title: Cardiovascular and pulmonary adverse events in patients treated with BCR-ABL inhibitors: Data from the FDA Adverse Event Reporting System.
abstract: Rare but serious cardiovascular and pulmonary adverse events (AEs) have been reported in patients with chronic myeloid leukemia treated with BCR-ABL inhibitors. Clinical trial data may not reflect the full AE profile of BCR-ABL inhibitors because of stringent study entry criteria, relatively small sample size, and limited duration of follow-up. To determine the utility of the FDA AE Reporting System (FAERS) surveillance database for identifying AEs possibly associated with the BCR-ABL inhibitors imatinib, dasatinib, and nilotinib in the postmarketing patient population, we conducted Multi-Item Gamma Poisson Shrinker disproportionality analyses of FAERS reports on AEs in relevant system organ classes. Signals consistent with the known safety profiles of these agents as well as signals for less well-described AEs were detected. Bone marrow necrosis, conjunctival hemorrhage, and peritoneal fluid retention events were uniquely associated with imatinib. AEs that most commonly reached the threshold for dasatinib consisted of terms relating to hemorrhage and fluid retention, including pleural effusion and pericardial effusion. Most terms that reached the threshold solely with nilotinib were related to peripheral and cardiac vascular events. Although this type of analysis cannot determine AE incidence or establish causality, these findings elucidate the AEs reported in patients treated with BCR-ABL inhibitors across multiple clinical trials and in the community setting for all approved and nonapproved indications, suggesting drug-AE associations warrant further investigation. These findings emphasize the need to consider patient comorbidities when selecting amongst BCR-ABL inhibitors.
authors.affiliation: Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Michael
authors.initials: M
authors.lastname: Mauro
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Steegmann
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Rachpal
authors.initials: R
authors.lastname: Malhotra
authors.forename: Jon A
authors.initials: JA
authors.lastname: Ukropec
authors.forename: Nicola T
authors.initials: NT
authors.lastname: Wallis
mesh_terms: D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology; D000069439:Dasatinib; D016208:Databases, Factual; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D016015:Logistic Models; D008171:Lung Diseases / Q000139:chemically induced* / Q000453:epidemiology; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011358:Product Surveillance, Postmarketing; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib