BACKGROUND Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING Acerta Pharma.

中文翻译：

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Waldenström巨球蛋白血症患者的Acalabrutinib单药治疗：单臂，多中心，2期研究。

背景化学免疫疗法通常是Waldenström巨球蛋白血症患者的标准治疗。然而，传染性和血液学毒性作用是有问题的。Acalabrutinib是一种选择性的，有效的Bruton酪氨酸激酶抑制剂。该试验的目的是评估acalabrutinib在Waldenström巨球蛋白血症患者中的活性和安全性。方法该单臂多中心2期试验在法国，意大利，希腊，荷兰和英国的19个欧洲学术中心以及美国的8个学术中心中进行。符合条件的患者年龄在18岁以上，并且曾接受过天真的治疗（拒绝接受化学免疫治疗或没有资格接受化学免疫治疗），复发或难治性（至少有一种以前的治疗方法）需要治疗的Waldenström巨球蛋白血症，东部合作肿瘤小组的表现状态为2或更低，并且以前未接受过Bruton酪氨酸激酶抑制剂治疗。患者在28天的周期中每天两次接受100 mg口服acalabrutinib，直到疾病进展或出现不可接受的毒性。主要终点是根据第六届Waldenström巨球蛋白血症国际研讨会（IWWM）和经修改的第三届IWWM研讨会标准，由研究者评估的总体缓解程度（至少是次要缓解）。在接受至少一剂治疗的所有患者中评估主要结局和安全性。这项研究已在ClinicalTrials.gov上注册，编号为NCT02180724，目前正在进行中，但不再招募。结果在2014年9月8日至2015年12月24日之间，对122例患者进行了资格评估，其中106位（87％）患者接受了acalabrutinib治疗（14位为初治患者，而92位患有复发或难治性疾病）。中位随访时间为27·4个月（IQR 26·0-29·7），其中14例未接受过治疗的患者中有13例（93％[95％CI 66-100]）总体缓解，86例（93％[ [86-98]）根据修改后的第3和第6个IWWM标准对92例复发或难治性患者进行了分析。14例初治患者中的7例（50％）和92例复发或难治患者中的23例（25％）在研究中中断了治疗。超过5％的患者发生3-4级不良反应是中性粒细胞减少症（106例患者中的17例[16％]）和肺炎（7例[7％]）。一名（1％）患者发生3-4级房颤，三名（3％）患者发生3-4级出血。最常见的严重不良事件是下呼吸道感染（n = 7 [7％]），肺炎（n = 7 [7％]），发热（n = 4 [4％]），蜂窝织炎（n = 3 [3％]），跌倒（n = 3 [3％]）和败血症（n = 3 [3％]）。肺炎（n = 5 [5％]）和下呼吸道感染（n = 4 [4％]）被认为与治疗有关。据报道有1例与治疗有关的死亡（颅内血肿）。解释这项研究提供的证据表明，对于初治，复发或难治性Waldenström巨球蛋白血症的患者，acalabrutinib可以作为单一药物有效治疗，安全性可控。需要进一步的研究来确定其对当前标准治疗的疗效，并研究联合治疗是否可以改善预后。资助Acerta Pharma。据报道有1例与治疗有关的死亡（颅内血肿）。解释这项研究提供的证据表明，对于初治，复发或难治性Waldenström巨球蛋白血症的患者，acalabrutinib可以作为单一药物有效治疗，安全性可控。需要进一步的研究来确定其对当前标准治疗的疗效，并研究联合治疗是否可以改善预后。资助Acerta Pharma。据报道有1例与治疗有关的死亡（颅内血肿）。解释这项研究提供的证据表明，对于初治，复发或难治性Waldenström巨球蛋白血症的患者，acalabrutinib可以作为单一药物有效治疗，安全性可控。需要进一步的研究来确定其对当前标准治疗的疗效，并研究联合治疗是否可以改善预后。资助Acerta Pharma。需要进一步的研究来确定其对当前标准治疗的疗效，并研究联合治疗是否可以改善预后。资助Acerta Pharma。需要进一步的研究来确定其对当前标准治疗的疗效，并研究联合治疗是否可以改善预后。资金Acerta Pharma。