Veno-occlusive Disease/sinusoidal Obstruction Syndrome Research Articles

Autotaxin is a potential predictive marker for the development of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT), and stratification of the high-risk group before transplantation is significant. Serum autotaxin (ATX) levels have been reported to increase in patients with liver fibrosis caused by metabolic inhibition from liver sinusoidal endothelial cells. Considering that the pathophysiology of VOD/SOS begins with liver sinusoidal endothelial cell injury, an increase in serum ATX levels may precede the onset of VOD/SOS. A retrospective study with 252 patients, including 12 patients with VOD/SOS, who had received allo-HCT was performed. The cumulative incidence of VOD/SOS was higher in the group with serum ATX levels before conditioning (baseline ATX) above the upper reference limit (high ATX group, p < 0.001), and 1-year cumulative incidences were 22.7% (95% confidence interval [95%CI], 3.1-42.4%) and 3.5% (95%CI, 1.1-5.8%), respectively. In the multivariate analysis, elevated baseline ATX was identified as an independent risk factor for VOD/SOS development and showed an additive effect on the predictive ability of known risk factors. Furthermore, the incidence of VOD/SOS-related mortality was greater in the high ATX group (16.7% vs. 1.3%; p = 0.005). Serum ATX is a potential predictive marker for the development of VOD/SOS.

Treatment Duration and Complete Response (CR) in Adult and Pediatric Patients (Pts) Treated with Defibrotide (DF) for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT) in the Defifrance and EBMT PASS Registries

Treatment Duration and Complete Response (CR) in Adult and Pediatric Patients (Pts) Treated with Defibrotide (DF) for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT) in the Defifrance and EBMT PASS Registries

Resolution of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) with Defibrotide Following HCT in Adult and Pediatric Patients: Pooled Analysis of Defifrance and EBMT PASS Registries

Introduction Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). Defibrotide is approved for the treatment of severe VOD/SOS post-HCT in patients aged &amp;gt;1 month in the European Union and for VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States. Outcomes from two real-world observational studies were pooled for analysis of treatment duration and time to resolution of VOD/SOS in patients given defibrotide for the treatment of severe or nonsevere VOD/SOS post-HCT. Methods DEFIFrance was an observational study that collected retrospective and prospective data on patients receiving defibrotide at 53 French transplant centers from July 2014 to March 2020. VOD/SOS severity was categorized retrospectively/prospectively using adult European Group for Blood and Marrow Transplantation (EBMT) criteria in patients aged ≥18 years, and in patients aged &amp;lt;18 years using pediatric EBMT criteria. EBMT PASS was a multinational, prospective, observational study that enrolled defibrotide-treated patients from April 2015 to July 2018. VOD/SOS severity was graded based on investigators' clinical expertise. For this pooled analysis, mild/moderate and severe/very severe cases in DEFIFrance were combined with nonsevere and severe cases in EBMT PASS, respectively. Investigators in both registries diagnosed VOD/SOS using classical/standard criteria. Results Overall, 414 defibrotide-treated patients with VOD/SOS post-HCT were included (336 from DEFIFrance and 78 from EBMT PASS). The median (interquartile range [IQR]) time from HCT to VOD/SOS diagnosis was 13 (IQR: 8, 21) and 14 (IQR: 8, 22) days in patients with severe and nonsevere VOD/SOS, respectively. Overall, 299/410 patients (73%) had resolution of VOD/SOS. Disease severity data was missing from 4 patients. Among 275 adult patients, VOD/SOS resolution was achieved in 44/60 (73.3%) with nonsevere and 128/215 (59.5%) with severe VOD/SOS. Median treatment duration was 15.5 days (IQR: 13, 22) for nonsevere and 18.5 days (IQR: 13.5, 22) for severe VOD/SOS. Of 135 pediatric patients, VOD/SOS resolution occurred in 47/48 (98%) with nonsevere and 80/87 (92%) with severe VOD/SOS. Median treatment duration was 16 days (IQR: 13, 21) in nonsevere and 21 days (IQR: 12.5, 29) in severe VOD/SOS. Among adult patients with resolution of VOD/SOS, symptoms resolved after day 21 in 32% of patients with nonsevere and 31% of patients with severe VOD/SOS. A higher proportion of pediatric patients with severe (44%) compared with nonsevere VOD/SOS (15%) required &amp;gt;21 days of treatment for resolution of symptoms; correspondingly, 85% of pediatric patients with nonsevere and 56% with severe VOD/SOS had resolution with ≤21 days of defibrotide treatment. Kaplan-Meier (KM)-estimated survival at day 100 post-HCT among patients with severe VOD/SOS was 84% (95% confidence interval [CI]: 78%, 88%) in those who achieved VOD/SOS resolution and 14% (95% CI: 8%, 22%) in those who did not; among patients with nonsevere VOD/SOS, this was 94% (95% CI: 87%, 98%) and 35% (95% CI: 15%, 57%), respectively. Serious treatment-emergent adverse events (TEAEs) of interest occurred in 25% of patients with VOD/SOS resolution. In patients treated for ≤21 days and &amp;gt;21 days, respectively, the most common serious TEAEs of interest by category were infection (14% and 15%) and hemorrhage (12% and 13%). Among patients with VOD/SOS resolution, the most common causes of death were infection (severe: 11%; nonsevere: 2%) and graft-versus-host disease (severe: 6%; nonsevere: 2%). Conclusion Time to resolution of VOD/SOS tended to be longer in patients with severe versus nonsevere VOD/SOS, with many patients requiring &amp;gt;21 days of therapy to achieve resolution. A higher proportion of adult vs pediatric patients attained a CR &amp;gt;21 days after initiation of defibrotide treatment. Day 100 survival was higher in patients with VOD/SOS resolution versus without, regardless of severity, highlighting the importance of VOD/SOS resolution. The safety profile of defibrotide in the real-world setting was consistent with reports from previous studies, supporting the utility of defibrotide treatment per the prescribing information.

Rare variants in complement system genes associate with endothelial damage after pediatric allogeneic hematopoietic stem cell transplantation.

Complement system has a postulated role in endothelial problems after hematopoietic stem cell transplantation (HSCT). In this retrospective, singlecenter study we studied genetic complement system variants in patients with documented endotheliopathy. In our previous study among pediatric patients with an allogeneic HSCT (2001-2013) at the Helsinki University Children´s Hospital, Finland, we identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome (CLS), venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS) or thrombotic microangiopathy (TMA). We performed whole exome sequencing (WES) on 109 patients having an adequate pre-transplantation DNA for the analysis to define possible variations and mutations potentially predisposing to functional abnormalities of the complement system. In our data analysis, we focused on 41 genes coding for complement components. 50 patients (45.9%) had one or several, nonsynonymous, rare germline variants in complement genes. 21/66 (31.8%) of the variants were in the terminal pathway. Patients with endotheliopathy had variants in different complement genes: in the terminal pathway (C6 and C9), lectin pathway (MASP1) and receptor ITGAM (CD11b, part of CR3). Four had the same rare missense variant (rs183125896; Thr279Ala) in the C9 gene. Two of these patients were diagnosed with endotheliopathy and one with capillary leak syndrome-like problems. The C9 variant Thr279Ala has no previously known disease associations and is classified by the ACMG guidelines as a variant of uncertain significance (VUS). We conducted a gene burden test with gnomAD Finnish (fin) as the reference population. Complement gene variants seen in our patient population were investigated and Total Frequency Testing (TFT) was used for execution of burden tests. The gene variants seen in our patients with endotheliopathy were all significantly (FDR < 0.05) enriched compared to gnomAD. Overall, 14/25 genes coding for components of the complement system had an increased burden of missense variants among the patients when compared to the gnomAD Finnish population (N=10 816). Injury to the vascular endothelium is relatively common after HSCT with different phenotypic appearances suggesting yet unidentified underlying mechanisms. Variants in complement components may be related to endotheliopathy and poor prognosis in these patients.

Concordance between HokUS-10 Scoring and Transjugular Liver Biopsy for the Diagnosis of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Allogeneic Stem Cell Transplantation

The aim of this study was to evaluate the concordance between clinical diagnosis and pathologic findings of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in post-hematopoietic stem cell transplantation recipients and to investigate the accuracy of the HOKUS-10 score in diagnosing VOD/SOS. We included 13 patients who underwent transjugular liver biopsy for clinical suspicion of VOD/SOS and collected their clinical, laboratory, imaging, and pathologic data. Eleven patients were confirmed to have VOD/SOS by pathologic examination. The median HokUS-10 score and hepatic venous pressure gradient were 6 points (range, 0 to 10 points) and 13 mmHg (range, 7 to 24 mmHg), respectively. There was no significant difference between these scores in VOD/SOS and non-VOD/SOS cases; however, patients with lower HokUS-10 scores tended to have milder histologic features of VOD/SOS compared with severe cases. This study highlights the potential discordance between clinical diagnosis and pathologic diagnosis of VOD/SOS and emphasizes the importance of liver biopsy to optimize treatment.

A phase 2 trial of defibrotide for the prevention of chimeric antigen receptor T-cell–associated neurotoxicity syndrome

AbstractChimeric antigen receptor T-cell (CAR-T) therapy represents a major advance in cancer immunotherapy; however, it can be associated with life-threatening neurotoxicity linked to blood-brain barrier disruption and endothelial activation. Defibrotide was shown to reduce endothelial cell activation in vitro and is approved in the United States for treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT), and in the European Union for severe VOD/SOS after HCT in patients aged >1 month. Defibrotide may stabilize the endothelium during CAR-T therapy and reduce the rate of CAR-T–associated neurotoxicity. This phase 2 study evaluated the safety and efficacy of defibrotide for prevention of CAR-T–associated neurotoxicity in patients with relapsed/refractory large B-cell lymphoma receiving axicabtagene ciloleucel. Part 1 established the recommended phase 2 dose (RP2D; 6.25 mg/kg); 20 patients (from parts 1 and 2) receiving the RP2D were evaluable for efficacy. Rate of CAR-T–associated neurotoxicity by day 30 (primary end point) was ∼50%, lower than reported in the ZUMA-1 trial (64%). Median event duration of grade ≥3 neurotoxicity was 7 days. No unexpected defibrotide-related safety findings and defibrotide-related treatment-emergent adverse events or deaths were reported. Results showed modest reduction in rate of CAR-T–associated neurotoxicity and high-grade neurotoxicity event duration relative to historical data; however, reduction was unlikely to meet the primary end point, so the study was terminated early. Nevertheless, results contribute valuable data for potential therapeutic insight on the management of CAR-T–associated neurotoxicity. This trial was registered at www.clinicaltrials.gov as #NCT03954106.

Pretransplantation EASIX Score Predicts Nonrelapse and Overall Mortality of Adult Patients Undergoing Single-Unit Unrelated Cord Blood Transplantation

The Endothelial Activation and Stress Index (EASIX) is a laboratory-based score used to estimate endothelial damage occurring after hematopoietic cell transplantation (HCT). The EASIX score exhibits dynamic changes during the course of transplantation and has been identified as a predictor of nonrelapse mortality (NRM) and worse overall survival (OS) in studies focused mainly on patients who received matched related or unrelated donor allogeneic HCT. However, the role of EASIX score in the setting of cord blood transplantation (CBT) is unclear. This study examined the association between pretransplant EASIX score and post-transplantation outcomes in adult patients undergoing single-unit CBT. We retrospectively evaluated the impact of EASIX score at different time points on post-transplantation outcomes in adults following single-unit unrelated CBT between 1998 and 2022 at our institution. EASIX scores were calculated at the start of conditioning (EASIX-PRE), at day 30 post-CBT (EASIX-d30), at day 100 post-CBT (EASIX-d100), and at the onset of grade II-IV acute graft-versus-host disease (GVHD) (EASIX-GVHD II-IV). A total of 317 patients were included in this study. In the multivariate analysis, log2-EASIX-PRE (continuous variable) was significantly associated with lower risks of neutrophil engraftment (hazard ratio [HR], .87; 95% confidence interval [CI], .80 to .94; P < .001) and platelet engraftment (HR, .91; 95% CI, .83 to .99; P=.047), lower risk of grade II-IV acute GVHD (HR, .85; 95% CI, .76 to .94; P=.003), and higher risk of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) (HR, 1.44; 95% CI, 1.03 to 2.02; P=.032). Log2-EASIX-PRE also was significantly associated with higher NRM (HR, 1.42; 95% CI, 1.08 to 1.86; P=.011) and worse OS (HR, 1.26; 95% CI, 1.08 to 1.46; P=.003), but not with relapse (HR, 1.02; 95% CI, .88 to 1.18; P=.780). Similarly, log2-EASIX-d30 (HR, 1.60; 95% CI, 1.26 to 2.05; P < .001), and log2-EASIX-d100 (HR, 2.01; 95% CI, 1.63 to 2.48; P < .001) were also significantly associated with higher NRM, but log2-EASIX-GVHD II-IV was not (HR, 1.15; 95% CI, .85 to 1.55; P=.360). Pretransplantation EASIX score is a powerful predictor of engraftment, VOS/SOS, NRM, and OS in adult patients undergoing single-unit unrelated CBT who mainly received intensified conditioning regimens. EASIX is an easily evaluable and dynamic prognostic score for accurately predicting post-transplantation outcomes in patients at any time during the course of allogeneic HCT, particularly for CBT.

Non-hematopoietic cell transplant-related veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in solid tumor and hematologic malignancies: A systematic review.

e24094 Background: VOD/SOS is a serious liver injury caused by toxic damage to sinusoidal endothelial cells. It has been linked to conditioning regimens preceding hematopoietic cell transplant (HCT) but little is known about its epidemiology and characteristics outside the HCT setting. We conducted a systematic review to examine the incidence, burden of illness, and management of non-HCT VOD/SOS. Methods: We searched MEDLINE, Embase (2002–2022), and relevant congress proceedings (2019–2022) for studies reporting incidence, diagnosis, clinical and patient characteristics, humanistic and economic burden, and treatments in non-HCT VOD/SOS. All study designs were eligible except case series of &lt; 5 patients. Pyrrolizidine alkaloid-induced VOD/SOS was excluded. Results: We identified 3,544 records and included 80 studies; 58% were retrospective cohort studies. Sample sizes ranged from 5 to 12,941; 38% of the studies included &gt; 100 patients. The highest incidences of non-HCT VOD/SOS were in patients with colorectal liver metastases (CLM) (median 41%) and Wilms tumor (median 14%) (table). Diagnostic criteria were heterogenous. Rubbia-Brandt histological criteria were used in CLM. In other disease settings, diagnosis varied and was based on clinical criteria (eg, McDonald, Seattle, or Baltimore). Management of VOD/SOS included defibrotide, supportive therapy (eg, fluid restriction, blood products) and switching/pausing chemotherapy. No usable data were found on humanistic/economic burden. Conclusions: Non-HCT VOD/SOS occurs in diverse disease areas, including hematologic and solid tumor cancers. Lack of consensus regarding diagnosis of non-HCT VOD/SOS may indicate underdiagnosis. Clinicians should be vigilant for VOD/SOS even in non-HCT patients. Defibrotide is approved for post-HCT VOD/SOS but there is no approved therapy for non-HCT VOD/SOS; future trials should focus on diagnosis and treatment outside the HCT setting, which represents a significant unmet need. A limitation of the current work is the suboptimal reporting and low methodological quality in some primary studies.[Table: see text]

THU-507 - Clinical impact and treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after liver transplant (LT): the role of transjugular intrahepatic porto-systemic shunt (TIPS)

THU-507 - Clinical impact and treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after liver transplant (LT): the role of transjugular intrahepatic porto-systemic shunt (TIPS)

Clinical impact and treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after liver transplant (LT). The role of transjugular intrahepatic porto-systemic shunt (TIPS)

Clinical impact and treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after liver transplant (LT). The role of transjugular intrahepatic porto-systemic shunt (TIPS)

175 - Treatment Duration, Symptom Resolution, and Survival in Defibrotide-Treated Patients (Pts) with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT): Pooled Analysis of Defifrance and EBMT PASS Registries

175 - Treatment Duration, Symptom Resolution, and Survival in Defibrotide-Treated Patients (Pts) with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT): Pooled Analysis of Defifrance and EBMT PASS Registries

171 - Outcomes of Defibrotide-Treated Patients (Pts) with Anicteric/Icteric Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT): Results from the Defifrance Registry Study

171 - Outcomes of Defibrotide-Treated Patients (Pts) with Anicteric/Icteric Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT): Results from the Defifrance Registry Study

Prior COVID-19 infection may increase risk for developing endothelial dysfunction following hematopoietic cell transplantation.

Endothelial dysfunction underlies many of the major complications following hematopoietic cell transplantation (HCT), including transplant-associated thrombotic microangiopathy (TA-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), and engraftment syndrome (ES). Emerging evidence similarly implicates endothelitis and microangiopathy in severe COVID-19-related multi-system organ dysfunction. Given the overlap in these two illness states, we hypothesize that prior COVID-19 infection may increase risk for HCT-related endotheliopathies. This retrospective, multicenter study included patients aged 0-25 years who underwent autologous or allogeneic HCT for any indication between January 1, 2020 and September 21, 2021, with close attention to those infected with COVID-19 in either the six months prior to transplant or twelve months following transplant. Incidences of TA-TMA, VOD/SOS, and ES were compared among patients with COVID-19 infection pre-HCT and post-HCT, as well as with historical controls who were never infected with SARS-CoV-2. Those who underwent HCT following COVID-19 infection displayed significantly increased rates of TA-TMA compared to those who were never infected. Additionally, our data suggests a similar trend for increased VOD/SOS and ES rates, although this did not reach statistical significance. Therefore, a history of COVID-19 infection prior to undergoing HCT may be a nonmodifiable risk factor for endothelial-related complications following HCT. Further studies are warranted to better clarify this relationship among larger cohorts and in the era of the Omicron SARS-CoV-2 variants.

Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan–Meier–estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan–Meier–estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.

A systematic literature review of the clinical signs and symptoms of veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation in adults and children.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a rare, serious complication following haematopoietic cell transplantation (HCT). This systematic literature review evaluated differences in clinical manifestations of VOD/SOS post-HCT in adults and children. Medline and Embase were searched up to 4 March 2021 for reports of VOD/SOS post-HCT; VOD/SOS diagnostic guidelines were included. Publications were evaluated based on inclusion of fivecardinal clinical features of VOD/SOS (ascites, hepatomegaly, hyperbilirubinaemia, right upper quadrant [RUQ] pain andweight gain ≥5%). Overall, 204 publications were included. At diagnosis, hyperbilirubinaemia was more common in adults (93%) versus children (82%), weight gain ≥5% and hepatomegaly were more common in children (86%, 89%) versus adults (73%, 76%) and ascites and RUQ pain were similar between age groups. While 40% of cases had all five cardinal features, age was not a substantial determinant of the likelihood of missing any single specific feature. The proportion of cases, where hyperbilirubinaemia was the first recorded feature, was higher in children versus adults; weight gain and RUQ pain appeared first in a greater proportion of adults versus children. VOD/SOS diagnosis can be challenging; features may not present in a distinct sequence. This necessitates continuous vigilance by those involved in patient monitoring post-HCT.

Prognostic Biomarkers for Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Myeloablative Allogeneic Hematopoietic Cell Transplantation: Results from the Blood and Marrow Transplant Clinical Trials Network 1202 Study

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). This study aimed to determine a blood biomarker signature early post-HCT that identifies patients at high risk for VOD/SOS. A set of 23 plasma biomarkers, selected from the VOD/SOS literature, was measured on days 0, 7, and 14 after myeloablative HCT using blood samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1202. Eligible cases were diagnosed with VOD/SOS in BMT CTN 1202 using the Baltimore criteria. Controls (without VOD/SOS) were matched to cases for conditioning regimen and age. Significant biomarkers were identified using the Bonferroni-adjusted Wilcoxon rank-sum test (P ≤ .002). Thirty-three patients with mild or severe VOD/SOS were identified (cases) and matched to 107 controls. Two, 8, and 5 biomarkers measured from the plasma of these patients were significantly associated with the development of VOD/SOS at days 0, 7, and 14, respectively, with the strongest associations on days 7 and 14. Biomarker associations were stronger for severe VOD/SOS risk and were stronger prognostic markers for VOD/SOS cases occurring within 28 days of HCT. Hyaluronan was most strongly associated with VOD/SOS risk, with an area under the receiver operating characteristic curve (AUC) of .81 on day 7 and .79 on day 14. Multivariate models of up to 5 biomarkers generated AUCs ranging from .82 to .85. All associations with VOD/SOS risk were independent of clinical risk factors. This study confirms previously identified biomarkers of VOD/SOS risk and identified novel prognostic biomarker signatures that identify patients at risk for VOD/SOS shortly after HCT. Multivariate analysis suggests that a combination of up to 5 of these protein biomarkers may provide a prognostic tool for identifying patients at risk for VOD/SOS.

Veno-Occlusive Disease Risk and Other Outcomes in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia Who Received Inotuzumab Ozogamicin and Proceeded to Hematopoietic Stem Cell Transplantation: A Registry-Based, Observational Study

Introduction: Inotuzumab ozogamicin (InO) is a CD22-directed antibody-drug conjugate indicated for the treatment of relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). InO has been associated with hepatotoxicity and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), particularly following hematopoietic stem cell transplantation (HSCT). This study examined post HSCT outcomes in patients who received InO prior to HSCT. Methods: This observational, post-authorization safety study included patients in the United States with B-cell precursor ALL who were treated with InO and received subsequent HSCT at a participating center, and whose data were reported to the Center for International Blood and Marrow Transplant Research. We report outcomes in adults (aged ≥18 years) with ALL, and the subset of adults with R/R ALL, who received InO and proceeded to first allogeneic HSCT. Post HSCT outcomes included disease status, overall survival, non-relapse (transplant-related) mortality (NRM), non-transplant-related mortality, and adverse events (AEs) of interest, including VOD/SOS. Multivariate analyses examined prognostic factors of NRM at 1 year and VOD/SOS incidence at 100 days post HSCT. This analysis is based on 4-year interim data, accrued from August 18, 2017, to August 17, 2021 (data lock: September 30, 2021). The study is ongoing and will continue for a total observational period of 5 years. Results: There were 196 adults (median age 39 years, 54% male) with ALL who received InO and proceeded to first allogeneic HSCT: 32% in first complete remission (CR1), 46% in CR2, 12% in CR≥3, 5% in first relapse, 2% in third or subsequent relapse, and 3% with primary induction failure (data unavailable in 1%). Prior to HSCT, 32%, 45%, and 17% received 1, 2, and ≥3 cycles of InO, respectively (data unavailable in 6%). Additional treatment- and transplant-related characteristics are presented in Table 1. Post HSCT outcomes are shown in 177 adults with ALL, and 120 adults with R/R ALL, with complete follow-up data at the data lock (Table 2). Median (range) follow-up was 8.4 (0.4-39.2) and 7.1 (0.4-38.8) months in the respective groups. The most common causes of NRM at 12 months were VOD/SOS (10/35; 29%) and graft-versus-host disease (GVHD; 8/35; 23%) in patients with ALL. AEs occurring in ≥30% of patients within 100 days post HSCT were bacterial infection (46%), viral infection (41%), and acute GVHD (grades II-IV; 38%). VOD/SOS incidence within 100 days post HSCT was 15% and 19% in patients with ALL and R/R ALL, respectively; corresponding mortality rates were 38% and 36% in patients who developed VOD/SOS within 100 days (6% and 7% as a percentage of all patients). Median (range) time from HSCT to VOD/SOS was 0.4 (0.2-2.6) months in both groups. Of 26 adults with ALL who developed VOD/SOS, 10 cases were mild and 16 severe; 5/26 patients received prophylactic defibrotide; and 12/26 patients received defibrotide treatment either alone or in combination with other treatment. In those who died, median (range) time to death was 4.5 (0.4-39.2) months. A total of 143 adults with ALL who were alive at the date of last contact and reported ≥1 year of follow-up or who died at any time after HSCT were included in multivariate analyses. Total serum bilirubin at or above the upper limit of normal before HSCT (hazard ratio [HR], 5.72; P=0.0001) and 4 cycles of InO (HR, 6.81; P=0.0009) were negative prognostic factors for NRM at 1 year. A conditioning regimen containing dual alkylators was the only negative prognostic factor for VOD/SOS incidence at 100 days (odds ratio, 8.3; P=0.0033). Conclusions: In this real-world population of adults with ALL who received InO before HSCT, including heavily pretreated patients, the incidence of VOD/SOS after HSCT was similar to that observed in the phase 3 INO-VATE study (23%; Kantarjian et al, Cancer 2019;125:2474-87) and a pooled analysis of 2 clinical trials of InO-treated patients with R/R ALL (19%; Marks et al, Biol Blood Marrow Transplant 2019;25:1720-29). Although the VOD/SOS mortality rate was higher (36% vs 26%), NRM at 12 months was lower (24% vs 38%) here vs the pooled clinical trial population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Machine Learning Based Prediction of Veno Occlusive Disease Following Allogenic Stem Cell Transplantation

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of stem cell transplantation. Hitherto, patient snap shots have been focussed upon, while predicting the onset and severity of VOD/SOS. We present a novel mechanistic learning of the score of VOD/SOS onset and progression using recorded values of pre-transplant parameters and during-transplant observations on 25 patients, as part of a longitudinal data comprising data stored in patient records at multiple institutes. Subsequently, we learn the relationship between such pre-transplant variables and this learnt score, using Machine Learning (ML) techniques that permit the desired avoidance of imposed forms of this relationship. This allows reliable prediction of the VOD/SOS score of a new patient with observed pre-transplant parameters. We discuss results of such undertaking. Using the learnt relationship between VOD/SOS score and patient pre-transplant attributes, we also identify relative potency of each pre-transplant variable, towards VOD/SOS onset and progression. Our ML-based learning and prediction offer protocols that enable early identification of VOD susceptibility in a new patient at the pre-transplant stage, thus permitting intervention, enabling VOD/SOS mitigation.

Endothelial Complications of Hematopoietic Cell Transplantation for Sickle Cell Disease

Introduction Hematopoietic cell transplantation (HCT) is a curative therapy for sickle cell disease (SCD), with especially favorable outcomes in young patients from HLA-identical donors. Unfortunately, HCT is associated with endothelial injury syndromes (EIS), including veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), transplant-associated thrombotic microangiopathy (TA-TMA), and also acute graft-versus-host disease (GVHD), that increase transplant risk. This is further complicated by hemolysis-mediated endothelial dysfunction in patients with SCD. The impact of EIS in this population is not certain. We thus sought to better evaluate endothelial complications of HCT for SCD in a large, international registry. Methods We examined de-identified records of HCT for SCD that were retrieved from data on patients transplanted between 1991 and 2020 in the United States submitted to the Center for International Blood and Marrow Transplant Research (CIBMTR) obtained through curesickle.org. Patients were followed longitudinally until death, loss to follow-up, or last contact through June 2021 at 3, 6, 12, and 24 months after HCT, and then every 2 years. Donors included HLA-matched siblings, haploidentical relatives, and HLA-matched and HLA-mismatched unrelated donors. We examined overall survival, event-free survival, and acute and chronic GVHD. Cox regression models were used to examine for risk factors associated with TMA and VOD. In addition, one-factor (univariate) analysis was used to identify factors associated with higher risk complications. Results A total of 1641 unique patients underwent a first allogeneic HCT between 1991 and 2020, with a median year of HCT of 2014. Of HCT recipients, 67.7% were below the age of 18 years at HCT and 74.7% had Karnofsky performance score ≥ 90. Acute GVHD grades II-IV developed in 18.3% and 22.3% developed chronic GVHD. Graft failure was reported in 17.6% following HCT, which was from an HLA-identical sibling in 61.5%, mismatched relative in 17.6%, matched unrelated donor in 10.2%, and mismatched unrelated donor in 10.7%. Conditioning regimen was myeloablative (50.8%), reduced intensity (23%), or non-myeloablative (22.3%). Patients were followed for a median of 47.8 months (0.3 - 312.9), with 3-year overall survival 91.2% and 3-year event-free survival 85.2%. Median time to death was 9.6 months for 152 patients. Estimated hazard ratio (HR) of death in 7/8 vs. 8/8 HLA matching was 1.5 (95% CI: 0.752, 2.445), which was not statistically significant. However, HR of death for ≤ 6/8 vs. 8/8 HLA matching was 1.7 (95% CI: 1.215, 2.445), indicating a statistically significant increased risk of death. TA-TMA was reported in 27 patients at a median of 2.8 months post-HCT. Univariate analysis of risk factors for TA-TMA indicated increasing incidence with the year of HCT. Age at HCT, HLA matching, and conditioning regimen intensity were not significantly associated. VOD was reported in 24 cases; Cox proportional hazards analysis indicated decreasing incidence with year of HCT. Estimated HR for VOD of patients who developed grade II-IV AGVHD group was 2.965, (95% C.I. 1.089, 8.074). Age at HCT, conditioning intensity, and donor type were not significant. Acute and chronic GVHD were associated with recipient age > 10 years and donors other than HLA-matched siblings; non-myeloablative conditioning was protective against GHVD development. Conclusion Incidence of endothelial complications following HCT for SCD is low, although TA-TMA has been increasingly recognized in recent years. VOD has been observed less frequently over time and correlates with acute GVHD. Donor type, recipient age, and conditioning intensity have the greatest impact on GVHD development.

Outcomes of Defibrotide-Treated Patients with Anicteric/Icteric Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT): Results from the Defifrance Registry Study

VOD/SOS is a potentially life-threatening complication of HCT. Historically, per Baltimore criteria, hyperbilirubinemia (bilirubin >2 mg/dL) has been a key criterion for VOD/SOS diagnosis, although recent guidelines also acknowledge VOD/SOS without elevated bilirubin. Recent studies have reported anicteric VOD/SOS (bilirubin ≤2 mg/dL at diagnosis) in >20% of patients. This post-hoc analysis of data from a large registry study in France presents patient characteristics and effectiveness and safety outcomes by bilirubin level at VOD/SOS diagnosis in patients treated for VOD/SOS post-HCT. DEFIFrance is a post-marketing registry study that collected retrospective and prospective real-world data on patients receiving defibrotide at 53 HCT centers in France. Included in this post-hoc analysis are all patients treated with defibrotide for VOD/SOS post-HCT. Diagnosis of VOD/SOS was at the investigator's discretion using standard criteria, per typical clinical practice. Disease severity was categorized using adult EBMT severity criteria in patients aged ≥18 years, and patients aged <18 years were retrospectively/prospectively categorized using pediatric EBMT severity criteria. The primary endpoints were Kaplan-Meier (KM)-estimated Day 100 post-HCT survival and complete response (CR; total serum bilirubin <2 mg/dL and multiorgan failure resolution per investigators' assessment). Serious treatment-emergent adverse events (TEAEs) of interest were also collected: hemorrhage, coagulopathy, immunogenicity, injection-site reaction, septicemia, infection, and thromboembolic event, irrespective of relationship to treatment. Of the 336 defibrotide-treated patients with VOD/SOS post-HCT, 109 (33%) had bilirubin ≤2 mg/dL, and 226 (67%) patients had bilirubin >2 mg/dL at diagnosis; 1 patient had missing data. Anicteric VOD/SOS was more common in pediatric patients (49% overall and 26% among patients with severe/very severe VOD/SOS) than adults (26% overall and 21% among patients with severe/very severe VOD/SOS), resulting in a lower median age in those with bilirubin ≤2 mg/dL (29.0 years; range: 0, 71) versus patients with bilirubin >2 mg/dL (47.5 years; range: 0, 74). The most common primary disease in each group, bilirubin ≤2 mg/dL and bilirubin >2 mg/dL, was AML (22% and 29%, respectively). Most patients in each group had no prior HCTs (91% and 88%, respectively) and underwent myeloablative conditioning (69% and 54%, respectively). Prior exposure to gemtuzumab or inotuzumab ozogamicin had occurred in 14% and 8% of patients with bilirubin ≤2 mg/dL and bilirubin >2 mg/dL, respectively. Rates of Day 100 survival post-HCT and resolution of VOD/SOS tended to be higher in patients with bilirubin ≤2 mg/dL versus patients with bilirubin >2 mg/dL (Figure). Outcomes in patients with mild/moderate VOD/SOS post-HCT were more favorable than in those with severe/very severe disease, regardless of bilirubin level at diagnosis. Serious TEAEs of interest occurred in 25% of mild/moderate and 40% of severe/very severe patients with bilirubin ≤2 mg/dL; in patients with bilirubin >2 mg/dL, 33% and 26% of patients with mild/moderate and severe/very severe VOD/SOS had serious TEAEs of interest. Most common serious TEAEs of interest by category in each group, bilirubin ≤2 mg/dL and bilirubin >2 mg/dL, were hemorrhage (mild/moderate: 20%, severe/very severe: 24%, respectively; mild/moderate: 17%, severe/very severe: 14%, respectively) and infection (mild/moderate: 6%, severe/very severe, 24%, respectively; mild/moderate: 10%, severe/very severe: 15%, respectively). In this post-hoc analysis, defibrotide-treated patients with anicteric VOD/SOS tended to have better outcomes than those with bilirubin >2 mg/dL at VOD/SOS diagnosis. Similarly, outcomes tended to be better in those treated at a less severe stage of disease. Taken together, these findings highlight the importance of prompt diagnosis and treatment of VOD/SOS without the requirement for elevated bilirubin, emphasizing the relevance of using VOD/SOS diagnostic criteria that do not require hyperbilirubinemia. The safety profile of defibrotide in the real-world setting was consistent with previous studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal