Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs

• Published in: Blood advances Vol. 3; no. 6; pp. 851 - 861
• Main Authors: Jain, Preetesh, Kantarjian, Hagop, Boddu, Prajwal C., Nogueras-González, Graciela M., Verstovsek, Srdan, Garcia-Manero, Guillermo, Borthakur, Gautam, Sasaki, Koji, Kadia, Tapan M., Sam, Princy, Ahaneku, Hycienth, O'Brien, Susan, Estrov, Zeev, Ravandi, Farhad, Jabbour, Elias, Cortes, Jorge E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.03.2019; American Society of Hematology
• Subjects: Adult; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Cardiovascular Diseases - etiology; Dasatinib - adverse effects; Dasatinib - therapeutic use; Female; Humans; Imatinib Mesylate - adverse effects; Imatinib Mesylate - therapeutic use; Imidazoles - adverse effects; Imidazoles - therapeutic use; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - complications; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Male; Middle Aged; Myeloid Neoplasia; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - therapeutic use; Pyridazines - adverse effects; Pyridazines - therapeutic use; Pyrimidines - adverse effects; Pyrimidines - therapeutic use; Thrombosis - etiology; Treatment Outcome
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2018025874

Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade 3/4 in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P < .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P < .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868. Jain et al take on a major issue in the era of tyrosine kinase inhibitor (TKI) therapy for patients with chronic myeloid leukemia (CML). While these patients now have many options for targeted therapy, many are expensive, and they prominently include cardiovascular and arteriothrombotic adverse events. The authors systematically analyzed 531 CML patients treated with multiple TKIs in different trials. These included imatinib, nilotinib, dasatinib, and ponatinib. The authors found an increased risk of hypertension with all TKIs. Furthermore, when compared to imatinib dosed at 400 mg, there was an increased risk of cardiovascular events in CML patients with preexisting cardiovascular risk factors, and importantly, in those treated with second and third generation TKIs, particularly ponatinib. This study underscores the importance of vigilant assessment and management of cardiovascular comorbidities in all CML patients treated with TKIs. [Display omitted]