Table 2 Common sequence variants and functional characteristics associated with targeted therapy resistance in CLL.

BTK

Cys481Ser

Kinase-preserved; Decreased binding affinity of C481S for cBTKi

Cys481Arg/Phe/Tyr

Kinase-impaired [3, 4]; Decreased inhibition of BTK auto-phosphorylation by cBTKi [4]

Leu528Trp

Kinase-impaired [3, 28]; Decreased binding affinity of L528W for both cBTKi and ncBTKi [3]; clinical resistance to ncBTKi and zanubrutinib

Thr474Ile/Met

Kinase-enhanced [3, 9]; In vitro resistance to cBTKi [74] clinical resistance to acalabrutinib and ncBTKi

Val416Leu

Kinase-impaired [3]; Observed in ncBTKi progression [28]; In vitro resistance to ncBTKi [75]

Ala428Asp

Kinase-impaired [3]; Observed in ncBTKi and BTK degrader progression [28, 33]

PLCG2

Arg665Trp

Hyper-responsiveness to upstream signaling [13]

Ser707Tyr

Hyper-responsiveness to upstream signaling [76, 77]; Causative variant for APLAID syndrome in germline context [78]

Leu845Phe

Hyper-responsiveness to upstream signaling [13]

Asp993His

Hyper-responsiveness to upstream signaling [79, 80]; Causative variant for APLAID syndrome in germline context [79]

Met1141Lys

Hyper-responsiveness to upstream signaling [81]; Causative variant for APLAID syndrome in germline context [81]

BCL2

Gly101Val

Decreases affinity of venetoclax for BCL2 [40]

Asp103Tyr

Decreases affinity of venetoclax for BCL2 [42, 43]

Asp103Glu

Decreases affinity of venetoclax for BCL2 [41]; Retained affinity and sensitivity for navitoclax [41]

Phe104Leu/Ile

Decreases affinity of venetoclax for BCL2 [40, 44, 82]

Val156Asp

Decreases affinity of venetoclax for BCL2 [42]