Early Detection and Treatment of Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy (HSCT-TMA)

PROJECT SUMMARY/ABSTRACT Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) is a common and often devastating condition following allogeneic hematopoietic stem cell transplantation, causing injury to small vessels, particularly in the kidney. HSCT-TMA occurs in 13-40% of patients post-HSCT, and is associated with a considerably higher risk of kidney replacement therapy (KRT) and death. There is a dire need to identify early markers of HSCT-TMA, as well as treatments to prevent morbidity and mortality. In Aim 1, we will examine whether markers of endothelial injury and complement overactivation are early predictors of HSCT-TMA. We will leverage Dana-Farber Cancer Institute’s Pasquarello Sample Bank, which contains plasma and serum samples from >3000 adult allogeneic HSCT patients. In a nested case-control study, we will obtain serum from 50 adults with HSCT-TMA and 50 without HSCT-TMA. Samples will be obtained prior to HSCT and at day 7 following HSCT. In Aim 1A, we will examine whether baseline-adjusted markers of endothelial injury (von Willebrand factor, soluble fms-like tyrosine kinase 1, and thrombomodulin) are elevated at day 7 in patients with vs. without HSCT-TMA. In Aim 2A, we will test for complement-mediated cell death in patients with vs. without HSCT-TMA at the same time points using the modified Ham test (primary exposure), a validated, cell-based assay, in collaboration with hematologists at Johns Hopkins with expertise performing this test. We will also measure other markers of complement activity (annexin 2, factor D, properdin, complement factor H) at each time point as secondary exposures. In Aim 2, we will examine whether treatment with eculizumab, a terminal complement inhibitor, is associated with improved renal and overall outcomes in patients with HSCT-TMA. Using data from >12,000 patients treated with HSCT at 4 major cancer centers, we will test whether early treatment of HSCT-TMA with eculizumab (i.e., within the first month of diagnosis) is associated with a lower risk of KRT or death compared to later or no treatment with eculizumab. We will apply the principles of target trial emulation to address common biases in observational studies. This proposal builds upon the PI’s expertise in onconephrology and expands on newly-obtained skills in biomarker and causal inference analyses. It also proposes a new direction focused on HSCT recipients, who are at high risk for kidney-related complications. The results of the proposed projects will have important implications for HSCT-TMA, as they will lay the foundation for larger prospective studies designed to develop and validate a larger panel of predictive markers, and for randomized clinical trials testing the efficacy of therapies for HSCT-TMA.