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sVEGF-R1 in acute non-infectious toxicity syndromes after pediatric allogeneic hematopoietic stem cell transplantation
Horan, D. E., Kielsen, K., Weischendorff, S. W., Sørum, M. E., Kammersgaard, M. B., Ifversen, M., Nielsen, C., Ryder, L. P., Johansson, P. I., Müller, K.
Transplant immunology. 2023;82:101975
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Editor's Choice
Abstract
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.
PICO Summary
Population
We prospectively included 113 children undergoing myeloablative HSCT
Intervention
Measurement of sVEGF-R1 in plasma samples obtained weekly during the early period of transplantation and 3 months post-transplant to explore associations with sinusoidal obstruction syndrome (SOS), capillary leak syndrome (CLS), engraftment syndrome (ES), and acute graft-versus-host disease (aGvHD)
Comparison
None
Outcome
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), 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). 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).
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Grade 3-4 cytokine release syndrome is associated with poor survival in haploidentical peripheral blood stem cell transplantation
Modi, D., Albanyan, O., Kim, S., Deol, A., Ayash, L., Ratanatharathorn, V., Uberti, J. P.
Leukemia & lymphoma. 2021;:1-11
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Editor's Choice
Abstract
The information on the impact of cytokine release syndrome (CRS) on haploidentical donor peripheral blood stem cell transplant (haploPBSCT) outcomes is limited. We retrospectively evaluated 98 patients who underwent haploPBSCT between June 2012 and June 2019 for the onset and severity of CRS per the ASTCT guidelines. The incidence of CRS was 93% (91/98). Outcomes were compared between grade 1-2 and 3-4 CRS. Eighty-one patients developed grade 1-2 CRS (89%) and 10 (11%) developed grade 3-4 CRS. Compared to grade 1-2 CRS, grade 3-4 CRS experienced adverse survival (73.7% vs. 30%, p<.001), inferior relapse-free survival (64.0% vs. 20%, p<.001), and higher non-relapse mortality (NRM) (16.4% vs. 60%, p<.001) at 1-year. Propensity score-based multivariable analyses revealed worse survival (HR 2.71, p=.04), and higher NRM (SHR 4.51, p=.006) with grade 3-4 CRS. Our study shows that grade 3-4 CRS was adversely associated with survival. Therefore, early identification and preventive strategies are warranted.
PICO Summary
Population
Patients who underwent haploidentical peripheral blood stem cell transplantation (haploPBSCT) between June 2012 and June 2019 (n=98)
Intervention
Evaluation of the onset and severity of cytokine release syndrome (CRS)
Comparison
None
Outcome
The incidence of CRS was 93% (91/98). Outcomes were compared between grade 1-2 and 3-4 CRS. Eighty-one patients developed grade 1-2 CRS (89%) and 10 (11%) developed grade 3-4 CRS. Compared to grade 1-2 CRS, grade 3-4 CRS experienced adverse survival (73.7% vs. 30%), inferior relapse-free survival (64.0% vs. 20%), and higher non-relapse mortality (NRM) (16.4% vs. 60%) at 1-year. Propensity score-based multivariable analyses revealed worse survival (HR 2.71), and higher NRM (SHR 4.51) with grade 3-4 CRS.
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Hemophagocytic Lymphohistiocytosis and Graft Failure Following Unrelated Umbilical Cord Blood Transplantation in Children
Noguchi, M., Inagaki, J.
Journal of pediatric hematology/oncology. 2020
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Editor's Choice
Abstract
Hemophagocytic lymphohistiocytosis (HLH) following hematopoietic stem cell transplantation is closely correlated with graft failure and poor prognosis. Because of its rarity, the incidence, risk factors, and optimal treatment strategy are unclear. We analyzed data from cases of HLH following umbilical cord blood transplantation (UCBT) performed for pediatric patients at our center. Among 66 UCBT recipients, 5 developed HLH and imminent graft failure. The median time of diagnosis of HLH was 22 (range, 19 to 30) days after UCBT, and the cumulative incidence of HLH was 7.6% (95% confidence interval, 2.8-15.7) at day 60. In univariate analysis, the cumulative incidence of HLH was significantly higher in patients with infused CD34 cells <1.0x10/kg than in patients with higher CD34 cells. Patients with preengraftment infection showed a trend toward higher incidence of HLH compared with patients without any infection. All 5 patients with HLH received corticosteroids and low-dose etoposide (VP-16), with or without high-dose intravenous immunoglobulin. Following these treatments, successful engraftment was observed in 2 patients. Corticosteroids and low-dose VP-16 may be worthy of a trial before attempting salvage hematopoietic stem cell transplantation. Further analyses are required to identify risk factors and to develop methods for prophylaxis, diagnosis, and treatment of HLH.
PICO Summary
Population
Paediatric patients who underwent umbilical cord blood transplantation (UCBT) (n=66)
Intervention
Identifying cases of haemophagocytic lymphohistiocytosis (HLH) following transplant
Comparison
None
Outcome
Among 66 UCBT recipients, 5 developed HLH and imminent graft failure. The median time of diagnosis of HLH was 22 (range, 19 to 30) days after UCBT, and the cumulative incidence of HLH was 7.6% at day 60. In univariate analysis, the cumulative incidence of HLH was significantly higher in patients with infused CD34 cells <1.0x10/kg than in patients with higher CD34 cells. Patients with preengraftment infection showed a trend toward higher incidence of HLH compared with patients without any infection. All 5 patients with HLH received corticosteroids and low-dose etoposide (VP-16), with or without high-dose intravenous immunoglobulin. Following these treatments, successful engraftment was observed in 2 patients.
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Prior Gemtuzumab Ozogamicin Exposure in Adults With Acute Myeloid Leukemia Does Not Increase Hepatic Veno-occlusive Disease Risk After Allogeneic Hematopoietic Cell Transplantation: A CIBMTR Analysis
Ho, V. T., Martin, A. S., Perez, W. S., Steinert, P., Zhang, M. J., Chirnomas, D., Hoang, C. J., Loberiza, F. R., Jr., Saber, W.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
Gemtuzumab ozogamicin (GO) therapy prior to allogeneic hematopoietic cell transplantation (alloHCT) has been historically associated with an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with acute myeloid leukemia (AML). The current analysis examined VOD/SOS risk and outcomes in a cohort of patients who in recent years reported to the Center for International Blood & Marrow Transplant Research. Adults with AML who had GO exposure prior to myeloablative alloHCT were matched 1:4 by age and disease status at transplant to recipients without GO exposure (controls). A total of 137 patients with GO exposure and 548 matched controls who underwent alloHCT between 2008 and 2011 were included in this analysis. With a median approximately 8-year follow-up of survivors, the 5-year overall survival probability was similar in the 2 cohorts: 38% and 38% in the GO-exposed versus control (P=.97) group. Incidence of VOD/SOS and severe VOD/SOS, respectively, at 100 days was 4% (95% confidence interval [CI]: 1-7) and 3% (95% CI: 1-6) in GO-exposed patients and 3% (95% CI: 2-5) and 1% (95% CI: 0-2) in controls. Correspondingly, among patients who developed VOD/SOS, 1-year survival probability after VOD/SOS diagnosis was 33% (95% CI: 5-72) and 27% (95% CI: 11-47) (P=.78). In multivariate analyses, GO exposure prior to alloHCT was not associated with an increased risk of VOD/SOS (odds ratio 1.10; P=.85) or death (hazard ratio 1.08; P=.57). Three (3%) deaths in the GO group and 3 (<1%) deaths in the control group were attributed to VOD/SOS. Our results suggest that GO treatment prior to myeloablative alloHCT in the recent era is not associated with an increased risk of post-transplant VOD/SOS or death.
PICO Summary
Population
Adults with acute myeloid leukaemia (n=685)
Intervention
Gemtuzumab ozogamicin (GO) therapy prior to myeloablative allogeneic transplant (n=137)
Comparison
Age- and disease-matched controls without GO exposure (n=548)
Outcome
The 5-year overall survival probability was similar in the 2 cohorts: 38% and 38% in the GO-exposed versus control group. Incidence of VOD/SOS and severe VOD/SOS, respectively, at 100 days was 4% and 3% in GO-exposed patients and 3% and 1% in controls. Correspondingly, among patients who developed VOD/SOS, 1-year survival probability after VOD/SOS diagnosis was 33% and 27%. In multivariate analyses, GO exposure prior to alloHCT was not associated with an increased risk of VOD/SOS or death. Three (3%) deaths in the GO group and 3 (<1%) deaths in the control group were attributed to VOD/SOS.
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"Risk Score for Development of Veno-Occlusive Disease After Allogeneic Hematopoietic Cell Transplant"
Strouse, C., Zhang, Y., Zhang, M. J., DiGilio, A., Pasquini, M., Horowitz, M. M., Lee, S., Ho, V., Ramanathan, M., Chinratanalab, W., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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Editor's Choice
Abstract
BACKGROUND A risk score identifying patients at high risk for veno-occlusive disease (VOD) may aid efforts to study preventive strategies for this uncommon complication of hematopoietic cell transplantation (HCT). METHODS Patients receiving a first allogeneic HCT between 2008-2013 as reported to the Center for International Blood & Marrow Transplant Research (N=13,097) were randomly divided into training and validation sets. Independent prognostic factors for development of VOD by day+100 post HCT were identified with a multivariate logistic regression model. A risk score was constructed in the training set using the significant factors and confirmed in the validation set. RESULTS Baseline characteristics of the training and validation sets were balanced. In total, 637 patients (4.9%) developed VOD by day+100. Younger age, positive hepatitis B/C serology (HBV, HCV), lower Karnofsky performance score (KPS), use of sirolimus, disease, disease status at transplant, and conditioning regimen were independent prognostic factors. Myeloablative (MAC) regimens were associated with higher risk of VOD. Busulfan-based MAC regimens guided by pharmacokinetic monitoring (PK) were associated with higher risk than those without PK. The patients were stratified into 4 distinct, statistically significantly different groups by their risk score percentile. CONCLUSION This pre-transplant risk score successfully stratified allogeneic HCT patients by risk of developing VOD, was validated in an independent set, and demonstrated strong discriminatory ability to identify a high-risk cohort.
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Improved short- and long-term outcome of allogeneic stem cell recipients admitted to the intensive care unit: a retrospective longitudinal analysis of 942 patients
Lueck, C., Stadler, M., Koenecke, C., Hoeper, M. M., Dammann, E., Schneider, A., Kielstein, J. T., Ganser, A., Eder, M., Beutel, G.
Intensive care medicine. 2018
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Editor's Choice
Abstract
PURPOSE Intensive care unit (ICU) admission of allogeneic hematopoietic stem cell transplant (HSCT) recipients is associated with relatively poor outcome. Since longitudinal data on this topic remains scarce, we analyzed reasons for ICU admission as well as short- and long-term outcome of critically ill HSCT recipients. METHODS A total of 942 consecutive adult patients were transplanted at Hannover Medical School from 2000 to 2013. Of those, 330 patients were at least admitted once to the ICU and included in this retrospective study. To analyze time-dependent improvements, we separately compared patient characteristics as well as reasons and outcome of ICU admission for the periods 2000-2006 and 2007-2013. RESULTS The main reasons for ICU admission were acute respiratory failure (ARF) in 35%, severe sepsis/septic shock in 23%, and cardiac problems in 18%. ICU admission was clearly associated with shortened survival (p < 0.001), but survival of ICU patients after hospital discharge reached 44% up to 5 years and was comparable to that of non-ICU HSCT patients. When ICU admission periods were compared, patients were older (48 vs. 52 years; p < 0.005) and the percentage of ARF as leading cause for ICU admission decreased from 43% in the first to 30% in the second period. Over time ICU and hospital survival improved from 44 to 60% (p < 0.01) and from 26 to 43% (p < 0.01), respectively. The 1- and 3-year survival rate after ICU admission increased significantly from 14 to 32% and from 11 to 23% (p < 0.01). CONCLUSIONS Besides ARF and septic shock, cardiac events were especially a major reason for ICU admission. Both short- and long-term survival of critically ill HSCT patients has improved significantly in recent years, and survival of HSCT recipients discharged from hospital is not significantly affected by a former ICU stay.