Next-generation ALK inhibitors are highly active in ALK-positive large B-cell lymphoma

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.