Thyroid Dysfunction Caused by Second-Generation Tyrosine Kinase Inhibitors in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia

Abstract

Background: Thyroid dysfunction is a well-known adverse effect of first-generation tyrosine kinase inhibitors (TKIs), like sunitinib. The aim of this study was to investigate the effect of second-generation TKIs on thyroid function. Methods: We retrospectively assessed the effect of the first-generation TKI imatinib and the second-generation TKI nilotinib and dasatinib on thyroid function tests in 73 Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia patients. Results: Overall, 33 of 73 (45%) had one or more thyroid function test abnormalities during follow-up. Hypothyroidism or hyperthyroidism were found in 18 of 73 (25%) and 21 of 73 (29%) cases after a median of 6 and 22 weeks, respectively. In most patients (29 of 39, 74%) thyroid dysfunction was transient without clinical symptoms. Therapy of hypo-/hyperthyroidism was required in three patients. Thyroid dysfunction never resulted in the discontinuation of TKI therapy. Under treatment with imatinib, nilotinib, and dasatinib, thyroid abnormalities were detected in 25%, 55%, and 70%, respectively. Four of 55 patients (7%) treated with nilotinib had evidence for an autoimmune thyroiditis (antibody positive in 3 of 4 patients) with an episode of hyperthyroidism preceding hypothyroidism. Conclusions: Thyroid dysfunction is a common adverse event with second-generation TKI therapy in patients with Ph-positive chronic myeloid leukemia. Although the mechanism is still unclear, the high frequency of thyroid abnormalities, including autoimmune thyroiditis, warrants regular and long-term monitoring of thyroid function in these patients.

Thyroid function, autoimmunity and nodules in hematological malignancies

“…Thyroid investigations in patients with hematological disorders have essentially focused on the thyroid complications ensuing from chemotherapy and/or external irradiation (4)(5)(6)(7)(8)(9)(10)14,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Because no study has simultaneously taken care of all clinically relevant thyroid aspects (namely, function, autoimmunity and nodules), we have conducted such a study on hematoncologic patients excluding those who had been treated with external irradiation.…”

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach

“…Other morbidities observed in adults, such as thyroid dysfunction 66 and cardiovascular toxicity, [67][68][69] have not been reported in children to date; however, because children with CML may receive TKI therapy for much longer periods of time than adults, they may also develop unanticipated comorbidities, and careful follow-up is imperative. Although it will be important to gather more data in prospective studies, we recommend that pediatric patients who are treated with TKIs off protocol are at least monitored for height, weight, and Tanner stage on every visit, in addition to periodic bone age and dual-energy x-ray absorptiometry scans, and that an endocrinology consultation is pursued if there are abnormal patterns (Table 3).…”

Chronic myeloid leukemia: Second‐line drugs of choice

“…Similarly, these findings could be also documented during treatment with other TKIs such as nilotinib and dasatinib [47,48]. Some reports also described cases of worsening of hypothyroidism or thyroid abnormalities during Imatinib and 2 nd generation TKIs, which needed increased dosages of hormone supplementation [49]. Finally, gynecomastia was found in male patients treated with imatinib because of inhibition of c-kit and PDGFR involved in testis testosterone production [50].…”