Veno-occlusive Disease In Patients Research Articles

Incidence and risk factors of early onset VOD/SOS differ in younger vs older adults after stem cell transplantation

AbstractVeno-occlusive disease (VOD) is a rare but potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Although increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with posttransplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single-center analysis of adult patients aged ≥18 years undergoing allo-SCT (N = 1561) using predominately PTCy as graft-versus-host disease (GVHD) prophylaxis (72%). We found a higher rate of VOD at 16.8% (20 of 119) in those aged ≤25 years compared with 3.8% (55 of 1442) in those aged >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. Among patients aged 18 to 25 years, disease risk index (DRI; 31% with high/very high DRI vs 12% low/intermediate DRI; P = .03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1; P = .03) were the strongest predictors of VOD. Incidence of VOD in patients aged >25 years of age consistently ranged between 3% and 5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase, alanine aminotransferase) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared with those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors of VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.

Usefulness of two-dimensional shear wave elastography in diagnosing hepatic veno-occlusive disease in pediatric patients undergoing hematopoietic stem cell transplantation.

This study aimed to evaluate the usefulness of two-dimensional shear wave elastography (2D-SWE) in diagnosing hepatic veno-occlusive disease (VOD) in pediatric patients. This study retrospectively included pediatric patients who underwent hematopoietic stem cell transplantation (HSCT) between November 2019 and January 2021. All 34 patients (8.7±5.0 years) were examined using 2D-SWE for an initial diagnosis. A subgroup analysis was performed using the data from follow-up examinations of patients diagnosed with VOD. The characteristics of the initial VOD diagnosis were compared with the longitudinal changes observed in VOD patients who underwent multiple ultrasound examinations. In total, 19 patients were diagnosed with VOD at 17.6±9.4 days after HSCT. All VOD patients showed hepatomegaly, ascites, and gallbladder wall thickening. Liver stiffness was higher in VOD patients than in non-VOD patients (12.4±1.1 vs. 6.3±0.8 kPa, P<0.001). Liver stiffness values above 7.2 kPa showed 84.2% sensitivity and 93.3% specificity in distinguishing VOD from non-VOD (area under the curve, 0.925; 95% confidence interval, 0.780 to 0.987; P<0.001). A subgroup analysis of 11 patients showed a linear decrease in liver stiffness values after VOD diagnosis with treatment (first, second, and third follow-ups; 13.5±1.7, 11.3±1.4, and 9.5±0.8 kPa, respectively), but without statistical significance in the pairwise analysis. Liver stiffness measured using 2D-SWE increased in pediatric patients who develop VOD after HSCT. Therefore, liver stiffness can be a predictive and quantitative parameter for diagnosing VOD.

Hypofibrinolysis in Pediatric Patients with Veno-Occlusive Disease in Hematopoietic Stem Cell Transplantation

Background Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplantation (HSCT) with a high incidence in pediatric patients (11-27%). In clinical practice, VOD is diagnosed with criteria including weight gain, ascites, hepatomegaly, hyperbilirubinemia, and refractory thrombocytopenia. To date, there are no established markers for an earlier diagnosis of VOD. The aspect of assessing hypofibrinolysis, which plays a role in VOD pathogenesis, has not been elucidated. This study aimed to detect signs of hypofibrinolysis in HSCT and VOD patients using thrombelastography parameters and to discover correlations between alterations of these parameters and established symptoms of VOD. Patients and Methods Patients admitted for HSCT to the pediatric HSCT ward at the University Children's Hospital Tübingen, Germany, between May 2020 and November 2021 were prospectively enrolled (study group). Patients who underwent minor surgical procedures or follow-up blood tests years after recovering from oncological diseases and who were otherwise healthy, were recruited as a control group. Blood samples for thrombelastography (EX and TPA test, including the coagulation time (CT), clot formation time (CFT), clot amplitude after 5 minutes (A05), maximum clot firmness (MCF), maximum lysis (ML), α-angle, and lysis time (LT)) were taken once to twice weekly in addition to daily routine blood tests in patients undergoing HSCT. Routine testing included blood counts, coagulation parameters, d-dimers, and bilirubin. VOD symptoms were monitored daily and body weight was measured twice a day. Ultrasound screenings for ascites, progredient hepatomegaly, and portal venous flow velocity were performed in case of suspected VOD. All patients received intravenous anticoagulation with 100 IU/kg and day of unfractionated heparin. Of the control group patients, 6 ml blood was collected once per patient for routine coagulation testing and thrombelastography. Results A total of 51 patients with a median age of 7.8 years were recruited in the study group. Of these patients, five (9.8%) developed VOD and received defibrotide treatment. The VOD was graded moderate (n=2; 4%), severe (n=1; 2%) or very severe (n=2; 4%). Defibrotide treatment was initiated for 4 weeks or until the resolution of symptoms in standard dosing (25 milligrams per kilogram per day (mg/kg/d)) in four doses over 2 hours). The control group consisted of 55 patients with a median age of 6.7 years. A significant difference in thrombelastographic measurements was observed when comparing the VOD to the HSCT group. The lysis time after activation of fibrinolysis in the TPA test was prolonged in the VOD group at 3 weeks after HSCT (d+14 to +21: VOD: 330±67 seconds, HSCT: 246±53 seconds, p=0.0106). Additionally, a significant difference between the VOD and control groups was observed in days +14 to +21 (control: LT 234±50 seconds, p=0.0299). For the time points of day 0 to +6 and day +7 and +13 after HSCT lysis time was also prolonged in VOD patients, but without statistical significance (LT: d0 to +6: VOD: 304±57 seconds; HSCT: 251±67 seconds, p=0.06; d+7 to +13: VOD: 278±34 seconds; HSCT: 255±70 seconds, p=0.12). It was observed that LT correlated positively with weight gain (>5%), progredient hepatomegaly, right upper quadrant pain and reduced portal venous flow velocity (d0 to d+6: weight gain: r=0.31, p=0.0351; pain: r=0.44, p=0.0018; hepatomegaly: r=0.37, p=0.0108; d+7 to +13: pain: r=0.35, p=0.0143; hepatomegaly: r=0.39, p=0.0058; d+14 to d+21: weight gain: r=0.42, p=0.0035; pain: r=0.37, p=0.0103; hepatomegaly: r=0.44, p=0.0020; reduced portal venous flow velocity: r=0.35, p= 0.0167). Conclusions The results suggest that HSCT patients and patients diagnosed with VOD show signs of hypofibrinolysis. Fibrinolysis can be assessed in a rapid and accessible way via thrombelastography. Therefore, thrombelastography might be a useful tool to facilitate early diagnosis of VOD and to identify high-risk patients. Larger studies are needed to determine specific cut-off-values. Stefanie Hammer and Michaela Döring contributed equally to this work.

Economic Burden of Veno-Occlusive Disease (VOD) in Patients with Acute Lymphoblastic Leukemia (ALL) in the US

IntroductionHepatic Veno-occlusive disease (VOD) is a potential life threatening complication of hematopoietic cell transplantation (HSCT) and may also occur after chemotherapy (Negrin et al. 2017). Severe VOD characterized by multi-organ failure (MOF) is fatal and associated with high mortality (Coppell et al. 2010). The economic burden of VOD in ALL patients has not been reported in the published literature.ObjectiveTo investigate the incidence, inpatient mortality and economic burden of VOD among adult B-cell ALL patients in the US.MethodsThis was a retrospective cohort study using Truven Health MarketScan® Commercial and Medicare Supplemental Databases. We first identified the adult B-cell ALL patients. Patients with ≥1 inpatient claims or ≥2 non-diagnostic outpatient claims at least 30 days apart for any ALL diagnosis (ICD-9-CM 204.00-204.02, ICD-10-CM C91.00-C91.02) during 4/1/2009 - 10/31/2016 were extracted. All patients were required to have ≥1 hospitalization with diagnosis-related group in 834-839 on or after the first ALL diagnosis, be ≥18 years old, and have ≥6 months of continuous enrollment prior to the first ALL diagnosis date. Patients with medications for T-Cell ALL during the study period were excluded. VOD patients were then identified based on clinical criteria (Coppell et al. 2010) and expert opinions. VOD patients must have one of the following: 1) a ICD-10-CM code specifically for VOD diagnosis (K76.5), 2) prescription for defibrotide sodium that is indicated for treatment of VOD in the US, 3) at least two VOD symptoms from either Baltimore or Seattle criteria for VOD (ascites, abnormal weight gain, hyperbilirubinemia, or hepatomegaly) within 60 days post HSCT admission, or 4) multi-organ failure (MOF) with liver failure within 60 days post HSCT admission. The VOD index date was the first observed VOD diagnosis date, defibrotide sodium prescription date, or HSCT admission date. HSCT patients were excluded if they had evidence of chronic graft-versus-host disease (GVHD) any time before or 100 days after the VOD index date or if they had acute GVHD or total parenteral nutrition cholestasis during 60 days before or 100 days after the VOD index date. Severe VOD patients were defined as VOD patients with MOF. Patients were followed until the earliest of inpatient death, end of continuous enrollment, end of the study period (10/31/2016), and capped at 100 days. Outcomes included incidence rates of VOD in ALL patients, inpatient mortality of the VOD patients, and VOD-related costs and hospital length of stay during the 100 days post-index period. Costs were sum of the plan paid amount and out-of-pocket amount in 2016 US dollars. Descriptive analyses were conducted for all VOD patients, severe VOD patients and non-severe VOD patients, respectively.ResultsA total of 2,571 ALL patients were identified and 3.4% of them had VOD. Severe VOD patients accounted for 52% of the VOD patients. All VOD patients had HSCT before the VOD event. VOD patients were younger (mean age: 44.2 vs. 50.1), more likely to be male (male: 62.5% vs 55.0%) but sicker (mean Charlson comorbidity index: 2.1 vs. 1.9) compared with the average ALL patients. Inpatient mortality was higher among severe VOD patients (37.0%) when compared to both non-severe VOD (14.3%) and average VOD patients (26.1%). Mean (SD) VOD-related costs were $55,975 ($160,335) for All VOD patients, $86,953 ($206,906) for severe VOD patients and $22,047 ($72,847) for non-severe VOD patients (Figure 1). Mean (SD) VOD-related length of stay was 39.3 (33.0) days among all VOD patients, 49.2 (36.8) days for severe VOD patients and 28.5 (24.3) days for non-severe VOD patients.ConclusionsThe incidence of VOD is low in adult B-cell ALL patients. The diagnosis of VOD is clinical and as such might be underdiagnosed within the current study. Approximately half of the VOD events among ALL patients are severe involving MOFs. VOD events are associated with considerable economic burden and high inpatient mortality, with greater economic burden and inpatient mortality rate among severe VOD patients. These results may potentially underestimate the burden of VOD in ALL patients due to the fact that the HCPCS code specific for defibrotide sodium was not available given its recent approval in the US (2016). Future studies with more recent data are needed to accurately quantify the economic burden of VOD in the US. [Display omitted] DisclosuresZhang:Amgen Inc.: Employment, Equity Ownership. Romanov:Amgen, Inc.: Employment, Equity Ownership. Cong:Amgen Inc.: Employment, Equity Ownership.

Incidence and Outcome of Hepatic Veno-Occlusive Disease After Blood or Marrow Transplantation: A Prospective Cohort Study of the European Group for Blood and Marrow Transplantation

AbstractTo determine the incidence and outcome of hepatic veno-occlusive disease (VOD) after blood or marrow transplantation (BMT), we prospectively evaluated all consecutive patients receiving a BMT during a 6-month period in participating EBMT centers. All of them were evaluated for occurrence of VOD according to previously defined clinical criteria. The clinical course, outcome, value of prophylactic and therapeutic interventions, and the influence of previously described risk factors were analyzed. During the study period, 1,652 BMT were performed in 73 centers. VOD was diagnosed in 87 patients (5.3%; 95% confidence interval [CI], 4.2% to 6.4%). Fifty-six of 631 allogeneic BMT (8.9%) and 31 of 1,010 autologous BMT (3.1%) developed this complication (P < .0001). VOD was classified as mild in 7 (8%), moderate in 56 (64.4%), and severe in 24 (27.6%) cases. Sixteen patients died of VOD (corresponding to 1% of the whole series, 18.4% of VOD patients, and 66.7% of severe VOD). The use of unfractionated heparin did not significantly decrease the incidence of VOD. Independent variables associated with an increased risk of VOD were allogeneic BMT (relative risk [RR], 2.8; P< .001), pre-BMT elevation of serum aspartate aminotransferase (RR, 2.4; P = .001), high-dose cytoreductive therapy (RR, 2.3;P = .003), Karnofsky performance score less than 90% (RR, 2.7; P = .006), and prior abdominal radiation (RR, 2.9;P = .03). In conclusion, this prospective study shows that (1) the incidence of VOD is lower than that reported in smaller studies from single centers, (2) about one fourth of cases of VOD progress to severe disease, (3) main risk factors have a major impact on incidence of VOD, and (4) the use of prophylactic unfractionated heparin does not seem to reduce the incidence of VOD.

Busulfan clearance does not predict the development of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a life-threatening complication following hematopoietic stem cell transplant (HSCT). Busulfan has a narrow therapeutic index and its concentration was found to correlate with VOD. Our primary objective was to assess the association between busulfan clearance and VOD in HSCT patients. In this retrospective analysis, we included patients who received their HSCT between 2003 and 2014 and followed at Sultan Qaboos University Hospital. All patientswho received dose-targeted busulfan-containing conditioning were included. Target steady-state concentration (Css) was 800-900ng/ml. VOD was assessed using modified Seattle criteria. The impact of busulfan clearance on VOD was analyzed using univariable logistic regression model. Seventy-three patients were included with a mean age of 15years. Of those, 47% were transplanted for hematological malignancies and 53% for inherited hemoglobinopathies. Target Css was achieved in 85% of patients. The rate of VOD was 17%. There was no significant impact of busulfan clearance (p = 0.919) or area-under-the-concentration-time-curve (p = 0.275) on VOD. Targeting busulfan Css into narrow therapeutic range may have accounted for the findings. The risk of VOD might be related to other factors such as the genetic background, and more studies are required to investigate these factors.

Introduction of new pediatric EBMT criteria for VOD diagnosis: is it time-saving or money-wasting? : Prospective evaluation of pediatric EBMT criteria for VOD.

Hepatic veno-occlusive disease (VOD) is a potentially fatal complication following hematopoietic stem cell transplantation (HSCT). We evaluated in prospective analysis the usefulness of the pediatric EBMT criteria for VOD diagnosis and their presumable impact on cost effectiveness and patients' outcome. Study included all 282 HSCT procedures performed in Department of Pediatric Hematology/Oncology and BMT in Wrocław between January 2016 and March 2019. Data were compared with previous VOD research conducted in our center before year 2016. Twenty-five (8.9%) patients (median age 3.5 years) were diagnosed with VOD. Duration of defibrotide (DF) administration varied from 4 to 34 days (median: 16.5), with 96% response rate. Overall survival was 88%. If applying Baltimore and modified Seattle criteria, VOD incidence was 2.13% and 5.7%, respectively. Median diagnosis delay based on modified Seattle criteria was 3 days. Before 2016, VOD incidence was 4.9%, with 74% DF response rate (p = 0.033) and 56.2% OS (p = 0.008). After implementing new criteria length of hospitalization for VOD patients decreased by median of 12 days (p = 0.009). Earlier VOD diagnosis, facilitated by EBMT criteria, resulting in implementing immediate treatment significantly improved patients' outcome. Furthermore, it allows shortening of DF administration and minimizes length of hospital stay.

Refractory Thrombocytopenia Is a Valid Early Diagnostic Criteria for Hepatic Veno-Occlusive Disease in Children.

We compared the incidence of refractory thrombocytopenia (RT) and platelet transfusion requirements (PTR) in 35 children who developed veno-occlusive disease (VOD) with 35 matched control subjects who underwent hematopoietic stem cell transplant but did not develop VOD. RT developed in 100% of the VOD patients, at a median of 8 days before VOD diagnosis, as compared with 71.5% of the control group. VOD patients required more platelet transfusions than control subjects (median PTR, 6.9 mL/kg [range, .57 to 17.59] versus 3.57 mL/kg [range, 0 to 14.63], respectively) with a statistically significant difference (P < .0001). The number of days with platelet requirements was significantly higher for VOD patients as compared with control subjects (median 68% versus 39%, P =< .0001). The PTR peaked at ~12 mL/kg/day, 2 days before VOD diagnosis, whereas the PTR in the control population was 5 mL/kg/day. The positive predictive value of developing VOD was 88.9% (95% confidence interval, 66.5% to 97%) in patients who were given >7 mL/kg/day of platelets during the at-risk period of days +3 to +13 after transplant. For patients who received >8 mL/kg/day of platelets, the positive predictive value of developing VOD was 86.7% (95% confidence interval, 61.2% to 96.4%). There was no difference in the PTR in patients with mild to moderate VOD as compared with severe VOD; however, the PTR was higher in patients whose VOD did not resolve. The median daily PTR after the diagnosis of VOD in 17 patients who got defibrotide as compared with those who did not get defibrotide was 6.04 mL/kg and 5.72 mL/kg, respectively, but the difference was not statistically significant (P=.56). On univariate and multivariate analysis use of intravenous immunoglobulin was significantly associated with VOD (P=.0088) but was not significantly associated with fatal VOD. In conclusion, RT occurs in 100% of patients at a median of 8 days before VOD diagnosis. VOD should be suspected in any patient with RT after the exclusion of other causes of consumptive thrombocytopenia, especially if they require >7 mL/kg/day of platelets.

Comparison of Parenteral Nutrition Usage in Pediatric Bone Marrow Transplant Patients with and without Gastrostomy Tubes

Purpose To determine whether placement of gastrostomy tubes (GT) in pediatric bone marrow transplant patients prior to transplant and provision of enteral nutrition (EN) can decrease the duration/necessity of parental nutrition (PN) usage during time of treatment related mucositis and nausea/vomiting. Methods We retrospectively reviewed the medical records of pediatric bone marrow transplant patients admitted to the Medical University of South Carolina (MUSC) Children's Hospital from July 2014 through July 2018. We collected data on type of transplant, chemotherapy regimen, presence of GT, PN initiation and duration, diagnosis of veno-occlusive disease (VOD), and hospital length of stay (LOS). Results We analyzed 63 transplant occurrences in 53 patients including 23 allogeneic, 35 autologous and 5 haplo-identical stem cell transplants. In 28 of 63 (44%) transplant occurrences, the patients had a GT placed prior to admission. PN was administered in 22 of 28 (79%) in the GT group and 28 of 35 (80%) in the no GT group. The average duration of PN was 10 days in the GT group (range 4 to 20 days) and 17 days in the no GT group (range 1 to 65 days). The incidence of VOD was 14% in both GT and no GT groups. The average length of stay was 36 days (range 23 to 59) in the GT group and 44 days (range 23 to 83) in the no GT group. Conclusion Placement of gastrostomy tubes and provision of EN in pediatric bone marrow transplant patients did not eliminate the need for PN but decreased the number of days patients require PN during the transplant process. Our data did not show a decrease in the incidence of VOD in patients with GT. Though many factors play a role, we demonstrated an association between GT placement and decreased length of stay.

Incidence and Predictors of Hepatic Veno-Occlusive Disease after Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Hepatic veno-occlusive disease (VOD)/Sinusoidal Obstruction Syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT) that is triggered, at least in part, by conditioning regimen-induced sinusoidal endothelial cell injury. VOD is thus commonly, but not exclusively, associated with myeloablative conditioning (MAC). The incidence of VOD in reduced intensity conditioning (RIC) HSCT was ≈2% in a single center series (Carreras et al. BBMT 2011), and risk factors for VOD in RIC HSCT remain poorly defined. Methods: We performed a retrospective review to confirm all cases of VOD among patients undergoing RIC HSCT at the Dana-Farber Cancer Institute/Brigham and Women9s Cancer Center between January 2007 and June 2017. Diagnosis of VOD was based on modified Seattle or Baltimore criteria and/or liver biopsy or RUQ ultrasound in conjunction with fluid retention/ascites and hepatomegaly/RUQ pain. Diagnosis dates for all VOD cases were confirmed and clinico-laboratory values collected in the 10 days preceding the diagnosis. The same data were collected for a randomly selected control non-VOD RIC cohort, calculated from the median day of VOD onset derived from the cases. Acute kidney injury was defined as an absolute increase in creatine by 0.3 mg/dL or a relative increase of > 50% within a 48-hour period. Increased platelet transfusion requirement was defined as requiring a platelet transfusion on 2 consecutive days in the 7 days prior to VOD diagnosis, excluding transfusions for procedures. Incidence of VOD at D50 was calculated using a competing risk framework. Cox regression was used to identify significant features for predicting VOD. Survival was compared to a concurrent cohort of 76 patients with VOD after MAC HSCT recently published from our center (Roeker et al. BBMT 2018). Results: A total of 1492 patients underwent RIC HSCT, of whom 1070 (67.8%) received sirolimus (Sir) with tacrolimus (Tac) as part of the GVHD prophylaxis, and 1217 (82%) received intravenous busulfan(Bu) 3.2 or 6.4mg/kg with fludarabine(Flu) as conditioning. Twenty-six developed VOD (median day of diagnosis = d+26, range 5-48 days), for a cumulative incidence of 1.6% (95%CI 1.1%-2.4%). The median bilirubin at diagnosis was 1.1 mg/dL(range 0.6-5.2). Only 5 (19.2%) patients had a bilirubin of ≥2.0 mg/dL on the date of VOD diagnosis, although total bilirubin peaked at ≥ 2 mg/dL in 17 of 26 (65.4%). VOD was mild/moderate in 16 and severe in 10 patients. Sixteen had received ursodiol as VOD prophylaxis. Defibrotide was used as treatment in 17 cases. The 2-year overall survival (OS) was 54% from VOD onset. VOD was associated with increased risk for NRM (HR 4.02, 95% CI 2.1-7.7, p 1, increasing platelet transfusion requirements, and increasing Tac and Sir trough levels (Table 1, Fig 1). Conclusions: The incidence of VOD in this large modern cohort of 1492 RIC HSCT patients was 1.6%, and was associated with the use of Sir with Tac. Onset of VOD in RIC patients was delayed (median D+26 vs. D+14) and 2 yr-OS is superior compared to MAC patients. Only 19% of the RIC VOD cases met the bilirubin threshold for Baltimore and Seattle criteria at diagnosis, suggesting that the rise in bilirubin is a later event in these RIC VOD cases, whereas increasing platelet transfusion requirements, sudden rise in Tac and Sir levels, elevated serum creatinine and acute renal injury appear to be early clinical predictors. Disclosures Nikiforow:Kite Pharma: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity9s Board of Directors or advisory committees; Janssen: Membership on an entity9s Board of Directors or advisory committees; Amgen: Membership on an entity9s Board of Directors or advisory committees; Oncopeptides: Membership on an entity9s Board of Directors or advisory committees; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Soiffer:Jazz Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees. Ho:Jazz Pharmaceuticals: Consultancy.

Economic Burden of Veno-occlusive Disease in Patients With B-cell Acute Lymphoblastic Leukemia in the United States

PurposeThe goal of this study was to evaluate the incidence, inpatient mortality, and economic burden of hepatic veno-occlusive disease (VOD) in adults with B-cell acute lymphoblastic leukemia (ALL) in the United States. MethodsUsing MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database, data for patients with B-cell ALL from April 1, 2009, to October 31, 2016, were extracted by using diagnosis codes. VOD was identified based on clinical criteria and expert opinions. Patients with VOD were followed up from diagnosis of VOD until the earliest occurrence of inpatient death, end of continuous enrollment, end of study period, or for a maximum of 100 days. The incidence of VOD and VOD-associated inpatient mortality were calculated. VOD-related health care costs based on paid adjudicated claims were calculated. FindingsOf the 2571 adults with B-cell ALL, the overall incidence of VOD was low at 3.4% (88 of 2571). Of these patients with VOD, 52% (46 of 88) experienced multiorgan failure and were identified as having severe VOD. VOD was only identified in patients having undergone hematopoietic stem cell transplantation (5.4% [88 of 1624]). The inpatient mortality rate of those with any VOD over the 100-day postindex period was 26.1%, and the inpatient mortality was even higher for patients with severe VOD (37.0%). Total mean (SD) medical costs per patient during the 100 days’ post-VOD diagnosis were $55,975 ($160,335); mean (SD) costs per patient were ∼4-fold higher for severe ($86,953 [$206,906]) versus nonsevere ($22,047 [$72,847]) VOD. ImplicationsClinical criteria were used to identify VOD events and thus VOD might be underdiagnosed. The mortality of VOD also might be underestimated because only inpatient deaths are captured in the data. The incidence and mortality of VOD could also be underestimated because we focused on adult patients who might receive reduced-intensity treatment. The economic burden of VOD may be underestimated because the Healthcare Common Procedure Coding System code specific for defibrotide was not available, and thus the cost for defibrotide might not be included. Finally, as the study population consisted of patients with commercial or Medicare supplemental insurance, results may not be generalizable to all patients with VOD in the United States. Although VOD occurred infrequently in adults with B-cell ALL, it was associated with high inpatient mortality and substantial costs. Patients with severe VOD were associated with highest mortality and highest costs. Given the clinical and economic burden associated with VOD, it is important that patients at high risk for VOD be identified and treated to minimize this risk.

Combination of High-Dose Methylprednisolone and Defibrotide for Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplant Recipients

Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplant (HSCT), with high mortality in severe cases and until recently very limited therapeutic options consisting largely of supportive care. Defibrotide was recently approved in the United States for the treatment of severe VOD in patients with renal or pulmonary dysfunction after HSCT. Our group previously published on the use of high-dose methylprednisolone (500 mg/m2 per dose every 12 hours for 6 doses) in patients with VOD, showing good success. A small subset of these individuals were also treated with defibrotide, but additional studies using the combination of high-dose methylprednisolone and defibrotide for the treatment of VOD are lacking. We present a single-institution retrospective chart review of 15 HSCT patients with VOD treated with the combination of high-dose methylprednisolone and defibrotide. VOD developed at a median of 17 days post-HSCT, and combination therapy was initiated within 1 day of VOD diagnosis. Twelve of 15 patients (80%) had multiorgan failure. Our single-center experience using both high-dose methylprednisolone and defibrotide showed a day +100 survival rate of 73% and an overall VOD complete resolution rate of 66.7%, higher than the rates reported in the recent literature using defibrotide alone (40% to 50% day +100 overall survival). These data suggest that the combination of high-dose steroids and defibrotide may be superior to defibrotide alone and warrant further investigation.

What are the latest advancements in acute myeloid leukemia therapy?

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Interventions for treatment of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation

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Pharmacokinetic Analysis of Continuous Intravenous Infusion of Lipo-Prostaglandin E1 As a Prophylaxis of Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation

Introduction: Prostaglandin E1 (PEG1) has various pharmacological effects such as vasodilation, inhibition of platelet aggregation, inhibition of superoxide anion generation, activation of the fibrinolytic system and inhibition of vascular smooth muscle cell proliferation. Continuous intravenous infusion of PGE1 as a prophylaxis of hepatic veno-occlusive disease (VOD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) have previously been shown to be effective. Further study has been done with continuous intravenous infusion of lipo-prostaglandin E1 (lipo-PGE1) because it can be used in smaller doses to avoid toxicities since it is a form of PGE1 dissolved in the lipid emulsion of soybean oil and thus has greater and long lasting effects. However, it has not been evaluated pharmacokinetically.Methods: We performed a prospective explorative pharmacokinetic study on patients who received continuous intravenous infusion of lipo-PGE1 at a dose of 1mcg/kg/day as a prophylaxis of VOD during HSCT at Seoul National University Children's Hospital. Eligible patients were those at high risk of developing VOD (previous abdominal irradiation, liver function abnormality, busulfan or total body irradiation based conditioning, age under 18 years old) but who cannot use low dose heparin due to low platelet count, bleeding tendency or allergy. Dose of lipo-PGE1 could be increased to 1.5mcg/kg/day if patients showed clinical symptoms of VOD, before the establishment of VOD diagnosis. Lipo-PGE1 level was measured before the start of infusion (B level), between 1 hour and 72 hours after the start of infusion (P1 level), and after neutrophil engraftment (P2 level). Additional samplings were done if the dose of infusion was changed or if the condition of the patient changed significantly. Patients were evaluated for the occurrence and severity of VOD. VOD was diagnosed without limitation of onset time, when patients had 2 or more of the following features: serum total bilirubin of greater than 2 mg/dL, hepatomegaly or right upper quadrant pain of liver origin, or unexplained weight gain of greater than 2% over baseline.Results: Thirty patients were enrolled between January 2015 and May 2016 and all of them were eligible for analysis. Patients underwent HSCT at median age of 12.2 years old for hematologic malignancies, solid tumors, brain tumors, and non-malignant diseases. Donors and stem cell sources were variable. Twenty patients received busulfan-based conditioning and 1 patient received total body irradiation based conditioning. Continuous intravenous infusion of lipo-PGE1 was started at median 1 day before the start of the conditioning regimen and was administered for a median duration of 29 days (range, 23-56 days). Dose of lipo-PGE1 was adjusted to 1.5mcg/kg/day in 2 patients at median 18 days (range, 14-21 days) from start of continuous infusion due to increasing serum total bilirubin or tender hepatomegaly. B level and P1 level were measured in all enrolled patients and P2 level was measured in all 28 of the patients who achieved neutrophil engraftment. The P1 level was 6.60 ± 2.88 (mean ± standard deviation) pg/mL and the clearance was 308.48 ± 233.04 L/h. The P2 level was significantly lower than P1 level at 5.55 ± 2.06 pg/mL (P=0.005) and the clearance was greater at 392.64 ± 302.78 L/h but it was not statistically significant (P=0.109). The coefficient of variability (CV%) of lipo-PGE1 level and clearance were 43.64% and 75.54% respectively at P1 and 37.12% and 77.11% respectively at P2. Between-subject variability of lipo-PGE1 level and clearance (11.18 and 51.65 %) were higher than intra-subject variability (7.19 and 7.40 %). No significant relationship was found between the level or clearance of lipo-PGE1 and occurrence or severity of VOD. VOD developed in 2 patients (6.7%) but both resolved completely with antithrombin-III based treatment at median 38 days from diagnosis. There was no adverse event or death related to lipo-PGE1 prophylaxis and there were no deaths related to VOD.Conclusions: We herein provide the first prospective explorative pharmacokinetic data of continuous infusion of lipo-PGE1 as a prophylaxis of VOD in patients undergoing HSCT. We also suggest that lipo-PGE1 is efficient and safe as a prophylaxis of VOD in patients undergoing HSCT. DisclosuresNo relevant conflicts of interest to declare.

Hospital Cost Associated with Veno-Occlusive Disease (VOD) in Patients with Hematopoietic Stem Cell Transplant (HSCT)

Introduction: VOD (also known as Sinusoidal Obstruction Syndrome) is a potentially life threatening complication of hematopoietic stem-cell transplantation (HSCT). Severe VOD (sVOD), defined as VOD with evidence of multi-organ dysfunction (MOD), leads to high morbidity and mortality in HSCT patients. This study assessed healthcare utilization and costs associated with VOD in patients undergoing HSCT. Methods: A retrospective cohort study was conducted using the Premier research database and had a starting population of all patients with inpatient HSCT between January 1, 2009 and May 31, 2014. The VOD cohort (all-VOD) included those who also had at least one discharge diagnosis indicating liver injury or at least two diagnoses for VOD symptoms, such as hyperbilirubinemia and/or hepatomegaly, during the study period. sVOD patients were identified using diagnoses for multi-organ dysfunction and were a subset of the VOD cohort. The non-VOD cohort was all patients from the starting cohort who did not have evidence of VOD. Primary outcomes were total hospitalization costs, hospital length of stay (LOS), and inpatient mortality. Secondary outcomes were intensive care unit (ICU) costs, ICU LOS, 30-day all-cause readmission rates and associated costs. Unadjusted descriptive analysis included Chi-squared or Wilcoxon Rank Sum tests for comparisons between cohorts, with non-VOD as the reference group. Multivariable analysis estimated the association between VOD status and primary outcomes, adjusting for differences in demographic, hospital, and clinical characteristics. Generalized linear models (GLM) were applied for total costs and LOS, and logistic regression was used for inpatient mortality. Recycled prediction was used to calculate the adjusted outcomes by VOD status. Results: A total of 5,418 patients had inpatient HSCT during the study period. The study included 291 all-VOD patients (134 sVOD and 157 non-severe VOD), in addition to 5,127 patients without evidence of VOD. Unadjusted descriptive analysis found that the all-VOD cohort had higher hospital costs (Median: $119,594, IQR: $59,793-$220,461) and longer LOS (Median: 28 days, IQR: 20-41) than the non-VOD cohort (Median cost: $62,747, IQR: $40,590-$120,974, p Discussion: This analysis is subject to limitations of administrative data. Since there is no diagnostic code for VOD, we used clinical judgment to sort through the codes most likely to be related to VOD/sVOD. Notably, the 40% mortality in the sVOD group is considerably lower than the approximately 80% mortality reported in the literature. One important reason for this difference is that our analysis measured mortality during initial HSCT hospitalization, while the higher rates in the literature are based on 100-day mortality. Additionally, our algorithm may have yielded less severe disease compared to the literature. Conclusions: VOD and sVOD were associated with increased healthcare utilization and costs compared with the HSCT patients without VOD. sVOD patients also had almost 6 times higher odds of inpatient mortality compared with patients without VOD. Disclosures Dvorak: Jazz Pharmaceuticals: Consultancy. Nejadnik: Jazz Pharmaceuticals: Employment, Equity Ownership. Cao: Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Lipkin: Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Robinson: Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Villa: Jazz Pharmaceuticals: Employment, Equity Ownership.

How We Treat Patients with Acute Lymphoblastic Leukemia

How We Treat Patients with Acute Lymphoblastic Leukemia

Hospital Cost Associated with Veno-Occlusive Disease (VOD) in Patients with Hematopoietic Stem Cell Transplant (HSCT)

Introduction: VOD (also known as Sinusoidal Obstruction Syndrome) is a potentially life threatening complication of hematopoietic stem-cell transplantation (HSCT). Severe VOD (sVOD), defined as VOD with evidence of multi-organ dysfunction (MOD), leads to high morbidity and mortality in HSCT patients. This study assessed healthcare utilization and costs associated with VOD in patients undergoing HSCT.Methods: A retrospective cohort study was conducted using the Premier research database and had a starting population of all patients with inpatient HSCT between January 1, 2009 and May 31, 2014. The VOD cohort ("all-VOD") included those who also had at least one discharge diagnosis indicating liver injury or at least two diagnoses for VOD symptoms, such as hyperbilirubinemia and/or hepatomegaly, during the study period. sVOD patients were identified using diagnoses for multi-organ dysfunction and were a subset of the VOD cohort. The non-VOD cohort was all patients from the starting cohort who did not have evidence of VOD. Primary outcomes were total hospitalization costs, hospital length of stay (LOS), and inpatient mortality. Secondary outcomes were intensive care unit (ICU) costs, ICU LOS, 30-day all-cause readmission rates and associated costs. Unadjusted descriptive analysis included Chi-squared or Wilcoxon Rank Sum tests for comparisons between cohorts, with non-VOD as the reference group. Multivariable analysis estimated the association between VOD status and primary outcomes, adjusting for differences in demographic, hospital, and clinical characteristics. Generalized linear models (GLM) were applied for total costs and LOS, and logistic regression was used for inpatient mortality. Recycled prediction was used to calculate the adjusted outcomes by VOD status.Results: A total of 5,418 patients had inpatient HSCT during the study period. The study included 291 all-VOD patients (134 sVOD and 157 non-severe VOD), in addition to 5,127 patients without evidence of VOD. Unadjusted descriptive analysis found that the all-VOD cohort had higher hospital costs (Median: $119,594, IQR: $59,793-$220,461) and longer LOS (Median: 28 days, IQR: 20-41) than the non-VOD cohort (Median cost: $62,747, IQR: $40,590-$120,974, p<0.001; Median LOS: 21 days, IQR: 16-27; p <0.001). The sVOD sub-cohort had much higher costs and LOS (Median cost: $198,436, IQR: $102,027-$406,683, p<0.001; Median LOS: 37.5 days, IQR: 27-66; p<0.001). Inpatient mortality rates in the all-VOD and sVOD groups were significantly higher than the non-VOD group (non-VOD: 3.0% vs VOD: 18.6%, p<0.001; sVOD: 39.6%, p<0.001). In multivariable regressions, the adjusted hospital costs for non-severe VOD was $8,988 higher than the non-VOD group (p=0.037), and sVOD was $41,703 higher than the non-VOD group (p<0.001). The adjusted hospital LOS for non-severe VOD was 0.90 days longer than the non-VOD group (p=0.023) and for the sVOD group was 7.02 days longer than the non-VOD group (p<0.001). The sVOD group had significantly higher inpatient mortality (10.6%) compared with non-VOD group (3.4%, Adjusted Odds Ratio=5.88, p<0.001), although the mortality difference between non-severe VOD and non-VOD groups was not significant.Discussion: This analysis is subject to limitations of administrative data. Since there is no diagnostic code for VOD, we used clinical judgment to sort through the codes most likely to be related to VOD/sVOD. Notably, the 40% mortality in the sVOD group is considerably lower than the approximately 80% mortality reported in the literature. One important reason for this difference is that our analysis measured mortality during initial HSCT hospitalization, while the higher rates in the literature are based on 100-day mortality. Additionally, our algorithm may have yielded less severe disease compared to the literature.Conclusions: VOD and sVOD were associated with increased healthcare utilization and costs compared with the HSCT patients without VOD. sVOD patients also had almost 6 times higher odds of inpatient mortality compared with patients without VOD. [Display omitted] [Display omitted] DisclosuresDvorak:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Cao:Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Lipkin:Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Robinson:Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership.

A Novel Protocol Decreased Incidence of Hepatic Veno-Occlusive Disease and Improved Results in Hematopoietic Cell Transplantation for Patients with b-Thalassemia Major

▪Hepatic veno-occlusive disease (VOD) is a common complication of hematopoietic cell transplantation (HCT), especially patients with β-thalassemia major (TM). To estimate whether incidence of VOD recently decreased after using NF-08-TM protocol (NP), 311 TM-HCTs performed from February 2003 to June 2013 were analyzed. 241 patients received NP in or after 2009 and 70 received non-NP before 2009. VOD was diagnosed by Seattle criteria (SC) or Baltimore Criteria (BC). Patients were stratified by Nanfang (NF) criteria. A total of 31(10.0%) and 14 (4.5%) HCTs developed VOD (6 and 5 developed severe VOD) in SC and BC cohorts, respectively. The incidence of VOD was significantly lower in NP versus non-NP groups and in Class 2 versus Class 3 groups. Overall survival was significantly higher in NP versus non-NP cohorts. Rate of VOD in alternative donor transplant (ADT) was similar to that in matched sibling transplant (MST). Requirement of platelet and value of D-dimer significantly increased in the VOD patients. Our study showed the incidence of VOD significantly decreased in our center after using NP. ADT was similar to MST on rate of VOD. NF criteria of stratification can indicate occurrence of VOD. The SC can be more suitable criteria for early diagnosis. DisclosuresNo relevant conflicts of interest to declare.

Experience from a single paediatric transplant centre with identification of some protective and risk factors concerning the development of hepatic veno-occlusive disease in children after allogeneic hematopoietic stem cell transplant

Hepatic veno-occlusive disease (VOD) is a frequent and severe complication of hematopoietic stem cell transplantation (HSCT) affecting 9.6-17.3 % of cases. 200 HSCT, performed between January 1995 and March 2013 in our Paediatric HSCT Centre in Trieste, were retrospectively analysed to evaluate the frequency of VOD and to identify the associated risk factors. The frequency of VOD according to the Seattle criteria was 17 %, within the range reported in literature. The mortality rate was 37.5 % (75 out of 200 transplantations) in the general population and 73.5 % (25 out of 34) in VOD patients (p < 0.05). Veno-occlusive disease significantly decreased from 38 % (1995-2000) to 8 % (2007-2013) p < 0.05. Univariate and multivariate analyses identified sepsis and pre-transplant ferritin levels above 1000 ng/ml as two significant risk factors for VOD, while the use of tacrolimus appeared to be associated with a lower VOD risk. Veno-occlusive disease still remains an important cause of transplant-related mortality even if it appears to have decreased over the last few years.