Hypercalcemia due to all trans retinoic acid in the treatment of acute promyelocytic leukemia potentiated by voriconazole

Abstract

All-trans-retinoic acid (ATRA) is a new and effective treatment of acute promyelocytic leukemia. It has many side-effects, including the retinoic acid syndrome and Sweet's syndrome. There have been only nine cases of hypercalcemia associated with ATRA described in the literature. We discuss a case of hypercalcemia, which we believe was due to inhibition of cytochrome P450 function by voriconizole when used concomitantly with ATRA.

Fluconazole-Associated Hypercalcemia in Patients with Coccidioidomycosis

“…All-trans retinoic acid, the active metabolite of vitamin A, is catabolized by CYP enzymes, including CYP3A4 and CYP2C9 [18]. Inhibition of these enzymes by high-dose triazoles and subsequent reduction in the rate of all-trans retinoic acid catabolism has been reported to potentiate the hypercalcemic effects [3,4]. The effect of fluconazole on calcium metabolism might be small or it might not become clinically significant until the dose is high (eg, the 1,200 mg daily dose in our index patient).…”

“…Triazoles can function as both a substrate for and inhibitor of CYP enzymes, resulting in a wide range of drug-drug interactions with varying properties that are defined by the individual drugs involved [1,2]. Voriconazole and itraconazole are thought to potentiate the adverse effects of all-trans retinoic acid, specifically hypercalcemia, by inhibiting CYP, thereby increasing serum concentration of all-trans retinoic acid [3,4]. Fluconazole, a first-generation triazole, is generally well tolerated, with few clinically significant toxicities.…”

All trans retinoic acid induced hypercalcemia and diffuse alveolar hemorrhage in acute promyelocytic leukemia: Practical guidelines for diagnosis and treatment based on a case report and literature review

“…Although the only bisphosphonate used with success in the literature was pamidronate 90 mg iv [27] , we believe that no biologic nor clinical reasons would contraindicate the use of other drugs in the same category (i.e. zoledronic acid).…”

“…After the introduction of azole drugs for fungal prophylaxis in the induction and consolidation phases of acute leukemias [25,26] , more reports have described hypercalcemia induced by the interaction between ATRA and azole (voriconazole, fosfluconazole and itraconazole). It was speculated that the later class of drugs increased serum ATRA concentration and toxicity by inhibiting CYP 450 enzymes needed to its metabolism [13,[27][28][29] .…”

Enhancement of 1,25-Dihydroxyvitamin D3- and All-transRetinoic Acid-Induced HL-60 Leukemia Cell Differentiation byPanax ginseng

“…13,14) Consequently, the introduction of a second biological or chemical agent which can potentiate the differentiation-inducing ability of ATRA or 1,25-(OH) 2 D 3 at a low, non-toxic concentration could be a useful strategy to solve the underlying problems.…”