Objective: Objective: All-trans-retinoic acid (ATRA) has been used in the treatment of acute promyelocytic leukemia (APL). Although the well-known side effects include retinoic acid syndrome and Sweet's syndrome, hypercalcemia associated with ATRA has rarely been reported. The metabolism of ATRA occurs through cytochrome p450 enzymes, and the azole antifungals are known to be potent inhibitors of the cytochrome p450 enzyme system. Here, we report a child who had severe hypercalcemia in the treatment of acute promyelocytic leukemia.

Case report: Case: A 8-years old boy presented with epistaxis and petechia. The patients’ bone marrow aspiration and flow cytometry results were compatible with APL, and t (15;17) was positive. The treatment of AML BFM 2013 protocol and ATRA were initiated. After induction treatment, voriconazole treatment was started prophylactically. While the patient was receiving voriconazole and ATRA, hypercalcemia (Ca: 12.4mg/dL) and hypertension (140/90mmHg) developed. Endocrine and nephrological evaluations of the patient were normal. After the voriconazole treatment was discontinued, hypercalcemia and hypertension improved and never recurred.

Conclusion: Discussion: Hypercalcemia associated with the treatment with ATRA has been described in the literature. The mechanisms of hypercalcemia due to ATRA include accelerated mineral resorption through increased osteoclastic activity, increased interleukin-6 levels that increase bone resorption, and increased parathyroid hormone-related protein. Hypercalcemia is due to the inhibition of ATRA metabolizing cytochrome p450 enzymes, by voriconazole. To decrease the incidence of this side-effect, the use of any medications that can inhibit the cytochrome P450 enzyme system during ATRA therapy is inappropriate unless mandatory.