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Browsing by Author "Krance, Robert A."
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Item A biomarker panel for risk of early respiratory failure following hematopoietic cell transplantation(American Society of Hematology, 2022) Rowan, Courtney M.; Smith, Lincoln; Sharron, Matthew P.; Loftis, Laura; Kudchadkar, Sapna; Duncan, Christine N.; Pike, Francis; Carpenter, Paul A.; Jacobsohn, David; Bollard, Catherine M.; Cruz, Conrad Russell Y.; Malatpure, Abhijeet; Farag, Sherif; Renbarger, Jamie; Little, Morgan R.; Gafken, Phillip R.; Krance, Robert A.; Cooke, Kenneth R.; Paczesny, Sophie; Pediatrics, School of MedicinePlasma biomarkers associated with respiratory failure (RF) following hematopoietic cell transplantation (HCT) have not been identified. Therefore, we aimed to validate early (7 and 14 days post-HCT) risk biomarkers for RF. Using tandem mass spectrometry, we compared plasma obtained at day 14 post-HCT from 15 patients with RF and 15 patients without RF. Six candidate proteins, from this discovery cohort or identified in the literature, were measured by enzyme-linked immunosorbent assay in day-7 and day-14 post-HCT samples from the training (n = 213) and validation (n = 119) cohorts. Cox proportional-hazard analyses with biomarkers dichotomized by Youden's index, as well as landmark analyses to determine the association between biomarkers and RF, were performed. Of the 6 markers, Stimulation-2 (ST2), WAP 4-disulfide core domain protein 2 (WFDC2), interleukin-6 (IL-6), and tumor necrosis factor receptor 1 (TNFR1), measured at day 14 post-HCT, had the most significant association with an increased risk for RF in the training cohort (ST2: hazard ratio [HR], 4.5, P = .004; WFDC2: HR, 4.2, P = .010; IL-6: HR, 6.9, P < .001; and TFNR1: HR, 6.1, P < .001) and in the validation cohort (ST2: HR, 23.2, P = .013; WFDC2: HR, 18.2, P = .019; IL-6: HR, 12.2, P = .014; and TFNR1: HR, 16.1, P = .001) after adjusting for the conditioning regimen. Using cause-specific landmark analyses, including days 7 and 14, high plasma levels of ST2, WFDC2, IL-6, and TNFR1 were associated with an increased HR for RF in the training and validation cohorts. These biomarkers were also predictive of mortality from RF. ST2, WFDC2, IL-6 and TNFR1 levels measured early posttransplantation improve risk stratification for RF and its related mortality.Item Prospective assessment of risk biomarkers of sinusoidal obstruction syndrome after hematopoietic cell transplantation(The American Society for Clinical Investigation, 2023-05-22) Han, Yan; Bidgoli, Alan; DePriest, Brittany P.; Méndez, Alejandra; Bijangi-Vishehsaraei, Khadijeh; Perez-Albuerne, Evelio D.; Krance, Robert A.; Renbarger, Jamie; Skiles, Jodi L.; Choi, Sung W.; Liu, Hao; Paczesny, Sophie; Biostatistics and Health Data Science, School of MedicineBACKGROUND: Currently, no laboratory tests exist to stratify for the risk of developing sinusoidal obstruction syndrome (SOS), an early endothelial complication after hematopoietic cell transplantation (HCT). Risk biomarkers of SOS have not been verified in a prospective cohort accounting for differences between practices across institutions. Herein, we aimed to define risk groups for SOS occurrence using 3 proteins: L-ficolin, hyaluronic acid (HA), and stimulation 2 (ST2). METHODS: Between 2017 and 2021, we prospectively accrued 80 pediatric patients across 4 US centers. Biomarkers were tested by ELISA blind to patient groupings and associated with SOS incidence on day 35 after HCT, and overall survival (OS) on day 100 after HCT. Cutpoints were identified using retrospective cohorts and applied to the prospective cohort. RESULTS: Combination of the 3 biomarkers measured on day 3 after HCT in the prospective cohort provided 80% (95% CI 55%–100%) sensitivity and 73% (95% CI 62%–83%) specificity for risk of SOS occurrence. Patients with low L-ficolin were 9 times (95% CI 3–32) more likely to develop SOS, while patients with high HA and ST2 were 6.5 (95% CI 1.9–22.0) and 5.5 (95% CI 2.3–13.1) times more likely to develop SOS. These 3 markers also predicted worse day 100 OS — L-ficolin: HR, 10.0 (95% CI 2.2–45.1), P = 0.0002; HA: HR, 4.1 (95% CI 1.0–16.4), P = 0.031; and ST2: HR, 3.9 (95% CI 0.9–16.4), P = 0.04. CONCLUSION: L-ficolin, HA, and ST2 levels measured as early as 3 days after HCT improved risk stratification for SOS occurrence and OS and may guide risk-adapted preemptive therapy.Item Safety and feasibility of virus-specific T cells derived from umbilical cord blood in cord blood transplant recipients(American Society of Hematology, 2019-07-23) Abraham, Allistair A.; John, Tami D.; Keller, Michael D.; Cruz, C. Russell N.; Salem, Baheyeldin; Roesch, Lauren; Liu, Hao; Hoq, Fahmida; Grilley, Bambi J.; Gee, Adrian P.; Dave, Hema; Jacobsohn, David A.; Krance, Robert A.; Shpall, Elizabeth. J.; Martinez, Caridad A.; Hanley, Patrick J.; Bollard, Catherine M.; Biostatistics, IU School of MedicineAdoptive transfer of virus-specific T cells (VSTs) has been shown to be safe and effective in stem cell transplant recipients. However, the lack of virus-experienced T cells in donor cord blood (CB) has prevented the development of ex vivo expanded donor-derived VSTs for recipients of this stem cell source. Here we evaluated the feasibility and safety of ex vivo expansion of CB T cells from the 20% fraction of the CB unit in pediatric patients receiving a single CB transplant (CBT). In 2 clinical trials conducted at 2 separate sites, we manufactured CB-derived multivirus-specific T cells (CB-VSTs) targeting Epstein-Barr virus (EBV), adenovirus, and cytomegalovirus (CMV) for 18 (86%) of 21 patients demonstrating feasibility. Manufacturing for 2 CB-VSTs failed to meet lot release because of insufficient cell recovery, and there was 1 sterility breach during separation of the frozen 20% fraction. Delayed engraftment was not observed in patients who received the remaining 80% fraction for the primary CBT. There was no grade 3 to 4 acute graft-versus-host disease (GVHD) associated with the infusion of CB-VSTs. None of the 7 patients who received CB-VSTs as prophylaxis developed end-organ disease from CMV, EBV, or adenovirus. In 7 patients receiving CB-VSTs for viral reactivation or infection, only 1 patient developed end-organ viral disease, which was in an immune privileged site (CMV retinitis) and occurred after steroid therapy for GVHD. Finally, we demonstrated the long-term persistence of adoptively transferred CB-VSTs using T-cell receptor-Vβ clonotype tracking, suggesting that CB-VSTs are a feasible addition to antiviral pharmacotherapy.