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Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low-intensity chemotherapy or other anti-ALL-targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher-risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T-cell therapy, to eliminate measurable residual disease and to prevent post-HSCT relapse. Veno-occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO-related veno-occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use.
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BACKGROUND: As a subtype of pulmonary hypertension (PH), pulmonary veno-occlusive disease (PVOD) is devastating and life-threatening disease without effective therapy. Hydrogen has been reported to exhibits antioxidant and anti-inflammatory effects in a rat model induced by monocrotaline of PH. In this study, we investigated the effects of inhaled hydrogen gas on the prevention and treatment of PVOD induced by mitomycin C (MMC) in rats. METHODS: PVOD was induced in female Sprague-Dawley rats through intraperitoneal injection of MMC at a concentration of 3 mg·kg- 1·wk- 1 for 2 weeks. Inhalation of hydrogen gas (H2) was administered through a designed rat cage concurrently or two weeks after MMC administration. The severity of PVOD was assessed by using hemodynamic measurements and histological analysis. The expression levels of general control nonderepressible 2 (GCN2), nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1) and endothelial-to-mesenchymal transition (EndoMT) related proteins in lung tissue were measured. Levels of lipid peroxidation pro-inflammatory cytokines in serum were determined. RESULTS: Inhaled H2 improved hemodynamics and right heart function, reversed right ventricular hypertrophy, and prevented pulmonary vessel reconstitution in both prevention and treatment approaches. It decreased malondialdehyde (MDA) levels in the serum and the expression of NADPH oxidase 1 (NOX-1) in lung tissue. It regulated Nrf2/HO-1 signaling pathway and anti-inflammatory factor GCN2 in lung tissue, accompanied by a decrease in macrophages and pro-inflammatory cytokines. Our data suggested that H2 inhalation effectively countered EndoMT induced by MMC, as evidenced by the detection of endothelial markers (e.g., VE-cadherin and CD31) and mesenchymal markers (e.g., vimentin and fibronectin). Further research revealed that H2 preserved p-Smad3 and induced p-Smad1/5/9. CONCLUSION: Inhalation of H2 effectively inhibits the pathogenesis of PVOD induced by MMC in rats. This inhibitory effect may be attributed to the antioxidant and anti-inflammatory properties of H2.
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Hidrógeno , Mitomicina , Enfermedad Veno-Oclusiva Pulmonar , Ratas Sprague-Dawley , Animales , Hidrógeno/farmacología , Hidrógeno/administración & dosificación , Femenino , Administración por Inhalación , Ratas , Mitomicina/administración & dosificación , Enfermedad Veno-Oclusiva Pulmonar/inducido químicamente , Enfermedad Veno-Oclusiva Pulmonar/prevención & control , Modelos Animales de Enfermedad , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patologíaRESUMEN
Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication which can develop after haemopoietic stem cell transplantation (HSCT) and some antibody-drug conjugates. Several SOS/VOD diagnostic and management guidelines exist, with the most recent and refined being the European Society for Blood and Marrow Transplantation adult and paediatric guidelines. Timely diagnosis and effective management (including the availability of therapeutic options) significantly contribute to improved patient outcomes. In Australia and New Zealand, there is variability in clinical practice and access to SOS/VOD therapies. This review aims to summarise the current evidence for SOS/VOD diagnosis, prevention and treatment and to provide recommendations for SOS/VOD in the context of contemporary Australasian HSCT clinical practice.
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BACKGROUND: Non-invasive imaging modalities are warranted for diagnosing and monitoring veno-occlusive disease because early diagnosis and treatment improve the prognosis. OBJECTIVE: To evaluate the usefulness of liver shear wave elastography (SWE) and shear wave dispersion (SWD) imaging in diagnosing and monitoring veno-occlusive disease in pediatric patients. MATERIALS AND METHODS: We conducted a prospective cohort study at a single tertiary hospital from March 2021 to April 2022. The study protocol included four ultrasound (US) sessions: a baseline US and three follow-up US after hematopoietic stem cell transplantation. Clinical criteria, including the European Society for Blood and Marrow Transplantation criteria, were used to diagnose veno-occlusive disease. We compared clinical factors and US parameters between the veno-occlusive disease and non-veno-occlusive disease groups. The diagnostic performance of US parameters for veno-occlusive disease was assessed by plotting receiver operating characteristic (ROC) curves. We describe temporal changes in US parameters before and after veno-occlusive disease diagnosis. RESULTS: Among the 38 participants (mean age 10.7 years), eight developed veno-occlusive disease occurring 17.0 ± 5.2 days after hematopoietic stem cell transplantation. Liver stiffness, as measured by SWE (15.0 ± 6.2 kPa vs. 5.8 ± 1.8 kPa; P<0.001), and viscosity, as assessed with SWD (17.7 ± 3.1 m/s/kHz vs. 14.3 ± 2.8 m/s/kHz; P=0.015), were significantly higher in the veno-occlusive disease group compared to the non-veno-occlusive disease group at the time of diagnosis. Liver stiffness demonstrated the highest area under the ROC (AUROC) curves at 0.960, with an optimal predictive value of >6.5 kPa, resulting in sensitivity and specificity of 100% and 83.3%, respectively. Viscosity demonstrated an AUROC of 0.783, with an optimal cutoff value of 13.9 m/s/kHz for predicting veno-occlusive disease, with a sensitivity of 100% and specificity of 53.3%, respectively. Liver stiffness increased with disease severity and decreased during post-treatment follow-up. CONCLUSION: SWE may be a promising technique for early diagnosis and severity prediction of veno-occlusive disease. Furthermore, liver viscosity assessed by SWD may serve as an additional marker of veno-occlusive disease.
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Diagnóstico por Imagen de Elasticidad , Estudios de Factibilidad , Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Humanos , Diagnóstico por Imagen de Elasticidad/métodos , Enfermedad Veno-Oclusiva Hepática/diagnóstico por imagen , Enfermedad Veno-Oclusiva Hepática/etiología , Masculino , Femenino , Niño , Estudios Prospectivos , Preescolar , Adolescente , Valor Predictivo de las PruebasRESUMEN
Multiple asparaginase products have been approved by the United States (US) Food and Drug Administration (FDA) for the treatment of acute lymphoblastic leukemia in pediatric and adult patients. Hepatic veno-occlusive disease (VOD) is a potentially life-threatening disorder resulting from damage to the liver sinusoidal endothelial cells. To evaluate this safety concern with asparaginase (i.e. Asparlas, Oncaspar, Rylaze, and Erwinaze) use, we performed a postmarketing review of hepatic VOD reports retrieved from the FDA Adverse Event Reporting System database and literature with these four products. We identified 55 cases of hepatic VOD following exposure to asparaginase products. The median time to onset of hepatic VOD from the first dose of asparaginase was 18 days (interquartile range 13-24 days). Notably, 80% (44/55) of cases reported grades 3-5 VOD per the Common Terminology Criteria for Adverse Events. Although patients received asparaginase with standard chemotherapeutic agents known to induce VOD, case-level data indicates that asparaginase products may have contributed to hepatic VOD. Asparaginase products are associated with hepatotoxicity and thrombosis, suggesting a plausible mechanism for asparaginase-induced hepatic VOD. Based on the totality of data, including temporality and biologic plausibility, we determined hepatic VOD to be a class effect with asparaginase products. These data contributed to the addition of hepatic VOD to the hepatoxicity warning in the US Prescribing Information for asparaginase class products.
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Objectives: Hepatic Veno occlusive disease (VOD), also known as sinusoidal obstruction syndrome (VOD/SOS), is a post-transplant life threatening complication. In this study, we aimed to discuss the incidence, management and outcome of VOD in post allogenic transplant patients of beta thalassemia major (BTM). Methods: A prospective study was conducted in Armed Forces Bone Marrow Transplant Center, between 2001-2022. A total of 385 fully Human Leucocyte Antigen (HLA) matched BTM patients, with Ursodeoxycholic acid for prophylaxis, were included in the study. Incidence of VOD was calculated through cumulative incidence estimates. Chi square test and Mann Whitney test were used to compare discrete and continuous variables respectively. VOD was diagnosed and graded according to European Society for Blood and Marrow Transplantation EBMT Pediatric diagnostic criteria. Risk factors for VOD were grouped as recipient, transplant and donor related. Univariate analysis was performed by log-rank test. All patients who developed VOD were managed primarily with fluid restriction and strict input output monitoring. Statistical analyses were performed using SPSS v 25.0. Results: Out of 385 transplant patients, forty developed VOD. Median time from date of transplant till onset of VOD was 14 days (range 6-30). Cumulative incidence of all grade VOD was 10.39% (95% CI, 7-14). Eleven out of 40 patients who developed VOD died. Cumulative incidence of Transplant related mortality (TRM) for patients with and VOD was 20.5% (95% CI, 16.6-25.1) vs 27.5% (95% CI, 16.1-42) (p value 0.318) respectively. Among risk factors, age of recipient and fibrosis (p value of 0.04 and 0.000 respectively) were found to be significantly associated with VOD. Conclusions: Careful selection of transplant candidates before transplant can help reduce the incidence of VOD.
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OBJECTIVE: Pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) sometimes accompanies pulmonary veno-occlusive disease (PVOD). We aimed to reveal the relation between clinical signs of PVOD and severing of pulmonary vasculopathy in SSc. METHODS: This study comprised 52 consecutive SSc patients who had pulmonary haemodynamic abnormalities (mPAP > 20 mmHg, PVR > 2 W.U. or PAWP > 15 mmHg). The chest CT scan was evaluated in all patients. Patients were divided into two groups, the 0-1 group and the 2-3 group, according to the number of chest CT signs for PVOD, including 1) mediastinal lymph node enlargement, 2) thickened interlobular septal wall, and 3) ground glass opacity. Pulmonary haemodynamics, echocardiography and MRI-based cardiac function, pulmonary function, and serum biomarkers were compared between the two groups. RESULTS: Mediastinal lymph node enlargement, thickened interlobular septal wall, and ground glass opacity were observed in 11 (21%), 32 (62%), and 11 (21%) patients, respectively. The 2-3 group (n = 15) had higher mPAP (p= 0.02) while lower DLco/VA (p= 0.02) compared with the 0-1 group (n = 37). Other parameters, including PAWP, cardiac output, left ventricular ejection fraction, left atrial diameter, forced vital capacity, brain natriuretic peptide, and Krebs von den Lunge-6 were not different between the two groups. CONCLUSION: The CT signs for PVOD had positive correlation with mPAP but negative correlation with DLco in SSc patients, indicating that PAH-SSc may reflect a spectrum of pulmonary vascular disease that ranges from the pulmonary artery to the vein.
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BACKGROUND AND AIMS: The definitive treatment for pyrrolizidine alkaloids (PAs)-induced hepatic sinusoidal obstruction syndrome (HSOS) is not available. The effectiveness of anticoagulation therapy remains controversial. The efficacy of low molecular weight heparin (LMWH) should be investigated in patients and animal models, and the underlying mechanism should be explored. METHODS: The prognosis of patients with PAs-HSOS who received anticoagulation therapy was retrospectively analysed. The effect of enoxaparin on the liver injury was determined in animal models of monocrotaline (MCT)-induced HSOS was determined, and the underlying mechanism was investigated using a murine model. RESULTS: The cumulative survival rate of patients with PAs-induced HSOS was 60.00% and 90.90% in the non-anticoagulation group and anticoagulation group. Enoxaparin attenuated liver injury effectively in a rat model of MCT-induced HSOS. Additionally, the improvement of severe liver injury was observed in MCT-treated mice after the administration of enoxaparin (40 mg/kg). The alleviation of liver injury was observed in mice with hepatocyte-specific deletion of oncostatin M (Osmâ³Hep ). In MCT-treated mice administrated with enoxaparin, no significant differences in liver injury were observed between Osmâ³Hep mice and Osmflox/flox mice. Additionally, adenovirus-mediated overexpression of Osm resulted in severe liver injury in MCT-induced mice after the administration of enoxaparin. CONCLUSIONS: LMWH attenuated severe liver injury in patients with PAs-Induced HSOS and animal models of MCT-induced HSOS, which provides a rationale for the application of anticoagulation therapy.
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Enfermedad Veno-Oclusiva Hepática , Alcaloides de Pirrolicidina , Ratas , Ratones , Animales , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Alcaloides de Pirrolicidina/efectos adversos , Enoxaparina , Estudios Retrospectivos , Heparina de Bajo-Peso-Molecular , Oncostatina M/efectos adversos , Monocrotalina/efectos adversos , Anticoagulantes/efectos adversosRESUMEN
BACKGROUND: Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) belongs to Group 1 pulmonary hypertension. Pulmonary veno-occlusive disease (PVOD), which is characterized by venous system aberrations, has been previously reported in CTD-PAH; however, it has rarely been observed in Sjogren's syndrome (SS). CASE PRESENTATION: Our 28-year-old female patient was admitted to the hospital with recurrent shortness of breath even after minimal physical activity. Her chest high-resolution CT scan demonstrated pulmonary artery dilatation and bilateral ground-glass nodules. A subsequent right heart catheterization confirmed pulmonary hypertension because her mean pulmonary arterial pressure was 62 mmHg. Our inquisitive genomic assessment identified a novel EIF2AK4 mutation at c.1021 C > T (p. Gln341*), the dominant causal gene of PVOD. Histological examination demonstrated stenosis and occlusions in the pulmonary veins. Because she presented with features such as dry eyes and Raynaud's phenomenon, we performed a biopsy on the labial salivary gland, which confirmed SS. Her treatment regimen included PAH-targeted therapies (tadalafil and macitentan) in combination with hydroxychloroquine. Although she was hospitalized several times due to acute exacerbation of PAH, her disease progression was under control, and she did not demonstrate any signs of pulmonary edema even after a three-year treatment period. CONCLUSION: Here, we report the case of an SS-PAH patient with PVOD who carried a novel biallelic EIF2AK4 mutation, and PAH-targeted therapies were well tolerated by our patient.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Enfermedad Veno-Oclusiva Pulmonar , Síndrome de Sjögren , Humanos , Femenino , Adulto , Enfermedad Veno-Oclusiva Pulmonar/complicaciones , Enfermedad Veno-Oclusiva Pulmonar/diagnóstico , Enfermedad Veno-Oclusiva Pulmonar/genética , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/genética , Pulmón , Hipertensión Pulmonar Primaria Familiar , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
BACKGROUND: Hepatic veno-occlusive disease or sinusoidal obstruction syndrome is a potentially life-threatening complication of hematopoietic stem cell transplantation. OBJECTIVE: To assess the usefulness of point shear-wave elastography (pSWE) for the early diagnosis of sinusoidal obstruction syndrome (SOS) in children. MATERIALS AND METHODS: A retrospective study was carried out in 43 patients with suspected SOS assessed between March 2018 and November 2021. Diagnosis of SOS was confirmed in 28 patients based on the European Society for Blood and Marrow Transplantation diagnostic criteria. Abdominal ultrasound and pSWE of the liver were performed before and after hematopoietic stem cell transplantation on first suspicion of SOS. RESULTS: Liver stiffness on initial suspicion was higher in patients diagnosed with SOS and these values increased compared to the pre-transplantation values. A cutoff value of 1.37 m/s was found for the diagnosis of SOS, with an area under the curve of 0.779 (95% CI 0.61-0.93). CONCLUSION: Point shear wave elastography of the liver is a promising technique for the early diagnosis of pediatric SOS.
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Diagnóstico por Imagen de Elasticidad , Enfermedad Veno-Oclusiva Hepática , Humanos , Niño , Adulto Joven , Enfermedad Veno-Oclusiva Hepática/diagnóstico por imagen , Enfermedad Veno-Oclusiva Hepática/complicaciones , Diagnóstico por Imagen de Elasticidad/métodos , Estudios Retrospectivos , UltrasonografíaRESUMEN
PURPOSE: Hepatic veno-occlusive disease (HVOD) after liver transplantation (LT) is almost always a fatal complication. We assessed the outcomes of HVOD in a single institute and analyzed a literature-based cohort. METHODS: We reviewed the medical records of recipients of LT performed between 1995 and 2020 at our institute and the literature on HVOD after LT. We then analyzed the clinical features based on a "pooled" cohort of cases identified in our institute and reported in the literature. RESULTS: HVOD was diagnosed in 3 of 331 LT recipients, all of whom died in hospital, on days 164, 12, and 13, respectively. Our comprehensive review of the literature, as well as our cases, identified eight cases of HVOD that developed within 14 days after LT (early-onset type). Early-onset HVOD had a significantly worse prognosis than HVOD that developed beyond 2 weeks after LT (non-early-onset type), which was identified in 22 cases (25.0% vs. 86.1% of the 3-month graft survival rate). The most common causes of early-onset and non-early-onset types were acute cellular rejection (50%) and drug-induced disease (50%), respectively. CONCLUSION: Early-onset HVOD developing within 14 days after LT has a poor prognosis.
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Home-inhaled nitric oxide therapy was effective and feasible in the patients with intractable pulmonary arterial hypertension. We present the case of a child with severe pulmonary arterial hypertension associated with post-operative pulmonary venous obstruction who was treated with home-inhaled nitric oxide therapy.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Enfermedad Veno-Oclusiva Pulmonar , Niño , Humanos , Óxido Nítrico/uso terapéutico , Pulmón , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/tratamiento farmacológico , Circulación Pulmonar , Enfermedad Veno-Oclusiva Pulmonar/complicaciones , Enfermedad Veno-Oclusiva Pulmonar/diagnóstico , Hipertensión Pulmonar Primaria Familiar , Administración por InhalaciónRESUMEN
Several novel agents (e.g., molecularly targeted drug, bispecific antibody, antibody-drug conjugate, chimeric antigen receptor T-cell therapy) have successively emerged in clinical practice and are occasionally used in allogeneic hematopoietic cell transplantation (allo-HCT) settings. These drugs are expected to reduce pretransplant tumors, lower the risk of relapse with posttransplant maintenance therapy, and consequently improve transplant outcomes. Additionally, some molecularly targeted drugs could be adapted to treat steroid-refractory acute and/or chronic graft-versus-host disease (GVHD), which remained the leading cause of nonrelapse mortality after allo-HCT. However, these agents develop an excessive immune reaction, including GVHD, or presented an increased risk of sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) as their "off-target" effects. Thus, this review aimed to summarize the risk assessment and management of post-posttransplant complications, focusing on GVHD and SOS/VOD, in the era of molecularly targeted therapy. Moreover, recent advances in GVHD or SOS/VOD prophylaxis and treatment using novel agents/devices are also discussed.
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Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Humanos , Enfermedad Veno-Oclusiva Hepática/etiología , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Enfermedad Veno-Oclusiva Hepática/patología , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Medición de RiesgoRESUMEN
BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury complication of hematopoietic stem cell transplant (HSCT) leading to end-organ damage and high morbidity and mortality. Defibrotide is an anti-inflammatory and antithrombotic agent that may protect the endothelium during conditioning. PROCEDURE: We hypothesized that prophylactic use of defibrotide during HSCT conditioning and acute recovery could prevent TA-TMA. A pilot single-arm phase II trial (NCT#03384693) evaluated the safety and feasibility of administering prophylactic defibrotide to high-risk pediatric patients during HSCT and assessed if prophylactic defibrotide prevented TA-TMA compared to historic controls. Patients received defibrotide 6.25 mg/kg IV q6h the day prior to the start of conditioning through day +21. Patients were prospectively monitored for TA-TMA from admission through week 24 post transplant. Potential biomarkers of endothelial injury (suppression of tumorigenicity 2 [ST2], angiopoietin-2 [ANG-2], plasminogen activator inhibitor-1 [PAI-1], and free hemoglobin) were analyzed. RESULTS: Twenty-five patients were enrolled, 14 undergoing tandem autologous HSCT for neuroblastoma and 11 undergoing allogeneic HSCT. Defibrotide was discontinued early due to possibly related clinically significant bleeding in 12% (3/25) of patients; no other severe adverse events occurred due to the study intervention. The other 22 patients missed a median of 0.7% of doses (0%-5.2%). One patient developed nonsevere TA-TMA 12 days post HSCT. This observed TA-TMA incidence of 4% was below the historic rate of 18%-40% in a similar population of allogeneic and autologous patients. CONCLUSIONS: Our study provides evidence that defibrotide prophylaxis is feasible in pediatric patients undergoing HSCT at high risk for TA-TMA and preliminary data indicating that defibrotide may reduce the risk of TA-TMA.
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Polidesoxirribonucleótidos , Microangiopatías Trombóticas , Niño , Trasplante de Células Madre Hematopoyéticas , Humanos , Proyectos Piloto , Polidesoxirribonucleótidos/efectos adversos , Medición de Riesgo , Microangiopatías Trombóticas/prevención & controlRESUMEN
Sinusoidal obstruction syndrome (SOS) is a unique form of liver injury that occurs after exposure to chemotherapeutic drugs and toxins. The diagnosis of SOS in humans remains a challenge as the clinical criteria have low specificity and there are no reliable noninvasive biomarkers. The mechanism of injury is believed to be damage to liver endothelial cells, primarily sinusoidal endothelial cells (SECs), which leads to sinusoidal dilation, central venous fibrosis, and/or nodular regeneration. Nonclinical data suggest that this uncommon liver toxicity can be recapitulated in cynomolgus monkeys, and it is critical that pathologists are familiar with its characteristic clinicopathologic features. Elevations in liver enzymes, in particular aspartate aminotransferase, associated with isolated thrombocytopenia, should raise the suspicion of SEC injury for specific drug classes. Characterization of liver microscopic findings in monkeys benefits from the use of appropriate stains, such as reticulin stain, and VEGFR2 and CD34 immunohistochemical (IHC) stains. CD41 IHC demonstrates platelet accumulation in injured sinusoids, the likely cause of thrombocytopenia commonly reported in SOS. In conclusion, this report provides a comprehensive characterization of the pathology findings of drug-induced SOS in monkeys with the objectives of ensuring appropriate nonclinical recognition of the liability and informing clinical development strategy and monitoring.
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Enfermedad Veno-Oclusiva Hepática , Patología Clínica , Animales , Células Endoteliales/patología , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Enfermedad Veno-Oclusiva Hepática/patología , Macaca fascicularisRESUMEN
Chemotherapy-induced veno-occlusive disease (VOD) is a rare liver dysfunction seen among pediatric cancer patients which could lead to severe morbidity and mortality. Defibrotide is the commonly used antidote in the management of both stem cell transplant and chemotherapy-associated VOD along with liver supportive measures. Defibrotide is costly and generally not accessible to majority of patients treated at resource poor settings. In this report, we describe the successful management of chemotherapy-induced VOD with timely administration of N-acetyl cysteine.
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Antineoplásicos , Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Enfermedades Vasculares , Niño , Humanos , Polidesoxirribonucleótidos/farmacología , Enfermedad Veno-Oclusiva Hepática/terapia , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Análisis Costo-Beneficio , Acetilcisteína/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/etiología , Antineoplásicos/efectos adversosRESUMEN
Hepatic veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS), is a rare and life threatening complication of hematopoetic stem cell transplantation (HSCT). Many conditions can mimic the clinical signs of VOD/SOS. Differential diagnosis and diagnosis of the disease at an early stage is important, since the severe form of the disease has higher mortality rates and early-initiated specific treatment has better response rates. A sensitive and specific non-invasive imaging technique that can diagnose the disease at an early stage is still an unmet need today. We aimed to determine the role of liver stiffness measurement (LSM) with transient elastograph (TE) for the diagnosis of VOD/SOS after allogeneic HSCT. Between January 2019 and October 2021, a total of 49 patients underwent allogeneic HSCT and were retrospectively analyzed. Thirty-one adult patients who had a two or more LSM value were included in the study. Revised European Society for Blood and Marrow Transplantation (EBMT) was the criteria used for the diagnosis of VOD/SOS. Two of 31 patients developed VOD/SOS (6.4 %). Very high LSM values were detected in all patients who developed VOD/SOS. Early and specific VOD/SOS treatment resulted in improvement of LSM values together with other related features. However, LSM values did not increase significantly in patients with high a bilirubin level (≥2 mg/dl) without VOD/SOS. This study demonstrates that TE might be a promising non-invasive imaging method for diagnosis, follow-up and differential diagnosis of this dismal complication of HSCT. Yet, these results need to be supported by prospective studies.
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Diagnóstico por Imagen de Elasticidad/métodos , Enfermedad Veno-Oclusiva Hepática/diagnóstico , Enfermedad Veno-Oclusiva Hepática/terapia , Hígado/diagnóstico por imagen , Adulto , Femenino , Enfermedad Veno-Oclusiva Hepática/patología , Humanos , Hígado/patología , Masculino , Persona de Mediana EdadRESUMEN
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is one of the most life-threatening early complications following hematopoietic cell transplantation (HCT). Due to the high mortality rate of severe VOD/SOS accompanied with multiorgan failure, there is a great interest in preventive strategies. The efficacy of defibrotide (DF) on the prevention of VOD/SOS has been clearly shown in high-risk pediatric patients, but evidence-based data on adults is scarce. In this report, we aimed to assess the impact of DF on the incidence of VOD/SOS in our center by posttransplant day 30 among patients who were treated with allogeneic HCT (allo-HCT). The study included a total of 56 patiens (28 males, 28 females). The median age of the study cohort was 43 (20-68). The daily dose of DF was 10 mg/kg and 25 mg/kg in 53 (94.6 %) and 3 (5.3 %) patients, respectively. Patients also recieved oral ursodeoxycolic acid (UDCA) 250 mg three-times daily started with conditioning until D + 90. Twenty-three (41.1 %) patients had at least one major EBMT-defined risk factor for development of VOD/SOS. One patient who belonged to a very high-risk group (with at least two major risk factors) developed very-severe VOD/SOS at posttransplant D + 20 and died as a result of multiorgan failure. The cumulative incidence of VOD/SOS at D + 30 was 1.9 %. Our findings indicate that 10 mg/kg daily intravenous DF combined with UDCA is quite effective in prevention of VOD/SOS in patients who underwent first allo-HSCT.
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Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Enfermedad Veno-Oclusiva Hepática/prevención & control , Polidesoxirribonucleótidos/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polidesoxirribonucleótidos/farmacología , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Trasplante Homólogo , Adulto JovenRESUMEN
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) affecting the liver is a rare, possibly life-threatening complication of hematopoietic stem cell transplantation (HSCT). Sinusoidal endothelial cell (SEC) damage triggered by various factors (especially conditioning regimen) results in post sinusoidal portal hypertension due to obstruction of the hepatic vein. Diagnosis is guided by traditional clinical diagnostic criteria; the modified Seattle criteria, the Baltimore and revised European Group for Blood and Marrow Transplantation (EBMT), specifically. While there are promising results of imaging techniques studies in the diagnosis of VOD/SOS, none of those imaging techniques are routinely utilized in diagnosis yet. However, risk stratification is essential; conflicting results have been shown in studies aiming to define risk factors for development of VOD/SOS conducted to date. The only approved drug for the treatment of VOD/SOS yet is defibrotide, with early treatment offering higher chances of survival. In this review, we will focus on pathogenesis, clinical presentation and diagnostic criteria, risk factors, prophylaxis, and treatment of the VOD/SOS occurring post-HSCT.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/diagnóstico , Enfermedad Veno-Oclusiva Hepática/terapia , Acondicionamiento Pretrasplante/efectos adversos , Enfermedad Veno-Oclusiva Hepática/fisiopatología , Humanos , Incidencia , Factores de RiesgoRESUMEN
Hepatic sinusoidal obstruction syndrome, also known as veno-occlusive disease, can occur as a complication of myeloablative chemotherapy, as a result of low-intensity chemotherapy-related liver toxicity or radiotherapy of the liver. Symptoms of sinusoidal obstruction syndrome can range from asymptomatic to liver dysfunction or severe disease with life-threatening acute multi-organ failure. Imaging features can suggest or support this clinical diagnosis. Familiarity with the imaging spectrum of sinusoidal obstruction syndrome is therefore important for both radiologists and clinical oncologists. Here, multi-modality radiologic appearances of sinusoidal obstruction syndrome in pediatric patients are illustrated, including outcome after follow-up.