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.

Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia

“…20 One study showed that the Systematic Coronary Risk Evaluation (SCORE) assessment may be a useful tool for identifying those with a higher risk of developing AOEs while on ponatinib treatment. 15 Jain et al 21 recently published a study using data from several different clinical trials with CP-CML patients who were treated with TKIs, to evaluate their cardiovascular impact, and found that ponatinib was associated with the highest incidence of CAEs/AOEs. Most of the patients in this cohort were at least in their third line of therapy upon starting ponatinib and .70% of the CP-CML patients were on nilotinib, which has been shown to increase the risks of cardiac ischemic events and peripheral arterial occlusive disease.…”

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

“…These must be considered when selecting a TKI for a patient with comorbidities [80], because some are contraindications for using a specific TKI first-line. Previous or concomitant arteriovascular disease represents a strong contraindication to nilotinib first-line and ponatinib second or third line [41,52,55,61,62,77,79,81,82], unless there is unique need. Respiratory failure and previous or concomitant pleuro-pulmonary disease are strong contraindications to dasatinib first line.…”

Experience with ponatinib in paediatric patients with leukaemia

“…One of the most serious AEs reported with ponatinib in adult patients is arterial thrombotic events (ATEs), concern for which halted the completion of a phase 3 trial of ponatinib versus imatinib in adult patients with newly diagnosed CML (EPIC) (Lipton et al , ; Jain et al , ). The EPIC study and phase 2 trial of ponatinib in adults with Ph + ALL and CML (PACE) demonstrated that ATEs were much more common in older patients and those with pre‐existing cardiovascular risk factors (Cortes et al , ; Lipton et al , ).…”