title: Off-target effects of BCR-ABL1 inhibitors and their potential long-term implications in patients with chronic myeloid leukemia.
abstract: In patients with chronic myeloid leukemia (CML), use of the BCR-ABL1-specific tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib has greatly improved patient survival and prolonged disease remission. More than 10 years of data from imatinib clinical studies and many years of data for nilotinib and dasatinib have demonstrated that these TKIs are well tolerated in most patients with CML. However, these inhibitors are not entirely BCR-ABL1-specific, and this lack of specificity could account for the off-target effects of these drugs. Adverse events (AEs) are off-target effects that are detrimental to the patient. The underlying mechanisms that contribute to these effects are poorly understood and the long-term consequences of chronic TKI therapy remain largely unknown, particularly with the newer agents. Here, we review the preclinical and clinical data for several of the more frequent AEs associated with TKIs and discuss the therapeutic relevance of these AEs for patients with CML.
authors.affiliation: Department of Hematology and Advanced Oncohematologic Therapies Group IIS-IP, Hospital Universitario de La Princesa, Madrid, Spain. jlsteegmann.hlpr@salud.madrid.org
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Steegmann
authors.forename: Francisco
authors.initials: F
authors.lastname: Cervantes
authors.forename: Philipp
authors.initials: P
authors.lastname: le Coutre
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
mesh_terms: D001549:Benzamides; D000069439:Dasatinib; D003967:Diarrhea / Q000139:chemically induced; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology*; D010879:Piperazines / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000009:adverse effects; D013844:Thiazoles / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib