Thyroid Function Abnormalities Associated with Ponatinib Therapy in Patients with Chronic Myeloid Leukemia

Dear Editor:

Ponatinib is a novel pan-BCR-ABL inhibitor effective in the management of patients with chronic myeloid leukemia (CML) who are refractory or intolerant to alternative tyrosine kinase inhibitors (TKIs) and for those bearing the T315I Abl kinase domain mutation (1). TKIs have characteristic side effects because of their off BCR-ABL1 target activity against other kinases, such as KIT and PDGFRα. However, ponatinib has additional activity against FLT-3 and VEGFR2 and may have antiangiogenic activity. Antiangiogenic agents are documented to cause hypothyroidism in up to 36% of cases (2).

Here we present single-center results on the evaluation of thyroid function in patients who received ponatinib therapy for CML. Twenty patients receiving ponatinib had thyroid function tests performed during ponatinib therapy because of symptoms of fatigue, including four patients routinely post-allogeneic stem cell transplant (allo-SCT). Baseline thyroid function tests were therefore not assessed in most patients. Biochemical diagnosis of subclinical hypothyroidism was defined in accordance with the European Thyroid Association. Clinical hypothyroidism was defined as low serum free thyroxine together with elevated thyrotropin (TSH).

The median duration of treatment with ponatinib was 28 months (range, 6–36), including brief periods of cessation because of hematologic and/or other treatment-related toxicities. Patients received ponatinib at a dose of 15–45 mg daily (median dose, 15 mg). Five of 20 patients (25%) were found to have biochemical subclinical or clinical hypothyroidism on routine testing (subclinical hypothyroidism n=2, clinical hypothyroidism n=3), 5–17 months after ponatinib initiation (Table 1). None of these patients had an arterial or venous thrombosis.

Three of five patients required thyroxine replacement therapy after the diagnosis of clinical hypothyroidism. Two patients were SCT recipients (reduced intensity matched unrelated donor SCT and haploidentical SCT with total body irradiation) and were diagnosed with clinical hypothyroidism at 12–15 months post-transplant, after 5–6 months of ponatinib therapy. The haploidentical SCT recipient had evidence of subclinical hypothyroidism at 10 months post-transplant, however, only developed clinical hypothyroidism after 5 months of ponatinib.

In studies of other tyrosine kinase receptor inhibitors with known VEGF inhibitory activity, 34% of patients had transient elevation of TSH not requiring therapeutic intervention, and 27% developed subclinical or clinical hypothyroidism requiring therapy, having had had normal TSH levels at baseline (3). Patients who developed thyroid abnormalities on therapy appeared to have an improved progression-free survival (4). Thyroid function should also be monitored after cessation of TKI therapy as recovery of thyroid function can occur. The mechanism of hypothyroidism is unclear, but may involve regression of thyroid capillaries due to VEGFR inhibition (5,6).

We report a clinically relevant observation of abnormal thyroid function on ponatinib therapy. As treatment with TKIs for CML patients is currently an indefinite therapy, we recommend that thyroid function should be analyzed at baseline and then sequentially while on therapy. The true incidence of this effect should be addressed in prospective studies.