trial drew participants from Germany and France. Four 3-weekly cycles of R-HAD (Rituximab 375 mg/m2 day 1), high dose Cytarabine (2 g/m2 day 2+3), Dexamethasone (40 mg/m2 days 1-4), and the same regimen combined with Bortezomib (1.5 mg/m2 s.c. day 1 and 4) were randomized in patients with relapsed or refractory MCL with 1-3 prior lines not appropriate for The cytarabine dose was lowered to 2x 1g/m2 in patients over the age of 65. Patients who did not achieve a PR after two cycles could stop treatment at the discretion of their local physician. Response to therapy (relapse vs. refractory), IPI, past autologous stem cell transplantation (SCT), prior exposure to cytarabine, and country were all used to stratify the randomization. A two-sided truncated sequential probability ratio test for the log-rank statistic with a 5% significance level was used to monitor the primary trial outcome, time to treatment failure (stable disease, progression, death from any cause) from randomization. The observation of 78 occurrences was expected to be required to obtain 95 percent power to detect a hazard ratio of 0.55 and a truncation at 160 events, with a maximum patient enrollment of 275 patients in up to 5.5 years. Secondary outcomes were response rates, remission length, overall survival, and toxicities.
Results:
A total of 128 patients were enrolled between May 2012 and December 2016, until enrollment was halted due to the registration of BTK inhibitors. The median patient age was 70 years (range 41-85), 76 percent were men, 82 percent had advanced stage III/IV, and 38 percent and 43 percent, respectively, had intermediate and high risk MIPI. 71% of patients had had one prior treatment, 36% had been exposed to cytarabine, and 40% had undergone an autologous SCT. TTF was 12 months in the R-HAD + Bortezomib arm and 2.6 months in the control arm at a median follow-up of 41 months (p=0.045, HR 0.68; corrected for sequential design, underrunning analysis). As a result, the Bortezomib arm had a significantly higher OR (63 percent vs 45 percent; p=0.049) and CR/CRu rates (42 percent vs 19 percent; p=0.006), while there was no significant difference in remission duration (median 21 months vs 14 months, p=0.32) or overall survival (median 31 months vs 35 months; p=0.83). The experimental arm had a higher number of major adverse events (34 vs 50), with hematological toxicities (3 vs 11), infections (9 in both arms), and fever (6 vs 3) being the most common.
Conclusions:
The addition of Bortezomib to R-HAD resulted in a longer time to treatment failure in this randomized trial, owing to increased response rates. There were no long-term impacts or significant variations in survival or toxicity.