Wang Michael, Salek David, Belada David, Song Yuqin, Jurczak Wojciech, Kahl Brad S, Paludo Jonas, Chu Michael P, Kryachok Iryna, Fogliatto Laura, Cheah Chan Y, Morawska Marta, Sancho Juan-Manuel, Li Yufu, Patti Caterina, Forsyth Cecily, Zhang Jingyang, Lesley Robin, Ramadan Safaa, Rule Simon, Dreyling Martin
Department of Lymphoma/Myeloma, MD Anderson Cancer Center, University of Texas, Houston, TX.
Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.
J Clin Oncol. 2025 Jul 10;43(20):2276-2284. doi: 10.1200/JCO-25-00690. Epub 2025 May 1.
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.
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/m once daily; days 1 and 2) and rituximab (375 mg/m 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.
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]; = .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]; = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively.
The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.
布鲁顿酪氨酸激酶抑制剂伊布替尼与苯达莫司汀-利妥昔单抗联合用于一线治疗套细胞淋巴瘤（MCL）可延长无进展生存期（PFS），但总生存期（OS）未得到改善，可能是由于毒性所致。在一项针对慢性淋巴细胞白血病的头对头试验中，阿卡替尼被证明比伊布替尼更有效且毒性更低，因此可能在MCL中带来更好的治疗效果。
65岁及以上既往未接受治疗的MCL患者接受阿卡替尼（每日两次，每次100 mg）或安慰剂（直至疾病进展或出现不可接受的毒性），加用六个周期的苯达莫司汀（每日一次，90 mg/m²；第1天和第2天）和利妥昔单抗（单次剂量375 mg/m²；第1天），随后对有反应的患者进行利妥昔单抗维持治疗2年。允许在疾病进展时交叉使用阿卡替尼。主要终点是独立审查委员会评估的PFS；总缓解率和OS为次要终点。
总共598例患者被随机分组，每组299例。采用反向Kaplan-Meier方法进行中位随访49.8个月时，阿卡替尼组的中位PFS为66.4个月，安慰剂组为49.6个月（风险比[HR]，0.73[95%CI，0.57至0.94]；P = 0.0160）。在所有亚组中均观察到获益，包括具有高危特征的亚组。阿卡替尼组和安慰剂组的总缓解/完全缓解率分别为91.0%/66.6%和88.0%/53.5%。OS无显著差异（HR，0.86[95%CI，0.65至1.13]；P = 0.27）。阿卡替尼组和安慰剂组分别有88.9%和88.2%的患者报告了3级或更高等级的不良事件。
阿卡替尼与苯达莫司汀-利妥昔单抗联合使用显著改善了PFS。阿卡替尼与苯达莫司汀-利妥昔单抗联合治疗具有可管理的毒性，并取得了临床获益。
