Cardiovascular and pulmonary adverse events in patients treated with BCR‐ABL inhibitors: Data from the FDA Adverse Event Reporting System

Abstract

Rare but serious cardiovascular and pulmonary adverse events (AEs) have been reported in patients with chronic myeloid leukemia treated with BCR-ABL inhibitors. Clinical trial data may not reflect the full AE profile of BCR-ABL inhibitors because of stringent study entry criteria, relatively small sample size, and limited duration of follow-up. To determine the utility of the FDA AE Reporting System (FAERS) surveillance database for identifying AEs possibly associated with the BCR-ABL inhibitors imatinib, dasatinib, and nilotinib in the postmarketing patient population, we conducted Multi-Item Gamma Poisson Shrinker disproportionality analyses of FAERS reports on AEs in relevant system organ classes. Signals consistent with the known safety profiles of these agents as well as signals for less well-described AEs were detected. Bone marrow necrosis, conjunctival hemorrhage, and peritoneal fluid retention events were uniquely associated with imatinib. AEs that most commonly reached the threshold for dasatinib consisted of terms relating to hemorrhage and fluid retention, including pleural effusion and pericardial effusion. Most terms that reached the threshold solely with nilotinib were related to peripheral and cardiac vascular events. Although this type of analysis cannot determine AE incidence or establish causality, these findings elucidate the AEs reported in patients treated with BCR-ABL inhibitors across multiple clinical trials and in the community setting for all approved and nonapproved indications, suggesting drug-AE associations warrant further investigation. These findings emphasize the need to consider patient comorbidities when selecting amongst BCR-ABL inhibitors.

Chronic myeloid leukemia: Second‐line drugs of choice

“…Rare events of QT prolongation with nilotinib therapy have also been reported [30]. An association between nilotinib and certain cardiovascular AEs has been supported from the FDA post-marketing AE database, and suggests this association is likely even in younger patients [31]. Several patients have experienced rapidly progressing PAOD with nilotinib therapy [65].…”

“…Safety findings of first-and second-line treatment in clinical studies of TKIs in patients with chronic phase CML suggest that the spectrum of AEs remains generally consistent between treatment lines [30]. Long-term follow-up and postmarketing data suggest in general that the safety profile of TKIs is stable, with no marked increase in symptoms over time [30,31]. A notable exception is represented by nilotinib, in which initial reports of second-line and even first-line therapy [15,32] did not identify the characteristic cardiovascular toxicity.…”

“…In patients with imatinib-resistant or -intolerant chronic phase CML, all-grade fluid retention occurred in 48% and grade 3/4 events occurred in 6% of patients treated with dasatinib at the recommended dose [22]. In an assessment of the Food and Drug Administration (FDA) AE database, pleural effusion and pericardial effusion with dasatinib showed the strongest post-marketing signal [31]. It is notable that another TKI wirh Src inhibitory effects, bosutinib, showed a much lower (<5%) incidence of this type of adverse effects.…”

The value of open access and a patient centric approach to oral oncolytic utilization in the treatment of Chronic Myelogenous Leukemia: A U.S. perspective

“…There are differences in the safety profiles of dasatinib and nilotinib. The most common adverse events associated with dasatinib are fluid retention events such as, pleural effusion, pericardial effusion, pulmonary arterial hypertension, and pulmonary edema [21,35]. Nilotinib-related adverse events include coronary artery stenosis, femoral arterial stenosis, peripheral arterial occlusive disease, and intermittent claudication [35,36].…”

“…Adverse events of TKIs may be very costly. A retrospective analysis [44] evaluated healthcare costs associated with adverse events among TKI-treated patients identified in the FDA Adverse Event Reporting System [35] that were potentially associated with TKIs. The study found (Figure 3) [44] that one year per patient total mean medical costs for these adverse events were $17,015 (femoral arterial stenosis, FAS), 15,145 (peripheral arterial occlusive disease, PAOD), $6,112 (intermittent claudication, IC), $4,944 (coronary arterial stenosis, CAS), $2,797 (pericardial effusion) and $1,908 (pleural effusion) [44].…”