Treatment of Severe, Eculizumab Refractory TA-TMA in a Pediatric Patient

Transplant associated thrombotic microangiopathy (TA-TMA) is an endothelial disease with hyperactive complement characterized by the presence of hemolytic anemia resulting in end-organ dysfunction and damage. Eculizumab is treatment of TA-TMA. The data on therapies for eculizumab-refractory TA-TMA is scant. We describe the clinical course and therapeutic management of a pediatric patient with refractory TA-TMA. We report a 2-year-old male who was diagnosed with high-risk neuroblastoma with a primary right adrenal mass. He received standard of care chemotherapy for 5 cycles, including resection of residual adrenal mass. His pre stem cell transplant (SCT) Curie score was 1. He tolerated his first autologous SCT (conditioned with thiotepa/cyclophosphamide) well without any toxicities. He initially tolerated the chemotherapy regimen (melphalan, etoposide, carboplatin) for his second autologous SCT. He began showing signs of TA-TMA two days prior to cell infusion with transaminitis (>16x ULN), proteinuria (8mg/dL), elevated lactate dehydrogenase (LDH), anemia and thrombocytopenia. Diagnosis was confirmed the day after cell infusion (D+1) with elevated sc5b9 (984 ng/mL). He began eculizumab every 72h and was titrated according to trough eculizumab levels. On D+10 he developed hematuria; work up was negative for viral and bacterial infections. Symptoms worsened with increasing clot burden and nephrostomy tubes were placed on D+28. Given concerns for TA-TMA of the bladder with features of hyper-inflammatory process (persistent fevers, cytopenias, elevated ferritin/triglycerides/sIL2/CXCL9) emapalumab and dexamethasone were added. TA-TMA worsened on D+43 with serositis (large volume ascites, small pleural and cardiac effusions). Emapalumab was discontinued on D+56 after CXCL9 was fully suppressed. Renal function continued to decline and therapeutic plasma exchange (TPE) was added from D+58 to D+84, as well as rituximab D+61 to D+72 given elevated Factor H. Renal replacement therapy began on D+58 and continued until D+97 when his organ dysfunction and TA-TMA began to improve. His eculizumab was spaced to weekly on D+132 as he transitioned to receiving dinutuximab therapy, abdominal radiation was delayed. His renal function continues to be less than baseline (average GFR 55ml/min/1.73m2) but he remains off of dialysis and has been able to proceed with neuroblastoma therapy. While there are a few options for treatment of refractory TA-TMA other than eculizumab, there is no data to direct additional lines of therapy. As TA-TMA continues to be more frequently diagnosed in this patient population it is imperative to discuss options for treatment in refractory cases. We aim to raise awareness of this need and report successful treatment with multiple lines of therapy that included dexamethasone, emapalumab, TPE, and rituximab.