Improved Outcomes of Transplant Associated Thrombotic Microangiopathy with Early Initiation of Eculizumab

Background Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare, potentially lethal complication of allogeneic stem cell transplant. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Endothelial injury and terminal complement activation contribute to the pathogenesis of TA-TMA. Several risk factors have been identified including certain conditioning regimens, acute graft versus host disease (GvHD) and/or calcineurin inhibitors (CNI), and viral infections. Eculizumab, a monoclonal antibody directed against C5 which prevents the formation of the C5b-9 membrane attack complex, is effective in treatment of TA-TMA, but with significant infection risk. Here, we review our institution's experience with TA-TMA treated with eculizumab. Methods A retrospective review was performed on all adult and pediatric patients with TA-TMA treated at our institution with eculizumab since 2015. Results Five patients with TA-TMA ages 4.5, 8.5, 11.4, 33, and 37 years (2 female) were treated with eculizumab. All patients received myeloablative conditioning, three TBI-based. Donor source was haploidentical (n=2), matched-unrelated (n=2), and cord (n=1). All patients were on a CNI at diagnosis. TA-TMA therapy required cessation of CNI in 3 of 5 patients. Median day of diagnosis from transplant was 73 days (range 17-251). All patients had renal impairment, three requiring dialysis. Median days from TMA diagnosis to treatment with eculizumab was 3 (range 1-5). Median doses received was 6 (range 4 - >25). Resolution of hemolysis with eculizumab was brisk, ranging from 25-59 days. Figure 1 illustrates a representative trend with regards to LDH, Haptoglobin, CH50, and eculizumab dosing. Four of five patients were alive with a median follow-up of 10.3 months (range 1 - 45 months). The one death was due to Stage IV GvHD and candidemia, present before diagnosis of TMA. Infections were common, including viral and fungal. There were no deaths due to TMA. Two patients continue on dialysis 2.5 and 34.5 months after diagnosis. Discussion Our experience confirms variable clinical presentations, as our patients differed in presence and severity of acute GvHD, confounding role of CNI or triggering of TA-TMA by viral infections. All patients were started on eculizumab promptly following diagnosis, with a high awareness for and prophylaxis of potential infectious complications, which has mitigated the reported high mortality risk of TA-TMA.