Table 2.

Resistance mechanisms to BTK inhibitors in B cell malignancies

B cell malignancy subtype	Covalent BTK inhibitors	Mechanisms underlying resistance
Primary resistance
MCL	Ibrutinib	Mutations involving NF-κB pathway: A20 mutations, TRAF2 mutations, BIRC3 mutations or BIRC2 mutations, RELA E39Q mutation, and others [76, 77] Sustained PI3K/AKT/mTOR activation [28, 78] Tumor microenvironment [79] Metabolic reprogramming toward oxidative phosphorylation and glutaminolysis [80] CCND1 mutation [81]
WM	Ibrutinib	CXCR4 WHIM-like mutations [82]
DLBCL	Ibrutinib	PIM1 mutation [83] PI3K/AKT activation [84] MAPK activation [84] Aberrations activating NF-κB pathway: CARD11 mutation, A20 aberrations [85] High expression of PDGFD [86]
Acquired resistance
CLL/SLL	Ibrutinib	BTK C481 and T474 mutations [24, 87, 88] PLCG2 mutations (R665W, S707, L845F, and others) [87] del(8p) [89]
CLL/SLL	Acalabrutinib	BTK C481 mutations and T474I mutation, PLCG2 mutations [29]
CLL/SLL	Zanubrutinib	BTK Leu528Trp mutation and C481 mutation [31]
MCL	Ibrutinib	BTK C481S mutation [28] PLCG2 mutations [76] CARD11 mutation [76] Tumor microenvironment [79]
WM	Ibrutinib	BTK C481 mutations [26] PLCG2 Tyr495His mutation [26]
MZL	Ibrutinib	BTK C481S mutation [90] PLCG2 R665W [90]
DLBCL	Ibrutinib	BTK C481S mutation [91]

BTK Bruton tyrosine kinase, MCL mantle cell lymphoma, WM Waldenstrom's macroglobulinemia, DLBCL diffuse large B cell lymphoma, CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma, MZL marginal zone lymphoma