New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy

• Published in: Transfusion and apheresis science 2016-04, Vol.54 (2), p.181-190
• Main Authors: Jodele, Sonata, Dandoy, Christopher E, Myers, Kasiani C, El-Bietar, Javier, Nelson, Adam, Wallace, Gregory, Laskin, Benjamin L
• Format: Article
• Language: English
• Subjects: Adolescent; Allografts; Child; Child, Preschool; Complement; Eculizumab; Female; Health technology assessment; Hematology, Oncology and Palliative Medicine; Hematopoietic stem cell transplant; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Infant; Male; TA-TMA; Thrombotic Microangiopathies - diagnosis; Thrombotic Microangiopathies - etiology; Thrombotic Microangiopathies - physiopathology; Thrombotic Microangiopathies - therapy; Thrombotic microangiopathy
• ISSN: 1473-0502; 1878-1683
• DOI: 10.1016/j.transci.2016.04.007

Abstract Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is an understudied complication of HSCT that significantly affects transplant-related morbidity and mortality. Over the past several decades, the cause of TA-TMA has remained unknown, limiting treatment options to non-specific therapies adapted from other diseases. Recent prospective studies dedicated to the study of TA-TMA have provided new insights into the pathogenesis of, and genetic susceptibility to TA-TMA, raising awareness of this important transplant complication and allowing for the identification of potentially novel therapeutic targets. Specifically, many patients with TA-TMA develop multi-organ tissue injury through endothelial damage mediated by the activation of the complement pathway, leading to rational therapeutic strategies including complement blockade. We present survival curves for pediatric patients with high-risk TA-TMA who were treated with the terminal complement blocker eculizumab (n=30) and historical controls from a prospective observational TA-TMA study with the same high-risk TMA features who did not receive eculizumab (n=11). Those receiving eculizumab had better survival than untreated patients (62% versus 9% at 1 year from TA-TMA diagnosis, p=0.0007) despite the fact that there were no significant differences in age (mean 5.3 years (range 3.6-11.1 years) for treated and 5.2 (1.8-11.8 years) for untreated individuals), with a similar fraction undergoing unrelated allogeneic transplants (approximately two-thirds), for a range of similarly distributed conditions (approximately 30% bone marrow failure, 45% immune deficiency, 10% benign hematology, and 10% malignancy). This new knowledge has the potential to favorably influence clinical practice and change the standard of care for how patients with TA-TMA are managed.