We identified 6 patients of our cohort who progressed on orelabrutinib treatment in clinical trial….Deep targeted-gene NGS showed that BTK mutations were detected in 5 of 6 patients (5/6, 83.3%, Figure B). Remarkably, BTK kinase domain mutation, BTK Thr474Ile (NM_000061.2: exon15: c.1421C>T: p.T474I) was detected in 2 patients progressed on orelabrutinib. BTK Cys481 mutation was found in other 3 patients progressed on orelabrutinib, among them one patient harboring both BTK Cys481Arg (NM_000061.2: exon15: c.1441T>C: p.C481R) and BTK Leu528Trp (NM_000061.2: exon16: c.1583T>G: p.L528W).