Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma is a rare large B-cell lymphoma subtype that is characterized by a plasmablastic phenotype and an ALK gene fusion. ALK-positive large B-cell lymphoma is resistant to the first-generation ALK inhibitor crizotinib and uniformly fatal with few if any complete responses in the relapsed setting, where no long-term survivors have been reported in the literature. No standard therapies exist for patients with relapsed or refractory disease, and its rarity and lethality have precluded prospective clinical research. Herein, we report the generation of the first ALK-positive large B-cell lymphoma patient-derived xenograft model, in which we show that next-generation ALK inhibitors are therapeutically active. On this basis, we administered the next-generation ALK inhibitor alectinib to four consecutive patients (three crizotinib-refractory). All four responded (two complete responses), one in ongoing remission after allogeneic transplantation >15 months. One with progressive disease was treated with lorlatinib and achieved complete response. These data support use of alectinib and lorlatinib as off-label therapeutic options for patients with relapsed or refractory ALK-positive large B-cell lymphoma.

中文翻译：

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下一代 ALK 抑制剂在 ALK 阳性大 B 细胞淋巴瘤中具有高度活性。

间变性淋巴瘤激酶 (ALK) 阳性大 B 细胞淋巴瘤是一种罕见的大 B 细胞淋巴瘤亚型，其特征为浆母细胞表型和 ALK 基因融合。ALK 阳性大 B 细胞淋巴瘤对第一代 ALK 抑制剂克唑替尼具有耐药性，并且一致致命，在复发情况下几乎没有完全缓解，文献中尚未报道长期幸存者。对于复发或难治性疾病患者，尚无标准疗法，其罕见性和致死性阻碍了前瞻性临床研究。在此，我们报告了第一个 ALK 阳性大 B 细胞淋巴瘤患者来源的异种移植模型的产生，其中我们表明下一代 ALK 抑制剂具有治疗活性。在此基础上，我们连续对四名患者（三名克唑替尼难治性患者）施用下一代 ALK 抑制剂艾来替尼。所有 4 名患者均出现缓解（2 名完全缓解），1 名患者在同种异体移植超过 15 个月后持续缓解。一名患有进展性疾病的患者接受了劳拉替尼治疗，并取得了完全缓解。这些数据支持使用艾来替尼和劳拉替尼作为复发性或难治性 ALK 阳性大 B 细胞淋巴瘤患者的标签外治疗选择。