TKIs Linked to Increased Cardiovascular and Arteriothrombotic Events in Chronic-Phase CML

In patients with chronic-phase chronic myeloid leukemia (CML), treatment with tyrosine kinase inhibitors (TKIs) has been shown to increase the risk of cardiovascular and arteriothrombotic adverse events (CV-AEs and AT-AEs), but a report published in Blood Advances provides new insights into which TKIs are associated with the greatest risks.

The authors, led by Preetesh Jain, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, also identified several patient and treatment characteristics associated with an increased incidence of these AEs.

With this analysis, “[we were] trying to shed light on the relative risk with each of the available TKIs by using uniform criteria for reporting and by performing a multivariate analysis to adjust for other risk factors,” they explained. To accomplish this goal, the authors reviewed the medical records of 531 patients with newly diagnosed chronic-phase CML who had participated in clinical trials with TKIs at MD Anderson.

The following TKIs were included in the clinical trials:

  • imatinib 400 mg/day (n=71)
  • imatinib 800 mg/day (n=203)
  • twice-daily nilotinib 400 mg (n=108)
  • dasatinib 100 mg/day or 50 mg twice daily (n=106)
  • ponatinib at a starting dose of 45 mg (n=43)

Each trial reported the incidence of new-onset AEs (e.g., CV-AEs or AT-AEs) following recruitment and 30 days after TKI discontinuation.

CV-AEs included: hypertension; arrhythmias; abnormal electrocardiogram or echocardiogram; palpitations; prolongation of QT interval; pericarditis, and peripheral vascular disease (PVD). Comparatively, AT-AEs included events associated with coronary artery disease (CAD), cerebrovascular disease, and peripheral arterial disease (PAD).

The median age of the entire population was 48 years (range = 15-86 years), and the median follow-up in the pooled cohort was 94 months (range = 2-195 months). At the start of TKI therapy, most patients (n=421; 79%) had at least one cardiovascular risk factor, including:

  • prior hypertension (51%)
  • obesity (BMI ≥30 kg/m2; 32%)
  • hyperlipidemia (28%)
  • smoking (23%)
  • diabetes mellitus (15%)
  • prior history of CAD (8%)
  • arrhythmias (3%)

“The distribution of patients with prior history of hypertension and prior smoking was significantly different among the TKI cohorts (p<0.001 for both),” the researchers noted. “There was also an imbalance in the frequency of prior history of CAD (p<0.06), but no significant difference between cohorts in the frequency of other risk factors.”

Across the studies, almost half of patients (45%; n=237) developed CV-AEs during follow-up, while only 9% of patients (n=46) developed AT-AEs. The median time to first CV-AE was 26 months (range = 0.1-154 months) and to first AT-AE was 46 months (range = 0.3-155 months).

The overall incidence rate (IR) of CV-AEs was 8.6 per 100 person-years, with the highest IR observed in patients treated with ponatinib (IR = 40.7 per 100 person years; p<0.001; TABLE). The most common CV-AE was hypertension (74%), followed by arrhythmias, palpitations, and peripheral vascular disease.

The overall IR of AT-AEs was lower, at 1.7 per 100 person-years, and again, ponatinib-treated patients had the highest IR (9.0 per 100 person-years; p<0.001). In the 46 patients who developed AT-AEs, the most common events were CAD, cerebrovascular disease, and PAD (TABLE).

“The incidence and the risk of CV-AEs and AT-AEs is significantly increased in patients with CML who are taking second- and third-generation TKIs and in patients with pre-existing cardiovascular risk factors,” the researchers reported. In a multivariate analysis, they also identified the following as predictors of a higher IR ratio (IRR) of CV-AEs (p<0.003 for all):

  • advanced age (IRR=1.03; 95% CI 1.02-1.04)
  • low serum albumin (IRR=0.57; 95% CI 0.42-0.78)
  • BMI ≥30 kg/m2 (IRR=1.59; 95% CI 1.21-2.09)
  • history of hypertension prior to TKIs (IRR=1.53; 95% CI 1.15-2.02)

Risk factors for AT-AEs were similar, but did not include hypertension.

“Because most [patients with CML] are long-term survivors who will continue to receive TKIs,” the researchers concluded, “newer guidelines for initial workup of [patients with CML] must include a thorough baseline evaluation of cardiovascular risk factors and regular assessment and management of any cardiovascular comorbidity during each visit while [they are] on TKI therapy.”

The relatively small number of patients in the final sample, the retrospective nature of the analysis, the reliance on medical record data, and the varying follow-ups across trials represent potential limitations of the study.

The authors report relationships with Novartis, ARIAD, and Bristol-Myers Squibb, which sponsored the studies.

References

Jain P, Kantarjian H, Boddu PC, et al. Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs. Blood Adv. 2019;3:851-61.

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