Interestingly, superior activity of BTK inhibition appears to be achievable in CLL with unmutated immunoglobulin heavy chain (IGHV) genes (U-CLL), which is currently deemed to be due to more growth-promoting and less anergic BCR signaling in this subset compared to CLL with mutated IGHV genes (M-CLL) [7, 8]. This evidence concerns the gene BCR and B-cell chronic lymphocytic leukemia.