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

Abstract

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.

Graphical abstract

Figure 1.

Changes in blood pressure readings (in mm Hg) before and after TKI treatment: overall and according to the TKI modality. (A) Shows linear prediction plot of the relationship between systolic blood pressure before TKI and systolic blood pressure post-TKI. Systolic blood pressure significantly increased after starting TKIs (P < .001 in all TKIs). (B) Shows linear prediction plot of the relationship between diastolic blood pressure before TKI and diastolic blood pressure post-TKI. Diastolic blood pressure also significantly increased after starting TKIs. There was a significant increase in blood pressure readings after starting TKIs (P < .001), however, there was no significant difference in the magnitude of blood pressure change among different TKIs.

Figure 2.

IR of overall and new-onset CV-AEs and AT-AEs per 100 person-years in all patients treated with frontline TKI treatments: trends per year. (A) The IR of patients with overall AEs per 100 person-years shows that the incidence of vascular AEs was highest in the first year of TKI therapy. (B) The IR of patients with new-onset CV-AEs per 100 person-years shows that the incidence of CV-AEs was highest in the first year of TKI therapy. (C) Similarly, the IR of patients with AT-AEs per 100 person-years shows that the incidence of AT-AEs was highest in the first year after TKI therapy and continued to occur at later years. P < .001 in all panels.

Figure 3.

IRs of new-onset CV-AEs, AT-AEs, overall hypertension, new-onset hypertension, and CV-AEs and AT-AEs according to the number of risk factors per 100 person-years by the frontline TKI modality. (A-B) The IR of patients with new-onset CV-AEs (A) and AT-AEs (B) was significantly higher with ponatinib therapy compared with other TKI modalities; P < .001 in both panels. (C-D) IR of patients with hypertension (overall [C] and new-onset [D]) was highest with ponatinib followed by imatinib 400 mg followed by other TKI modalities; P < .001 in both panels. (E-F) As the number of cardiovascular risk factors increases, the IRs of new-onset CV-AEs (E) and AT-AEs (F) increase within each TKI modality. Patients who received ponatinib had the highest IR (compared with other TKIs) with ≥2 risk factors; P < .001 in both panels.