sVEGF-R1 in acute non-infectious toxicity syndromes after pediatric allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute non-infectious toxicities, including sinusoidal obstruction syndrome (SOS), engraftment syndrome (ES) and capillary leak syndrome (CLS) among others. These complications are thought to be driven by a dysfunctional vascular endothelium, but the pathophysiological mechanisms remain incompletely understood, and the diagnoses are challenged by purely clinical diagnostic criteria that are partly overlapping, limiting the possibilities for progress in this field. There is, however, increasing evidence suggesting that these challenges may be met through the development of diagnostic biomarkers to improve diagnostic accuracy of pathogenetically homogenous entities, improved pre-transplant risk assessment and the early identification of patients with increased need for specific treatment. Soluble vascular endothelial growth factor receptor-1 (sVEGF-R1) is emerging as an important biomarker of endothelial damage in patients with trauma and sepsis but has not been studied in HSCT. OBJECTIVES: To investigate sVEGF-R1 as a marker of endothelial damage in pediatric HSCT patients by exploring associations with SOS, CLS, ES, and acute graft-versus-host disease (aGvHD). METHODS: We prospectively included 113 children undergoing myeloablative HSCT and measured sVEGF-R1 in plasma samples obtained weekly during the early period of transplantation and 3 months post-transplant. RESULTS: All over, sVEGF-R1 levels were significantly increased from day +7 after graft infusion, peaking at day +30, most pronounced in patients receiving busulfan. Patients considered to be at increased risk of SOS and therefore commenced on prophylactic defibrotide had significantly elevated levels of sVEGF-R1 before start of conditioning (446 pg/mL vs. 281 pg/mL, p = 0.0035), and this treatment appeared to stabilize sVEGF-R1 levels compared to patients not treated with defibrotide. Thirteen (11.5%) children meeting the modified Seattle criteria for SOS at median day +8 (1-18), had significantly elevated sVEGF-R1 levels on day +14 (489 pg/mL vs. 327 pg/mL, p = 0.007). In contrast. sVEGF-R1 levels in the much broader group of patients (45.1%) meeting EBMT-SOS criteria, including patients with very mild disease, did not overall differ in sVEGF-R1 levels, but higher sVEGF-R1 levels were seen in EBMT-SOS patients with an increased need for diuretic treatment. Importantly, sVEGF-R1 levels were not associated with ES and CLS but were significantly increased on day +30 in patients with grade III-IV aGvHD (OR = 4.2 pr. quartile, p = 0.023). CONCLUSION: VEGF-R1 levels are found to be increased in pediatric patients developing SOS, reflecting the severity of morbidity. sVEGF-R1 were unassociated with both CLS and ES. The potential of sVEGF-R1 as a clinically useful biomarker for SOS should be further explored to improve pre-transplant SOS-risk assessment, SOS-severity grading, and to guide treatment.

Plasma Levels of MRP-8/14 Associate With Neutrophil Recovery, Bacterial Bloodstream Infections, and Engraftment Syndrome Following Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.

Neutrophil engraftment is essential for the successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT), but neutrophil activation may also induce transplant-related complications. Myeloid-related protein (MRP)-8/14 is expressed in granulocytes during inflammatory conditions and secreted in response to tissue damage along with the release of pro-inflammatory cytokines together with leukocyte recruitment and activation. In this study, we investigated associations between levels of the neutrophil activition marker MRP-8/14, neutrophil recovery and toxicities after pediatric HSCT. We included 73 children undergoing allogeneic HSCT using bone marrow or peripheral blood stem cell grafts from matched sibling or unrelated donors. Plasma levels of MRP-8/14 were measured by enzyme-linked immunosorbent assay from preconditioning until 6 months after transplantation. Overall, MRP-8/14 levels decreased from pre-conditioning to a nadir at day 7 and then rose again until day 28, preceding the reappearance of neutrophils. MRP-8/14 levels were significantly reduced at day 14 in patients with delayed neutrophil engraftment compared with patients who engrafted by day 21 (0.20 versus 0.48 µg/mL, P = .0012) and in patients who developed bacterial bloodstream infections compared to patients without this complication (0.2 versus 0.36 µg/mL, P = .048). Patients developing engraftment syndrome had significantly elevated MRP-8/14 levels at day 7 and 21 compared to patients without engraftment syndrome (0.32 versus 0.2 µg/mL, P = .042 and 1.9 versus 0.80 µg/mL, P = .039, respectively), as well as increased neutrophil counts from day 9 to 25 (P ≤ .016). Similarly, neutrophil counts were increased at day 13 to 17 in patients with acute graft-versus-host disease grade III-IV compared with grade 0-II. This study is the first to monitor neutrophil activation by MRP-8/14 in HSCT patients in relation to infectious, as well as noninfectious post-transplantation complications. Our results provide increased insights into the pathophysiology of these complications, and further studies should explore the potential use of MRP-8/14 as a clinically useful biomarker.

Assessment of the proposed EBMT pediatric criteria for diagnosis and severity grading of sinusoidal obstruction syndrome.

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the proposed pediatric EBMT criteria along with the Baltimore and modified Seattle criteria in a population-based cohort. Eighty-seven children (1.1-17.3 years) undergoing myeloablative HSCT from 2010 to 2017 were consecutively included at the Danish National Transplantation Center. In total, 39 (44.8%) patients fulfilled the EBMT criteria and 30 patients (35%) fulfilled the criteria for severe or very severe SOS. Nine (10.3%) patients fulfilled the modified Seattle criteria while none met the Baltimore criteria. Patients fulfilling the EBMT criteria for SOS had longer primary admission (31 days (23-183) vs. 27 days (17-61), p = 0.001), were treated more intensively with diuretics within the first 3 months (29 days (0-90) vs. 3.5 days (0-90), p < 0.0001), and had a longer time to stable platelet counts >50 × 109/L (32 days (16-183) vs. 23 days (14-101), p < 0.0001). Two patients, fulfilling neither Baltimore nor Seattle criteria, but selectively fulfilling EBMT criteria, died of treatment-related acute inflammatory complications within 1 year post-HSCT. In conclusion, application of the pediatric EBMT diagnostic and severity criteria may be helpful in identifying patients at increased risk of severe treatment-related complications and mortality, although with a risk of over-diagnosing SOS.