A Case of Ponatinib Induced Hypothyroidism

A Case of Ponatinib Induced HypothyroidismChronic myelogenous leukemia (CML) is a myeloproliferative neoplasm caused by abnormal fusion of genes BCR and ABL1 and unregulated growth of granulocytes. BCR-ABL1 tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for CML. There is limited information regarding ponatinib, a third generation TKI, and endocrine dysfunction. This case describes a patient who developed new-onset primary hypothyroidism following initiation of ponatinib.

Case Description:

A 71-year-old man presented to the hospital with fatigue, unintentional weight gain of 25 lbs, cold intolerance, impaired concentration, new scaly rash over his chest and extremities, and acute on chronic hyponatremia. Admission lab work notable for TSH 47.420 (0.450 – 5.330 UIU/mL), Free T4 < 0.3 (0.6 – 1.4 ng/dL), and Free T3 0.4 (0.9 – 1.8 ng/mL). Serum osmolality 258 (276 - 304 mOsm/kg) and urine osmolality was 361 (100-1,200 mOsm/kg). The patient had no prior history of thyroid disease and approximately 1.5 years prior had TSH 1.590 and FT4 1.0. His medical history included CML, type 2 diabetes, hypertension, hyperlipidemia, and chronic back pain. Treatment history for CML notable for initial therapy with imatinib, then over three years he was cycled through bosutinib, dasatinib, and nilotinib due to loss of response to each TKI. Ponatinib started in February 2021 and held six months later due to new rash. The rash, diagnosed as ichthyosiform dermatitis secondary to new-onset hypothyroidism, dramatically improved with initiation of levothyroxine. Ponatinib therapy was resumed and levothyroxine required ongoing dose titration.

Discussion:

The TKIs used to treat CML include imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. The first three have known associations with thyroid lab abnormalities, though majority of cases do not require treatment. The mechanism for thyroid dysfunction is unclear, though some proposed mechanisms include inhibition of thyroid peroxidase or iodine uptake, thyroiditis, or thyroid hormone plasma membrane transport inhibition.

Ponatinib is a pan BCR-ABL inhibitor used in refractory CML or if intolerant to other TKIs. Ponatinib, unlike the other BCR-ABL TKIs, has additional activity against FLT-3 and VEGFR2 leading to antiangiogenic activity. Other antiangiogenic agents have been documented to cause hypothyroidism with the theorized mechanism of VEGFR inhibition induces capillary regression in the thyroid.

This case is one of very few case reports detailing hypothyroidism secondary to ponatinib therapy. Uniquely, this patient is still requiring levothyroxine dose adjustments above his weight-based dose in the absence of pre-existing thyroid dysfunction.