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Breaking good: the inexorable rise of BTK inhibitors in the treatment of chronic lymphocytic leukaemia
Author(s) -
Hutchinson Claire V.,
Dyer Martin J. S.
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12895
Subject(s) - bruton's tyrosine kinase , ibrutinib , lymphocytosis , chronic lymphocytic leukemia , breakpoint cluster region , b cell receptor , tyrosine kinase , immunology , medicine , cancer research , lymphocyte , b cell , leukemia , receptor , antibody
Summary Although expressed in several haematological lineages and involved in multiple different signalling pathways, Bruton tyrosine kinase ( BTK ) plays an indispensible role in B cells in signalling from the B cell receptor ( BCR ) for antigen. Many B cell malignancies remain dependent on constitutive BCR signalling, making BTK a functional therapeutic target. Several BTK inhibitors ( BTK i) with different kinomes and modes of action are being assessed clinically. This review documents the efficacy and toxicity of BTK i in chronic lymphocytic leukaemia ( CLL ). Clinically, the furthest in development is ibrutinib (trade name, Imbruvica), an irreversible BTK i, which has shown spectacular preliminary efficacy, with rapid reductions in lymph nodes accompanied by peripheral blood lymphocytosis. The lymphocytosis resolves slowly and most patients do not enter a complete remission. Nevertheless, it is possible to maintain many CLL patients, even those with adverse cytogenetic features, on drug for many months with minimal toxicities, thus potentially transforming the therapeutic paradigms for CLL . The efficacy, lack of toxicity and oral administration of BTK i will ensure their adoption in a wide range of B cell malignancies. An outstanding challenge is to incorporate BTK i with other precision medicines in a mechanism‐based manner in order to dispense with conventional chemotherapy.