Safety Profile and Efficacy of Cidofovir for Adenovirus in Pediatric Stem Cell Transplant Recipients Following Reduced-Intensity Conditioning

Abstract

Background Adenovirus (ADV) infection remains a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in the pediatric population. Pre-emptive monitoring by polymerase chain reaction (PCR) assay for ADV viremia in high risk patients permits prompt initiation of therapy. Cidofovir (CDV) is a nucleotide analogue which is utilized for treatment of ADV infections in immunocompromised patients; however, CDV can be associated with substantial dose-dependent nephrotoxicity. The use of reduced intensity conditioning (RIC) has invariably necessitated the use of anti-thymocyte globulin or alemtuzumab for rejection prophylaxis, putting patients at higher risk for viral infections. We report our single-center experience with CDV for treatment of ADV infection in 20 allo-HSCT patients. Methods We performed a retrospective review, from 2012-2019, of children with non-malignant diseases that received RIC with alemtuzumab, fludarabine, melphalan, and thiotepa. ClinicalTrials.gov Identifier: NCT01962415 Recipients of CDV were identified and reviewed for ADV PCR results (blood, stool, urine, respiratory viral panel), CDV course characteristics (mg/kg dose, frequency, and duration), and changes in renal function. All patients received a combination of probenecid and hydration to reduce nephrotoxicity. Results A total of 25 CDV courses, in 20 patients (median age: 4 years, range 0.6-22) were identified. Of the 20 patients, 18 patients (90%) received umbilical cord blood as their graft source. Of the 25 courses prescribed, 20 courses (80%) were in patients with a positive blood ADV PCR, and 19 courses (76%) with a positive stool ADV PCR. Typically, 5 mg/kg/dose (range 1-9) was given weekly, then every 2 weeks once viral load declined. The median number of doses of CDV was 8 doses (range 2-32) with treatment duration ranging from 7-169 days. Renal dysfunction with CDV appeared to be reversible, with 14 courses (56%) having peak serum creatinine (SCr) >50% of baseline during CDV treatment, though average rise in SCr when comparing baseline to CDV discontinuation values was 20%. Only 2 courses had a peak SCr ≥ 1 mg/dL during CDV treatment. In 16 courses (64%) CDV therapy was discontinued due to clinical resolution, PCR negativity, or a combination of both, in 6 courses (24%) patients were switched to brincidofovir, and in 1 course (4%) the patient transferred care. 18 of 20 are alive, one child died of complications of multiple infections including ADV, and another due to accelerated CNS demyelination. Conclusion CDV appeared remarkably safe and effective post RIC conditioning. Prospective screening allowed for early initiation of CDV and limiting poor outcomes associated with ADV.