P1344: METHODOLOGY OF AN INTERNATIONAL MULTI-CENTER RETROSPECTIVE REVIEW OF TRANSPLANT-ASSOCIATED THROMBOTIC MICROANGIOPATHY (TA-TMA) BY THE TA-TMA WORKING GROUP

Abstract

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious and potentially life-threatening complication after allogeneic hematopoietic cell transplantation (alloHCT). Multiple sets of clinical diagnostic criteria for TA-TMA have been developed in adult and pediatric settings based on single-institution chart review or expert panels, but none have been rigorously evaluated across multiple centers to assess validity or reproducibility. The TA-TMA Working Group is conducting a multi-national, multi-center, retrospective study to identify and confirm potential adult and pediatric cases of TA-TMA. The aim of creating a large cohort of adjudicated TA-TMA cases is to better understand the incidence, risk factors, clinical outcomes, and healthcare resource utilization (HRU) associated with this condition. Aims: To describe the multiple-adjudication methodology employed to confirm diagnosis of TA-TMA across adult and pediatric transplant centers. Methods: Twelve US and EU centers retrospectively screened medical records of patients who received alloHCT between 2015 and 2017 using 5 criteria: schistocytosis (>2 per high-power field); LDH level above ULN; doubling of baseline creatinine; platelet refractoriness (50% decrease in platelet count and/or platelet count less than individual center’s transfusion threshold x 4 days despite transfusions); and decreased haptoglobin. Cases meeting ≥3 criteria within a 10-day period during the first 12 months after alloHCT were considered potential TA-TMA and were further evaluated by 2 clinicians from each transplant center. Patients who had a positive biopsy, were diagnosed with TA-TMA or aHUS, or had received eculizumab following alloHCT were considered to have definite TA-TMA. Of all positive cases determined by local adjudications, 30% will be randomly selected for central adjudication by independent adult and pediatric adjudication committees. Central adjudicators have access to relevant laboratory and radiologic data. In cases with 2 discordant decisions, a third central adjudicator will be assigned to break the tie. In cases of 3 discordant decisions regarding the diagnosis of TA-TMA, the case will be forwarded for discussion led by the central adjudication chair. All cases determined as positive TA-TMA after local and central adjudication will be aggregated and analyzed to evaluate clinical outcomes, risk factors for TA-TMA, disease course, survival and non-relapse mortality, and HRU. Results: As of March 1, 2022, 3,732 cases have been screened at 11 transplant centers and 836 were considered potential TA-TMA that met ≥3 criteria. To date, local adjudication at 8 centers determined 179 cases were positive TA-TMA. Due to variations in laboratory standards at different centers, a challenge encountered in this study was harmonization of screening criteria. For example, labs at several centers did not quantify number of schistocytes as part of their CBC, which restricted screening of potential TA-TMA cases to 4 criteria, leading to some cases being categorized as “unknown.” These outcomes highlight the differences in assessing TA-TMA at multiple centers. Summary/Conclusion: This is the first multi-center comprehensive retrospective study to evaluate TA-TMA with a formalized process for independent local and central adjudication to verify TA-TMA diagnosis. The large cohort of TA-TMA cases identified in this study should enable validation of current and future diagnostic criteria, improve our understanding of prognostic/risk factors, and enhance awareness of this disease.