<scp>BCR‐ABL1</scp> tyrosine kinase inhibitor‐associated thyroid dysfunction: A review of cases reported to the <scp>FDA Adverse Event Reporting System</scp> and published in the literature
Authors: Shital Patel, Afrouz Nayernama, Steven Christopher Jones, Romeo Angelo de Claro, Peter E. Waldron
Journal: American Journal of Hematology (2020)

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph+) producing a constitutively active tyrosine kinase, BCR-ABL1.1 BCR-ABL1 tyrosine kinase inhibitors (TKIs) are the mainstay treatment for patients with CML. Currently, there are five BCR-ABL1 TKIs approved by the U.S. Food and Drug Administration (FDA), including imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, most of which have indications beyond CML. Thyroid dysfunction, specifically hypothyroidism and hyperthyroidism, is a well-known adverse event observed with many TKIs.2 Among the BCR-ABL TKIs, hypothyroidism, hyperthyroidism, and thyroiditis were identified in clinical trials with dasatinib and nilotinib, whereas a distinct risk of hypothyroidism in thyroidectomy patients on levothyroxine was identified with imatinib in the postmarket setting. The latter was observed in studies conducted by DeGroot and colleagues, in which thyroidectomized patients receiving imatinib required increased thyroid hormone replacement, while patients with intact thyroid glands receiving imatinib remained euthyroid.3 The FDA approved prescribing information for imatinib with this risk in 2008. We evaluated postmarketing adverse event reports from the FDA Adverse Event Reporting System (FAERS) and published in the literature from the product approval date through September 10, 2019, to investigate an association between BCR-ABL1 TKI exposure and thyroid dysfunction as a potential class effect. A confirmed case of thyroid dysfunction was supported by laboratory evidence or initiation of thyroid treatment. An unconfirmed case of thyroid dysfunction did not provide this level of evidence. We further characterized the cases as new-onset or worsening thyroid dysfunction as indicated by modification of thyroid medication regimen or worsening thyroid function tests. The severity of thyroid dysfunction was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.4 We identified 326 unique cases of thyroid dysfunction from FAERS (n = 239) and the literature (n = 87) associated with imatinib (n = 112), dasatinib (n = 41), nilotinib (n = 126), bosutinib (n = 8), and ponatinib (n = 39) use. We applied the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality assessment and determined causality as probable in five and possible in all others. Descriptive characteristics of the cases are summarized in Table 1. Overall, 74% (240/326) described hypothyroidism, 20% (67/326) hyperthyroidism, and 6% (19/326) did not specify the type of thyroid dysfunction. Among 122 cases that reported sufficient clinical information to assess baseline thyroid function, new-onset and worsening thyroid dysfunction occurred in 83% (n = 101) and 17% (n = 21) of cases, respectively. Half of the cases reported a time to onset, which varied widely. Among these cases, 54% (88/162) of thyroid dysfunction occurred within the first nine months of BCR-ABL1 TKI initiation. This may reflect gradual progression of drug-induced thyroid toxicity. Alternatively, inadequate monitoring requirements for thyroid function tests may have limited earlier detection of thyroid dysfunction.5 All forms of thyroid disorders may be associated with significant morbidity and mortality if unsuspected and untreated.6 Among cases that reported severity grading information, 83% (156/189) were CTCAE grade 2 thyroid dysfunction. Most cases required intervention with thyroid replacement or antithyroid therapy, and patients were able to continue BCR-ABL1 TKI therapy at the same or reduced dose. One fatal case of hyperthyroidism reported with imatinib therapy occurred in a patient with pre-existing hyperthyroidism, but the report was missing sufficient detail to adequately assess the cause. Clinical management of thyroid dysfunction depends on severity; however, as observed in our case series, cases of low severity tolerated continuing BCR-ABL1 TKI therapy with appropriate management, such as levothyroxine supplementation or anti-thyroid directed therapy. We assessed any contributory role between BCR-ABL1 TKIs and thyroid dysfunction by considering competing causes, temporality, existence of positive rechallenge and dechallenge, and potential biologic mechanisms of toxicity. All cases had a compatible temporal relationship and a suspected biologic mechanism. Cases deemed probable included one positive rechallenge case with imatinib and those cases without known confounding factors. Most cases were deemed to have possible causality due to missing data, presence of potential confounding, or a history of thyroid dysfunction. All cases that did not report thyroidectomy were presumed to have an intact thyroid. It is noteworthy that four cases of worsening thyroid dysfunction resulted in increased levothyroxine requirements after imatinib initiation in patients with pre-existing hypothyroidism and an intact thyroid. This supports an imatinib-induced exacerbation of hypothyroidism in patients with an intact thyroid. The exact mechanism underlying BCR-ABL1 TKI-induced thyroid dysfunction is not fully understood; however, multiple mechanisms have been proposed for TKIs. Thyroid angiogenesis is regulated by vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor (PDGFR) signaling.7 Although the BCR-ABL1 TKIs are selective for BCR-ABL1, they also exemplify variable affinity for other tyrosine kinases, including PDGFR and VEGFR. Imatinib, dasatinib, and nilotinib are selective for PDGFR with no VEGFR activity. Ponatinib selectively inhibits PDGFR and VEGFR, whereas bosutinib does not inhibit signaling through either of these receptors.8 Inhibition of VEGFR and PDGFR dysregulates thyroid angiogenesis, which may result in an ischemic thyroiditis followed by hyperthyroidism or gradual thyroid destruction followed by hypothyroidism.7 Other proposed mechanisms included thyroid peroxidase activity inhibition, iodine uptake inhibition, autoimmune thyroiditis, irreversible thyroid destruction, thyroid hormone plasma membrane transport inhibition, and increased clearance of thyroid hormones through enzyme induction. We observed different forms of thyroid dysfunction (ie, hypothyroidism, hyperthyroidism, autoimmune thyroiditis) in our case series and recognize the variable spectrum of activity of BCR-ABL1 TKIs.7 Therefore, consistent with the literature, we believe that more than one mechanism is likely involved with BCR-ABL1 TKI-induced thyroid dysfunction. To our knowledge, this is the largest published case series describing thyroid dysfunction with the BCR-ABL1 TKIs. All members of the BCR-ABL1 TKI class have had cases of thyroid dysfunction reporting an association between drug exposure and thyroid dysfunction. Although our analysis is limited by the quality of FAERS data and other limitations inherent to spontaneous reporting systems (eg, under-reporting, reporting biases), the temporal association, biologic plausibility, and positive rechallenge data provide evidence supportive of a drug-event causal association between the BCR-ABL1 TKIs and thyroid dysfunction. The U.S. prescribing information for imatinib, bosutinib, and ponatinib was recently updated to include the risk of hypothyroidism and hyperthyroidism under Adverse Reactions. This revision of the prescribing information is intended to increase clinicians' awareness of the risk for thyroid dysfunction with BCR-ABL1 TKIs and to mitigate the risk for serious outcomes by improving monitoring and early therapeutic interventions. Given that dasatinib and nilotinib are labeled for hypothyroidism and hyperthyroidism under Adverse Reactions, this labeling revision of the remaining BCR-ABL1 TKIs will harmonize the prescribing information among the BCR-ABL1 TKIs regarding this safety issue. The authors report no conflict of interest.