End Organ Damage Following Refractory/Recurrent Transplant Associated Thrombotic Microangiopathy (TA-TMA) in Pediatric Patients Undergoing Autologous Hematopoietic Cell Transplantation

Abstract

Background Transplant associated thrombotic microangiopathy (TA-TMA) is a known complication of autologous hematopoietic cell transplantation (aHCT), particularly in neuroblastoma. We describe our single institution experience of after aHCT in children. Methods Data were extracted from patients receiving an aHCT at Dana-Farber/Boston Children's between 01/08 and 07/18. Patients were diagnosed with after aHCT using either the international working group criteria or probably TA-TMA by Cho et al. Results Overall, 318 aHCT were performed in 243 patients, nine (3.7%) were diagnosed with TA-TMA. occurred most frequently in children with neuroblastoma (n=7 [78%]), all of whom were conditioned with carboplatin, etoposide, and melphalan (CEM). The total prevalence of after aHCT in children with neuroblastoma was 6% (7/118). also occurred after aHCT for Hodgkin Lymphoma (n=1) and medulloblastoma (n=1). Median age at aHCT in children who developed was 3 years 5 months (range 18 months to 25 years). Six (67%) were male. TMA was diagnosed a median of 35 days (range 8-106) after stem cell infusion. All patients had renal involvement, 8/9 had nephrotic range proteinuria and 8/9 had severe hypertension at presentation requiring a range of 2-6 antihypertensive medications. Two patients presented with multiorgan failure. Six patients were treated with eculizumab a median of 0 days after diagnosis (range 0 to 11 days). Two (33%) died of multiorgan failure and had no response to eculizumab. The remaining 4 had both a hematologic response defined as transfusion independence and renal response as resolution of nephrotic range proteinuria. Among eculizumab-treated survivors, we describe two previously unreported long-term sequelae. Two patients required prolonged eculizumab therapy for blood pressure control, despite hematologic and renal responses. An additional child had recurrence of after discontinuation of eculizumab and is now on indefinite maintenance therapy. All 6 eculizumab treated survivors have a/multiple long-term complications including stage 3 chronic kidney disease (CKD) (n=2), persistent hypertension (n=1), congestive heart failure (n=1), and developmental delay and a seizure disorder (n=1). Three children were treated with supportive care only, 2 died of relapsed cancer and the third is alive with stage 2 CKD. While the 1 year overall survival was 78% (SE=14%), no survivor recovered all organ function even if promptly treated with eculizumab. Conclusion This experience broadens the spectrum of by describing cases requiring prolonged treatment or recurrence of after cessation of eculizumab. Further study is warranted to understand what patients are vulnerable to developing TMA and the depth and duration of response to eculizumab.