Effects of fluconazole and voriconazole on cyclosporine levels and toxicity in allogenic hematopoietic stem cell transplant recipients: A comprehensive analysis

ObjectiveHematopoietic stem cell transplant (HSCT) is the only curative option for genetic, immunological, and hematological disorders such as leukemia, lymphoma, and bone marrow failure syndromes. Graft-versus-host disease (GVHD) remains the most frequent post-transplant complication and is commonly managed with cyclosporine. However, recipients of HSCT are at high risk of life-threatening infections despite prophylaxis, and azole antifungals can alter cyclosporine concentrations, predisposing patients to toxicities. This study is the first from Pakistan to evaluate the effect of azole antifungals on cyclosporine levels and associated toxicities.Material and methodsA retrospective analysis was performed on 150 HLA-matched HSCT recipients at the National Institute of Blood Disease and Bone Marrow Transplantation (NIBD and BMT) who received cyclosporine with either fluconazole or voriconazole between October 2018 and December 2022. Cyclosporine levels and toxicities were assessed on day +14. Primary outcomes included cyclosporine-related adverse effects (hypertension, nephrotoxicity, hepatotoxicity, neurotoxicity, electrolyte imbalance), while the secondary objective was to correlate toxicities with cyclosporine drug concentrations in the presence of triazole antifungals.ResultsThe study included 97 males (64.4%) and 53 females (35.3%), with a median age of 11 years (range: 6-20). Beta-thalassemia major was the most common indication (<i>n</i> = 71, 47%). According to NCI-CTCAE criteria, the most frequent Grade 2 toxicity was hypokalemia (20%), and hepatotoxicity (16%) was the most common Grade 3 event. No Grade 4 toxicities were observed. Supratherapeutic cyclosporine levels occurred with both fluconazole and voriconazole.ConclusionWhile dose adjustment is standard with voriconazole, our findings suggest the need for similar consideration with fluconazole. Larger studies are required to confirm this observation.