Thrombotic Microangiopathy after Pediatric Allogeneic Stem Cell Transplant: Potential Early Markers to Predict Individuals at High-Risk

Background Transplant associated thrombotic microangiopathy (TMA) is a severe complication of stem cell transplant (SCT), characterized by endothelial damage leading to microangiopathic hemolytic anemia, thrombocytopenia and organ damage. Mild cases of TMA do not require treatment, but severe cases are associated with organ damage and mortality. Soluble suppression of tumorigenicity-2 (ST2) is a member of the interleukin 1 receptor family and has been associated with cardiac as well as endothelial injury. Elevated soluble terminal complement complex (sC5b-9) has recently been shown to be associated with high-risk TMA. We hypothesize that both complement activation (indicated by increased Sc5b9) and endothelial injury (indicated by increased ST2) occur early in the transplant process, setting up later tissue injury and organ damage, and these markers may be used to predict individuals at high-risk of later TMA, perhaps even before the start of the conditioning regimen. Methods We evaluated 276 consecutive pediatric allogeneic SCT patients at our center. Patients were diagnosed with high-risk TMA if they received eculizumab therapy and demonstrated laboratory and clinical markers of TMA on at least two consecutive tests, including evidence of complement activation, or the patient demonstrated evidence of microangiopathy on a tissue specimen. We compared early serum levels of ST2 and sC5b-9 between patients who later developed or did not develop high-risk TMA at two-time points: prior to the start of the chemotherapy/radiation (baseline) and 7 days after stem cell infusion (Day +7). Results 42 patients (15%) developed high-risk TMA requiring eculizumab at a median of 23 days (IQR: 10-46) post-SCT. Demographics were similar between the groups (Table 1). Patients with high-risk TMA were more likely to receive grafts from mismatched unrelated donors (52% vs. 29%, p=0.013). Patients with high-risk TMA had increased rates of acute GVHD at day 100 (33% vs 11%, p=0.001) and 1-year all-cause mortality (31 vs. 14%, 0.013). ST2 and sC5b-9 levels were significantly higher at baseline and day +7 in patients with high risk-TMA (Table 2). The area under the curve for high risk TMA using a log fold change in ST2 and sC5b-9 from baseline to day +7 was 0.802 (Figure 1). Discussion Plasma levels of sC5b-9 and ST2 are increased at baseline and 7 days after SCT in allogeneic recipients who develop high-risk TMA compared with those who do not. These data suggest complement activation and endothelial injury associated with high-risk TMA may occur before SCT and/or early on after the initiation of therapy. These markers could be used to identify high risk persons for increased screening and we are investigating whether genetic susceptibility, diagnosis of prior therapy might lead to increased baseline complement activity and pre-existing endothelial injury that might be ameliorated prior to start of transplant.