Management of a Complex Case of Transplant-Associated Thrombotic Microangiopathy in a Pediatric Patient with High-Risk Neuroblastoma
Authors: Olaosebikan Rasaq , Smink Gayle M 
Published: December 2024

Introduction
We present a case of a 4-year-old female with high-risk neuroblastoma complicated by transplant-associated thrombotic microangiopathy (TA-TMA). TA-TMA is a rare but severe complication of stem cell transplantation and includes microangiopathic hemolytic anemia, renal dysfunction, and neurologic changes. TA-TMA and resulting complications can be fatal. This case outlines the challenges of managing TA-TMA in a patient with neuroblastoma.
Case Presentation
A 4-year-old female with stage IV high-risk neuroblastoma initially presented with a left adrenal primary tumor and diffuse bone metastases, including sphenoid bones, calvarium, entire spine, and sternum. Bone marrow evaluation at diagnosis showed greater than 80% involvement. She underwent induction chemotherapy per Children's Oncology Group (COG) protocol ANBL0532, which included six cycles of chemotherapy and a laparoscopic left adrenalectomy following the completion of cycle 5 of chemotherapy. Pathology showed negative margins with 35% tumor necrosis.
Restaging before autologous bone marrow transplant showed a partial response to treatment, with improved MIBG-avid disease and no evidence of bone marrow involvement. Consolidation therapy with tandem autologous bone marrow transplant was as per COG ANBL1531. Disease response following consolation showed continued response to treatment. The patient proceeded with proton beam radiation, targeting the primary tumor site along with residual sites of MIBG avid disease (skull, spine, pelvis, and left femur).
After radiation, the patient developed hypertension and thrombocytopenia. This led to the diagnosis of TA-TMA, complicated by persistent hypertension and renal failure. The patient initially required platelet transfusions as well as aggressive treatment for hypertension. Initial treatment included Eculizumab with minimal response. Treatment was changed to Narsoplimab (OMS721), and Defibrotide was added with minimal response. Approval from Omeros Pharmaceuticals, the FDA, and institutional IRB was obtained for the compassionate use of Narsoplimab (OMS721) for TA-TMA. Defibrotide was discontinued, and further therapy with plasmapheresis/PLEX (Plasma Exchange) and Rituximab was added. Following the initiation of plasmapheresis, her TA-TMA improved, and she did not require ongoing transfusion support. Her other laboratory tests normalized, including evaluation for schistocytes, LDH, haptoglobin, CH50, and SC5b9. With improvement in her TA-TMA, she was started on Eflornithine (DFMO) for the treatment of her neuroblastoma. Following the initiation of DFMO, she developed thrombocytopenia and declining haptoglobin, with an increase in LDH, SC5b9, and CH50, consistent with TA-TMA recurrence. DFMO was discontinued, and plasmapheresis/PLEX was restarted. Re-initiation of treatment of her TA-TMA improved her laboratory findings, including improvement of platelet count, LDH, and haptoglobin.
Currently, the patient has renal failure, necessitating peritoneal dialysis. She also continues to have hypertension treated with multiple antihypertensive medications. Treatment of her TA-TMA is currently twice-weekly plasmapheresis/PLEX. Recent imaging shows no active neuroblastoma.
Discussion
Transplant-associated thrombotic microangiopathy is a rare but severe side effect of hematopoietic stem cell transplant. TA-TMA is characterized by microvascular hemolytic anemia, endothelial damage, and complement dysregulation. This can lead to end organ dysfunction, as detailed in this case. The mainstay of treatment includes complement inhibition, supportive care, and the management of end-organ dysfunction. Without prompt recognition and treatment, the risk of morbidity and mortality remains high. This case highlights the challenges in managing high-risk neuroblastoma complicated by TA-TMA. The case underscores the necessity of a multidisciplinary approach to address TA-TMA and highlights the importance of adjusting therapy based on the response.
Conclusion
TA-TMA in patients with high-risk neuroblastoma is rare but is a serious complication of treatment, and the management is complex. This case demonstrates the need for a coordinated, personalized treatment strategy to optimize treatment outcomes.