Viral Kinetics and Outcomes of Adenovirus Reactivation Following Allogeneic Hematopoietic Cell Transplant or CAR-T Cell Therapy

Abstract

Adenovirus (AdV) viremia occurs in up to 10% of patients following allogeneic hematopoietic cell transplant (HCT). Although AdV disease can be severe and associated with high mortality among those with pneumonia or disseminated disease, little is known about the viral kinetics of AdV and the natural history of untreated viremia following HCT or CAR-T cell therapy. Cidofovir is the only available therapy for AdV and is associated with significant toxicity. Thus, establishing an optimal threshold for pre-emptive therapy is urgently needed. To bridge this gap in knowledge, we conducted a retrospective study of 18 allogeneic HCT or CAR-T cell recipients with documented AdV viremia treated at our center between 12/2014 and 7/2019. Median follow up time was 102 days (IQR 56 - 318). The median absolute lymphocyte count (ALC) at time of AdV reactivation was 425 (IQR 124 - 695) for HCT and 425 (IQR 410 – 440) for CAR-T cell patients. 12/18 (67%) of the patients received corticosteroids within 30d prior to AdV (median prednisone dose 33.75 mg/d). The median time to AdV reactivation after HCT was 176 days (IQR 77 - 424), and after CAR-T cell was 366 days (IQR 173 to 558). Median initial VL was 1100 copies/mL (IQR 263 – 4000). Median peak viral load was 79,550 copies/mL (IQR 2,225 - 243,750). 11 (61%) patients received cidofovir therapy, even though, except for 2 cases of possible cystitis, 16/18 (89%) were asymptomatic at the time of AdV viremia. Median duration of viremia was 23 days for treated and 13 days for untreated patients. Among treated patients, median duration of viremia was shorter when treatment was initiated at viral loads All-cause mortality was 44%. Median time to death after AdV diagnosis was 59 days. Only 1 of 7 (14%) patients (included 5 untreated patients) with peak viremia The median AdV DNA level prior to initiation of therapy was 126,000 copies/mL (IQR, 7200-610,500). The median duration of treatment was 16 days (IQR 9 - 34). 4/11 (36%) patients treated with cidofovir had acute kidney injury (AKI) while on therapy. Median cumulative cidofovir dose was higher in patients who developed AKI vs those who did not, but this finding didn't reach statistical significance (25 vs 15mg/kg; P=0.18). In conclusion, AdV viremia is associated with high all-cause mortality, especially among those with viral loads >10,000 copies/mL. Delaying initiation of therapy until AdV ≥10,000 copies/mL is associated with more protracted viremia and longer courses of antivirals with associated nephrotoxicity. Although larger studies are needed, an AdV viral load >10,000 copies/mL following allogeneic HCT and CAR-T cell is a reasonable cutoff for initiation of pre-emptive antiviral therapy