Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma

Author(s): Michael Wang, MD1; David Salek, MD2; David Belada, MD3; Yuqin Song, MD4; Wojciech Jurczak, MD, PhD5,6; Brad S. Kahl, MD7; Jonas Paludo, MD8; Michael P. Chu, MD9; Iryna Kryachok, MD10; Laura Fogliatto, MD11; Chan Y. Cheah, DMSc12,13; Marta Morawska, MD, PhD14,15; Juan-Manuel Sancho, MD16; Yufu Li, MD17; Caterina Patti, MD18; Cecily Forsyth, MD19; Jingyang Zhang, PhD20; Robin Lesley, PhD20; Safaa Ramadan, MD, PhD21; Simon Rule, MD, PhD21; Martin Dreyling, MD, PhD22
Source: doi.org/10.1200/JCO-25-00690
Original Article
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The phase III ECHO trial evaluated acalabrutinib + bendamustine-rituximab (A+BR) vs placebo + BR in previously untreated mantle cell lymphoma (MCL) patients ≥65 years, showing a significant improvement in progression-free survival (PFS) (66.4 vs 49.6 months) with A+BR, including in high-risk subgroups. Objective response rate (ORR)/complete response (CR) rates were higher with A+BR (91.0%/66.6% vs 88.0%/53.5%), but overall survival (OS) was not significantly different (HR 0.86). Grade ≥3 adverse events (AEs) were similar between arms (88.9% vs 88.2%), with more COVID-19–related events in the acalabrutinib group, likely reflecting longer exposure. Bottom line: adding acalabrutinib to BR gives us a real PFS advantage in older, untreated MCL, with manageable toxicity, but OS benefit remains elusive—likely due to crossover and effective salvage BTKi at relapse.

Michael Wang, MD1; David Salek, MD2; David Belada, MD3; Yuqin Song, MD4; Wojciech Jurczak, MD, PhD5,6; Brad S. Kahl, MD7; Jonas Paludo, MD8; Michael P. Chu, MD9; Iryna Kryachok, MD10; Laura Fogliatto, MD11; Chan Y. Cheah, DMSc12,13; Marta Morawska, MD, PhD14,15; Juan-Manuel Sancho, MD16; Yufu Li, MD17; Caterina Patti, MD18; Cecily Forsyth, MD19; Jingyang Zhang, PhD20; Robin Lesley, PhD20; Safaa Ramadan, MD, PhD21; Simon Rule, MD, PhD21; Martin Dreyling, MD, PhD22

PURPOSE

The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL.

METHODS

Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m2 once daily; days 1 and 2) and rituximab (375 mg/m2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points.

RESULTS

In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively.

CONCLUSION

The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Author Affiliations

Michael Wang, MD1; David Salek, MD2; David Belada, MD3; Yuqin Song, MD4; Wojciech Jurczak, MD, PhD5,6; Brad S. Kahl, MD7; Jonas Paludo, MD8; Michael P. Chu, MD9; Iryna Kryachok, MD10; Laura Fogliatto, MD11; Chan Y. Cheah, DMSc12,13; Marta Morawska, MD, PhD14,15; Juan-Manuel Sancho, MD16; Yufu Li, MD17; Caterina Patti, MD18; Cecily Forsyth, MD19; Jingyang Zhang, PhD20; Robin Lesley, PhD20; Safaa Ramadan, MD, PhD21; Simon Rule, MD, PhD21; Martin Dreyling, MD, PhD22

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