Use Of Defibrotide Research Articles

Use of defibrotide in COVID-19 pneumonia: comparison of a phase II study and a matched real-world cohort control.

The coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented burden on healthcare systems around the world and a severe global socioeconomic crisis, with more than 750 million confirmed cases and at least 7 million deaths reported by December 31, 2023. The DEFI-VID19 study (clinicaltrials gov. Identifier: NCT04335201), a phase II, single-arm, multicenter, open-label trial was designed in mid-2020 to assess the safety and efficacy of defibrotide in treating patients with COVID-19 pneumonia. Defibrotide was administered at a dose of 25 mg/kg intravenously, divided into four daily doses over a planned 14-day period for patients with COVID-19 pneumonia receiving non-invasive ventilation. The primary endpoint was respiratory failure-free survival (RFFS). Overall survival (OS), the number of post-recovery days, and adverse events were the secondary endpoints. For comparison, a contemporaneous control cohort receiving standard of care only was retrospectively selected by applying the eligibility criteria of the DEFI-VID19 trial. To adjust for the imbalance between the two cohorts in terms of baseline variable distributions, an outcome regression analysis was conducted. In adjusted analysis, patients receiving defibrotide reported a trend towards higher RFFS (hazard ratio [HR]=0.71; 95% confidence interval [CI]: 0.34-1.29; P=0.138) and OS (HR=0.78; 95% CI: 0.33-1.53; P=0.248]) and showed a significantly increased number of post-recovery days (difference in means =3.61; 95% CI: 0.97-6.26; P=0.0037). Despite concomitant thromboprophylaxis with low molecular weight heparin, the safety profile of defibrotide proved to be favorable. Taken together, our findings suggest that defibrotide may represent a valuable addition to the COVID-19 therapeutic options.

Systematic Literature Review of Incidence and Management of Non-HCT-Related Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS)

Background: VOD/SOS is a potentially life-threatening complication caused by damage to sinusoidal endothelial cells. It has historically been associated with toxicity from conditioning regimens preceding hematopoietic cell transplantation (HCT), but its epidemiology and characteristics outside the HCT setting are not well understood. We conducted a systematic review to examine the incidence, mortality, diagnosis, and the burden of illness of non-HCT VOD/SOS. Methods: We searchedMEDLINE and Embase (2002-2023), as well as recent congress proceedings (2019-2023) for studies reporting the following in the non-HCT VOD/SOS setting: incidence, diagnosis, relevant medical history, disease management, clinical burden, health-related quality of life, costs, and patients' (pts) unmet needs. All study designs were eligible except case series with <5 participants. Studies of pulmonary VOD or VOD/SOS resulting from ingestion of pyrrolizidine alkaloids were excluded. Two independent reviewers screened titles/abstracts and full-text articles and assessed the methodological quality of studies. Results: Of 3874 records screened, 92 studies were included; 57% were retrospective cohort studies and 70% were conducted in the United States or Europe. VOD/SOS was reported in 17 acute myeloid leukemia (AML) studies and 13 acute lymphoblastic leukemia (ALL) studies. The highest incidences of non-HCT VOD/SOS occurred in pts with colorectal liver metastases (CLM; median 35%) and Wilms tumor (median 14%; Table 1). The occurrences of severe non-HCT VOD/SOS and mortality are provided in Table 2. Clinical criteria (eg, McDonald, Seattle, or Baltimore) were widely used to diagnose both hematological (i.e., AML and ALL) and nonhematological disease (i.e., Wilms tumor), while Rubbia-Brandt histological criteria were used to diagnose VOD/SOS in pts with CLM. While most studies did not report how non-HCT VOD/SOS was managed, 26 studies reported defibrotide use: 80/112 pts (71%) with hematologic cancer and 223/309 pts (72%) in other disease settings. In 7/26 studies, all pts who received defibrotide recovered. Two of 26 studies reported high rates of recovery from VOD/SOS at 70 days following defibrotide initiation: one with 71% of patients alive at day 70 following the start of defibrotide (58/82 pts) and one with 83% of patients alive at day 70 (5/6 pts). Nine studies did not report any outcomes related to defibrotide and another did not distinguish between outcomes in pts treated with defibrotide compared with other treatments. No defibrotide use was reported in studies evaluating pts with CLM. Among non-defibrotide treatments, the most reported VOD/SOS treatment was supportive therapy (14%; 13/92 studies), followed by switching or pausing chemotherapy (11%; 10/92 studies). One study reported outcomes for 206 children who received supportive care for VOD/SOS during 6-thioguanine therapy for ALL; only three pts had acute hepatic failure and all pts recovered from VOD/SOS. Of the studies reporting switching or pausing chemotherapy to manage VOD/SOS, four studies reported 100% recovery from VOD/SOS, and five studies did not report treatment outcomes. The severity of VOD/SOS in these pts was unknown. Four studies reported any adverse events (AEs) in pts treated for VOD/SOS: two reported zero AEs (in four children with ALL treated with defibrotide and two children with Wilms tumor treated with N-acetylcsteine); one reported AEs in 27% (of 82 defibrotide-treated pts, mostly with hematologic cancers); and one reported ≥1 treatment-emergent serious AE of interest in 15% (of 46 pts with hematologic or nonhematologic cancers treated with defibrotide), including infection (9%) and hemorrhage (9%). Conclusions: Non-HCT VOD/SOS occurs in diverse disease areas, including hematologic and solid tumor cancers. A lack of consensus regarding VOD/SOS diagnosis in the non-HCT setting may lead to underdiagnosis; therefore, clinicians should be vigilant for VOD/SOS even in non-HCT pts. Though defibrotide is approved for post-HCT VOD/SOS, 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. Limitations include a lack of population-based studies to estimate true incidence and that the evidence is based on studies whose main objective was not to investigate non-HCT VOD/SOS.

Sinusoidal Obstruction Syndrome (SOS) Biomarkers-Derived Predictive Model to Individualize SOS Preemption in Patients Undergoing Allogeneic Stem Cell Transplant

Background: We have previously reported that the predictive model based on 3 biomarkers [L-ficolin, hyaluronic acid (HA), and stimulation 2 (ST2)] can accurately stratify the risk of sinusoidal obstruction syndrome (SOS) in high (>30%) vs low (<5%) risk groups [ JCI Insight. 2023; 8(10):e168221]. However, the improved risk stratification for SOS does not necessarily help guide the administration of the risk-adapted preemptive therapy. Here we set out to assess the clinical utility of the SOS model by integrating its prediction with the consequences (benefits and harms) of preemptive treatment with defibrotide. Methods: We used the data set from the prospective evaluation of the accuracy of the SOS predictive model. We have reformulated the SOS predictive model as a simple fast-and-frugal (FFT) decision tree. FFT consisted of sequentially ordered cues of 3 biomarkers [L-ficolin, HA, and ST2] via a series of binary (yes/no) classification decisions according to the optimal cutpoints chosen by Youden's index. After assessing the model's performance (discrimination, calibration) we applied a generalized decision curve analysis (gDCA) to integrate the effects of treatments with the predictive accuracy of the model. This, in turn, allowed us to develop individualized recommendations for the use of preemptive treatment of SOS with defibrotide. We calculated net benefits (NB) to compare 3 management strategies: don't provide any treatment vs. administer prophylaxis to all patients undergoing allo-transplant vs. use the SOS model to guide the preemption treatment with defibrotide. According to gDCA the best treatment is the one with the highest net benefits. We informed gDCA analysis using data from the published randomized trial comparing defibrotide vs. placebo treatment effects [ Lancet. 2012; 379 :1301]. Adverse events (AE) were seen in 2.5% more patients compared with placebo, and defibrotide reduced the risk of SOS by 40% (=relative risk reduction [RRR]). Results: The model had a good performance characteristic. Harell's C discrimination statistics was 0.77 with good calibration properties (with intercept and the slope not statistically significantly different from 0 and 1, respectively). Assuming AE of 2.5%, offering prophylaxis to all patients with defibrotide represents the best management strategy for very large RRR (>65%). Similarly, for RRR<2.5%, no prophylaxis should be offered. For all other values of treatment effects (ranging from RRR 2.5% to 65%), relying on the SOS model represents the best strategy to guide the use of defibrotide preemptively (Figure 1A). Assuming the baseline treatment values [AE=2.5%, RRR=40%], the SOS model almost perfectly individualizes the use of prophylaxis: all patients with a risk of SOS>6.25% should be given prophylaxis, otherwise not (Figure 1B). However, the risk threshold was sensitive to the assumptions about defibrotide treatment effects. Conclusion: The SOS biomarker-based model offers a new method to guide risk-adapted prophylactic or preemptive therapy for SOS.

Peritoneal and Pleural Drains in Pediatric Hematopoietic Cell Transplant Recipients with Veno-Occlusive Disease are Safe and Do Not Adversely Impact Clinical Outcomes.

There is a lack of data on the safety and efficacy of peritoneal drain (PD) and chest tube (CT) in the management of effusions in stem cell transplant recipients with veno-occlusive disease (VOD). In this retrospective pediatric study, clinical outcomes and health resource utilization (HRU) were compared in 32 patients with VOD who had a PD (PD+) post-HCT versus 27 patients who did not (PD-). Nine patients also had a CT (7 PD+ and 2 PD-). PD + patients were more likely than PD-patients to have received myeloablative conditioning (100% vs. 85.2%; p = 0.04) and have severe or very severe VOD (100% vs. 56% p < 0.01). Mechanical obstruction (38%) and hypotension (38%) were common complications, and 13% developed peritonitis. While the frequencies of cardiac dysfunction and acute kidney injury were comparable between both groups, respiratory support and its median duration were higher in PD + patients. The hospital and intensive care unit length of stay, albumin use, and the duration of defibrotide and albumin therapy was significantly longer in PD + patients. At a median follow-up of 1.04 years (range:0.03-14.6), the 2-year overall survival was similar in both groups (53.8% vs. 51.5%; p = 0.73). Although PD use was similar between 1995 and 2007 vs. 2008-2021; (47% vs. 58%; p = 0.65), day+100 mortality was improved in recent years (53.3% vs. 17.8%; p = 0.01), coinciding with the use of defibrotide (0% vs. 84%; p < 0.01). PD in pediatric patients with VOD post-HCT, although associated with increased HRU, was safe when clinically indicated and did not adversely impact clinical outcomes.

Incidence of Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease and Treatment with Defibrotide in Allogeneic Transplantation: A Multicenter Australasian Registry Study

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is an established complication in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT). Defibrotide is an effective and safe pharmacologic option for treating diagnosed SOS/VOD. By exploring data provided to the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) by centers in Australia and New Zealand, this study aimed to describe the incidence of SOS/VOD and patterns of defibrotide use from 2016 to 2020. Patients who underwent allogeneic hemopoietic stem cell transplantation between 2016 and 2020 were identified from the ABMTRR. Data were extracted for a total of 3346 patients, 2692 from adult centers and 654 from pediatric centers, with a median follow-up of 21.5 months and 33.3 months, respectively. Descriptive statistics were used to describe the patient population, including the incidence of SOS/VOD and defibrotide use. Comparisons were made between patients without SOS/VOD and those with SOS/VOD, divided into defibrotide and no defibrotide cohorts. Associations with overall survival (OS) and day 100 survival with such variables as sex, age, disease at transplantation, stem cell source, conditioning agents, SOS/VOD diagnosis, and use of defibrotide, were determined. The reported incidence of SOS/VOD was 4.1% in adult centers and 11.5% in pediatric centers. Defibrotide was administered to 74.8% of adult patients and 97.3% of pediatric patients with SOS/VOD. Significant variability in the use, dosage, and duration of defibrotide was seen across the adult centers. The day 100 survival rate and median OS for patients managed with defibrotide was 51.8% and 103 days, respectively, for adult patients and 90.4% and not reached, respectively, for pediatric patients. In adults, older age at transplantation, an HLA-matched nonsibling relative donor, and a diagnosis of SOS/VOD treated with defibrotide were associated with reduced OS. In pediatric patients, the patient and transplantation characteristics associated with reduced OS were a diagnosis of SOS/VOD and a ≥2 HLA-mismatched related donor. A collaborative approach across Australasia to diagnosing and managing SOS/VOD, particularly with respect to consistent defibrotide use, is recommended.

Defibrotide impact on the acute GVHD disease incidence in pediatric hematopoietic stem cell transplant recipients.

Despite advances in acute graft-versus-host disease (aGVHD) prophylaxis, current pharmacological approaches fail to prevent aGVHD. The protective effect of defibrotide on GVHD incidence and GVHD-free survival has not been sufficiently studied. 91 pediatric patients included in this retrospective study were divided into two groups based on defibrotide use. We compared the incidence of aGVHD and chronic GVHD-free survival between the defibrotide and control groups. The incidence and severity of aGVHD were significantly lower in patients who received defibrotide prophylactic administration than in the control group. This improvement was observed in the liver and intestinal aGVHD. No defibrotide prophylaxis benefit was observed in the prevention of chronic GVHD. The pro-inflammatory cytokine levels were significantly higher in the control group. Our findings suggest that prophylactic administration of defibrotide in pediatric patients significantly reduces the incidence and severity of aGVHD, with a modification of cytokine pattern, both strongly coherent with the protective drug's action. This evidence adds to pediatric retrospective studies and preclinical data suggesting a possible defibrotide role in this setting.

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.

Is Defibrotide Prophylaxis Effective on Graft Versus Host Disease in Patients with Allogeneic Stem Cell Transplantation?

Introduction: Sinusoidal obstruction syndrome (SOS) is one of the complications of allogeneic stem cell transplantation (allo-SCT). Defibrotide (DF) is used effectively in SOS prophylaxis and treatment. Graft versus host disease (GVHD) is a significant cause of morbidity and mortality in allo-SCT. Here, we retrospectively investigated the effect of DF on the development of GVHD in these patients.&#x0D; Methods: We evaluated 81 allo-transplanted patients due to various diagnoses (benign or malignant), retrospectively. Thirty-four patients used DF as prophylaxis while 47 patients did not receive it. Acute and chronic GVHD assessments were performed at +30/100th day and throughout the life of the patients, respectively.&#x0D; Results: Acute GVHD was more common with DF use (82% vs 61%). There was no statistical significance in terms of the effect on chronic GVHD. We observed that one patient in the non- DF group developed SOS.&#x0D; Conclusions: DF may be beneficial to prevent acute GVHD. However, we observed that GVHD and mortality were more common in patients using DF. This is probably due to the similarity of high-risk criteria between GVHD and SOS. We have not found a significant association between defibrotide use and the development of chronic GVHD.

P1355: VENO-OCCLUSIVE DISEASE/SINUSOIDAL OBSTRUCTION SYNDROME (VOD/SOS) AFTER AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION (HCT): OUTCOMES OF DEFIBROTIDE-TREATED ADULT PATIENTS FROM THE DEFIFRANCE STUDY

Background: Hepatic VOD/SOS is a potentially fatal complication of HCT conditioning. Although allogeneic HCT (allo-HCT) and autologous HCT (auto-HCT) conditioning regimens often contain the same drugs, their protocols differ. VOD/SOS is more common after allo-HCT, but it also occurs after auto-HCT. Defibrotide is approved for the treatment of severe VOD/SOS post-HCT in patients aged >1 month in the European Union and for VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States. The DEFIFrance study collected real-world data on the effectiveness and safety of defibrotide from HCT centers in France. Aims: This post-hoc analysis presents patient characteristics and effectiveness and safety outcomes in adult patients who received defibrotide treatment for VOD/SOS after auto-HCT. Methods: This post-marketing registry study collected retrospective and prospective real-world data on patients receiving defibrotide at 53 HCT centers in France. 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. 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) in patients with severe/very severe VOD/SOS. A secondary endpoint was the evaluation of treatment-emergent serious adverse events (SAEs) of interest: hemorrhage, coagulopathy, immunogenicity, injection-site reaction, septicemia, infection, and thromboembolic event, irrespective of relationship to treatment. Results: Of 249 adult patients in the post-HCT population treated with defibrotide, 22 (9%) underwent auto-HCT. Median age of this subgroup was 53.7 (range: 22, 66) years. The most common primary disease was lymphoma/chronic lymphocytic leukemia (n = 18 [82%]), and 1 (5%) patient each had either ALL, AML, neuroblastoma/solid tumor, or myeloma. The majority of patients with available data (20/21 [95%]) received intensive, myeloablative conditioning. The median time from auto-HCT to VOD/SOS diagnosis was 14.0 (range: 0, 185) days. At diagnosis, 17 (77%) patients had ascites, 16 (73%) had refractory thrombocytopenia, and 10 (45%) had anicteric VOD/SOS. Seven (32%) patients had mild/moderate VOD/SOS, 9 (41%) had severe, and 4 (18%) had very severe. The median duration of defibrotide treatment was 15.0 (range: 3, 55) days. By Day 100 post-HCT, the KM–estimated survival rate was 73% (95% CI: 49%, 87%). The CR rate at Day 100 was 55% (95% CI: 32%, 76%). Treatment-emergent SAEs of interest occurred in 4 (18%) patients, specifically: catheter site hemorrhage, gastrointestinal hemorrhage, coagulopathy, and hypotension, each occurring in 1 patient. Summary/Conclusion: VOD/SOS can develop after auto-HCT and can be severe. Defibrotide treatment has previously demonstrated efficacy among patients with VOD/SOS after auto-HCT. The DEFIFrance study represents the largest collection of real-world data on post-registration use of defibrotide. The effectiveness and safety observed in this post-hoc analysis support the real-world use of defibrotide in adult patients who develop VOD/SOS after auto-HCT.

Interest of the preventive and curative use of defibrotide on the occurrence and severity of sinusoidal obstruction syndrome after hematopoietic stem cell transplant in children.

Defibrotide (DF) is indicated for the treatment of severe sinusoidal obstruction syndrome (SOS) following hematopoietic stem cell transplantation (HSCT), but its prophylactic use against SOS is not recommended yet. This study describes the impact of the preventive and curative use of DF on reducing the incidence and severity of SOS in children. Patients aged 0–19 years, who received allogenic HSCT after myeloablative conditioning regimen with busulfan or total body irradiation in our comprehensive cancer center, between 2013 and 2017, were included. The Baltimore or modified Seattle criteria were used for SOS diagnosis. SOS was graded using the 2017 European Society for Blood and Marrow Transplantation classification defining severity criteria of SOS in children. SOS occurrence tended to decrease with prophylactic DF, but no significant difference was observed in terms of severity. When not treated with preventive DF, 50% (19/38) of the patients with SOS were graded severe to very severe, but only 37% (7/19) had organ dysfunction. Curative DF was administered at a median of 2 days post‐HSCT, for a median of 6.5 days. The absence of fatal SOS supports the use of early curative DF with acceptable toxicities and questions the optimal duration of DF treatment.

Defibrotide Therapy for SARS-CoV-2 ARDS

BackgroundSARS-CoV-2-related ARDS is associated with endothelial dysfunction and profound dysregulation of the thrombotic-fibrinolytic pathway. Defibrotide is a polyanionic compound with fibrinolytic, antithrombotic, and antiinflammatory properties.Research QuestionWhat is the safety and tolerability of defibrotide in patients with severe SARS-CoV-2 infections?Study Design and MethodsWe report a prospective, open-label, single-center safety trial of defibrotide for the management of SARS-CoV-2-related ARDS. Eligible participants were 18 years of age or older with clinical and radiographic signs of ARDS, no signs of active bleeding, a serum D-dimer of more than twice upper limit of normal, and positive polymerase chain reaction-based results for SARS-CoV-2. Defibrotide (6.25 mg/kg/dose IV q6h) was administered for a planned 7-day course, with serum D-dimer levels and respiratory function monitored daily during therapy.ResultsTwelve patients (median age, 63 years) were treated, with 10 patients receiving mechanical ventilation and 6 receiving vasopressor support at study entry. The median D-dimer was 3.25 μg/ml (range, 1.33-12.3) at study entry. The median duration of therapy was 7 days. No hemorrhagic or thrombotic complications occurred during therapy. No other adverse events attributable to defibrotide were noted. Four patients met the day 7 pulmonary response parameter, all four showing a decrease in serum D-dimer levels within the initial 72 h of defibrotide therapy. Three patients died of progressive pulmonary disease 11, 17, and 34 days after study entry. Nine patients (75%) remain alive 64 to 174 days after initiation of defibrotide. Day 30 all-cause mortality was 17% (95% CI, 0%-35%). All patients with a baseline Pao2 to Fio2 ratio of ≥ 125 mm Hg survived, whereas the three patients with a baseline Pao2 to Fio2 ratio of < 125 mm Hg died.InterpretationThe use of defibrotide for management of SARS-CoV-2-related ARDS proved safe and tolerable. No hemorrhagic or thrombotic complications were reported during therapy, with promising outcomes in a patient population with a historically high mortality rate.Trial RegistryClinicalTrials.gov; No.: NCT04530604; URL: www.clinicaltrials.gov

Use of Defibrotide in Patients with COVID-19 Pneumonia; Results of the Defi-VID19 Phase 2 Trial

Background: The clinical spectrum of COVID-19 ranges from pauci-symptomatic forms to severe disease characterized by respiratory failure requiring mechanical ventilation and intensive care unit (ICU) management, as well as multisystem involvement characterized by sepsis, organ dysfunction and death. Treatment of COVID-19 is not standardized, and respiratory failure from ARDS is the leading cause of mortality; in-hospital mortality at 28-days in our tertiary care center in Lombardia, northern Italy was 23% during the first wave in 2020(Ciceri et al. 2020). Endothelial damage and thrombo-inflammation have been identified as common to both COVID-19 pathophysiology and veno-occlusive disease (VOD/SOS). Defibrotide (DF) has endothelial-protective properties, with pro-fibrinolytic, anti-thrombotic, anti-ischemic, anti-inflammatory, and anti-adhesive activity, but no significant systemic anticoagulant effects and is approved for the treatment of severe VOD/SOS.Aim: A prospective, multicenter, phase II, single-arm, open label trial (DEFI-VID19, NCT04335201) was conducted in patients (pts) with COVID-19 ARDS to evaluate the efficacy of DF in addition to best available therapy per institutional guidelines. The primary endpoint was respiratory-failure rate (RFR) defined as progression of respiratory failure, i.e. severe gas transfer deficit (PaO2/FiO2<200 mmHg), need of ICU or death at day+14 from treatment start. Secondary endpoints included overall survival (OS) at 28 days, duration of hospitalization and safety.A sample size of 50 pts was calculated to detect an absolute reduction of 20% in RFR at day+14, assuming a failure rate in non-treated pts of 70% (alpha=5%, power=90%, two-sided test). Pts received DF intravenously at 6.25 mg/kg/dose by 2-hour infusion repeated every 6 hours. Expected treatment duration was 14 days, with earlier discontinuation if clinical improvement occurred. LMWH at prophylactic dose was allowed. Approval was provided by the National IRB for COVID-19 trials at Institute Spallanzani (Rome) and by the Italian Agency for Drug (AIFA). All patients provided written informed consent.Results: Overall, 52 pts were enrolled from September 2020 to April 2021; 48 were evaluated for efficacy and safety; 4 pts were excluded due to screen failure (n=2) or withdrawal of informed consent at day 2 after defibrotide was initiated (n=2). Median age was 60.5 years (range 53-71); 35 pts (73%) were male and 65% had comorbidities, with high blood pressure, obesity and COPD most common. Two pts had pre-existing diagnoses of non-Hodgkin lymphoma. Median time from onset of COVID-19 symptoms and from Sars-COV2 PCR by nasal swab to enrollment were 8 (range 7-10) and 3 days (range 1-6), respectively. All pts were hospitalized and scale 5 of 8-category ordinal scale by WHO criteria, requiring noninvasive ventilation with CPAP or high-flow oxygen, with a median P/F ratio of 211 (range 134-275) mmHg. At treatment start, the median and (range) lymphocyte counts, LDH, CRP, ferritin, D-dimer and IL-6 were 0.7 (0.5-0.9) x 10e9/L; 404 (291-491) U/L; 49 (22-97) mg/L; 823 (363-1088) ng/ml; 0.44 (0.28-1.29) µg/mL and 20 (11-32), respectively.Median treatment duration was 8.5 days (range 6-11). Overall, 13/48 pts (27%) discontinued the treatment due to clinical worsening and/or need of further therapies: 9 pts experienced progressive respiratory failure and 6 of those were transferred to ICU for IOT (one pt required ECMO), and 4 required full anticoagulation due to pulmonary embolism (n=1), ischemic stroke (n=1), and femoral deep venous thrombosis (n=2). All pts who completed the treatment 35/48 (73%) were discharged with no need of oxygen support. Overall, 14 SAEs have been reported in a median time of 6 days (range 2-10): all unrelated to DF. No pts experienced hemorrhagic events. The incidence of RFR at day 14 was 25 (+/- 6)%, and at day 28, 27 (+/- 6) %. Probability of OS at day 28 was 89 (+/-4) %, at day 60 83 (+/- 5)%. Overall, 8 pts died from COVID-19 -related complications. No pts required re-admission after hospital discharge (median 14 days) or died after discharge.Conclusion: Treatment with DF in pts with grade 5 WHO COVID 19 ARDS does not induce bleeding, and is associated with rapid restoration of respiratory function (73% of pts). Notably, no oxygen support was needed at discharge and a 1-month OS rate of 89% was observed, which is higher than historical controls (77%) treated in the same setting. DisclosuresRichardson: Takeda: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Sanofi: Consultancy. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Carlo-Stella: Incyte: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Research Funding; AstraZeneca: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Final Long-Term Results from the Defifrance Registry Study: Efficacy and Safety of Defibrotide for the Treatment of Severe/Very Severe Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation

Introduction: Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) conditioning that may also develop after high-dose chemotherapy. Multiorgan failure (MOF) is associated with the most severe form of VOD/SOS and, if untreated, may result in a mortality rate of >80%. Defibrotide is approved for the treatment of hepatic VOD/SOS with renal or pulmonary dysfunction post-HCT in the US and for severe hepatic VOD/SOS post-HCT in patients aged >1 month (mo) in the EU. The DEFIFrance study collected real-world data on the efficacy and safety of defibrotide from HCT centers in France. This analysis presents final, long-term data on the primary study population: patients who received defibrotide treatment for severe/very severe VOD/SOS post-HCT.Methods: This post-marketing registry study collected retrospective and prospective real-world data on patients receiving defibrotide at 53 HCT centers in France. 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 (y), and patients aged <18 y were retrospectively/prospectively categorized using pediatric EBMT severity criteria. The primary endpoints were Day 100 post-HCT survival and complete response (CR; total serum bilirubin <2 mg/dL and MOF resolution per investigators' assessment) in patients with severe/very severe VOD/SOS. A secondary endpoint was the evaluation of treatment-emergent serious adverse events (SAEs) of interest: hemorrhage, coagulopathy, injection-site reactions, infections, and thromboembolic events, irrespective of relationship to treatment.Results: Of 798 defibrotide-treated patients enrolled in the study, 251 patients received defibrotide for the treatment of severe/very severe VOD/SOS post-HCT (severe: 117 [47%]; very severe: 134 [53%]). Median age was 45 y (range: 0, 74) and 58 (23%) patients were <18 y of age. The most common primary diagnoses were acute myeloid leukemia (68 [27%]) and acute lymphoblastic leukemia (49 [20%]). Common (>50%) risk factors included prior treatment with hepatotoxic drugs (150 [60%]), iron overload (133 [58%]), and relapsed/refractory disease (137 [55%]). Risk factors of interest included prior HCT (29/239 [12%]), and prior treatment with gemtuzumab ozogamicin (17/251 [7%]) and inotuzumab ozogamicin (6/251 [2%]). At diagnosis, 55/250 (22%) patients had anicteric VOD/SOS (bilirubin levels ≤2 mg/dL). Median (range) time from VOD/SOS diagnosis to defibrotide administration was 0 (-1, 24) days.The Kaplan-Meier (KM)-estimated Day 100 post-HCT survival rate was 61% (95% confidence interval [CI]: 55%, 67%) in patients with severe/very severe VOD/SOS, with a higher survival rate seen in patients with severe versus very severe disease. The post-HCT survival rate in patients with severe/very severe VOD/SOS was 50% at 6 mo and 43% at 12 mo (Figure). KM-estimated survival rates at 6 and 12 mo were also higher for those with severe versus very severe disease (Figure). The KM-estimated CR rate by Day 100 among patients with severe/very severe VOD/SOS post-HCT was 74% (95% CI: 66%, 81%). Similar to the pattern observed for the survival rate, a higher CR rate was observed by Day 100 in patients with severe (84% [95% CI: 74, 92]) versus very severe (63% [95% CI: 52, 74]) VOD/SOS.Treatment-emergent SAEs of interest occurred in 29% of patients with severe/very severe VOD/SOS post-HCT; the most common (≥2%) treatment-emergent SAE categories were infection (17%), hemorrhage (16%), and hypotension (2%). Mortality due to VOD/SOS at 12 mo was 15%.Conclusions: The DEFIFrance study represents the largest collection of real-world data on post-registration use of defibrotide. The efficacy and safety observed in this study add to evidence from prior studies supporting the utility of defibrotide for treating patients with severe/very severe VOD/SOS post-HCT in a real-world setting. Among patients receiving defibrotide for VOD/SOS post-HCT, outcomes were better in patients with severe versus very severe VOD/SOS, highlighting the importance of early VOD/SOS diagnosis and treatment, before patients reach the most severe stage of VOD/SOS. [Display omitted] DisclosuresMohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Peffault De Latour: Amgen: Consultancy, Other, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Jazz Pharmaceuticals: Honoraria. Labopin: Jazz Pharmaceuticals: Honoraria. Detrait: Jazz Pharmaceuticals: Research Funding. Huynh: Jazz Pharmaceuticals: Honoraria. Renard: Jazz Pharmaceuticals: Research Funding. Asubonteng: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Delaval: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Dalle: Jazz Pharmaceuticals: Honoraria.

COVID-19-induced endotheliitis: emerging evidence and possible therapeutic strategies.

The coronavirus disease 2019 (COVID‐19) pandemic, a viral illness caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), 1 has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries, 2 causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis. As the pandemic spreads, knowledge on the disease course, as well as potential risk factors and predictors of severity is increasing daily, and initial data from randomised controlled studies have allowed care providers to refine therapeutic strategies. Nonetheless, mortality is markedly elevated among those presenting with severe disease, long‐term sequelae among survivors are unknown, and vaccine‐based therapies currently remain at early stages of development. Most reported cases are asymptomatic or present with mild symptoms; however, 7–26% of hospitalised patients experience severe disease, often requiring admission to intensive care units (ICUs), with progressive multiple organ dysfunction and high mortality. 3 , 4 , 5 Such differences in clinical outcomes have led physicians to initiate diverse pharmacological therapies at various stages of the disease, generating challenges as to the most appropriate therapeutic choice for COVID‐19. In this context, the use of dexamethasone has significantly reduced mortality rates in critically ill patients requiring supplemental oxygen or mechanical ventilation, 6 and remdesivir has demonstrated clinical benefit in hospitalised patients, but with unknown survival benefit to date 7 ; additional effective treatment options are therefore urgently needed. In an initial attempt to provide a uniform and widely reproducible methodology to guide systematic treatment strategies, a three‐stage classification of COVID‐19 has been proposed. 8 The Stage I or ‘early infection’ occurs at the initial establishment of disease with high viral replication, and commonly presents with a range of complaints that can include mild and often non‐specific influenza‐like signs and symptoms. Stage II is the ‘pulmonary phase’, with preferential viral‐mediated injury of the lung parenchyma and this is characterised by shortness of breath, hypoxia and pulmonary infiltrates with some degree of lung inflammation. Stage III is characterised by an exaggerated host immune‐inflammatory response to the virus, leading to acute respiratory distress syndrome (ARDS) and multi‐organ failure (MOF).

Final Primary Results from the Defifrance Registry Study: Effectiveness and Safety of Defibrotide in the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication that occurs after hematopoietic cell transplantation (HCT) conditioning. In its most severe form, VOD/SOS is associated with multi-organ failure (MOF) and a mortality rate of &amp;gt;80% if untreated. Defibrotide is approved for the treatment of hepatic VOD/SOS with renal or pulmonary dysfunction post-HCT in adult and pediatric patients in the United States and severe hepatic VOD/SOS post-HCT in patients aged &amp;gt;1 month in the European Union. The DEFIFrance study collected real-world data on the safety and effectiveness of defibrotide in France. This analysis presents final primary data on the subgroup of DEFIFrance patients who received defibrotide for the treatment of severe/very severe VOD/SOS post-HCT. This post-marketing study collected retrospective and prospective real-world data on patients receiving defibrotide at 53 HCT centers in France from July 15, 2014 to March 31, 2020. VOD/SOS severity was categorized using European Society for Blood and Marrow Transplantation criteria (adults) or study steering committee member adjudication (pediatric patients). The primary endpoints included Kaplan-Meier (KM)-estimated Day 100 (post-HCT) survival and Day 100 complete response (CR; total serum bilirubin &amp;lt;2 mg/dL and MOF resolution per investigators' assessment) in patients with severe/very severe VOD/SOS post-HCT. Secondary endpoints included evaluation of adverse events (AEs) of interest, such as hemorrhage, coagulopathy, injection-site reactions, infections, and thromboembolic events, irrespective of their relationship to treatment. Of the 775 defibrotide-treated patients included in the study analysis, 250 received defibrotide for the treatment of severe/very severe VOD/SOS post-HCT (severe: 119 [48%]; very severe: 131 [52%]). The median patient age was 45 years (range: 5 months, 74 years) and 52 (21%) patients were less than 18 years of age. A total of 219 (88%) patients had received allogeneic HCT and 95 (38%) patients had an unrelated donor. The Day 100 KM-estimated survival was 58% (95% confidence interval [CI]: 52%, 64%) in patients with severe/very severe VOD/SOS post-HCT. The estimated Day 100 survival rate was higher in patients with severe (74% [95% CI: 65%, 81%]) versus very severe (43% [95% CI: 35%, 52%]) VOD/SOS. Among patients with severe/very severe VOD/SOS post-HCT, the CR rate at Day 100 was 53% (95% CI: 47%, 59%). The Day 100 CR rate was higher in patients with severe (68% [95% CI: 60%, 77%]) versus very severe (39% [95% CI: 30%, 47%]) VOD/SOS. Treatment emergent AEs of interest occurred in 41% of patients with severe/very severe VOD/SOS, with infection (23%) and bleeding (17%) being the most commonly reported. The DEFIFrance study represents the largest collection of real-world data on the use of defibrotide. The effectiveness and safety observed in this study build upon prior studies supporting the utility of defibrotide for treating severe/very severe VOD/SOS post-HCT in a real-world setting. Among patients receiving defibrotide for VOD/SOS post-HCT, outcomes were better in patients with severe versus very severe disease, highlighting the importance of early diagnosis and treatment of VOD/SOS before patients reach the most severe stage of VOD/SOS. Disclosures Mohty: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Renard:Jazz Pharmaceuticals: Research Funding. Jubert:Jazz Pharmaceuticals: Research Funding. Ryan:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bouvatier:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Dalle:Bellicum: Consultancy, Honoraria; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Consultancy, Honoraria; Gilead: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Peffault De Latour:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

A Pilot Trial of Pre-Transplant Risk Stratification and Prophylactic Defibrotide to Prevent Serious Thrombotic Microangiopathy in High-Risk Pediatric Hematopoietic Stem Cell Transplant Patients

Background: Transplant associated thrombotic microangiopathy (TA-TMA) is a known complication of hematopoietic stem cell transplant (HSCT) associated with endothelial injury that leads to end organ damage and high morbidity and mortality. No proven method for prevention of TA-TMA exists. One strategy is to decrease or even prevent the initial endothelial injury during conditioning. Defibrotide is an anti-inflammatory and anti-thrombotic agent that has been shown to protect the endothelium from damage and treat TA-TMA. We hypothesize that prophylactic use of defibrotide during HSCT conditioning and acute recovery may potentially prevent TA-TMA. Methods: We initiated a pilot single-arm phase II trial (NCT#03384693) to evaluate the safety and feasibility of administering prophylactic defibrotide to pediatric patients at high risk for the development of TA-TMA following HSCT. Additionally, we sought to determine if administration of prophylactic defibrotide would prevent the development of TA-TMA in clinically high-risk patients compared to historic controls. High-risk patients were defined as either patients with high-risk neuroblastoma whose treatment plan included autologous tandem transplants conditioned with cyclophosphamide/thiotepa (Cy/TT) and carboplatin/etoposide/melphalan (CEM), or allogeneic transplant patients undergoing myeloablative conditioning, with at least three of the following: age ≥10 years old, race/ethnicity other than Caucasian, ABO minor incompatibility, or haploidentical donor. Based on prior analysis at our center, we anticipated an incidence of TA-TMA of 28% in the high-risk patients undergoing allogeneic transplants and 40% in the neuroblastoma patients. Patients received defibrotide 6.25mg/kg IV q6h the day prior to the start of conditioning through day +21 and received supportive care per institution guidelines, including maintaining platelets above 30 x10^9/L. Patients were prospectively monitored for TA-TMA from admission through week 24. Results: Twenty-five patients were enrolled, 14 with neuroblastoma and 11 undergoing allogeneic HSCT. The median age was 3.45 (2.1-10.1) and 15.7 (0.8-27.4) years for autologous and allogeneic patients, respectively. Ten of the allogenic transplants were with an alpha-beta T-cell depleted haploidentical HSCT, while one was with a matched unrelated HSCT. Follow-up is complete on all patients. Defibrotide was stopped early due to clinically significant bleeding in 3 patients (day +3, +6 and +10, respectively). Bleeding episodes were excessive bleeding from oral hematoma, diffuse alveolar hemorrhage, and melanic stools and epistaxis and were classified as "possibly related" to the study drug. The other 22 patients missed a median of 0.7% of doses (0-5.2%), most often due to concomitant medication infusions. There were no allergic or hypersensitivity reactions. One patient with acute lymphoblastic leukemia (ALL) in CR4 died during the study period from respiratory failure in the setting of disseminated aspergillus and veno-occlusive disease (VOD), leading to a TRM of 0% and 9.1% in the autologous and allogeneic patients, respectively. Of the neuroblastoma patients, 4 did not go on to receive a second transplant; three due to development of moderate to severe VOD and one per parental preference. Five of the 14 neuroblastoma patients developed VOD, 4 after Cy/TT (1 mild, 2 moderate, 1 severe) and 1 after CEM (mild); all of which resolved. One patient developed non-severe TA-TMA, diagnosed 12 days post-HSCT (4% incidence). She received an alpha-beta T-cell depleted peripheral blood HSCT from her mother for ALL after conditioning with total body irradiation, cyclophosphamide, thiotepa, and ATG. Her course was complicated by diffuse alveolar hemorrhage on day +6 for which defibrotide was stopped. Her TA-TMA was treated with eculizumab and resolved without sequelae. Conclusions: 12% (3/25) patients required early discontinuation of defibrotide due to clinically significant bleeding; no other severe adverse events occurred due to the study intervention. The observed TA-TMA incidence of 4% was far below the anticipated rate of 28-40%. Our study provides preliminary evidence that defibrotide prophylaxis is safe and feasible in children and adolescents undergoing HSCT at high risk for TA-TMA and may reduce the risk of TA-TMA. Future larger randomized studies are needed to verify these findings. Disclosures Higham: Jazz Pharmaceuticals: Research Funding. Shimano:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding. OffLabel Disclosure: Defibrotide- off label use as prophylaxis for transplant associated thrombotic microangiopathy (TA-TMA)

Risk Factors, Mortality & Cost Analysis of Sinusoidal Obstructive Syndrome in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Multi-Institutional Review

Background: Sinusoidal obstructive syndrome (SOS) is a life-threatening complication of hematopoietic stem cell transplant (HSCT) characterized by hepatomegaly, jaundice, weight gain, and hyperbilirubinemia. SOS can be associated with prolonged hospitalizations and significantly increased health care costs in HSCT patients. However, studies evaluating the healthcare burden associated with SOS are limited. In this study we used a large inpatient Pediatric Health Information System database (PHIS) to complete a comprehensive review of pediatric patients undergoing HSCT to identify risk factors for SOS development and morbidity, mortality and healthcare resource utilization associated with this complication. Methods: PHIS is an administrative database containing data from 49 US children's hospitals. We identified patients under 21 years admitted between 01/01/2016 - 12/30/2019 with a primary or secondary ICD-10 diagnosis of SOS and procedure code for HSCT. We collected the following: 1) Demographics: age, sex, race, geographic location; 2) Length of stay (LOS); 3) ICU admission; 4) Infections; 5) Graft-versus-host disease (GVHD); 6) Mortality; 7) Hospitalization costs; 8) Hospital resource utilization; and 9) Medications including defibrotide use. Differences in outcomes between patients with and without SOS were assessed by Chi-square tests or Wilcoxon nonparametric test for categorical and continuous variables respectively. Univariate and multivariate regression models were used to identify risk factors associated with SOS and the association of SOS on outcomes. P-values &amp;lt;0.05 were considered significant. Results: In 6,153 patients undergoing HSCT 263 patients (4.3%) experienced SOS. Median age at diagnosis was 5 years and males represented 60.8% of patients with SOS. The majority of patients experiencing SOS identified as white, though patients identifying as Asian or American Indian disproportionately experienced SOS. Allogeneic HSCT represented 81.75% of patients with SOS. Patient age, gender and race were not associated with significantly increased odds of SOS, the odds of SOS were 3 times greater in patients undergoing allogeneic transplantation (OR 3.0, 95% CI 2.2-4.1). Average LOS was significantly higher in patients diagnosed with SOS (71 days vs 43 days, p&amp;lt;0.001). ICU admission was more common in patients with SOS (68% vs 22%) with significantly longer ICU LOS as well (16.6 days vs 4.3 days, p&amp;lt;0.001). Mean hospitalization costs were greater in patients diagnosed with SOS ($803,956 vs $326,853, p &amp;lt; 0.001). Patients who experienced SOS had increased odds of developing GVHD (OR 2.7, 95%CI 1.9-3.8) and infection (OR 4.4, 95% CI 3.4-5.7). Mortality was greater in patients who developed SOS (17.5% vs 3.7%, p&amp;lt;0.001). However, SOS was not associated with a significant increase in mortality after adjusting for GVHD, infection and ICU admission (OR 1.4, 95% CI 0.9-2.1). In patients with medication data available (n=1956), defibrotide was administered to 67.1% of patients who experienced SOS and 5.8% of patients who did not. There was no significant difference in mortality between patients who received defibrotide and those who did not in patients with SOS (p=0.4). Conclusions: In this largest inpatient cohort of pediatric HSCT recipients to date, morbidity and healthcare resource utilization remain high among patients who experience SOS. This stresses the importance of early recognition and treatment of SOS, and the importance of novel therapeutic approaches to decrease the morbidity and improve quality of life in these patients. Disclosures No relevant conflicts of interest to declare.

Transjugular Intrahepatic Portosystemic Shunt for Very Severe Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-transplantation Cyclophosphamide.

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT), with high mortality rates despite early medical treatment, including the use of defibrotide (DF). We retrospectively analyzed 185 unmanipulated haploidentical (haplo-) HSCT with post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis performed consecutively between 2011 and June 2019 in a single center. Seventeen patients (9.2%) were diagnosed with VOD/SOS. Based on revised European Society for Blood and Marrow Transplantation severity criteria, the VOD/SOS cases were classified as mild in 2 patients (11.7%), moderate in 2 (11.7%), severe in 2 (11.7%), and very severe in 11 (64.9%). Thirteen patients (76%) were treated with DF, including all patients with severe or very severe VOD/SOS, except 1 patient with CNS hemorrhage. Sixteen patients (94%) were alive at day +100 after HSCT. Seven patients (41%) with very severe VOD/SOS were treated with transjugular intrahepatic portosystemic shunt (TIPS) owing to rapid clinical or analytical deterioration or refractory hepatorenal syndrome despite medical treatment, including DF. TIPS insertion was performed at a median time since VOD/SOS diagnosis of 4 days (range, 1 to 28 days) without technical complications in any case. The median hepatic venous pressure gradient before and after TIPS treatment was 24 mmHg (range, 14 to 29 mmHg) and 7 mmHg (range, 2 to 11 mmHg), respectively, with a median drop of 16 mmHg (range, 9 to 19 mmHg). Following TIPS insertion, all patients showed clinical improvement with hepatomegaly, ascites, and renal failure resolution, and all showed analytical improvement with reduced alanine aminotransferase (ALT), creatinine, and international normalized ratio values, except for patient 2, whose indication for TIPS was refractory hepatorenal syndrome with a normal ALT level. The 6 patients who had initiated DF before TIPS insertion completed 21 days of treatment. All patients met the criteria for complete remission (CR) at a median of 8 days after TIPS insertion (range, 2 to 82 days). The 100-day overall survival was 100%. For patients with rapid progressive VOD/SOS, early TIPS insertion allowed completion of DF therapy. The use of TIPS together with DF resulted in CR and no associated complications with no VOD/SOS-associated mortality despite high severity. In our experience, timely and individualized use of TIPS significantly improves outcomes of very severe VOD/SOS after haplo-HSCT. Therefore, TIPS should be promptly considered in rapidly progressive cases.

Incidence and Cost of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with and without Multi-Organ Dysfunction: Analysis of the Premier Healthcare Database

<h3>Introduction</h3> Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication that occurs after hematopoietic cell transplantation (HCT). The incidence of VOD/SOS post-HCT is estimated to be ∼14% (Coppell JA, et al. <i>BBMT</i>. 2010). A prior study defined severe VOD/SOS as the presence of multi-organ dysfunction (MOD) and reported higher medical costs in patients (pts) with severe VOD/SOS vs. those without. The prior study assessed pts in the Premier Healthcare Database (2009-2014), in the absence of formal diagnostic codes, and reported an incidence of VOD/SOS of 5.3% and 6.3% in adult and pediatric pts, respectively. <h3>Objectives</h3> This study created an algorithm to identify VOD/SOS using diagnosis codes and assessed healthcare resource utilization, costs and outcomes in post-HCT pts with VOD/SOS, with or without MOD, vs. pts with no VOD/SOS. <h3>Methods</h3> This retrospective, observational study included post-HCT pts in the Premier Healthcare Database (2015-2018) with an inpatient hospitalization and ICD-10-CM/PCS, CPT, HCPCS or MS-DRG codes for HCT. VOD/SOS pts were identified using ICD-10-CM diagnosis code K76.5, VOD/SOS-related codes, or use of defibrotide within 90 days of index hospitalization. VOD/SOS pts with codes for MOD in the same hospitalization comprised the VOD/SOS with MOD group. VOD/SOS pts without MOD and pts without VOD/SOS comprised the VOD/SOS without MOD group and no VOD/SOS group, respectively. Total hospital length of stay (LOS) and costs were examined during index hospitalization and 90 days after index discharge. Bivariate analysis was used to study the difference in unadjusted outcomes between post-HCT pts with and without VOD/SOS. Wilcoxon test was used for continuous variables and Chi-square test was used for categorical variables. Adjusted analysis based on multivariable regressions was used to control for pt and hospital characteristics. <h3>Results</h3> The analysis included 4,642 pts (no VOD/SOS: n = 4,352; VOD/SOS with MOD: n = 177; VOD/SOS without MOD: n = 113). Overall, VOD/SOS occurred in 6.2% of pts; 3.8% and 2.4% of pts had VOD/SOS with and without MOD, respectively. VOD/SOS was more common in pediatric (14.3%) than adult (5.7%) pts and in allogeneic (11.4%) vs. autologous HCT (3.5%) pts. After adjustment, total LOS was longer in VOD/SOS pts with and without MOD vs. no VOD/SOS (Table). Total costs and inpatient mortality were higher in VOD/SOS pts with MOD vs. no VOD/SOS. The 90-day all-cause readmission rates were not different across groups. <h3>Conclusion</h3> The results were consistent with VOD/SOS rates reported in the literature. The slightly higher rate of VOD/SOS reported here vs. a prior study was driven by higher incidences in pediatric and allogeneic populations. VOD/SOS, especially with MOD, in post-HCT pts was associated with increased healthcare resource utilization, LOS, and costs vs. HCT pts without VOD/SOS.

A Meta-Analysis Evaluating the Incidence of Bleeding Events With Intravenous Defibrotide Treatment Outside the Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Setting.

Defibrotide is approved to treat hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal/pulmonary dysfunction following hematopoietic cell transplantation (HCT) in adult and pediatric patients in the United States, and to treat severe hepatic VOD/SOS post-HCT in adult and pediatric patients aged >1 month in the European Union. The defibrotide prescribing information warns that defibrotide may increase bleeding risk in VOD/SOS patients. To broaden our understanding of the incidence of bleeding with defibrotide, we performed a meta-analysis of the published literature of defibrotide use outside of the post-HCT VOD/SOS setting. Of 1857 records identified, 125 reported on defibrotide; 23 contained data on bleeding events. The estimated overall incidence of bleeding events was 1% (95% confidence interval [CI]: 0%-2%) and 8% (95% CI: 3%-14%) in studies using intravenous defibrotide and studies with controls, respectively. The risk ratio for bleeding events with intravenous defibrotide versus controls was 0.36 (95% CI: 0.24-0.52; P < .00001) among studies with data on intravenous defibrotide and controls. This meta-analysis of defibrotide use outside of the post-HCT VOD/SOS setting suggests that the incidence of bleeding with defibrotide is lower than controls.