Incidence Of Veno-occlusive Disease 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.

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.

Evaluation of Circulating Endothelial Cells (CECs) As Marker of Endothelial Damage in Allo-Transplanted Patients at High Risk of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS): The Cecinvod Study

INTRODUCTION Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially fatal complication after allogeneic stem cell transplantation (alloSCT). Identifying a predictive biomarker for VOD has been challenging. Since endothelial injury is considered one of the main pathogenic factors for VOD onset, with the CECinVOD prospective study we aimed to evaluate Circulating Endothelial Cells (CEC) in allo-transplanted patients (pts) at higher risk to develop VOD. METHODS From October 2020 to November 2022, 150 pts have been enrolled in the CECinVOD study from 11 Italian Bone Marrow Transplantation Units. All pts must be older than 18 years and undergoing myeloablative alloSCT. CECs were detected using the CellSearch system, the FDA-approved immunomagnetic selection approach incorporating ferrofluid nanoparticles (anti CD146) and fluorophore-labelled antibodies (anti CD105, CD45 and DAPI). CEC were defined as CD146+, CD105+, DAPI+ and CD45-. CEC were collected at the following timepoints: before conditioning regimen (T0), at the end of conditioning regimen and before alloSCT (T1), at the time of neutrophils engraftment (T2), and 7-10 days after engraftment (T3). In pts who developed VOD, additional timepoints were collected as follows: at any time of suspected or proven VOD onset (T4), and then weekly during Defibrotide treatment (T5-T8). SOS/VOD was defined according to the 2016 European Group for Blood and Marrow Transplantation criteria. RESULTS Pts' main characteristics are summarized in Table 1. Six out of 150 pts (4%) developed VOD during the follow up (4 “severe”, and 2 “very severe”). All pts were treated with Defibrotide, obtaining a complete remission in 5 of them, while 1 pt died due to VOD complications. Pts receiving TBI-based regimen were more likely to develop VOD compared to those receiving Treosulfan (10 to 14 g/m2) or Busulfan ev (9.6 to 12.8 mg/kg) (p 0.08). Similarly, higher baseline levels of bilirubin were associated with a higher incidence of VOD (p 0.08). Considering the CECs analysis, 615 samples were evaluated. At the enrollment, CECs levels were not related with any of clinical characteristics analyzed, except for the number of previous treatments. Indeed, those pts with 2 or more previous lines of treatments had higher levels of CECs (OR=0.53; p<0.001). Considering the different timepoints, conditioning regimen and alloSCT result in higher levels of CECs. Thus, CEC were higher at T1 than at T0 (p 0.02), as well as they were even higher at T2 than at T1 (p<0.0001) (Fig.1). Conversely, no significant differences have been observed between T3 and T2. No other clinical characteristic was correlated with CEC counts at the different timepoints. Pts who developed VOD had higher median levels of CEC at all the timepoints analyzed, but this difference has not achieved statistical significance, probably due to the low number of pts in the VOD group. At VOD onset, the pts always had an increase in CEC levels compared with the previous timepoint. After defibrotide treatment, the CEC levels increased in the first week, while they progressively decreased during the VOD treatment (T6 and T7, -50,7% and -71,5%, respectively). Recently, another endothelial activation marker has been considered: the Easix score. We didn't find any relationship between the Easix score at transplant and the VOD onset, even if a trend may be observed. We also investigated whether the CEC levels may be related with Easix score, but we didn't find any relationship at each timepoint. Interestingly, in a subgroup of pts CECs have been observed as a cluster of multiple cells. This data is firstly described in allo-SCT. Its functional significate remains unclear, but we found a relationship between CECs cluster and the number of CECs (p < 0.001). CONCLUSIONS The incidence of VOD in our prospective study was low with respect to the one reported in the literature. This can be explained by the changes in alloSCT from the past (better selection of the pts, lower use of TBI, higher use of reduced intensity regimen) and the retrospective nature of most of the previous reports. We show that CECs can be considered reliable marker of endothelial damage in alloSCT pts, highlighting the impact of previous treatments, the conditioning regimen, and allo-SCT itself. Increased CEC level may be helpful to confirm VOD diagnosis, as well as their monitoring may be useful to evaluate the response to the treatment for VOD.

Inotuzumab Use: A Single-Center Experience in B-Cell Acute Lymphoblastic Leukemia

Introduction: Inotuzumab Ozogamicin (InO) is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic agent used in B-Acute Lymphoblastic Leukemia (B-ALL). The conjugate is internalized and produces DNA cleavage and subsequent apoptosis. InO has shown better results than conventional chemotherapy. Patients and methods: We present the results of a single-center experience with a small cohort of 13 patients diagnosed with ALL who received InO outside of clinical trials. Results: Of the 13 patients, 69% (9) were male. The median age was 38 years old (range 16-64). 10 patients younger than 55 years 9 patients had relapsed diseases, 3 refractory diseases and one patient was newly diagnosed. Regardless of relapsed disease, 7 patients used InO as a first line of salvage and 2 as a second line. In refractory disease, 1 patient used InO as the second salvage and 2 as third or more. White blood cells range from 1,500 to 285,000 mm3. Peripheral blood blast from 50-80%. Before InO administration, all the patients had bilirubin lower than 2 mg/DL (range 0.15-1.26 mg/dL), an ALT (alanine aminotransferase) medium value of 34 U/dl, and an AST (aspartate aminotransferase) medium value of 33 U/dL. The most common type of leukemia was CALLA in 8 patients: B-ALL Phi positive in 2, Lymphoid blast crisis in1, pre-B ALL 1, and t (8;22) 1 patient. 10 patients had CD-22 positivity in flow cytometry, and 3 had negative results. There was no relation between the intensity of CD 22 and the rate of response. 11 patients received InO as monotherapy, and 2 were associated with Mini-HyperCVAD-InO. 7 patients received 1 cycle and 6 patients received 2 cycles of InO; the average dose received was 2,7 mg/m2. 7 (53%) patients in complete response (CR) plus MDR (Minimal Residual disease) negative after treatment, 4 progressive diseases and 2 missing. Three patients received HCT (hematopoietic cell transplantation) post-InO, and two are waiting in complete remission. One patient relapsed while she was waiting for HCT and died. 4 patients received InO as a salvage after relapse post-HCT. All these patients had progressive diseases and died. In the patients that used InO as a bridge to HCT, the average time to transplant was 94 days. Regardless of Veno-Occlusive Disease (VOD), 1 patient developed it after InO treatment; no patients had VOD associated with HCT. Overall survival: 38 months; progression-free survival: 4.1 months. Mortality rate was 53% (7 patients). Causes were: 4 with progressive disease, 1 hemorrhagic stroke, 1 septic shock, and 1 suicide. Conclusion: We show our small local experience using this new drug in B-ALL patients. Patients who use InO as a bridge to HCT could have a good outcome. We had not found good results when InO was used in relapse post-HCT. There was no relation between the intensity of CD22 at flow cytometry and the rate of responses. The incidence of VOD was low. Rates of response are comparable to other real-world reports. This small experience could be the beginning of a multicenter Real-World study in Latin America.

A Novel Protocol Improves Engraftment in Tαβ + Cell Depleted Haplo-HSCT for Patients with Thalassemia Major

Background: Hematopoietic stem cell transplantation (HSCT) remains a proven curative approach for patients with thalassemia major (TM) over long-term practice. However, achieving successful engraftment and managing graft-versus-host disease (GVHD) continue to pose significant challenges. While low incidence of GVHD has been observed in Tαβ + cell-depleted HSCT (TDH) from haploidentical donors, graft failure (GF) remains a considerable concern, particularly in patients with TM. To enhance the engraftment in TM-TDH, we conducted this prospective/retrospective single-center clinical study. Method: A total of 137 patients diagnosed with TM received TDH at the BMT-center, Taixin Hospital, between March 2021 and April 2023. The median age of the patients was 7 years (ranging from 2 to 19 years), with 89 males and 48 females. The median follow-up time was 408 days (ranging from 99 to 857 days). The conditioning regimen consisted of Thymoglobulin on -day 21, followed by 3-Gy total body irradiation on -day 11. On -day 10, the patients received an infusion of donor lymphocytes (2*10 8/kg), followed by cyclophosphamide (Cy) at a dose of 50mg/kg on days -8, -7, and -2, and 25mg/kg on day -1. Additionally, blood-concentration adjusted busulfan was administered on days -6 to -4, fludarabine at a dose of 40mg/kg on days -6 to -2, and thiotepa at 10mg/kg on day -3. For GVHD prophylaxis, short-term (< 6 months) low-dose tacrolimus or sirolimus with or without mycophenolate mofetil was used. The mean infused CD34+ cells were 31.09 (ranging from 14.25 to 61.12) *10 6/kg, TCRγδ+ cells were 39.49 (ranging from 5.18 to 140.39) *10 6/kg, and NK cells were 109.18 (ranging from 27.52 to 309.41) *10 6/kg, respectively. The targeted infusion of TCRαβ+ cells was aimed at 1.5-2.0*10 5/kg. Results: Out of the 137 patients, 133 achieved successful engraftment (97.1%) with median engraftment times of 16 days (ranging from 9 to 48 days) for ANC to reach 0.5x10 9/L, 11 days (ranging from 1 to 23 days) for HB to reach 80g/L, and 10 days (ranging from 5 to 22 days) for platelets to reach 20x10 9/L, respectively. GF was observed in four patients. Among them, two patients with GF underwent salvage alternative donor second HSCT on +day 19 and +day 32, respectively, and are currently thalassemia-free. One patient received infusion of cryopreserved auto-peripheral blood stem cell and continues to live with TM. Unfortunately, four patients passed away, with one GF patient dying from suspected virus myocarditis on +day 11, one potentially due to virus hepatitis or hepatic GVHD on day +188, and the remaining two from virus bronchiolitis obliterans on +day 211 and +day 254, respectively. The overall survival (OS) and thalassemia-free survival (TFS) rates were 96.5% and 94.3%, respectively. The incidence of GF and transplant-related mortality (TRM) were 2.9% and 3.5%, respectively (Fig.). Acute GVHD of grade I-II and grade III-IV was observed in 10.53% and 9.02% of patients, respectively, while mild and moderate chronic GVHD occurred in 7(5.1%) and 1(0.7%) patient(s), respectively. The incidence of veno-occlusive disease was mild and limited. C onc lusion: The current study demonstrates the efficacy of a novel protocol in enhancing engraftment in TDH for patients with TM and with low incidence of both acute GvHD and chronic GvHD. This approach represents a significant advancement in the field of TM-TDH. Fig.1 Curve of OS, TFS, TRM and Rejection in TM-TDH

Serum follistatin level as a prognostic marker in Haploidentical stem cell transplantation

BackgroundThe treatment of hematological diseases with Haploidentical transplantation has made significant progress. Follistatin is an angiogenic factor that is elevated in the circulation after allogeneic Hematopoietic Cell Transplantation (HCT). Elevated follistatin levels have been linked to poor survival after graft versus host disease (GVHD). ObjectivePre- and post-transplant Follistatin levels were measured in patients subjected to Haploidentical HSCT and correlated with transplant outcomes. Patients and methodsThis study included 45 patients who underwent allogeneic stem cell transplants from Haploidentical donors. ResultsThe mean Follistatin level before stem cells infusion (88.81 ± 49.11 ng/ml) and at day 28 post-transplant (78.61 ± 45.50 ng/ml). The mean follistatin level was higher among the patients who had acute severe GVHD grade 3–4 pre-transplant at day zero and day 28 without statistical significance.The incidence of veno-occlusive disease was higher in patients with elevated serum follistatin levels on day 0 (108.58 ± 64.12 Vs 82.16 ± 46.05 ng/ml. p value = 0.134) and day 28 (112 ± 49.36 vs 66.06 ± 38.96 ng/ml) with statistically significance at day 28 post-transplant (p value = 0.011).After 180 days of follow-up, patients with high serum follistatin (i.e. >60 ng/ml) on day 28 post-transplant had lower OS, (P = 0.381). ConclusionIn the setting of Haploidentical HSCT, higher follistatin levels post-transplant are associated with severe acute GVHD and inferior overall survival.

CT-255: Progressive Substitution of Post-Transplant Cyclophosphamide with Bendamustine as GVHD Prophylaxis Reduces GVHD while Preserving GVL

Context Post-transplant cyclophosphamide (PTCy) is approved in haploidentical stem cell transplant setting. However, disease relapse and CMV or BK/JC viral reactivation veno-occlusive disease of the liver (VOD) remains a major challenge with the use of PTCy. Progressive substitution of PTCy with bendamustine (PT-BEN) may be a suitable option as evidenced by murine models. Objective To compare the outcomes for patients receiving PTCy with PT-BEN compared to historical cohorts receiving PTCy alone. Design This is a single arm, retrospective and prospective, single centre study in which all the patients undergoing allogeneic stem cell transplantation with a T-cell replete graft were recruited. Patients or Other Participants All patients received T-cell replete stem cells followed by PTCy 50mg/kg on day +3 and bendamustine 90mg/m2 on day +4. Calcineurin inhibitors with mycophenolate mofetil was given. Main Outcomes Measures The main outcome measures included myeloid and platelet engraftment, viral reactivations, disease status, incidence and severity of acute GVHD, incidence of veno-occlusive disease until D+28 post-transplant. Results Five patients have been recruited, all males, median age being 17 years. Two patients had relapsed/refractory (R/R) ALL after 2 lines of therapy, 1 had R/R AML, 1 had very severe aplastic anemia, 1 was high risk ALL in CR1. 3 fully matched a sibling, whereas 2 had haplomatched donors from mother. All the donors and recipients had seropositivity for CMV. Two patients received FluCyTBI, 2 received FluCyATG, and 1 received FluTreoTBI as conditioning. One patient expired due to neutropenic septic shock on D+8 and has been excluded from analysis. The median day for myeloid engraftment was 12 and platelet engraftment was 14. No patient had VOD, thrombotic microangiopathy, or culture positive bacterial infections. All the patients were in CR, 100% donor chimerism at D+28. Three patients had CMV reactivation, controlled with antivirals. One patient had Gr1 skin GVH and 1 patient had Gr1 gut GVH managed with topical and oral steroids respectively. Conclusions Progressive substitution of PT-BEN may ameliorate the toxicities associated with PT-Cy in post-transplant setting.

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.

Safety and Efficacy of Once-Daily Intravenous Busulfan in Allogeneic Transplantation: A Matched-Pair Analysis

[Background] Intravenous administration of busulfan (ivBU) has been widely used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT), especially in patients with myeloid malignancies. IvBU was originally administered 4-times-daily (ivBU4) at 0.8 mg/kg over 2 hours according to the established way of administration in oral busulfan, but ivBU4 needs frequent preparations and a midnight administration. A once-daily infusion of ivBU (ivBU1) at 3.2 mg/kg over 3 hours seemed to be safe and convenient by resolving these problems, but clinical data of direct comparison of ivBU1 and ivBU4 has been scarce. We demonstrated that ivBU1 was safely performed based on a pharmacokinetic profile in a small cohort of Japanese patients (Int J Hematol. 2015;101:497-504), and therefore we planned a large matched-pair analysis using the nation-wide registry data to demonstrate the safety and efficacy of ivBU1 in Japanese patients.[Methods] Patients aged more than 15 years with myeloid malignancies who underwent HSCT using ivBU1 in conditioning regimen were selected in our institutions. Control patients of ivBU4 matched for age, sex, performance status, disease risk, conditioning regimen, and donor type were selected from the Transplant Registry Unified Management Program (TRUMP), which is the registry data of the Japanese Society for Hematopoietic Cell Transplantation (JSHCT), using optimal matching algorithms in a 1:3 ratio. Patients who had ivBU for 2 days or 4 days were selected separately, and were combined when clinical outcomes were analyzed. Primary outcome measure was an overall survival after HSCT. This study was approved by the data management committee of TRUMP and the Institutional Review Board of Saitama Medical Center, Jichi Medical University.[Results] A total of 91 patients who received ivBU1 for 2 days (n = 18) or 4 days (n = 73) after 2010 in our institutions were matched with 273 control patients who received ivBU4 between 2007 and 2013 (Table 1). In patients who received ivBU for 2 days of both groups, ivBU was mainly combined with fludarabine (Flu). On the other hand, in patients who received ivBU for 4 days of both groups, half of them received ivBU combined with cyclophosphamide (CY), and the remaining patients did combined with Flu. Overall survival (1y OS: 56.8 % vs 57.1 %, P= 0.94, Figure 1), disease-free survival (1y DFS: 51.6 % vs 50.8 %, P= 0.73), relapse rate (1y RR: 28.5 % vs 26.2 %, P= 0.94), non-relapse mortality (1y NRM: 19.9 % vs 23.0 %, P= 0.71), and the incidence of graft-versus-host disease (grade 2-4 acute GVHD: 26.6 % vs 36.8 %, P= 0.07, chronic GVHD: 38.6 % vs 32.5 %, P= 0.46) were not significantly different between the ivBU1 and ivBU4 groups. In patients who received ivBU1, neutrophil recovery was slower (median days: 22 vs 17, P < 0.001), and incidence of veno-occlusive disease (VOD) was lower (2.6% vs 17.4%, P= 0.04) than in those who received ivBU4. The former might have resulted from the less frequent usage of granulocyte-colony stimulating factor (25.3 % vs 84.2 %, P < 0.01), and the latter from the different criteria used for the diagnosis of VOD (Seattle criteria vs Baltimore criteria). [Conclusion] IvBU1 can be safely administered in Japanese patients. Clinical outcomes were similar between ivBU1 and ivBU4 groups. [Display omitted] DisclosuresKako:Otsuka Pharmaceutical Co., Ltd.: Honoraria. Hidaka:Chugai: Research Funding; Eisai: Honoraria. Suzuki:Mochida Pharmaceutical: Honoraria; Novartis: Honoraria; Gilead Sciences: Consultancy; MundiPharma: Consultancy; Meiji Seika Pharma: Honoraria; Shionogi: Honoraria; Takeda Pharmaceuticals: Honoraria; Kyowa-Hakko Kirin: Honoraria; Ohtsuka: Honoraria; Chugai Pharmaceutical: Honoraria; Sawai Pharmaceutical: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria; Jazz Pharmaceuticals: Consultancy. Atsuta:Otsuka Pharmaceutical Co., Ltd.: Honoraria.

Outcome After Cord Blood Transplantation Using Busulfan Pharmacokinetics-Targeted Myeloablative Conditioning for Hurler Syndrome

We report the outcomes of cord blood transplantation (CBT) with a busulfan (Bu) pharmacokinetics-targeted myeloablative conditioning regimen in 97 children with Hurler syndrome (HS) performed between 2004 and 2016. The median age at CBT was 10.8 months (range, 0.23 to 63.2 months). The median duration of follow-up for surviving patients was 4.2 years (range, 1.0 to 12.8 years). Five-year overall survival (OS) and engrafted survival (ES) were 88% and 79%, respectively. OS was 95% in patients who received Bu/fludarabine (Flu)/antithymocyte globulin (ATG) conditioning, 90% in those who received Bu/cyclophosphamide (Cy)/ATG, and 74% in those who received Bu/Cy/alemtuzumab (P = .02). ES was 84% for recipients of Bu/Flu/ATG conditioning, 83% for recipients of Bu/Cy/ATG conditioning, and 65% for recipients of Bu/Cy/alemtuzumab conditioning (P = .34). Receipt of washed CB units (P = .03) and HLA matching ≤6/10 (P = .02) were associated with significantly lower ES. The 1-year cumulative incidence of graft failure was 11% (95% confidence interval, 6% to 21%). Five patients (5%) had grade III-IV acute GVHD, 5 patients had limited chronic GVHD, and 1 patient had extensive GVHD. The incidence of veno-occlusive disease was higher in patients conditioned with Bu/Cy compared with those conditioned with Bu/Flu (19% [n = 10] versus 5% [n = 2]: P = .03). Of the 11 patients with graft failure, 8 (73%) were aplastic, and 3 (27%) had autologous reconstitution. Of 11 patients with graft failure, 9 underwent a second CBT, and 8 (89%) survived. Full donor chimerism was observed in 89% patients after first CBT and in all patients after second CBT. Survival after CBT for HS has improved, but better strategies are still needed to improve graft outcomes.

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.

Conditioning Regimens and Outcomes after Allogeneic Hematopoietic Cell Transplant for Hyperinflammatory Inborn Errors of Immunity

Introduction: Inborn errors of immunity such as hemophagocytic lymphohistiocytosis (HLH) and chronic granulomatous disease (CGD) are characterized by hyperinflammation. Hematopoietic cell transplantation (HCT) in the setting of hyperinflammation leads to high morbidity and mortality. Consequently, there is increasing use of less intense conditioning regimens, which can increase risk of mixed chimerism or graft failure. We sought to study the effect of common regimens on outcomes after HCT using data reported to the Center for International Blood and Marrow Transplant Research. Methods : 365 patients aged &amp;lt;21 years with HLH (n=263) and CGD (n=102) were transplanted in the US between 2005-2018. Included are recipients of HLA-matched sibling (n=58; 16%) and HLA-matched (n=149; 41%) and mismatched unrelated (n=158; 43%) donor HCT. The analysis considered 3 conditioning regimen intensity groups: 1) fully myeloablative conditioning with busulfan (Bu; median dose 16 mg/kg [IQR 13-17]), cyclophosphamide (Cy) ± anti-thymocyte globulin (ATG) or alemtuzumab, n=142; 2) reduced intensity conditioning consisting of fludarabine (Flu), melphalan (Mel; 140mg/m2 [60%], 100 mg/m2 [40%]) ± alemtuzumab or ATG, n=131; and 3) reduced toxicity myeloablative conditioning consisting of either Flu, Mel (140mg/m2 [75%], 100 mg/m2 [25%]), and thiotepa (TT; 8 mg/kg or 10 mg/kg), or Flu, Bu (12mg/kg, IQR 9-15) ± alemtuzumab or ATG, n=92. The cumulative incidence rates of veno-occlusive disease (VOD) and infections were calculated. The probabilities of overall survival and event-free survival were calculated using Kaplan-Meier estimator. For event-free survival, an event was defined as the first occurrence of any of the following: primary graft failure, secondary graft failure, cellular product intervention for mixed chimerism, donor chimerism &amp;lt;5%, second transplant, or death. The Fine and Gray method for acute and chronic GVHD and Cox regression analysis for event-free and overall survival were used to determine factors affecting outcomes. Results : Patient demographics were similar across the three treatment groups. Patients with HLH were more likely to receive the Flu/Mel regimen. Although unrelated donor HCTs were predominant across the treatment groups, cord blood graft was more common in the Bu/Cy group. Conditioning regimens changed over the study period with most Flu/Mel/TT and Flu/Bu regimens used after 2010. Consequently, outcomes were censored 2-years post-HCT to account for differences in follow-up. The day-100 incidence of VOD was higher with Bu/Cy (18%) compared to Flu/Mel (4%) and Flu/Mel/TT or Flu/Bu (7%) regimens (p&amp;lt;0.001). The 6-month incidence of bacterial infection was higher after Bu/Cy (50%) and Flu/Mel (58%) compared to Flu/Mel/TT or Flu/Bu (43%) regimens (p=0.013). Viral infections were higher in Flu/Mel group (72%) compared to Bu/Cy (44%) and Flu/Mel/TT or Flu/Bu (56%), p&amp;lt;0.001. There were no differences in overall survival (Figure 1A), but event-free survival (Figure 1B) was lowest with the Flu/Mel regimen, after adjusting for donor type (Table 1). Compared to matched sibling, survival was lower with matched (HR 2.41, p=0.05) and mismatched (HR 2.89, p=0.01) unrelated donor HCT. Chronic GVHD but not grade II-IV acute GVHD was lower with Flu/Mel regimen. Table 2 shows the results of multivariate analysis for HLH disorders and findings consistent with the main analysis. Conclusion : The data does not support the use of a reduced intensity Flu/Mel regimen for hyperinflammatory inborn errors of immunity. Although we did not observe differences in event-free survival between Bu/Cy and Flu/Mel/TT or Flu/Bu regimens, lower incidences of VOD and bacterial infections favor Flu/Mel/TT or Flu/Bu regimens. Disclosures Pulsipher: Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria; Miltenyi: Honoraria, Research Funding; Mesoblast: Honoraria; Adaptive: Research Funding. Stenger:ISCT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding.

Efficacy of low dose and short duration defibrotide prophylaxis for hepatic veno-occlusive disease after autologous haematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a serious systemic endothelial complication after stem cell transplantation. Defibrotide is under investigation as a prophylactic agent for VOD; however, high costs limit its utility. We evaluated the prophylactic efficacy of a low-dose defibrotide regimen for VOD. We retrospectively enrolled 147 paediatric patients who underwent autologous haematopoietic stem cell transplantation (HSCT; 69 with defibrotide prophylaxis and 78 historical controls) at the Yonsei Cancer Center in Seoul, Korea, between March 2013 and Feb 2020. Low-dose defibrotide (12.5 mg/kg/day) was administered from D-3 to D+10 after HSCT. The most common diagnosis in the cohort was brain tumour (N = 86). VOD developed in 10 (12.8%) and 3 (4.3%) patients in the control and prophylaxis groups, respectively (P = 0.071). In the second HSCT group, VOD incidence was significantly lower in the prophylaxis group [2.9% (1/35)] than in the control group (28.6%, 6/21, P = 0.005). VOD severity was significantly higher in the control group than in the prophylaxis group (P = 0.006). Three VOD-related mortalities occurred in the control group, whereas no VOD-related mortality occurred in the prophylaxis group. In conclusion, low-dose defibrotide prophylaxis is a promising and economical strategy for preventing VOD, especially in second-round HSCT.

Hepatic veno-occlusive disease development in the hematopoietic stem cell transplantation patients: incidence and associated risk factors, a meta-analysis.

Now there are no efficient prophylactic or treatment strategies for hepatic veno-occlusive disease (VOD). Therefore, it is critical to early identify patients at high risk of VOD. To analyze the risk factors of VOD in the hematopoietic stem cell transplantation (HSCT) patients. A comprehensive search of the population was conducted. Twenty-one studies with 27 679 HSCT patients were eligible. The incidence of VOD was 15% [95% confidence interval (CI) 13-17%]. The following were the risk factors for VOD: mismatched HLA [odds ratio (OR) 2.34, 95% CI 1.20-4.57, P = 0.01], history of liver disease (OR 2.72, 95% CI 2.03-3.64, P < 0.00001), elevated AST before transplant (OR 2.49, 95% CI 1.49-4.15, P = 0.0005), months from diagnosis to HSCT > 12 months (OR 1.76, 95% CI 1.15-2.69, P = 0.009), previous radiation (OR 1.86, 95% CI 1.49-2.31, P < 0.00001), busulphan (OR 3.69, 95% CI 2.58-5.29, P < 0.00001) and MTX (OR 1.81, 95% CI 1.22-2.69, P = 0.003). There were no significant differences for VOD presentation in the patients with regards to sex, number of HSCT, Karnofsky score <90%, unrelated donor, autologous HSCT, CYA and heparin prophylaxis. Mismatched HLA, liver disease (history of liver disease, elevated AST), months from diagnosis to HSCT >12 months, previous radiation and use of hepatotoxic drugs (BU and MTX) are the independent risk factors for VOD in the HSCT patients.

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.

Veno-occlusive disease in children and adolescents after hematopoietic stem cell transplantation: Did the Modified Seattle Criteria fit the characteristics of pediatric population?

Hepatic veno-occlusive disease (VOD) is a life-threatening complication following hematopoietic stem cell transplantation (HSCT) and associated with a high mortality rate. Therefore, accurate and immediate diagnosis is crucial for implementing appropriate treatment. In our single-center retrospective study, we assessed the accuracy of the Modified Seattle Criteria in children and adolescents undergoing HSCT, and compared them to the diagnostic criteria recently established by the European Society for Blood and Marrow Transplantation (EBMT). Retrospective analysis of medical records of 951 HSCT procedures performed in 850 children and young adults in the years 2001-2015 in the Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation of Wroclaw Medical University Supraregional Center of Pediatric Oncology "Cape of Hope" in Wrocław, Poland. Among the 850 children, 48 were diagnosed with VOD according to the Modified Seattle Criteria (5.05%). Thirteen patients (27%) developed VOD later than within 20 days after transplantation, as required in the diagnostic criteria. Five of the 6 patients who died from VOD were diagnosed with late-onset VOD. Using the categories of symptoms described in the Modified Seattle Criteria, hepatomegaly and weight gain were the most common symptoms in the analyzed cohort (81.25% and 68.75%). Fourteen patients (29%) never demonstrated elevated plasma bilirubin level (>2 mg/dL), as suggested in the Modified Seattle Criteria. Twenty-nine patients (64%) had increased platelet consumption requiring daily transfusions. Only 5 patients with decreased plasma antithrombin III (ATIII) activity level (<80%) on the day of HSCT developed VOD despite supplementation of ATIII. The Modified Seattle Criteria seemed to not meet the special needs of the pediatric population. The new diagnostic criteria proposed by the EBMT appear to be more adequately tailored to the pediatric population and may significantly change the conception of VOD in the future. The surprisingly low incidence of VOD in our cohort may suggest a beneficial role of monitoring and early supplementation of ATIII.

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.

Transjugular Intrahepatic Portosystemic Shunt (TIPS) for Very Severe Veno-Occlusive Disease after Unmanipulated Haploidentical HSCT with Post-Transplant Cyclophosphamide

Background: The use of unmanipulated Haploidentical HSCT (Haplo-HSCT) with post-transplant Cyclophosphamide (PT-Cy) as GVHD prophylaxis has widely extended. Veno-occlusive disease (VOD) is a threatening complication after both autologous and allogeneic HSCT, with high mortality rates despite early medical treatment, including the use of defibrotide. The objective of this study was to describe characteristics and outcomes of patients with refractory very severe VOD after Haplo-HSCT with PT-Cy, treated with TIPS as salvage procedure. Methods: We retrospectively analysed 176 Haplo-HSCT with Cy-post consecutively performed between 2011 and May 2019 in a single centre. VOD was defined according to modified Seattle, Baltimore or revised EBMT criteria. Severity was retrospectively graded according to revised EBMT severity criteria into four categories: mild, moderate, severe and very severe. Complete response (CR) was defined as a normal total bilirubin level (&lt;2 mg/dL) or, in patients with normal bilirubin or alternative causes of hyperbilirubinemia, as normalized renal function, reduction of elevated transaminase level &lt;50%, tense ascites resolution, and no need for oxygen supplement in the absence of alternative hypoxemia causes. Results: Sixteen patients (9.1%) met the modified Seattle, Baltimore or revised EBMT diagnostic criteria for VOD. Ultrasound with Doppler ultrasonography was performed in all patients, and at least indirect signs of VOD were found in all cases. Based on revised EBMT severity criteria, there were 2 mild (12.5%), 2 moderate (12.5%), 2 severe (12.5%) and 10 very severe (62.5%) grade VOD. Twelve patients (75%) were treated with defibrotide, including all patients with very severe VOD, except one with CNS hemorrhage (Patient 1). Six patients with very severe VOD, were treated with TIPS due to rapid clinical or analytical deterioration or refractory hepatorenal syndrome, despite medical treatment including defibrotide (Table 1). All were male patients, with a median age of 31 years (range 22-36), all transplanted with myeloablative conditioning regimen. TIPS insertion was performed on a median time since VOD diagnosis of 5 days (range 1-28) without technical complications in any case. Median total bilirubin, ALT, creatinine and INR the day of procedure were 3 mg/dL (range 2.2-11.2), 1120 UI/L (range 10-2595), 2.45 mg/dL (range 2.06-3.58) and 1.96 (range 1.1-4) respectively. Median hepatic venous pressure gradient (HVPG) prior to and after TIPS was 22.5 (range 14-29) and 6.5 (range 2-10) mmHg respectively, with a median drop of 16.5 mmHg (range 9-19). Following TIPS, all patients showed clinical improvement with hepatomegaly, ascites and renal failure resolution, and all showed analytical improvement with bilirubin, creatinine and ALT values reduction, except for patient 2, whose TIPS indication was refractory hepatorenal syndrome with normal ALT levels (Figure 1). The 5 patients who had iniciated defibrotide before TIPS, completed 21 days of treatment. All patients met criteria for CR in a median of 8 days after TIPS insertion (range 2-82). The 100-day overall survival (OS) was 100%. Five patients were alive with normal liver and renal function at last follow up, and one patient died due to infection 7 months after Haplo-HSCT, with VOD in complete resolution. Conclusions: Incidence of VOD after Haplo-HSCT with PT-Cy is comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe VOD according to revised EBMT severity criteria. For patients with rapid progressive VOD, early TIPS insertion allowed completion of defibrotide therapy. The use of TIPS together with defibrotide resulted in complete response and no associated complications with a 0% of VOD associated mortality in spite of high severity. ALT values may be the best predictor of CR after TIPS procedure. In our experience, timely and individualized use of TIPS significantly improves outcome of very severe VOD after Haplo-HSCT. Therefore, TIPS should be promptly considered in rapid progressive cases. Disclosures No relevant conflicts of interest to declare.

Vascular and Parenchymal Alterations of the Liver and Liver Surveillance in Patients Who Received Inotuzumab Ozogamicin As the Standard of Care for Relapse/Refractory Acute Lymphoblastic Leukemia

Vascular and Parenchymal Alterations of the Liver and Liver Surveillance in Patients Who Received Inotuzumab Ozogamicin As the Standard of Care for Relapse/Refractory Acute Lymphoblastic Leukemia