Risk Factors For Veno-occlusive Disease Research Articles

Incidence, management and outcome of Hepatic Veno-Occlusive disease /Sinusoidal Obstruction Syndrome after hematopoietic stem cell transplant in Thalassemia major patients: A prospective study of Pakistani BMT.

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). 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. 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. Careful selection of transplant candidates before transplant can help reduce the incidence of VOD.

Incidence and Risk Factors of Veno-Occlusive Disease Are Different in Younger Versus Older Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background: Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication following allogeneic stem cell transplantation (allo-SCT). Improved transplant techniques and increased awareness of modifiable risk factors have reduced VOD incidence. However, the interaction of historic risk factors in the current era, particularly with the increasing use of calicheamicin-based therapies and post-transplant cyclophosphamide as GVHD prophylaxis, remains unclear. Methods: We conducted a retrospective, single center, chart-based study of consecutive adult patients (age ≥ 18 years) undergoing allo-SCT at MD Anderson Cancer Center between January 1 st, 2017 and December 31 st, 2021. VOD cases were defined using the classic VOD EBMT criteria or if patients received defibrotide treatment for VOD based on clinical judgment of the treating physician. Risk factors for VOD were evaluated in univariate analysis using Fine and Grey regression analysis. Multivariate analysis was performed using Classification and Regression Tree (CART) analysis to validate the findings of univariate analysis and evaluate independent effects accounting for potential interaction effects. Results: A total of 1561 patients were included in our analysis. Median age was 56 years and 60% were male. Patients primarily had acute myeloid leukemia/myelodysplastic syndrome (AML/MDS; 60%), acute lymphoblastic leukemia (ALL; 13%), or myeloproliferative neoplasms (13%). Most patients had matched related (28%) or unrelated donors (48%), and 21% underwent haploidentical transplantation. Forty-nine (3%) patients received inotuzumab ozogamicin (InO) containing regimens prior to allo-SCT, and 30 (2%) were exposed to gemtuzumab ozogamicin (GO). Post-transplant cyclophosphamide (PTCy) was used as GVHD prophylaxis in 72% of patients. Incidence of VOD in the entire study population was 4.8%. There was a significant difference in the median age of patients diagnosed with VOD compared to those without VOD (46 years vs 56 years, respectively, p=0.001). Further examination of the incidence of VOD within different age groups identified a VOD rate of 16.8% (20/119) in those aged ≤ 25 years compared to 3.8% (55/1442) in those > 25 years (Table 1). Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD (Figure 1). Given these findings, risk factor analysis was stratified according to age. In patients ≤25 years of age, 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. Within the younger cohort of patients with AML/MDS, 2 of 3 patients (67%) who received gemtuzumab ozogamicin (GO) developed VOD compared to 10% who did not receive GO (p=0.05). In patients aged >25 years, elevated baseline bilirubin, AST, ALT, and GO exposure were associated with increased VOD rates. VOD incidence based on baseline bilirubin levels (WNL, >ULN to 1.5x ULN, and >1.5x ULN) was 3%, 14%, and 16%, respectively (p<0.001). For baseline ALT levels (WNL, >ULN to 2.5x ULN, and >2.5x ULN), VOD rates were 4%, 3%, and 8%, respectively (p=0.02). Similarly, VOD rates with baseline AST levels (WNL, >ULN to 2.5x ULN, and >2.5x ULN) were 3%, 4%, and 27%, respectively (p≤0.001). In patients aged >25 years with AML/MDS, those receiving GO had a higher incidence of VOD compared to AML/MDS patients not exposed to GO (15% vs. 3%; p=0.01). There was no significant difference in VOD rates between those receiving PTCy and those receiving alternate GVHD prophylaxis in either age cohort. Conclusion: In summary, our data highlight that young adults (age 18 - 25 years) represent a distinct adult population with increased rates of VOD compared to their older counterparts, which are exacerbated by disease and treatment related factors (DRI and number lines of therapy). In contrast, patients > 25 years of age had low rates of VOD even in the presence of historical predictors, with only hepatic risk factors identified as increasing baseline VOD risk. There was no observed increased incidence of VOD among those receiving PTCy as GVHD prophylaxis.

Incidence and Outcomes for Veno-Occlusive Disease in a Pediatric Transplant Cohort on Retrospective Application of Modified Seattle and EBMT Criteria

Background Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplant (HSCT) and is associated with significant mortality. There are published clinical criteria applied for diagnosis, including Baltimore, modified Seattle, and European Society of Bone Marrow Transplantation (EBMT). The lack of consensus on what defines VOD and the subjective nature of clinical criteria used in its definition likely account for the broad range of VOD incidence (10-35%). Given improved outcomes with earlier treatment with defibrotide, there exists a need to be more precise and prompt in diagnosing VOD. The primary goal of this study was to assess the incidence of VOD, as designated in the electronic medical record (EMR) and compare this to when the actual clinical definitions were met. The secondary goal was to identify additional clinical or laboratory trends that could be predictive of VOD risk and outcome. Methods A retrospective analysis was performed on pediatric patients that underwent HSCT at a single institution from 2009-2018. Various patient and transplant data were collected and analyzed in a univariate and multivariate manner to assess potential risk factors. Outcomes included VOD, 100-day survival, and length of hospitalization post-HSCT. FisherOs exact test was used for categorical variables; t test or ANOVA were used for continuous variables. Results A total of 215 transplants in 184 pediatric patients met inclusion for the analysis. Twenty-seven patients were diagnosed with VOD per the EMR (15%), 22 were treated with defibrotide. There were 63 transplants that met the modified Seattle criteria; however, these patients were not clinically diagnosed with VOD by the treating physician (30%). On application of the EBMT criteria, the estimated incidence was 50%. In the entire cohort, 16 patients died within day 100 from the HSCT (100-day survival=91%). Interestingly, percent survival at 100 days for those who met either modified Seattle or EBMT criteria but were not clinically diagnosed with VOD was similar to those who did not meet criteria (92% vs 95%) yet differed from those given a clinical diagnosis of VOD (78%, p=0.013, Figure 1). Only those with a clinical diagnosis of VOD had a longer hospitalization post-HSCT (Figure 2). An increase in VOD was observed for patients receiving myeloablative conditioning (p=0.033) while age, sex, stem cell source, transaminitis at the time of transplant, number of blood transfusions pre-HSCT ( 10), and rapidity of weight gain were not risk factors for VOD. Late diagnosis (>14 days post-HSCT) and rapid rise in total bilirubin were associated with a poor outcome (Figure 3). In conclusion, our study demonstrates the challenges in using defined clinical criteria to diagnose VOD and verifies earlier studies noting the importance of prompt diagnosis and treatment for optimal outcomes.

Çocuklarda Allojenik Hematopoetik Kök Hücre Transplantasyonu Sonrası Veno-oklusif Hastalık Sıklığı ve Risk Faktörleri

Çocuklarda Allojenik Hematopoetik Kök Hücre Transplantasyonu Sonrası Veno-oklusif Hastalık Sıklığı ve Risk Faktörleri

Incidence and Risk Factors For Veno-Occlusive Disease Of The Liver After Allogeneic Stem Cell Transplantation Using a Reduced Intensity Regimen

Introduction Veno-occlusive disease (VOD) of the liver occurs after hematopoietic stem cell transplantation (HSCT) as a result of the toxic damage on sinusoidal and hepatic cells caused by the conditioning regimen. Diagnosis of VOD is usually based on clinical criteria. Intensity of preparative regimen, pre-existing liver disease, busulfan (Bu) as part of the conditioning, etc. have been proposed as significant risk factors with myeloablative conditioning (MAC). In the present study, we examined the incidence and the risk factors for VOD after allogeneic-HSCT using a reduced intensity conditioning regimen (RIC). Patients and Methods From April 1996 until November 2012, 271 consecutive patients with various hematological malignancies underwent allo-HSCT in our department with the same RIC regimen. The RIC regimen consisted of fludarabine 30 mg/m2/day x 6, oral Bu 4 mg/kg/day or i.v. Bu 3.2 mg/kg/day x 2, and ATG. Oral Bu was given to 138 patients, while 133 patients were treated with the intravenous formulation. Diagnosis of VOD was confirmed using the Seattle criteria. Clinical characteristics of patients are shown in Table 1. Cumulative incidence was calculated using a competitive risk model. In multivariate analysis the following variables were entered: age, sex, disease risk status, year of transplant, donor status, previous myeloablative conditioning, pre-existing liver disease, and route of Bu administration. Results Incidence of VOD and outcome: VOD was developed in 24 out of 271 patients. The cumulative incidence of VOD in the whole cohort of patients was 8.5% (95% CI, 5.8 - 12.6%). VOD onset occurred in a median of 3 days post graft infusion (range, 0 -24 days). Moderate and severe VOD was observed in 20 and 4 patients respectively. Risk factors for VOD: Using a univariate and multivariate analysis the only variable associated with VOD incidence was the route of Bu administration. The cumulative incidence of VOD was 11.7% (95% CI, 7.3 - 18.5%), and 5.3% (95% CI, 2.5 - 10.8%) in the groups of patients who received Bu per-os and intravenously respectively (p=0.02). (Figure 1). Severe VOD was observed in only 4 patients and none of the variables tested in multivariate analysis was significantly associated with the incidence of severe VOD. Outcome of patients with VOD: VOD resolved in most of the patients (20/24) in a median of 21 days (range, 8-82 days). The cumulative incidence of VOD resolution was 83%. All 4 patients with severe VOD died before day 100 and before VOD resolution. The overall cumulative incidence of VOD-related mortality was 1.8%. In multivariate analysis, none of the variables tested was significantly associated with VOD-related mortality. Discussion As compared with the reported incidence of VOD with MAC, RIC with low dose Bu is associated with reduced incidence of VOD, VOD severity and mortality. In our study, we observed that Bu administered intravenously was associated with significantly reduced incidence of VOD in comparison with Bu administered per-os. Disclosures: No relevant conflicts of interest to declare.

Excess of Veno-Occlusive Disease in a Randomized Clinical Trial on a Higher Trigger for Red Blood Cell Transfusion after Bone Marrow Transplantation: A Canadian Blood and Marrow Transplant Group Trial

Previous studies have shown that maintaining high hemoglobin levels in patients after chemotherapy reduced the length of neutropenia. Thus, we undertook a randomized, controlled, clinical trial in children undergoing allogeneic bone marrow transplantation after receiving a myeloablative conditioning regimen to compare 2 hemoglobin thresholds as triggers for red blood cell transfusion: 120 g/L in the experimental arm and 70 g/L in the control arm. The Data and Safety Monitoring Board closed the study after enrollment of the sixth patient because 3 patients in the experimental arm contracted veno-occlusive disease, but none in the control arm did (P = .05). Ascites was present in all 3 patients, pleura effusion in 2, and portal vein thrombosis in 2. One patient experienced hepatic failure and required treatment with the molecular adsorbent recycling system. Another patient required hemodialysis for renal failure. No major imbalance between groups was seen with regard to risk factors for veno-occlusive disease. Therefore, maintaining the hemoglobin at higher levels should be avoided after hematopoietic stem cell transplantation.

Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial

Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting. In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948. Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT. Gentium SpA, European Group for Blood and Marrow Transplantation.

Abstract 5447: Investigating the relationship between pharmacogenetic variation in ABCB1 and ABCC2 tagSNPs and actinomycin D pharmacokinetics in children

Abstract Actinomycin D (Act D) has been used successfully to treat adult and childhood cancers for over 30 years. It continues to play a key role in the treatment of Wilms tumour patients, with 5-year survival rates >80% currently observed. While treatment is generally well tolerated, veno-occlusive disease (VOD) is a potentially life-threatening side effect observed in 1.7-13.5% of patients. Dose-intensity of Act D treatment has been highlighted as a possible risk-factor for VOD in paediatric patient populations. ATP binding cassette (ABC) transporters are expressed throughout the body to protect against exogenous compounds. In the liver and kidney, ABC transporters facilitate the removal of compounds via biliary or renal excretion and have previously been shown to play a major role in the transport of anti-cancer agents such as doxorubicin and irinotecan. Common single nucleotide polymorphisms (SNPs) for these transporters have been shown to alter clinical exposure to various anti-cancer agents. We have therefore carried out translational and clinical studies focusing on Act D pharmacokinetics in Wilms tumour patients and pharmacogenetic variation in key ABC transporters. Initial experiments were carried out to determine the potential importance of ABC transporter expression on the in vitro activity and transport of Act D, using MDCKII-WT alongside ABCB1, ABCG2 and ABCC2 over-expressing cell lines. Growth inhibition (GI) and intracellular accumulation experiments were carried out over a range of Act D concentrations (0-10µM). Pharmacokinetic analysis of samples obtained from patients receiving Act D was carried out using a validated LC/MS method and blood samples were obtained from all patients for pharmacogenetic analysis. Finally, the International HapMap database was used to determine tagSNPs for ABCB1 and ABCC2 with minor allele frequencies of greater than 0.1 in a Caucasian population, allowing the link between ABCB1 and ABCC2 haplotypes and Act D exposure to be investigated. GI experiments indicated a 40-fold decrease in Act D sensitivity in cells over-expressing ABCB1 (GI50: 0.85µM) and a 3-fold decrease in cells over-expressing ABCC2 (GI50: 0.06µM) compared to the control cell line (GI50: 0.02µM). Higher intracellular levels of Act D (normalized per mg protein) were observed in the WT parental cell line (650nM) as compared to those over-expressing ABCB1 (215nM), following a 6h incubation with 2µM Act D. This effect was abrogated by use of the ABCB1 inhibitor verapamil. Pharmacokinetic analysis of samples obtained from 56 patients indicated a large inter-patient variability in Act D exposure (AUC0-24h range: 1.6 – 11.4 µg/ml.min). Ongoing investigations into pharmacogenetic variation in ABCB1 and ABCC2 tagSNPs in these patients provide novel preliminary data relating to links between ABCB1 and ABCC2 haplotypes and Act D exposure in children with cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5447. doi:10.1158/1538-7445.AM2011-5447

Defibrotide Low-Dose Continuous Infusion After Allogeneic Stem Cell Transplantation as Prophylaxis for Veno-Occlusive Disease of the Liver.

AbstractAbstract 3483Defibrotide (DF) has been shown to be effective in the treatment and prophylaxis of the veno-occlusive disease (VOD) of the liver, a relatively common complication after allogeneic stem cell transplant (SCT). We report our experience in 46 consecutive adult patients (pts). The pts (mean age 41 yrs, range 16–66) were affected by leukemia (22), lymphoma (15), multiple myeloma (4), myelodisplasia (2), solid tumor (2), Fanconi anemia (1). Risk factors for VOD were: resistant disease 9, previous transplant 8, B virus hepatitis 6, liver metastases 1, lymphoma of the liver 1, increased transaminases before conditioning 7. All were transplanted from their HLA-identical siblings; the conditioning regimen was reduced in 17, while it was conventional in 29. All the pts received a combination of drugs as conditioning regimen, 23 of them received Busulfan and 8 of them oral Busulfan. 15 received bone marrow and 31 peripheral blood as source of stem cells. None was T-cell depleted; the GVHD prophylaxis regimen was: CsA alone or combined with MTX 45, FK506+MTX 1. For VOD prophylaxis no heparin was administered, while DF was given at the dose of 10 mg/Kg in continuous iv infusion starting on day +1 until day +21 after the SCT. DF was very well tolerated and no hemorrhagic complications were seen. Blood coagulation significant alterations were: prolonged PT (4/46), prolonged aPTT (3/46), elevated fibrinogen (24/46), (never over 800 mg/dl), low level (less than 50%) of ATIII and/or protein C and or protein S (2/46). By using the VOD Baltimore criteria, only 1 case of VOD was observed on day +29 in a patient who died at day +36 with VOD, aspergillosis and CMV pneumonia. The bilirubin was more than 2 times the normal value in 26/46; US-scan of the liver and Doppler, performed in 16 pts with a possible sign of VOD, was positive only in the patient who died for VOD. We documented 32 infectious complications (16 FUO, 9 gram positive bacteremias, 3 pneumonia and 4 invasive aspergillosis). We documented acute GVHD in 14 pts (12 grade I-II and 2 grade III). Five pts died between +36 and +100 but none for VOD (3 for progression of their disease and 2 for aspergillosis). Our laboratory data demonstrated modest alterations of the coagulative parameters, low consumption of coagulative factors and reduced fibrinolysis. Since in this at risk transplanted population only 1 VOD has been observed, DF low-dose continuous infusion, without heparin, seems able to play a relevant role in the VOD prophylaxis. On considering the favourable results by us and others, the absence of toxicity and the low cost of the drug, we intend to continue this experience with DF as VOD prophylaxis, even if we foretell a large randomized study to find better indications. Disclosures:No relevant conflicts of interest to declare.

Prediction of Veno-Occlusive Disease Using Biomarkers of Endothelial Injury

Predicting the development of veno-occlusive disease (VOD) of the liver remains challenging. We hypothesized that biomarkers of endothelial injury in myeloablative allogeneic transplantation recipients could predict VOD occurrence. We evaluated 4 biomarkers-von Willebrand Factor (vWF), thrombomodulin, E-selectin, and soluble intercellular adhesion molecule-1 (sICAM-1)-weekly in the peritransplantation period in an attempt to predict VOD. In the patients who received sirolimus, vWF, thrombomodulin, and sICAM-1 levels were significantly elevated in patients with VOD compared with those without VOD on day -1 (P <or= .035), day +7 (P <or= .0001), and day +14 (P <or= .004). E-selectin was predictive on day +7 (P = .007). Levels of vWF >or=1400 IU/mL and thrombomodulin >or=100 ng/mL on day +7 were both 100% sensitive and 100% specific in predicting VOD. These biomarkers were informative when adjusted for other risk factors for VOD in regression analysis. Among patients not receiving sirolimus, biomarkers of endothelial injury were not informative. We conclude that vWF, thrombomodulin, and sICAM-1 elevations before and early after transplantation may be useful in predicting VOD in patients receiving sirolimus.

Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation: incidence, risk factors, and outcome

Four hundred and sixty-seven hematopoietic stem cell transplantations (HSCTs) (217 autologous and 250 allogeneic HSCT) were performed in 374 children at four pediatric HSCT centers in Korea from January 2005 to December 2007. Among 467 transplants, veno-occlusive disease (VOD) developed in 72 transplants (15.4%) at a median of 10 days after HSCT. Multivariate analysis showed that BU or TBI-containing regimen (P=0.002), VOD prophylaxis without lipo-prostaglandin E1 (PGE1) (P=0.012), number of previous HSCT (P=0.014), and pretransplant serum ferritin (P=0.018) were independent risk factors for developing VOD. Mean serum ferritin levels were significantly higher in HSCT with VOD (2109.6+/-2842.5 ng/ml) than in HSCT without VOD (1315.9+/-1094.4 ng/ml) (P<0.001). The relative risk of death within 100 days of HSCT in transplants with VOD compared with transplants without VOD was 3.39 (confidence interval: 1.78-6.45). Our results suggest that lipo-PGE1 might have a protective effect against the development of VOD, and pretransplant serum ferritin could act as a risk factor for VOD. A larger prospective study is needed to confirm a possible role of lipo-PGE1 and iron chelation therapy in reducing the incidence of VOD.

Plasma protein C is a useful clinical marker for hepatic veno‐occlusive disease (VOD) in stem cell transplantation

Hepatic veno-occlusive disease (VOD) is one of the most serious complications in stem cell transplantation (SCT). Although plasma protein C activity decreases in VOD after SCT, the timeframe of plasma protein C activity decreases during SCT is not known. We examined levels of plasma protein C serially during the course of SCT to determine the critical level and risk factors for VOD. Of 151 children who received SCT, 12 of them (7.9%) developed VOD. The mean minimum protein C activity in patients with VOD was significantly lower compared to that in patients without VOD (P < 0.0001). Receiver operating characteristic curve analysis revealed that the critical plasma protein C activity (cut-off point) for VOD was identified to be 34.5% with high sensitivity (100%) and specificity (83.3%), and the reduction of plasma protein C below the cut-off level (day +6.50 +/- 2.43) was observed mostly prior to the onset of VOD (day +7.33 +/- 2.64). The patients receiving melphalan in conditioning were found to be at high risk for VOD (P = 0.003). Among the melphalan containing regimens, melphalan + carboplatin + etoposide was a significant risk factor for depression of plasma protein C (P = 0.037). Plasma protein C level was a useful parameter of VOD after SCT, and activity below 34.5% was critical for VOD. The use of melphalan in conditioning causes a high risk for VOD.

Prediction of VOD Using Biomarkers of Endothelial Injury

Veno-occlusive disease (VOD) of the liver occurs with a frequency of 5–15% after myeloablative conditioning and allogeneic stem cell transplantation (SCT). While risk factors for VOD are well known, predicting the occurrence of VOD in individuals remains challenging. Since the primary mechanism of injury in VOD is conditioning-related damage to hepatic sinusoidal endothelial cells and hepatocytes, we measured soluble biomarkers of endothelial injury in the peri-transplant period to determine if they correlated with the occurrence of VOD. Methods: 59 patients received cyclophosphamide (1800 mg/m 2 x 2) and TBI (14 Gy) as conditioning therapy, and tacrolimus with sirolimus (Sir+) or methotrexate (Sir-) as GVHD prophylaxis. Only patients with HLA-matched donors were included and selected for analysis based on the occurrence of VOD (VOD+ n=18, VOD- n=41), diagnosed by clinical, radiologic and pathologic criteria. Banked samples collected after conditioning but prior to SCT (day -1) and weekly after SCT (day 7, 14, 21) were thawed and analyzed by ELISA using commercially available kits and quantified using a VersaMax plate reader. Von Willebrand Factor (vWF) and thrombomodulin were assayed in plasma, and E-selectin and soluble intercellular adhesion molecule-1 (ICAM) were assayed in serum. Assays were performed in duplicate and results are the mean of two assays. Not all patients had every time point analyzed due to missing specimens. The within-sample results were compared using the 2-sided Wilcoxon rank-sum test, and the Bonferroni method was used to adjust for multiple comparisons (p value for significance=0.0125). Results: Comparing patients who did and did not develop VOD, patients with VOD had significantly elevated levels of vWF suggestive of endothelial damage at all timepoints prior to the development of VOD in comparison with controls (p≤0.0118, Figure). Thrombomodulin levels were predictive of VOD at all post-SCT timepoints (p≤0.0013, Figure). ICAM levels were significantly elevated up to Day 21 (p≤0.0028). E-selectin was less useful and statistically significant increases in levels were not observed. Since sirolimus has effects on endothelial function that may contribute to VOD through mechanisms different than the conditioning regimen, we stratified the analyses by sirolimus exposure, comparing Sir+VOD+ patients with Sir+VOD- controls. vWF levels in Sir+VOD+ patients were predictive for VOD at all timepoints when compared with controls (p≤0.003). Thrombomodulin levels were informative against controls for all post-SCT timepoints (p≤0.003). ICAM was informative as well (p≤0.003 pre-SCT, day 7, 14), while E-selectin levels were uninformative. The discriminative value of elevated serum and plasma biomarkers was limited to Sir+ patients in this small dataset, since other than some vWF timepoints, biomarkers could not distinguish Sir- patients who developed VOD patients from control groups without VOD. There were no differences in biomarkers among VOD- patients, suggesting that in the absence of VOD, markers of endothelial injury are not elevated even when sirolimus is used. Conclusions: Plasma vWF and thrombomodulin and serum ICAM elevations before and early after SCT can be used to predict the occurrence of VOD. These assays are most useful in patients receiving sirolimus. This analysis demonstrates the contribution of sirolimus to endothelial injury and VOD after SCT, and may help select patients in whom prophylactic or pre-emptive strategies against endothelial damage and VOD may be useful.

Prediction of VOD Using Biomarkers of Endothelial Injury.

Veno-occlusive disease (VOD) of the liver occurs with a frequency of 5–15% after myeloablative conditioning and allogeneic stem cell transplantation (SCT). While risk factors for VOD are well known, predicting the occurrence of VOD in individuals remains challenging. Since the primary mechanism of injury in VOD is conditioning-related damage to hepatic sinusoidal endothelial cells and hepatocytes, we measured soluble biomarkers of endothelial injury in the peri-transplant period to determine if they correlated with the occurrence of VOD.Methods: 59 patients received cyclophosphamide (1800 mg/m2 x 2) and TBI (14 Gy) as conditioning therapy, and tacrolimus with sirolimus (Sir+) or methotrexate (Sir-) as GVHD prophylaxis. Only patients with HLA-matched donors were included and selected for analysis based on the occurrence of VOD (VOD+ n=18, VOD- n=41), diagnosed by clinical, radiologic and pathologic criteria. Banked samples collected after conditioning but prior to SCT (day -1) and weekly after SCT (day 7, 14, 21) were thawed and analyzed by ELISA using commercially available kits and quantified using a VersaMax plate reader. Von Willebrand Factor (vWF) and thrombomodulin were assayed in plasma, and E-selectin and soluble intercellular adhesion molecule-1 (ICAM) were assayed in serum. Assays were performed in duplicate and results are the mean of two assays. Not all patients had every time point analyzed due to missing specimens. The within-sample results were compared using the 2-sided Wilcoxon rank-sum test, and the Bonferroni method was used to adjust for multiple comparisons (p value for significance=0.0125).Results: Comparing patients who did and did not develop VOD, patients with VOD had significantly elevated levels of vWF suggestive of endothelial damage at all timepoints prior to the development of VOD in comparison with controls (p≤0.0118, Figure). Thrombomodulin levels were predictive of VOD at all post-SCT timepoints (p≤0.0013, Figure). ICAM levels were significantly elevated up to Day 21 (p≤0.0028). E-selectin was less useful and statistically significant increases in levels were not observed. Since sirolimus has effects on endothelial function that may contribute to VOD through mechanisms different than the conditioning regimen, we stratified the analyses by sirolimus exposure, comparing Sir+VOD+ patients with Sir+VOD- controls. vWF levels in Sir+VOD+ patients were predictive for VOD at all timepoints when compared with controls (p≤0.003). Thrombomodulin levels were informative against controls for all post-SCT timepoints (p≤0.003). ICAM was informative as well (p≤0.003 pre-SCT, day 7, 14), while E-selectin levels were uninformative. The discriminative value of elevated serum and plasma biomarkers was limited to Sir+ patients in this small dataset, since other than some vWF timepoints, biomarkers could not distinguish Sir- patients who developed VOD patients from control groups without VOD. There were no differences in biomarkers among VOD- patients, suggesting that in the absence of VOD, markers of endothelial injury are not elevated even when sirolimus is used.Conclusions: Plasma vWF and thrombomodulin and serum ICAM elevations before and early after SCT can be used to predict the occurrence of VOD. These assays are most useful in patients receiving sirolimus. This analysis demonstrates the contribution of sirolimus to endothelial injury and VOD after SCT, and may help select patients in whom prophylactic or pre-emptive strategies against endothelial damage and VOD may be useful. [Display omitted]

Viral Hepatitis: Manifestations and Management Strategy

Viral hepatitis is the third most common cause of liver disease in allogeneic transplant recipients and causes significant morbidity and mortality. When treating patients with hematological malignancies, an emphasis should be placed on identification of patients at risk for viral hepatitis with appropriate screening. Initial screening serology should include anti-HCV, HBsAg, anti-HBs, and anti-HBc testing. When hepatitis B exposure has been documented, prophylaxis of viral reactivation for all HBsAg-positive patients with a nucleoside analogue should be implemented. HCV infection appears to have little short-term impact on survival after bone marrow transplantation, but is a risk factor for veno-occlusive disease (VOD) and graft-versus-host disease (GVHD). In the long-term survivor, HCV infection can lead to significant morbidity and mortality due to the development of cirrhosis, decompensation, and liver cancer. Since effective antiviral therapies are available for both hepatitis B and C, routine screening and selected intervention is recommended once reactivation and disease recurrence is documented. In this chapter we will highlight the mechanisms of virus reactivation, clinical manifestations, and management strategies to minimize acute and chronic morbidity in this population.

Ursodiol-based prophylaxis for veno-occlusive disease (VOD): A retrospective risk-based review of outcomes following allogeneic stem cell transplantation

Ursodiol-based prophylaxis for veno-occlusive disease (VOD): A retrospective risk-based review of outcomes following allogeneic stem cell transplantation

Veno-occlusive disease of the liver in children with solid tumors undergoing autologous hematopoietic progenitor cell transplantation: a high incidence in patients with neuroblastoma.

We retrospectively analyzed the incidence and risk factors for veno-occlusive disease (VOD) in 83 consecutive children with solid tumors, who underwent autologous blood or bone marrow (BM) transplantation at UCSF between 1992 and 2000. Forty-one patients were diagnosed with neuroblastoma and 42 had another solid tumor (Ewing's sarcoma, soft tissue sarcomas, germ cell tumors, etc). Patients with neuroblastoma were more likely than patients with other solid tumors (ST) to be < or =7 years of age, to have a decreased serum albumin level, and to have received abdominal radiation and surgery prior to transplant. Patients with neuroblastoma received a different conditioning regimen and a purged stem cell product. Twenty patients (24%) developed VOD. VOD was self-limited in 15 (75%) patients and severe in five (25%) patients. Univariate analysis identified the following risk factors for VOD: diagnosis of neuroblastoma (odds ratio 6.1, P < 0.01), abdominal radiation (odds ratio 4.1, P < 0.01), abdominal surgery (odds ratio 4.1, P < 0.01), and age < or =7 years of age (odds ratio 3.3, P = 0.02). Disease status at transplant, intensity of previous chemotherapy, conditioning regimen, progenitor cell source, ALT, AST, albumin level, renal function prior to transplant, or use of amphotericin, growth-factor or heparin during transplant, did not affect the incidence of VOD. On multivariate analysis, only the diagnosis of neuroblastoma remained significant (odds ratio 7.8, P = 0.03). Larger studies of patients with neuroblastoma are necessary in order to confirm our findings and better define the risk factors for VOD development in neuroblastoma patients.

Acute and Long-Term Toxicities Associated with Gemtuzumab Ozogamicin (Mylotarg®) Therapy of Acute Myeloid Leukemia

Gemtuzumab ozogamicin (Mylotarg®) targets leukemia cells that express CD33 by means of a humanized anti-CD33 monoclonal antibody conjugated to a modified antitumor antibiotic, calicheamicin. The effects of gemtuzumab ozogamicin (given intravenously at a dose of 9 mg/m2 for 2 doses separated by 2 weeks) have been evaluated in 3 phase II studies involving patients (n = 188) with acute myeloid leukemia (AML) in first relapse. Interim analysis has revealed that 30% of patients achieved remission, characterized by ≤ 5% blasts in the marrow, neutrophil count ≥ 1500/μL, hemoglobin ≥ 9 g/dL, and independence from red blood cell and platelet transfusion. Grade 3/4 acute toxicities included nausea or vomiting (11%); elevated serum aminotransferase enzyme (16%) and bilirubin (26%) levels; and infusion-related chills (9%), fever (6%), and hypotension (5%). As predicted with CD33-targeted therapy, most patients had neutropenia (98%) and thrombocytopenia (99%). However, the incidence of grade 3/4 bleeding events (14%) and infection rates (pneumonia, 7%; sepsis, 15%) was low. No patients were reported to have treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Veno-occlusive disease (VOD) after gemtuzumab ozogamicin treatment (but prior to other therapies) occurred in 2% of patients (4/188), and the VODrelated death rate was < 1% (1/188). Prior hematopoietic stem cell transplant may be a risk factor for VOD (P = 0.002, univariate analysis). Gemtuzumab ozogamicin is a safe and effective treatment in carefully selected patients with AML in first relapse.

Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation.

Mylotarg (Wyeth-Ayerst Laboratories, St. Davids, PA) is the brand name for a calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab ozogamicin, CMA-676) and has been approved recently for the treatment of a subset of elderly patients who have relapsed acute myeloid leukemia (AML). Mylotarg is associated with an incidence of approximately 20% Grade 3 or 4 hyperbilirubinemia and liver transaminitis in this patient population. Hepatic venoocclusive disease (VOD) has been reported in patients who have undergone stem cell transplantation (SCT) after Mylotarg therapy. Outside of the SCT setting, VOD has been associated very rarely with cytotoxic therapy. The authors assessed the incidence of VOD in 119 patients who were receiving Mylotarg-containing non-SCT regimens. VOD was diagnosed through the use of standard Seattle and Baltimore criteria. A cohort of 119 (61 previously untreated, 58 with relapsed disease) patients with AML (92 patients), advanced myelodysplastic syndrome (25 patients), or chronic myeloid leukemia in blast phase (2 patients), received Mylotarg-based regimens. Fourteen (12%) developed VOD. The diagnosis of VOD was supported by histology in 2 patients and radiologic studies in a further 10 patients. Five (36%) of 14 patients with VOD had received no prior antileukemic cytotoxic therapy, including 2 patients who received single-agent Mylotarg therapy. Mylotarg was shown to be associated with the development of potentially fatal VOD in patients with leukemia who had not received SCT. VOD occurred when Mylotarg was used either as a single agent or when it was given with other cytotoxic agents. VOD occurred in Mylotarg-treated patients who had received no prior cytotoxic therapy. The current study concluded that risk factors for VOD should be assessed when considering Mylotarg therapy, and that attempts to avoid and treat VOD are warranted in patients who receive Mylotarg therapy.

Veno-occlusive disease of the liver.

The success of high-dose cytoreductive strategies depends not only on antitumor activity but also on the tolerability of treatment. Although advances in supportive care have significantly reduced mortality due to infection and hemorrhage, regimen-related toxicities remain problematic. Hepatic veno-occlusive disease (VOD) is the most serious regimen-related toxicity after high-dose cytoreductive therapy. Risk factors for VOD are well established, but the biology of the syndrome remains poorly understood. Unfortunately, no pharmacologic approaches that clearly prevent or treat VOD have been identified. A better understanding of the pathogenesis of VOD will lead to more effective prevention and treatment strategies.