Mantle cell lymphoma (MCL) remains an incurable, aggressive B-cell lymphoma with significant therapeutic challenges in older patients. While intensive chemoimmunotherapy followed by autologous stem-cell transplantation benefits younger, fit patients, older individuals often receive bendamustine-rituximab due to tolerability. Building on the success of Bruton’s tyrosine kinase inhibitors (BTKis) in relapsed disease, the ECHO trial investigated whether the addition of the second-generation BTKi acalabrutinib to bendamustine-rituximab could improve outcomes in previously untreated older patients with MCL.1
METHODS
The ECHO trial was a randomised, multi-centre, double-blind phase III study that enrolled 598 patients aged ≥65 years with untreated MCL. Patients were randomised 1:1 to receive either acalabrutinib (100 mg bid) or placebo, plus six cycles of bendamustine-rituximab, followed by rituximab maintenance for up to two years in responders. Acalabrutinib/placebo was continued until disease progression or unacceptable toxicity. Crossover to acalabrutinib was permitted upon progression in the placebo group. The primary endpoint was progression-free survival (PFS) per independent review. Secondary endpoints included overall response rate (ORR), overall survival (OS), and safety.
RESULTS
With a median follow-up of 49.8 months, median PFS was significantly longer in the acalabrutinib arm compared to placebo (66.4 versus 49.6 months; HR[95% CI]: 0.73[0.57-0.94], p= 0.0160). The PFS benefit was consistent across key subgroups, including patients with high-risk features. When censoring for COVID-19 deaths, median PFS was not reached in the acalabrutinib arm compared to 61.6 months in the placebo arm (HR[95% CI]: 0.64[0.48-0.84], p= 0.0017). ORR was high in both arms (91.0% versus 88.0%), with higher complete response rates in the acalabrutinib arm (66.6% versus 53.5%). There was no statistically significant difference in OS (median OS not reached in either arm; HR[95% CI]: 0.86[0.65-1.13], p= 0.2473). When censoring for COVID-19 deaths, the difference in OS did not reach statistical significance (HR[95% CI]: 0.75[0.53-1.04], p= 0.0797). In the placebo arm, 51 patients crossed over to acalabrutinib after experiencing disease progression on placebo and an additional 25 patients switched to BTKi outside of the study.
Grade ≥3 adverse events occurred in 88.9% and 88.2% of patients in the acalabrutinib and placebo arms, respectively. The most common adverse events with acalabrutinib and placebo, respectively, included nausea (42.8% and 37.7%), neutropenia (40.1% and 41.4%), diarrhoea (37.4% and 27.9%), and COVID-19-related complications (30.6% and 20.9%). Atrial fibrillation and hypertension occurred in 6.7% and 12.5% of patients in the acalabrutinib arm.
CONCLUSIONS
The addition of acalabrutinib to bendamustine-rituximab significantly improves PFS in older patients with previously untreated MCL, with manageable toxicity. These results support the use of BTKi-based combinations in the frontline setting for this patient population.
Reference
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