1.
Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplant Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation (EBMT), American Society for Transplantation and Cellular Therapy (ASTCT), Asia-Pacific Blood and Marrow Transplantation Group (APBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR)
Schoettler, M., Carreras, E., Cho, B., Dandoy, C. E., Ho, V. T., Jodele, S., Moissev, I., Sanchez-Ortega, I., Srivastava, A., Atsuta, Y., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND/RATIONALE Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplant (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis and multiple criteria are proposed without universal application. While some patients have a self-resolving disease, others progress to multi-organ failure and/or death. Poor prognostic features are also not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers have precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives, forming an expert panel to come to a consensus on diagnostic and prognostic criteria. METHODS The panel reviewed literature, generated consensus statements using the Delphi Method regarding diagnostic and prognostic features of TA-TMA, and identified future directions of investigation. SUMMARY OF CONSENSUS STATEMENTS Consensus was reached on four key concepts. 1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue. However, a biopsy is not required. 2) Consensus diagnostic criteria are proposed using modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥ 4/7 following features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment, hemoglobin decline by ≥1 gm/dL, or new onset transfusion dependence, thrombocytopenia defined as failure to achieve platelet engraftment, higher than expected transfusion needs, refractory to platelet transfusions, or ≥ 50% reduction in baseline platelet count after full platelet engraftment, lactate dehydrogenase (LDH) >ULN, schistocytes, hypertension, sC5b-9>ULN and proteinuria (≥ 1mg/mg random urine protein creatinine ratio, rUPCR). 3) Patients with any of the following features have an increased risk of non-relapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2X ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft versus host disease, or infection (bacterial or viral). 4) All allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. If patients are diagnosed with TA-TMA, they should be risk stratified. Patients with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. FUTURE DIRECTIONS We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indication, and transplant characteristics. As these criteria are broadly utilized, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Lastly, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications such as steroid-refractory GVHD and infection, is critically needed.