Despite the biological rationale of inhibiting kinases upstream of BTK and PLCG2, the spleen tyrosine kinase (SYK) inhibitor entospletinib (GS-9973) achieved an ORR of only 24% and a median PFS of 3-8 months in ibrutinib exposed R/R CLL[181]. This evidence concerns the gene PLCG2 and B-cell chronic lymphocytic leukemia.