Prospective Multi-Center Study of Pediatric Cellular Therapy Patients at Risk for Endothelial Dysfunction, Sinusoidal Obstruction Syndrome and/or Multi-Organ Dysfunction Syndrome (POEM Interim Analysis): Baseline Levels of Circulating Angiogenic Factors May Predict Risk of Sinusoidal Obstructive Syndrome.

Pediatric and adolescent-young adult (P-AYA) patients undergoing hematopoietic cell transplantation (HCT) are at disproportionately higher risk of developing endotheliopathies including sinusoidal obstructive syndrome (SOS) and thrombotic microangiopathy (TMA) with potential for progression to pediatric multi-organ dysfunction syndrome (p-MODS). POEM, a multi-center prospective registry/biorepository at 12 Pediatric Acute Lung Injury and Sepsis Investigators (PALISI)-Network sites, aims to evaluate the proportion of P-AYA patients who develop endotheliopathies and/or p-MODS within 100 days of HCT and interrogate the proportion who develop abnormal levels of circulating angiogenic factors within that period. Plasma was collected at baseline, day 0, and weekly for 100 days. An interim analysis of the first 150 subjects compared circulating factors at baseline (with start of preparative regimen) between all subjects who developed SOS (n=17) and controls (n=20) who did not, using luminex platform and an 18 factor angiogenesis panel. Controls were matched for age, HCT indication, race/ethnicity, sex, donor type. Sample at time of SOS diagnosis was matched to the corresponding weekly sample among controls. Overall incidence of SOS was 11%. The median age of subjects with SOS was 9 (range: 0.6-15.2) years. Subjects were predominantly male (59%), white (65%) and had a pre-HCT indication of acute leukemia (46%), inherited metabolic disorders (12%), immunodeficiency (12%) and juvenile myelomonocytic leukemia, hemoglobinopathy, neuroblastoma, inherited bone marrow failure and lymphoma (each 6% respectively). The majority received a myeloablative (71%), busulfan based (65%) preparative regimen and allogenic (94%), matched unrelated (58%) HCT with bone marrow (41%), cord blood (35%) and peripheral blood stem cell (24%) as donor source. Comparison of circulating angiogenic factors identified several factors that were significantly lower at baseline in patients who developed SOS compared to controls: CD31 (p< .0001), VEGF-D (p<.0005), EMMPRIN (p<.005), and Lyve-1 (p<.005). In contrast, at the point of SOS diagnosis, only two factors were lower in patients with SOS, BMP-9 (p < 0.005) and VEGF-D (p <0.05), while HGF (p<0.05) was higher in patients with SOS, at the time of diagnosis compared to controls. Patients who develop SOS may have different circulating angiogenic factors at baseline. This is important because it may lead to identification of a signature to predict which patients are at highest risk of SOS. Future work will validate these findings in a larger number of patients (total planned enrollment, n = 500) and will assess the predictive power of measuring CD31, VEGF-D, EMMPRIN, and Lyve-1 together at baseline in patients preparing for HCT.