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Incidence and Risk Factors of Early Onset VOD/SOS Differ in Younger vs Older Adults After Stem Cell Transplantation
Marcoux, C., Saliba, R. M., Wallis, W., Khazal, S. J., Ragoonanan, D., Rondon, G., Tewari, P., Popat, U. R., Oran, B., Olson, A. L., et al
Blood advances. 2024
Abstract
Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-SCT). While increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with post-transplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single center analysis of adult patients 18 years or older undergoing allo-SCT (N=1561) using predominately PTCy as GVHD prophylaxis (72%). We found a higher rate of VOD at 16.8% (20/119) in those aged ≤ 25 years compared to 3.8% (55/1442) in those >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Within patients aged 18-25 years, disease risk index (DRI) (31% with high/very high DRI vs 12% low/intermediate DRI; p=0.03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1, p=0.03) were the strongest predictors of VOD. Incidence of VOD in patients > 25 years of age consistently ranged between 3-5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase (AST), alanine aminotransferase (ALT)) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared to those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors in VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.
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2.
External Validation of the HIGH-2-LOW Model: A Predictive Score for Venous Thromboembolism after Allogeneic Transplant
Li, A., Martens, K. L., Nguyen, D., Basom, R., Rondon, G., Jin, S., Young, E., Amos, C. I., Lee, S. J., Davis, C., et al
American journal of hematology. 2022
Abstract
In patients undergoing hematopoietic cell transplantation (HCT), venous thromboembolism (VTE) remains a serious complication that lacks validated risk assessment models (RAM) to guide thromboprophylaxis. To address this dilemma, we performed a temporal and external validation study of the recently derived HIGH-2-LOW RAM. We selected adult patients undergoing allogeneic HCT from Fred Hutchinson Cancer Research Center (FHCRC) and MD Anderson Cancer Center (MDACC). Patients who died, received anticoagulation, or did not engraft platelets by day 30 were excluded. Primary outcomes were defined as overall VTE and pulmonary embolism +/- lower-extremity deep venous thromboembolism (PE/LE-DVT) by day 180. Covariates were weighted according to the original model, except that grade 2-4 GVHD was substituted for grade 3-4. Discrimination and calibration were assessed. A total of 765 patients from FHCRC and 954 patients from MDACC were included. Incident VTE by day 180 was 5.1% at FHCRC and 6.8% at MDACC. The HIGH-2-LOW score had a c-statistic of 0.67 (0.59-0.75) for VTE and 0.75 (0.64-0.81) for PE/LE-DVT at FHCRC, and 0.62 (0.55-0.70) for VTE and 0.70 (0.56-0.83) for PE/LE-DVT at MDACC. Twenty-five percent and 23% of patients were classified as high-risk (2+ points) in the two cohorts, respectively. High vs. low-risk was associated with OR of 2.80 (1.46-5.38) for VTE and 4.21 (1.82-9.77) for PE/LE-DVT at FHCRC, and OR of 3.54 (2.12-5.91) for VTE and 6.82 (2.30-20.16) for PE-LE-DVT at MDACC. The HIGH-2-LOW RAM identified allogeneic HCT recipients at high-risk for VTE in both validation cohorts. It can improve evidence-based decision-making for thromboprophylaxis post-transplant. This article is protected by copyright. All rights reserved.
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3.
Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy for Hemorrhagic Cystitis Following Allotransplantation
Olson, A., Lin, R., Marin, D., Rafei, H., Bdaiwi, M. H., Thall, P. F., Basar, R., Abudayyeh, A., Banerjee, P., Aung, F. M., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;:Jco2002608
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Editor's Choice
Abstract
PURPOSE BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.
PICO Summary
Population
Patients who developed BK-virus associated haemorrhagic cystitis (BKV-HC) following allogeneic transplantation (n=59)
Intervention
HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs)
Comparison
Matched-pair analysis of historical controls
Outcome
Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement.
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4.
Impact of anticoagulation on recurrent thrombosis and bleeding after hematopoietic cell transplantation
Martens, K. L., Amos, C. I., Hernandez, C. R., Kebriaei, P., da Costa, W. L., Jr., Basom, R., Davis, C., Kesten, M., Carrier, M., Garcia, D. A., et al
American journal of hematology. 2021
Abstract
History of venous thromboembolism (VTE) is prevalent among patients undergoing hematopoietic cell transplantation (HCT). Management of anticoagulation is particularly challenging as most patients will have chemotherapy-induced thrombocytopenia while awaiting engraftment post-HCT. We conducted a retrospective study of autologous and allogeneic HCT recipients with prior VTE from 2006-2015 to 1) compare anticoagulant strategies on short-term VTE recurrence and bleeding and 2) assess predictors for VTE recurrence beyond 30?days. After inverse probability of weighting, patients with VTE were allocated to two cohorts based on anticoagulant strategy at thrombocytopenia onset to assess primary outcomes of VTE recurrence and bleeding within 30?days post-HCT. Multivariable logistic regression model was designed to assess the association of 100-day VTE recurrence by the HIGH-2-LOW VTE risk assessment score and whether patients resumed anticoagulation at platelet recovery. Thirteen percent of recipients had VTE prior to HCT; of those meeting inclusion criteria, 227 continued anticoagulation and 113 temporarily discontinued. Anticoagulant strategy was not significantly associated with decreased risk of VTE recurrence within 30?days (3% vs 4%, p=0.61); however, risk of overall bleeding was non-significantly higher in those who continued vs. discontinued anticoagulation (41% vs 31%, p=0.08). Among 250 allogeneic HCT patients, every 1-point increase of HIGH-2-LOW score was significantly associated with VTE recurrence at 100?days (OR 1.57 [95% CI 1.10-2.23]), while anticoagulation resumption upon platelet engraftment was associated with lower recurrent risk (OR 0.48 [0.20-1.14]). Temporarily withholding anticoagulation during thrombocytopenia may optimize risk-benefit tradeoffs, though additional strategies are essential to prevent VTE recurrence after hematopoietic recovery. This article is protected by copyright. All rights reserved.
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Improved detection of sinusoidal obstructive syndrome using pediatric-AYA diagnostic criteria and severity grading
Ragoonanan, D., Khazal, S. J., Wang, J., Payne, A., Kohorst, M., Harden, A., Tewari, P., Petropoulos, D., Shoberu, B., Kebriaei, P., et al
Bone marrow transplantation. 2020
Abstract
New diagnostic criteria and severity grading for sinusoidal obstructive syndrome (SOS) among pediatric and adolescent young adult (AYA) patients have been recently endorsed by international consensus. The extent to which these have been adopted in the US remains unclear. We sought to assess the potential impact via retrospective application of these criteria among patients treated at a large academic center in the United States. This is a single center retrospective study of pediatric-AYA patients who underwent hematopoietic cell transplantation (HCT) between July 2009 and 2019. The incidence of SOS was assessed using historic Baltimore and Seattle diagnostic criteria and compared with more recent guidelines (pEBMT) as proposed by the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation. Among 226 patients, application of the pEBMT diagnostic criteria was associated with a higher incidence (15.9%) and earlier time to diagnosis of SOS (by 2.5-3 days) compared with the modified Seattle (12.3%), and Baltimore (6.6%) criteria, respectively. The pEBMT criteria were sensitive and highly specific. Refractory thrombocytopenia was present in 75% of patients at diagnosis. Approximately 61% of patients with SOS were anicteric at diagnosis, though the majority (94.4%) developed hyperbilirubinemia as SOS progressed over a median time of 4 (1-57) days. Application of pEBMT criteria may have resulted in earlier indication for definitive treatment by 3 days. Timely diagnosis and administration of definitive treatment of SOS has been associated with improved outcomes. Prospective studies may better characterize the risk factors and natural course of SOS using pEBMT criteria.
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6.
Idiopathic refractory ascites after allogeneic stem cell transplantation: a previously unrecognized entity
Varma, A., Abraham, S. C., Mehta, R. S., Saini, N. Y., Honhar, M., Rashid, M., Chen, J., Srour, S. A., Bashir, Q., Rondon, G., et al
Blood advances. 2020;4(7):1296-1306
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Abstract
At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)-related portal hypertension after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient [HVPG] >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension. From our institutional database, we identified 40 patients who developed IRA after allo-HSCT between 2004 and 2018. The patients' median age at the time of allo-HSCT was 54 years (range, 21-73 years). The median time to development of IRA after allo-HSCT was 80 days (range, 16-576 days). The median number of paracentesis was 3 (range, 1-11), and 15 (38%) patients had an intraperitoneal catheter placed for continued drainage of the rapidly accumulating ascites. Portal pressures were measured in 19 patients; 6 (15%) had moderate portal hypertension (HVPG 6-9 mm Hg), and 13 (33%) had severe portal hypertension (HVPG ≥ 10 mm Hg). Liver biopsy was performed in 24 patients. None of the patients met the criteria for classical VOD/SOS (clinical/histological) or cirrhosis (histological). The cumulative incidence of nonrelapse mortality was 63%, and the median survival duration after the development of the IRA was 7 months (range, 0.8-125.6 months). IRA is a poorly understood and often fatal complication of allo-HSCT.
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Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syndrome: an international expert position statement
Mahadeo, K. M., Bajwa, R., Abdel-Azim, H., Lehmann, L. E., Duncan, C., Zantek, N., Vittorio, J., Angelo, J., McArthur, J., Schadler, K., et al
The Lancet. Haematology. 2019
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Editor's Choice
Abstract
Sinusoidal obstructive syndrome, also known as hepatic veno-occlusive disease, is a potentially life-threatening complication that occurs in children undergoing haemopoietic stem-cell transplantation (HSCT). Differences in the incidence of genetic predisposition and clinical presentation of sinusoidal obstructive syndrome between children and adults have rendered the historical Baltimore and Seattle diagnostic criteria insufficient for children. In 2017, the European Society for Blood and Marrow Transplantation (EBMT) proposed the first paediatric diagnostic and severity grading guidelines for sinusoidal obstructive syndrome, intended for implementation across European centres. However, universally accepted paediatric criteria are needed to ensure prompt diagnosis, definitive treatment, and improved outcomes for children, adolescents, and young adults with sinusoidal obstructive syndrome, and to facilitate international clinical research collaboration. We convened an international panel of multidisciplinary experts including physicians with expertise in HSCT, paediatric intensive care, nephrology, hepatology, radiology, pathology, and transfusion medicine; HSCT advanced-practice providers and medical trainees; pharmacists; and translational and basic science researchers from the Pediatric Acute Lung Injury and Sepsis Investigators Network, the EBMT, the Pediatric Blood and Marrow Transplant Consortia, and several other institutions with extensive experience in sinusoidal obstructive syndrome. Panellists convened at The University of Texas, MD Anderson Cancer Center (Houston, TX, USA) in February, 2019, to evaluate the available evidence. In this expert position statement paper, we provide consensus recommendations for the international implementation of guidelines for the diagnosis, severity grading, and treatment of sinusoidal obstructive syndrome among children, adolescents, and young adults. We endorse universal adoption of paediatric diagnostic guidelines for sinusoidal obstruction syndrome as proposed by the EBMT, and provide implementation guidance for standardisation across centres; we have further proposed adjunctive use of age-appropriate organ-specific toxicity criteria for severity grading and provided prophylaxis and treatment considerations among children and adolescent and young adult patients. Key recommendations include: (1) liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of sinusoidal obstructive syndrome in children, adolescents, and young adults; (2) platelet refractoriness can be defined as a corrected count increment of less than 5000-7500 following at least two sequential ABO-compatible fresh platelet transfusions; (3) hepatomegaly is best defined as an absolute increase of at least 1 cm in liver length at the midclavicular line; and if a baseline measurement is not available, hepatomegaly can be defined as greater than 2 SDs above normal for age; and (4) the presence and volume of ascites can be categorised as mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all three regions with >1 cm fluid in at least two regions).
PICO Summary
Population
Paediatric patients with sinusoidal obstruction syndrome / hepatic veno-occlusive disease
Intervention
Guidelines produced by an international panel of multidisciplinary experts from the Pediatric Acute Lung Injury and Sepsis Investigators Network, the EBMT, the Pediatric Blood and Marrow Transplant Consortia, and several other institutions with extensive experience in sinusoidal obstructive syndrome.
Comparison
None
Outcome
Key recommendations include: (1) liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of sinusoidal obstructive syndrome in children, adolescents, and young adults; (2) platelet refractoriness can be defined as a corrected count increment of less than 5000-7500 following at least two sequential ABO-compatible fresh platelet transfusions; (3) hepatomegaly is best defined as an absolute increase of at least 1 cm in liver length at the midclavicular line; and if a baseline measurement is not available, hepatomegaly can be defined as greater than 2 SDs above normal for age; and (4) the presence and volume of ascites can be categorised as mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all three regions with >1 cm fluid in at least two regions).
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Etiologies and Impact of Readmission Rates in the First 180 Days After Hematopoietic Stem Cell Transplantation in Children, Adolescents, and Young Adults
Maher, O. M., Silva, J. G., Huh, W. W., Cuglievan, B., DePombo, A., Kebriaei, P., Park, M., Liu, D., Tillman, C., Tarek, N., et al
Journal of Pediatric Hematology/Oncology. 2017;39(8):609-613
Abstract
INTRODUCTION High rates of patients require readmission to the hospital within 6 months of hematopoietic stem cell transplantation (HSCT). We investigated the relationship between readmission rates and outcomes after HSCT in children, adolescents, and young adults (CAYA). MATERIALS AND METHODS A retrospective analysis of patients (26 years or younger) treated with HSCT was conducted. RESULTS A chart review of 435 CAYA who underwent HSCT from 2008 to 2015 revealed that 171 patients (39%) had at least 1 hospital readmission within 180 days of transplant; 87% received allogeneic and 13% received autologous HSCT. A total of 312 readmission events were reported. The median follow-up time was 31 months. Documented infection (n=99) and graft-versus-host disease complications (n=60) were the most common causes. Higher than 2 readmission rates were associated with lower overall survival (OS) (P=0.001) and disease-free survival (P<0.001) in patients who received allogeneic HSCT. These findings were not found in the autologous HSCT. In a multivariate analysis of those who received allogeneic HSCT, prior treatment with >=2 chemotherapy regimens (P=0.03) was independent predictor of lower OS. There were also trends noted toward lower OS for patients with documented infections at index admission or subsequent readmissions (P=0.09). CONCLUSIONS More than 2 hospital readmissions within 6 months of allogeneic HSCT in CAYA, who are either heavily pretreated or had documented infections at index admission or subsequent readmissions adversely affected the outcomes.