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PULMONARY HYPERTENSION ASSOCIATED WITH BCR-ABL TYROSINE KINASE INHIBITORS: A PHARMACOVIGILANCE ANALYSIS

      TOPIC: Pulmonary Vascular Disease
      TYPE: Original Investigations
      PURPOSE: Bcr-Abl tyrosine kinase inhibitors (Bcr-Abl TKIs) are the first line agents for most patients with chronic myeloid leukemia (CML). Limited data suggests that Bcr-Abl TKIs are associated with multiple cardiovascular and pulmonary adverse events, including pulmonary hypertension (PH). Postulated mechanisms for pulmonary hypertension due to TKIs include, pulmonary endothelial injury, attenuated hypoxic vasoconstriction, apoptosis, and increased susceptibility to other contributing factors for pulmonary hypertension. The data regarding high-risk patient profiles and long-term outcomes remains largely unknown.
      METHODS: We interrogated the Food and Drug Administration (FDA)’s Adverse Event Reporting System (FAERS) database for adverse events reported with five different tyrosine kinase inhibitors: dasatinib, imatinib, nilotinib, bosutinib, and ponatinib. The data on types of patient profiles and outcomes for events reported as ‘pulmonary hypertension’ was collected and analyzed using descriptive statistics.
      RESULTS: Our analysis of FAERS database from 2002 - present generated a total of 499 adverse events reported as PH. Average age for reported adverse events was 58.8 years, which was the highest and lowest in imatinib (62 years) and bosutinib (53 years) respectively. Reported adverse events were noted predominantly among females (48.7%) than males (36.67%). The burden of PH was the highest in the dasatinib group (56.01%), followed by imatinib (19.25%), nilotinib (11.34%), bosutinib (6.48%), and ponatinib (6.94%). Out of 499 adverse events, 222 (44.4%) resulted in hospitalizations and 66 (13.2%) deaths were reported.
      CONCLUSIONS: The current analysis suggests that the incidence of PH related to Bcr-Abl TKIs is underreported in the literature. Patients who are females, are aged >55 years and on dasatinib are particularly at risk for PH. PH related to Bcr-Abl TKIs may be associated with increased risk of hospitalizations and mortality. Discontinuation of an offending agent has shown to improve PH in these patients. In some cases, with severe PH, initiation of vasodilator has been suggested.
      CLINICAL IMPLICATIONS: Our analysis highlights the need for prospective clinical studies to identify patients at high risk of developing PH on Bcr-Abl TKIs. These patients may benefit from personalized therapeutic plans or closer surveillance aimed at prevention and early identification of adverse outcomes.
      DISCLOSURES: No relevant relationships by Lawrence Goldstein, source=Web Response
      No relevant relationships by Krutarth Pandya, source=Web Response
      No relevant relationships by Parth Shah, source=Web Response
      No relevant relationships by Noha Soror, source=Web Response