Defibrotide Prophylaxis Research Articles

Analysis of Risk Factors for Hepatic Sinusoidal Obstruction Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients

Background: Hepatic sinusoidal obstruction syndrome (SOS), which is also called veno-occlusive disease of the liver, remains a serious complication after hematopoietic stem cell transplantation (HSCT). Over the last years, some risk factors have already been identified to be associated with SOS. However, the cause of SOS is still not fully understood and the mortality remains high, especially for SOS leading to multi-organ failure with a mortality rate up to 84%. The aim of our study was to analyze several risk factors of SOS in pediatric patients undergoing allogeneic HSCT. In addition, we investigated new potential risk factors. Methods: We retrospectively analyzed 105 children who underwent allogeneic HSCT for the first time and did not receive a defibrotide prophylaxis. All transplantations were performed between January 2007 and December 2018 in a single center. The median age was 8.6 years and stem cell source was either bone marrow (n = 74) or peripheral blood (n = 31). Underlying diseases were acute lymphoblastic leukemia (n = 27), acute myeloid leukemia (n = 25), myelodysplastic syndrome (n = 14), lymphoma (n = 2), solid tumor (n = 12) and genetic disease (n = 25). All patients received a myeloablative conditioning regimen. We analyzed the transplantation-related factors graft source, donor-recipient human leukocyte antigen match, donor age, donor sex and conditioning regimen based on busulfan or total body irradiation. Furthermore, we investigated the patient-related factors patient age, patient sex, prior treatment with gemtuzumab ozogamicin as well as the following laboratory parameters: aspartate transaminase, alanine transaminase, cholinesterase, glutamyl transpeptidase, lactate dehydrogenase, alkaline phosphatase, ferritin, albumin, total bilirubin, C-reactive protein and international normalized ratio (INR). All laboratory parameters were measured before HSCT and cutoffs were determined by reference values and receiver operating characteristic (ROC) curves. SOS was defined by modified pediatric Seattle criteria up to day +30 after HSCT because nearly all transplantations were performed before the new pediatric criteria of the European Society for Blood and Marrow Transplantation have been published. In univariate analysis, chi-square test and Fisher's exact test were used. Additionally, the Mann-Whitney U-test was performed to compare the median values of continuous variables. Significant variables (P < .05) were entered in multivariate analysis, which was carried out by using backward stepwise logistic regression. Results: SOS occurred in 15 out of 105 transplantations (14.3%). The median time of SOS onset was 12 days after HSCT (range, 1 day - 26 days). Three patients died of multi-organ failure following SOS (20%). This mortality rate was very low compared to other studies because our patients were treated with defibrotide immediately after being diagnosed with SOS. In univariate analysis, we found a significant association between patient age <1 year and SOS (Odds Ratio (OR) = 7.25, P = .037). Furthermore, a prior treatment with gemtuzumab ozogamicin (OR = 11.00, P = .020) showed a significant correlation. Patients who developed SOS had a significantly higher median ferritin level (2816.9 ng/mL vs. 1554.0 ng/mL, P = .026). Based on this observation, different ferritin cutoffs were selected by ROC analysis. Ferritin >1500 ng/mL (OR = 4.00, P = .033), ferritin >2000 ng/mL (OR = 4.69, P = .016) as well as ferritin >2400 ng/mL (OR = 5.29, P = .005) revealed significant P values. Besides these results, INR ≥1.3 (OR = 5.91, P = .009) was significantly associated with SOS. In multivariate analysis, the following variables showed P values less than .05: treatment with gemtuzumab ozogamicin (OR = 9.24, P = .048), ferritin >2400 ng/mL (OR = 5.74, P = .023) and INR ≥1.3 (OR = 8.02, P = .007). Conclusions: Our data confirm the risk factors of young patient age (<1 year), prior treatment with gemtuzumab ozogamicin and high serum ferritin (>2400 ng/mL) in the pediatric population. Moreover, we report for the first time that there is a significant association between high INR (≥1.3) before HSCT and the occurrence of SOS. Especially this new finding could improve the risk stratification of SOS and should be evaluated in further trails. Disclosures No relevant conflicts of interest to declare.

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

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

Incidence and risk factors for hepatic sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: A retrospective multicenter study of Turkish hematology research and education group (ThREG)

Hepatic sinusoidal obstruction syndrome (HSOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively evaluated the incidence, risk factors, treatment and survival for HSOS after allo-HSCT in Turkey. We also reported our experience of defibrotide (DF) for HSOS prophylaxis in high-risk (HR) patients. Across Turkey, 1153 patients from 10 centers were enrolled in the study. We evaluated the medical records of patients who were treated with allo-SCT between January 2012 and December 2015. The study included 1153 patients (687 males/466 females) with median age of 38 (15−71) years. The incidence of HSOS was 7.5 % (n = 86). The incidences of HSOS in the HR/DF+, HR/DF- and standard risk (SR) group were 8%, 66.7 % and 6.2 %, respectively. The rate of HSOS development was not statistically different between HR/DF + and SR group (p = 0.237). HSOS prophylaxis (defibrotide) was significantly decreased HSOS-related mortality (p = 0.004). The incidence of HSOS was found similar to literature in this large Turkish cohort. Defibrotide prophylaxis appears to be associated with low incidence of HSOS development and reduced HSOS-related mortality. Although these results are promising, future studies are needed to support the efficacy of defibrotide prophylaxis in patients with risk of HSOS.

Determining the Safety and Efficacy of Prophylactic Defibrotide Administration in Children, Adolescents, and Young Adults with Sickle Cell Disease Following Myeloimmunoablative Conditioning (MAC) and Haploidentical Stem Cell Transplantation Utilizing CD34+ Selection and T-Cell (CD3) Addback (IND127812)

<h3>Background</h3> Sickle cell disease (SCD) is a hemoglobinopathy and vasculopathy resulting in vaso-occlusive crises, chronic end-organ damage, and shortened life span. The only curative therapy is allogeneic stem cell transplant (AlloSCT) (Talano/Cairo, EJH, 2015). Unfortunately, only approximately 16% of the sickle cell population has an HLA matched unaffected sibling (Bhatia/Cairo, BMT, 2014). We have demonstrated the safety and efficacy of familial haploidentical transplants (FHI) in this population with 100% engraftment (Cairo et al, JAMA Peds, 2019). However, the incidence of sinusoidal obstructive syndrome (SOS) in SCD AlloSCT recipients is approximately 32% (McPherson, BMT, 2011). Defibrotide primarily targets endothelium and can reduce endothelial cell injury (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996). Corbaciolgu et al (Lancet 2012) demonstrated the safety and efficacy of prophylactic defibrotide in high-risk pediatric AlloSCT recipients to significantly reduce the incidence of SOS. <h3>Objective</h3> To determine the safety and efficacy of defibrotide prophylaxis for SOS in children, adolescents and young adults (CAYA) with high-risk SCD following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. <h3>Design/Methods</h3> Patients with SCD aged 2 to 35 years with high-risk SCD (stroke, ≥2 acute chest syndrome in past 2 years, ≥3 pain crises in last 2 years, abnormal TCD study, ≥1 silent infarct lesion on MRI) were enrolled after being consented (NCT02675959). Patients were in two cohorts (2 to 17.99 years and 18 to 34.99 years of age) for age-based analysis and treatment (Table 1 and 2). All patients received a MAC regimen prior to receipt of an FHI with CD34+ selection and CD3 addback peripheral blood stem cell transplantation (PBSCT), as we have already demonstrated (Cairo et al, ASH, 2018). Defibrotide was given day -10 during conditioning through day +21 following transplant. Baseline studies of organ function and biomarkers were obtained prior to transplantation. <h3>Results</h3> We have enrolled eight patients, five in cohort 1 (median age 9.9 years) and three in cohort 2 (median age of 24 years) with a gender ratio (M/F) of 4/4. Patients had hemoglobin SS (n=7) or hemoglobin SC (n=1). Patients had either a maternal (n=7) or sibling (n=1) donor. Patients had early neutrophil engraftment (median day +11 (day +7 to day +14)). All tolerated 109 ± 11doses of defibrotide. There were no severe adverse or bleeding events probably or directly related to defibrotide. No patient developed SOS. <h3>Conclusion</h3> The preliminary data suggests defibrotide is safe and well tolerated in CAYA patients with high-risk SCD following MAC and FHI AlloSCT, utilizing CD34+ selection with CD3 addback. A larger cohort and/or follow-up will be required to confirm these preliminary findings. Supported by FDA R01FD004090 and Jazz Pharmaceuticals.

A Systematic Review of Studies of Defibrotide Prophylaxis for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

Introduction Defibrotide (DF) is approved for adult and pediatric patients (pts) with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT) in the United States and Canada, and for severe hepatic VOD/SOS post-HCT in patients aged >1 month in the European Union. The recommended dose is 25 mg/kg/day given as a 2-hour intravenous (IV) infusion in 4 divided doses. Several studies have examined whether DF can reduce the incidence of VOD/SOS in high-risk pts. Objectives To provide an estimate of the overall incidence and risk of developing VOD/SOS after IV DF using published literature. Methods PubMed and Embase were searched through July 8, 2019 for studies using DF in VOD/SOS and or prophylaxis in the title/abstract. Phase 1 studies, case reports with Results A total of 349 records were identified; 22 had ≥10 pts and were included in the analysis. Overall, 14 of 22 studies reported IV DF administration (5 pediatric studies, 3 adult studies, and 6 both/not specified); 10 of these 14 reported on incidence of severe/very severe VOD/SOS (per the investigator). Overall incidence of VOD/SOS was 5% (95% CI: 2%-8%) with IV DF prophylaxis. The incidence of severe/very severe VOD/SOS was 2% (95% CI: 0%-4%) in the 10 studies reporting disease severity. Among the 6 studies with data on IV DF and controls (eg, heparin or no prophylaxis), the risk ratio for developing VOD/SOS with DF vs control was 0.43 (95% CI: 0.20-0.96; P = 0.040; Figure). DF safety results in individual studies were generally consistent with the profile reported by Corbacioglu et al. (Lancet. 2012;379:1301-1309), which reported a similar proportion of pts with adverse events for DF (87%) and control groups (88%), with a cumulative hemorrhage incidence of 22% for DF and 21% for controls. Conclusion This analysis suggests a low incidence of VOD/SOS following with IV DF and a reduction in relative risk for VOD/SOS with defibrotide vs controls. Limitations include the limited number of controlled, peer-reviewed studies, variations in VOD/SOS diagnostic/severity criteria and DF doses used across studies. Results support further evaluation of DF for the prevention of VOD/SOS, particularly in adults; a phase 3 study in adult and pediatric pts is ongoing.

Incidence, Risk Factors and Outcomes of Veno-Occlusive Disease / Sinusoidal Obstruction Syndrome (VOD/SOS) in Children with Severe Thalassemia (ST) Conditioned with Busulfan- Cyclophosphamide (Bu-Cy) Based Regimen

Introduction Sinusoidal obstruction syndrome / Veno-occlusive disease (VOD/SOS) is one of the major complication which increases morbidity and mortality following allogeneic stem cell transplant. Busulfan-cyclophosphamide (Bu-Cy) based conditioning regimen, use of busulfan and patients with thalassaemia are considered to be among the important risk factors for development of VOD/SOS (Barker et al. Bone Marrow Transplantation (2003) 32, 79-87, Dix et al Bone Marrow Transplantation 1996 Feb;17(2):225-30). We routinely use oral busulfan in our low and intermediate risk thalassemia transplant conditioning regimen. We summarize the incidence, risk factors, severity and outcomes of VOD/SOS in our patient population. Methods We studied the incidence of VOD/SOS defined by EBMT criteria (Corbacioglu et al. Bone marrow transplantation 2018 Feb;53(2):138-145) in 121 consecutive patients with ST (thalassemia syndrome with the inability to spontaneously maintain hemoglobin levels ≥ 7 g/dl) on a single uniform protocol across three collaborating centers from India - People Tree hospitals, Bangalore (PTH), Care Institute of Medical sciences, Ahmedabad (CIMS), South- East Asia Institute of Thalassaemia (SEAIT). Our conditioning regimen comprised of Fludarabine (150 mg/m2, days -17 to -13), anti-thymocyte globulin (ATG) (Genzyme 4 mg/kg, days -12 to -10, dose was increased to 7 mg/kg in case of splenomegaly and or sex mismatched transplants), busulfan (14 mg/kg oral, not adjusted to serum levels over days -9 to -6) and cyclophosphamide (200 mg/kg, days -5 to -2). G-CSF-primed bone marrow (5 μg/kg/dose twice daily for 5 days prior to harvest) was the source of hematopoietic stem cells in all cases. The majority of patients (111) were low - intermediate risk based on liver size &lt; 2 cm from costal margin and age less than 15 years (median 6.9 years, range 1.1 to 14.5) while 10 patients might have been high-risk based on Pesaro classification due to liver &gt;3 cm by palpation at transplant. In fact, liver biopsies were not performed. All matched related donors were HLA-compatible by high resolution typing. None of the patients received routine defibrotide prophylaxis and all patients have at least one year follow up. Results Out of the 121 patients studied, 18 developed VOD/SOS (14.9%). One patient developed massive intracranial haemorrhage (ICH) on day 9 and subsequently died on day 11, had some features of VOD/SOS which may have contributed to the ICH. Another patient needed admission in intensive care with respiratory distress was treated with defibrotide for 5 days and recovered. In all others VOD/SOS resolved spontaneously with supportive care only. There was a trend towards decreased overall (94% vs 97%) and disease-free survival (83% vs 89%) in the VOD/SOS group, both did not reach statistical significance (Fig 1 and 2). None of the previously known risk factors studied such as age at BMT (p =0.16), Ferritin level at BMT (p = 0.2), hepatitis C status (p = 0.28) and raised pre-transplant ALT levels (&gt; 3 times normal upper limit) (p = 0.7) showed significant variation between VOD/SOS group and unaffected group. Factors which showed significant difference were Major ABO mismatch (p = 0.041), presence of splenomegaly at BMT (p = 0.0015) and duration of Hydroxyurea (HU) treatment pre-transplant for more than 12 months (p = 0.04). Longer duration of HU may be related to the prolonged down-staging process for poorly managed ST patient pre-transplant. As expected, the VOD/SOS group required increased blood product support (Table 1). Conclusion Our results suggest that even though about 15% of low/intermediate risk thalassaemia transplants using Bu-Cy may develop VOD/SOS, in the great majority of cases this complication is mild and resolves spontaneously with supportive care alone. Many of the known risk factors did not seem to be relevant in our patient population. The possible role of splenomegaly at BMT and major ABO mismatch as risk factors for VOD/SOS may warrant further studies. Disclosures No relevant conflicts of interest to declare.

Defibrotide for Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease Prophylaxis in High-Risk Adult Patients: A Single-Center Experience Study

Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a serious complication after hematopoietic stem cell transplantation (HSCT). SOS/VOD usually occurs within 3 weeks of HSCT, but the 2016 European Society for Blood and Marrow Transplantation diagnosis criteria have been revised to include late forms. Prophylactic use of defibrotide is recommended in the pediatric setting, but its value remains uncertain in the adult population. We report here a single-center series of 63 adult patients considered at high risk for SOS/VOD who received defibrotide prophylaxis in combination with ursodeoxycholic acid between May 2012 and August 2016. The median duration of defibrotide therapy was 23 days. Bleeding occurred in 14 patients (21.5%). Defibrotide prophylaxis was discontinued in 7 patients (10.8%): 4 cases (6.3%) due to bleeding and 3 cases (4.6%) because of the need for antithrombotic therapy. Overall, SOS/VOD occurred in 4 cases (6.3%) within 21 days after HSCT (days 13 and 14) in 2 cases and late-onset SOS/VOD (days 57 and 58) in the other 2 cases. SOS/VOD was moderate in 1 case, very severe in 3 cases, with 2 deaths related to SOS/VOD. Cumulative incidence of grades II to IV acute graft-versus-host disease and transplant-associated thrombotic microangiopathy were 22.2% and 3.2%, respectively. With a median follow-up of 31 months (range, 10.7 to 60.3), the rates of 2-year overall survival, progression-free survival, incidence of relapse, and nonrelapse mortality were 56.5%, 49%, 28.7%, and 22.3%, respectively. In our experience defibrotide prophylaxis is associated with a low incidence of SOS/VOD after allogeneic HSCT in a high-risk adult population with an acceptable safety profile.

Defibrotide: An Oligonucleotide for Sinusoidal Obstruction Syndrome.

To review the efficacy and safety of defibrotide as well as its pharmacology, mechanism of action, pharmacokinetics (PK), drug-drug interactions, dosing, cost considerations, and place in therapy. A PubMed search was performed through August 2017 using the terms defibrotide, oligonucleotide, hepatic veno-occlusive disease (VOD), sinusoidal obstruction syndrome (SOS), and hematopoietic cell transplantation (HCT). Other data sources were from references of identified studies, review articles, and conference abstracts plus manufacturer product labeling and website, the Food and Drug Administration website, and clinicaltrials.gov. English-language trials that examined defibrotide's pharmacodynamics, mechanism, PK, efficacy, safety, dosing, and cost-effectiveness were included. Trials have confirmed the safety and efficacy of defibrotide for treatment of VOD/SOS in adult and pediatric HCT patients, with complete response rates and day +100 overall survival rates ranging from 25.5% to 76% and 35% to 64%, respectively. The British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation Guidelines recommend defibrotide prophylaxis in pediatric and adult HCT patients with risk factors for VOD/SOS; however, its prophylactic use in the United States is controversial. Although there are efficacy data to support this strategy, cost-effectiveness data have not shown it to be cost-effective. Defibrotide has manageable toxicities, with low rates of grade 3 to 4 adverse effects. Defibrotide is the first medication approved in the United States for the treatment of adults and children with hepatic VOD/SOS, with renal or pulmonary dysfunction following HCT. Data evaluating defibrotide for VOD/SOS prevention are conflicting and have not shown cost-effectiveness.

Efficient Prophylaxis with Defibrotide for Sinusoidal Obstruction Syndrome (SOS) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Backgound: Sinusoidal obstruction syndrome [SOS, also known as hepatic veno-occlusive disease (VOD)] is frequent after HSCT and may have a mortality rate of up to 85%. Defibrotide has shown efficacy not only in the treatment of established SOS (Richardson et al. Blood 1998:92;737 and 2016:127;1656) but also in SOS prevention in children (prospective study: Corbacioglu et al. Lancet 2012:379;1301) as well as in adults (several retrospective studies).Patients and methods: Between 1999 and 2009, we gave defibrotide intravenously to 248 successive patients transplanted for hematological diseases starting at day -7 up to day +20 post-transplantation (dose range 800-2400 mg/d) in combination with heparin. We previously published the data of the 52 first patients compared to 52 historical controls who were transplanted just prior to the study period. We now expand the study with 196 additional patients treated successively with defibrotide prophylaxis while adding patients transplanted after 2010 when patients did not receive defibrotide as prophylaxis anymore (2011-2015) to the control group. The characteristics of patients are shown in Table 1.Results: Median follow-up for the study group was 10 (range 2-16) years and for the control group 2.7 (range 1-18) years. None of the 248 patients in the defibrotide group developed SOS (Baltimore criteria). The 100 day cumulative incidence (CI) of SOS was 0% in the defibrotide group as compared to 4.8% (95%CI 2.6-8%) in the control group, p=0.00046. The day 100 event free survival (EFS) where an event was defined as the 1st occurrence of one of the following: SOS, acute graft versus host disease (GvHD) ≥2, relapse or death, was not significantly different with 60% (95%CI 54%-66%) in the defibrotide group vs 53% (95%CI 47%-59%) in the controls, p=0.165, but the one year EFS was statistically different with 38% (95%CI 32%-44%) vs 28% (95%CI 22%-34%), p=0.00969. The 100 day CI of acute GVHD was not significantly different between the two groups [27% (95%CI 22%-33%) in the defibrotide group vs 29% (95%CI 24%-35%) in the control group, p= 0.707] while the 1 year acute GvHD CI was significantly reduced in the defibrotide group [31% (95%CI 25%-37%)] compared with the control group [42% (95%CI 36%-48%), p=0.026]. The one year overall survival (OS), relapse incidence (RI) and non-relapse mortality (NRM) were not statistically different being respectively 73% (95%CI 67%-78%) vs 65% (95%CI 59%-71%), p=0.0704, 32% (95%CI 27%-38%) vs 28% (95%CI 22%-34%), p=0.331 and 14% (95%CI 10%-18%) vs 19% (95%CI 14%-24%), p=0.148. Multivariate analysis, performed taking into account clinical factors known to influence the risk of SOS, confirmed the favorable impact of defibrotide on 100 day SOS CI [HR 7.5x10-7 (95%CI 1.8x10-7-3.2x10-6), p<0.00001] (Table 2). Conversely, multivariate analysis failed to confirm the impact of defibrotide on 1 year EFS or acute GvHD CI.Conclusion: To the best of our knowledge, this is the largest study on prophylaxis of SOS with defibrotide and it suggests that this drug has a potential benefit in the prevention of this liver complication. Our retrospective study needs to be confirmed in a prospective randomized trial. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Fludarabine/Treosulfan/Thiotepa/ATG Conditioning for Related Transplantation in β Thalassaemia Major Leads to Early and Sustained Engraftment with Low Incidence of VOD and GvHD

▪Haemopoietic stem cell transplantation is a well-established treatment modality for β thalassaemia. The challenge is to minimise graft failure due to the expanded haemopoietic compartment whilst reducing the risk VOD due to the effects of iron load. From 2011 to 2016 thirty-five consecutive sibling transplants were conditioned with fludarabine 160 mg/m2, treosulfan 42 g/m2, thiotepa 10 mg/kg and ATG (Thymoglobulin) 7.5 mg/kg (FTTA). Endogenous haemopoiesis was suppressed pre-transplantation with hypertransfusions for a minimum of 8 weeks. GvHD prophylaxis was provided with ciclosporin and MMF. The median age was 5 years (2 - 16). The source of stem cells was BM in 30 patients and mixed cord blood and BM in 5 patients. The median cell dose was 4.17 x108 TNC/kg (range 0.23 - 8.51, including patients having red cell depletion for major ABO incompatibility) and 7.28 x 106 CD34+/kg (range 2.05 - 14.43) for the patients receiving bone marrow only; 1.64 x 108 TNC/kg (range 1.22 - 3.9) and 4 x 1 06 CD34+/kg (range 2.06 - 8.79) for BM and 3.8 x 107 TNC/kg (range 0.8 - 7.32) and 0.53 x 106CD34+/kg (range 0.06 - 1.8) for cord blood for the patients receiving a combination of cord blood and bone marrow. The median survival was 21.1 months (0.4-50.7). Patients were Pesaro class I or II (Pesaro class III patients were intensively chelated pre-transplantation to reduce the stage of fibrosis and return to class I or II). All patients were evaluated with liver biopsy pre-transplantation and defibrotide prophylaxis given if Ishak stage ≥ 3.All patients engrafted and achieved evidence of donor haemopoiesis on day +28, and all but one patient achieved transfusion-independence and donor haematological values. Two patients had secondary graft failure: one patient had progressive reduction of donor haemopoiesis with reestablishment of ineffective thalassaemic haemopoiesis and transfusion dependence on day +313, another patient had reestablishment of ineffective thalassaemic and myelodysplastic haemopoiesis with 7 deletion on day +532; both patients established normal haemopoiesis following a second BMT. There was one death (2.9%), on day +89 due to idiopathic pneumonia syndrome. Acute GvHD ≥ grade 2 occurred in 4 patients (11.4%). Chronic limited GvHD occurred in 5 patients (14.3%) and extensive in 1 patient (2.9%). Chronic GvHD was only present at 18 months in one patient (2.9%). VOD occurred in 2 patients (5.7%, days +7 and +9 respectively) and responded to standard measures and defibrotide treatment. The median neutrophil engraftment was 11 days (range 9 to 21). The median platelet engraftment >20 x109/L was 28 days (range 16 to 73) and >50 x109/L was 32 days (range 19 to 73). The median time to cessation of immunosuppression was 160 days (105-309).Chimerism studies on day +28 demonstrated 97.1% in whole blood (WB) and 76.9% in T cells (T) >95%, 2.9% WB and 3.8% T >90-95%, 0% WB and 19.2% T >50-89%, and 0% WB and 4.8% T <50%; day +90: 81.3% WB and 56.7% T >95%, 3.1% WB and 13.3% T >90-95%, 12.5% WB and 23.3% T >50-89%, 3.1% WB and 6.7% T <50%; day +180: 48.1% WB and 42.3% T >95%, 33.3% WB and 19.2% T >90-95%, 11.1% WB and 38.5% T >50-89%, 7.4% WB and 0% T <50%; and day +365: 56% WB and 41.7% T >95%, 8% WB and 20.8% T >90-95%, 16% WB and 20.8% T >50-89%, 20% WB and 16.7% T <50%.In conclusion, the 3 year's overall survival was 97.1% and the disease-free survival 89.2%. Hence, FTTA leads to early and sustained engraftment with low rate of graft failure, and minimal occurrence of VOD and IPS, whilst the incidence of GvHD is low, though there is a high rate of mixed chimerism, the large majority which is stable. Further improvements should focus on minimising unstable cases. DisclosuresNo relevant conflicts of interest to declare.

Fludarabine/Treosulfan/Thiotepa/ATG Conditioning for Matched and Single Antigen Mismatched Unrelated Bone Marrow Transplantation in Haemoglobinopathies Is Feasible and Leads to Early and Sustanined Engraftment with No Long-Term Toxicity or GvHD

Related haemopoietic stem cell transplantation is a well-established treatment modality for haemoglobinopathies, but it is limited by the availability of related donors. The results of unrelated transplantation have been variable with historical variable results, concern about GvHD and usually restricted to 10/10 matches. From 2011 to 2016 twelve consecutive unrelated bonemarrow transplants were conditioned with fludarabine 160 mg/m2, treosulfan 42 g/m2, thiotepa 10 mg/kg and ATG (Thymoglobulin) 11.25 mg/kg (FTTA). Endogenous haemopoiesis was suppressed pre-transplantation with hypertransfusions for a minimum of 8 weeks. GvHD prophylaxis was provided with ciclosporin and MMF. 7 patients were transplanted for β thalassaemia major, one of α thalassaemia major and 4 for sickle cell disease. The median age was 9.5 years (2 - 17). The source of stem cells was BM in all patients: five 10/10 matched, six 9/10 matched and one 11/12 matched. The median cell dose was 3.01 x 108 TNC/kg (range 1.53 - 11.07) and 4.27 x 106 CD34+/kg (range 1.16 - 27.41). The median survival was 9.9 months (6.9-44.1). Patients with thalassaemia were Pesaro class I or II (Pesaro class III patients were intensively chelated pre-transplantation to return to class I or II). Patients with sickle cell disease were transplanted for stroke or recurrent vaso-oclusive crises and/or acute chest syndrome not responding to hydroxycarbamide. All patients were evaluated with liver biopsy pre-transplantation and defibrotide prophylaxis given if Ishak stage ≥3.All patients engrafted and achieved evidence of donor haemopoiesis on day +28 and achieved transfusion-independence and donor haematological values. No patient suffered primary or secondary graft failure. There was one death, one on day +257 due to idiopathic pneumonia syndrome in a patient with b thalassaemia major. Acute GvHD ≥ grade 2 occurred in 5 patients (41.7%). Chronic limited GvHD did not occur in any patient, but extensive occurred in the 5 patients developing acute GvHD. None of the patients had chronic GvHD at 18 months. VOD occurred in 4 patients (33.3%) and responded to standard measures and defibrotide treatment. The median neutrophil engraftment was 13 days (range 9 to 22). Patient with sickle cell disease had the platelet count maintained >50 x 109/L at all times. The median platelet engraftment >50 x 109/L was 37 days (range 15 to 86) and >50 x 109/L was 32 days (range 15 to 111). The median time to cessation of immunosuppression was 134 days (68-219).Chimerism studies on day +28 demonstrated 100% in whole blood (WB) and 88.9% in T cells (T) >95%, and 0% WB and 11.1% T >50-89% [n=11]; day +90: 91.7% WB and 91.7% T >95%, 8.3% WB and 0% T >50-89%, 0% WB and 8.3% T <50% [n=12]; day +180: 91.7% WB and 91.7% T >95%, and 8.3% WB and 8.3% T >50-89% [n=12]; and day +365: 50% WB and 50% T >95%, 25% WB and 25% T >90-95%, and 25% WB and 25% T >50-89% [n=4].In conclusion, unrelated bone marrow transplantation for all haemoglobinopathies is feasible and the overall survival and disease-free survival is 90.9%. FTTA leads to early and sustained engraftment with low rate of graft failure, and whilst the occurrence of VOD despite adequate chelation pre-transplantation and the incidence of GvHD was significant, these complications resolved with standard therapies and long-term outcomes approach those of related transplantation with no treatment required by 18 months. DisclosuresNo relevant conflicts of interest to declare.

Haemopoietic Stem Cell Transplantation for Diamond Blackfan Anaemia Leads to Early and Sustained Engraftment with Good Long-Term Outcomes, but Has an Increased Risk of Gut Toxicity and Lung GvHD

Haemopoietic stem cell transplantation (HSCT) is able to achieve normal haemopoiesis in patients with Diamond Blackfan anaemia. However, historically the results of alternative donors have been poor limiting its application. Little is known about the spectrum of toxicities encountered and whether it is different from other transfusion dependent anaemias using similar conditioning regimens. Furthermore, there has not been molecular data of engraftment to ascertain the intensity of available protocols. From 2006 to 2015 thirteen consecutive patients received a HSCT with either a busulfan/cyclophosphamide or a fludarabine/thiotepa/treosulfan conditioning. In addition, four other patients cared for in our centre had the HSCT elsewhere for practical reasons. Serotherapy with either alemtuzumab or ATG (Thymoglobulin) was included in all transplants. GvHD prophylaxis was provided with ciclosporin and MMF or methotrexate. The median age was 8 years (4 - 19). The donors were 10/10 matched siblings in ten patients, 10/10 unrelated donors in two patients and one 5/6 unrelated cord. The source of stem cells was BM in 9 patients, mixed cord blood and BM in 3 related patients, and unrelated cord blood in one patient. The median cell dose was 3.56 x 108 TNC/kg (range 1.91 - 8.83) and 7.11 x 106 CD34+/kg (range 5.39 - 10.37) for the patients receiving bone marrow only; 1.73 x 108 TNC/kg (range 0.7 - 2.7) for BM and 3.94 x 107 TNC/kg (range 2.54 - 5.4) and 0.93 x 106 CD34+/kg (range 0.43 - 1.4) for cord blood for the patients receiving a combination of cord blood and bone marrow, and 9.61 x 107 TNC/kg and 3.7 x 106 for the unrelated cord. The median survival was 31.1 months (1.7-122.5). All patients were evaluated with liver biopsy pre-transplantation and defibrotide prophylaxis given if Ishak stage ≥ 3.All patients engrafted and achieved evidence of donor haemopoiesis on day +28, and none suffered secondary graft failure. There was one death (7.7%), on day +53 due to idiopathic pneumonia syndrome in a busulfan containing regimen. Acute GvHD ≥ grade 2 occurred in 4 patients (30.8%). Chronic limited GvHD occurred in 1 patient (7.7%) and extensive in 3 patients (23.1%). Chronic GvHD resolved in all patients by 18 months. VOD occurred in 2 patients and responded to standard measures and defibrotide treatment. The median neutrophil engraftment was 17 days (range 11 to 27). The median platelet engraftment >20 x109/L was 33 days (range 19 to 24) and >50 x109/L was 36 days (range 19 to 94). The median time to cessation of immunosuppression was 171 days (99-356). Analyzing the entire cohort of 17 patients, it was unusual in comparison with transplants for haemoglobinopathies that 2 patients had acute and 3 chronic GvHD of the lungs, and that six had serious gut toxicity unrelated to GvHD requiring prolonged used of total parenteral nutrition and often hemorrhagic.Chimerism studies on day +28 demonstrated 100% in whole blood (WB) and 100% in T cells (T) >95% [n=12]; day +90: 100% WB and 66.7% T >95%, and 33.3% T >50-89% [n=11]; and day +365: 100% WB and 100% T >95% [n=10].In conclusion, related and unrelated transplantation with modern conditioning regimens leads to early and sustained engraftment with low rate of graft failure and mortality. However, there is an increased risk of serious gut toxicity and lung GvHD that in view of the low rate of mixed chimerism, may be decreased by reducing the intensity of conditioning. DisclosuresNo relevant conflicts of interest to declare.

Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplantation: Subanalysis Data from an Open-Label, Phase III, Randomized Trial

Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of conditioning for hematopoietic stem cell transplantation (HSCT) and is associated with patient and transplant-related risk factors, such as prior therapies, underlying diagnoses, and conditioning regimen. Unpredictable in its occurrence and severity, VOD/SOS is clinically characterized by painful hepatomegaly, hyperbilirubinemia, ascites, and weight gain. Overall estimated prevalence is 14% post-HSCT, while rates in some high-risk populations (eg, osteopetrosis or prior gemtuzumab ozogamicin) are >60% (Wadleigh M et al. Blood . 2003;102:1578-82; Corbacioglu S et al. Bone Marrow Transplant . 2006;38:547-53). Evidence suggests that defibrotide stabilizes endothelial cells, with direct and endothelial-cell mediated restoration of the thrombo-fibrinolytic balance. Defibrotide is approved in the European Union for the treatment of severe hepatic VOD/SOS in patients receiving HSCT, and is available in the United States through an expanded-access study. In a previously reported randomized clinical trial, defibrotide prophylaxis for VOD/SOS in high-risk pediatric patients undergoing HSCT reduced the overall incidence of VOD/SOS by day +30 post-HSCT. Here we report novel subgroup analyses of VOD/SOS incidence from this trial in patients with specific VOD/SOS risk factors at baseline. Methods This was a phase 3, multicenter, open-label, randomized, controlled trial in patients aged 5% weight gain. Patients were randomized to standard care with or without defibrotide prophylaxis dosed at 25 mg/kg/day in 4 divided infusions of 6.25 mg/kg. Osteopetrosis was a stratification variable. Defibrotide began the same day as HSCT conditioning and continued for 30 days post-HSCT, or ≥14 days for patients discharged from hospital before day +30 post-HSCT. Control patients who developed VOD/SOS received defibrotide treatment. The primary endpoint was incidence of VOD/SOS at day +30 post-HSCT. Results The intent-to-treat population included 356 patients: 180 randomized to defibrotide prophylaxis and 176 in the control group. Mean (SD) age was 6.6 (5.3) years, and 40.7% of patients were female. Demographic and clinical characteristics, including VOD/SOS risk factors (Table), were well-matched in the defibrotide and control groups. The most common risk factors among all patients were conditioning with busulfan and melphalan (58%), preexisting liver disease (27%), and second myeloablative transplantation (13%). VOD/SOS occurred by day +30 post-HSCT in 22 (12%) patients in the defibrotide prophylaxis group vs 35 (20%) patients in the control group. For the stratification variable, osteopetrosis, rates of VOD/SOS were 14% in the defibrotide prophylaxis arm and 67% in the control arm (Table). Differences in rates of VOD/SOS were lowest for adrenoleukodystrophy (no cases) and prior abdominal irradiation (11% vs 13%, respectively) (Table). Conclusions Across risk-factor subgroups, the rate of VOD/SOS was lower in patients receiving defibrotide compared with controls (except adrenoleukodystrophy: no VOD/SOS in either group). In particular, rates of VOD/SOS by day +30 were reduced by ≥50% in the defibrotide arm vs the control arm among patients with osteopetrosis, hemophagocytic lymphohistiocytosis, second myeloablative transplantation, and prior gemtuzumab treatment. Although the total numbers of patients with these risk factors were small, these between-group differences are of clinical interest and should be further explored. | Risk Factor | Defibrotide (n=180) | Control (n=176) | | ------------------------------------ | ----------------------------------------------- | --------------- | ----------------------------------------------- | | Total n | VOD/SOS incidence (n=22; 12.2%) n (%*) | Total n | VOD/SOS incidence (n=35; 20.0%) n (%*) | | Adrenoleukodystrophy | 1 | 0 (0) | 1 | 0 (0) | | Osteopetrosis | 7 | 1 (14) | 6 | 4 (67) | | Prior abdominal irradiation | 9 | 1 (11) | 8 | 1 (13) | | Hemophagocytic lymphohistiocytosis | 10 | 0 (0) | 15 | 6 (40) | | Prior gemtuzumab | 11 | 2 (18) | 5 | 2 (40) | | Allogeneic HSCT for leukemia | 17 | 2 (12) | 11 | 2 (18) | | Second myeloablative transplantation | 25 | 2 (8) | 23 | 4 (17) | | Pre-existing liver disease | 41 | 6 (15) | 54 | 12 (22) | | Busulfan/melphalan conditioning | 106 | 15 (14) | 99 | 17 (17) | * *Percent of patients with VOD/SOS. Table. Support: Jazz Pharmaceuticals Disclosures Corbacioglu: Gentium S.p.A.: Consultancy, Honoraria. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Bader: Amgen: Consultancy; Medac: Other: Institutional grants; Neovii: Other: Institutional grants; Riemser: Other: Institutional grants; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy.

Risk Factors for Human Papilloma Virus Reactivation in the Genital Tract of Female Stem Cell Transplant Survivors

s / Biol Blood Marrow Transplant 22 (2016) S19eS481 S26 Methods: This was a phase 3, multicenter, open-label, randomized, controlled trial in patients 5% weight gain). Patients were randomized to standard care with or without DF prophylaxis (25 mg/kg/day, 4 divided 6.25 mg/kg infusions). Osteopetrosis was a stratification variable. DF began the same day as conditioning, continuing for 30 days post-SCT or 14 days for patients discharged from hospital before day +30 post-SCT. Control patients developing VOD/ SOS received DF treatment. Primary endpoint: day +30 incidence of VOD/SOS post-SCT. Results: The intent-to-treat population included 356 patients: 180 randomized to DF prophylaxis and 176 in the control group. Mean (SD) age: 6.6 (5.3) years. 40.7% of patients were female. Demographic and clinical characteristics were well-matched. Most common risk factors: busulfan/melphalan conditioning (58%) and preexisting liver disease (27%). VOD/SOS occurred by day +30 post-SCT in 22 (12%) patients in the DF prophylaxis group vs 35 (20%) in the control group. Rates of VOD/SOS in osteopetrosis patients were 14% in the DF prophylaxis arm vs 67% in the control arm. VOD/SOS rates by day +30 were reduced by 50% in the DF arm vs the control arm in patients with hemophagocytic lymphohistiocytosis (0%, 40%), second myeloablative transplantation (8%, 17%), and prior gemtuzumab treatment (18%, 40%, respectively). Differences in VOD/SOS rates were lowest for adrenoleukodystrophy (ALD, no cases) and prior abdominal irradiation (11% vs 13%, respectively). The overall AE incidence was similar between patients receiving defibrotide prophylaxis (80%) and control arm patients (80%). Conclusions: Across risk-factor subgroups, the rate of VOD/ SOS was lower in patients receiving DF compared with controls (except ALD: no VOD/SOS in either group). Although the total numbers of patients with these risk factors were small, these between-group differences are of clinical interest and should be further explored. Support Jazz Pharmaceuticals

Does defibrotide prophylaxis decrease the risk of acute graft versus host disease following allogeneic hematopoietic cell transplantation?

There is some preliminary evidence, that veno-occlusive disease prophylaxis with defibrotide (DF) may also have a role in decreasing risk of acute graft-versus-host disease (aGvHD) by preventing tissue damage. In this study, we aimed to investigate the role of DF prophylaxis on the development of aGvHD at D + 180. One hundred ninety-five consecutive adult patients receiving allogeneic HCT were retrospectively evaluated in 3 groups: no DF, DF/post-HCT (DF D + 1 to D + 14) and DF/pre-HCT (DF for 14 days concurrently with conditioning). The total (p: 0.057) and grades III/IV (p: 0.051) aGvHD rates at D + 180 were 46.5%, 40%, 25.5% and 15.5%, 11.2%, 0% in patients on no DF, DF/post-HCT and DF/pre-HCT. DF may have a role in decreasing incidence and severity of aGvHD, especially if used concurrently with conditioning regimen.

Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplantation: Subanalysis Data from an Open-Label, Phase III, Randomized Trial

Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of conditioning for hematopoietic stem cell transplantation (HSCT) and is associated with patient and transplant-related risk factors, such as prior therapies, underlying diagnoses, and conditioning regimen. Unpredictable in its occurrence and severity, VOD/SOS is clinically characterized by painful hepatomegaly, hyperbilirubinemia, ascites, and weight gain. Overall estimated prevalence is 14% post-HSCT, while rates in some high-risk populations (eg, osteopetrosis or prior gemtuzumab ozogamicin) are &gt;60% (Wadleigh M et al. Blood. 2003;102:1578-82; Corbacioglu S et al. Bone Marrow Transplant. 2006;38:547-53). Evidence suggests that defibrotide stabilizes endothelial cells, with direct and endothelial-cell mediated restoration of the thrombo-fibrinolytic balance. Defibrotide is approved in the European Union for the treatment of severe hepatic VOD/SOS in patients receiving HSCT, and is available in the United States through an expanded-access study. In a previously reported randomized clinical trial, defibrotide prophylaxis for VOD/SOS in high-risk pediatric patients undergoing HSCT reduced the overall incidence of VOD/SOS by day +30 post-HSCT. Here we report novel subgroup analyses of VOD/SOS incidence from this trial in patients with specific VOD/SOS risk factors at baseline. Methods This was a phase 3, multicenter, open-label, randomized, controlled trial in patients aged &lt;18 years, undergoing myeloablative conditioning before allogeneic or autologous HSCT, with ≥1 risk factor for VOD/SOS. VOD/SOS was diagnosed according to modified Seattle criteria plus &gt;5% weight gain. Patients were randomized to standard care with or without defibrotide prophylaxis dosed at 25 mg/kg/day in 4 divided infusions of 6.25 mg/kg. Osteopetrosis was a stratification variable. Defibrotide began the same day as HSCT conditioning and continued for 30 days post-HSCT, or ≥14 days for patients discharged from hospital before day +30 post-HSCT. Control patients who developed VOD/SOS received defibrotide treatment. The primary endpoint was incidence of VOD/SOS at day +30 post-HSCT. Results The intent-to-treat population included 356 patients: 180 randomized to defibrotide prophylaxis and 176 in the control group. Mean (SD) age was 6.6 (5.3) years, and 40.7% of patients were female. Demographic and clinical characteristics, including VOD/SOS risk factors (Table), were well-matched in the defibrotide and control groups. The most common risk factors among all patients were conditioning with busulfan and melphalan (58%), preexisting liver disease (27%), and second myeloablative transplantation (13%). VOD/SOS occurred by day +30 post-HSCT in 22 (12%) patients in the defibrotide prophylaxis group vs 35 (20%) patients in the control group. For the stratification variable, osteopetrosis, rates of VOD/SOS were 14% in the defibrotide prophylaxis arm and 67% in the control arm (Table). Differences in rates of VOD/SOS were lowest for adrenoleukodystrophy (no cases) and prior abdominal irradiation (11% vs 13%, respectively) (Table). Conclusions Across risk-factor subgroups, the rate of VOD/SOS was lower in patients receiving defibrotide compared with controls (except adrenoleukodystrophy: no VOD/SOS in either group). In particular, rates of VOD/SOS by day +30 were reduced by ≥50% in the defibrotide arm vs the control arm among patients with osteopetrosis, hemophagocytic lymphohistiocytosis, second myeloablative transplantation, and prior gemtuzumab treatment. Although the total numbers of patients with these risk factors were small, these between-group differences are of clinical interest and should be further explored. Table. Risk Factor Defibrotide (n=180) Control (n=176) Total n VOD/SOS incidence (n=22; 12.2%) n (%*) Total n VOD/SOS incidence (n=35; 20.0%) n (%*) Adrenoleukodystrophy 1 0 (0) 1 0 (0) Osteopetrosis 7 1 (14) 6 4 (67) Prior abdominal irradiation 9 1 (11) 8 1 (13) Hemophagocytic lymphohistiocytosis 10 0 (0) 15 6 (40) Prior gemtuzumab 11 2 (18) 5 2 (40) Allogeneic HSCT for leukemia 17 2 (12) 11 2 (18) Second myeloablative transplantation 25 2 (8) 23 4 (17) Pre-existing liver disease 41 6 (15) 54 12 (22) Busulfan/melphalan conditioning 106 15 (14) 99 17 (17) *Percent of patients with VOD/SOS. Support: Jazz Pharmaceuticals Disclosures Corbacioglu: Gentium S.p.A.: Consultancy, Honoraria. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Bader:Amgen: Consultancy; Medac: Other: Institutional grants; Neovii: Other: Institutional grants; Riemser: Other: Institutional grants; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy.

Fludarabine/Treosulfan/Thiotepa/ATG Conditioning for Related Transplantation in Haemoglobinopathies Leads to Early and Sustanined Engraftment with Low Incidence of VOD and GvHD

Haemopoietic stem cell transplantation is a well-established treatment modality for haemoglobinopathies. The challenge is to minimise graft failure due to the expanded haemopoietic compartment whilst reducing the risk VOD due to the effects of iron load. From 2011 to 2015 fifty-four consecutive sibling transplants were conditioned with fludarabine 160 mg/m2, treosulfan 42 g/m2, thiotepa 10 mg/kg and ATG (Thymoglobulin) 7.5 mg/kg (FTTA). Endogenous haemopoiesis was suppressed pre-transplantation with hypertransfusions for a minimum of 8 weeks. GvHD prophylaxis was provided with ciclosporin and MMF. 33 patients were transplanted for b thalassaemia major and 21 for sickle cell disease. The median age was 7 years (2 - 16). The source of stem cells was BM in 49 patients and mixed cord blood and BM in 5 patients. The median cell dose was 3.48 x108 TNC/kg (range 0.23 - 8.51) and 6.73 x106 CD34+/kg (range 1.3 - 14.72) for the patients receiving bone marrow only; 1.64 x108 TNC/kg (range 1.22 - 3.9) and 4 x106 CD34+/kg (range 2.06 - 8.79) for BM and 3.8 x107 TNC/kg (range 0.8 - 7.32) and 0.53 x106 CD34+/kg (range 0.06 - 1.8) for cord blood for the patients receiving a combination of cord blood and bone marrow. The median survival was 14.4 months (1-41.9). Patients with thalassaemia were Pesaro class I or II (Pesaro class III patients were intensively chelated pre-transplantation to return to class I or II). Patients with sickle cell disease were transplanted for stroke or recurrent vaso-oclusive crises and/or acute chest syndrome not responding to hydroxycarbamide. All patients were evaluated with liver biopsy pre-transplantation and defibrotide prophylaxis given if Ishak stage ≥ 3.All patients engrafted and achieved evidence of donor haemopoiesis on day +28, and all but one patient achieved transfusion-independence and donor haematological values. One patient (1.9%) had progressive reduction of donor haemopoiesis with reestablishment of ineffective thalassaemic haemopoiesis and transfusion dependence on day +313. There were two deaths, one on day +89 due to idiopathic pneumonia syndrome in a patient with b thalassaemia major and one on day +189 due to an intracranial haemorrhage caused by refractory immune thrombocytopenia off immunosuppression in a patient with sickle cell disease and moya moya. Acute GvHD ≥ grade 2 occurred in 6 patients (11.1%). Chronic limited GvHD occurred in 7 patients (13%) and extensive in 3 patients (5.6%). Chronic GvHD was only present at 18 months in one patient (1.9%). VOD occurred in 2 patients (3.7%, days +7 and +9 respectively) and responded to standard measures and defibrotide treatment. The median neutrophil engraftment was 12 days (range 8 to 21). The median platelet engraftment >20 x109/L was 27 days (range 15 to 73) and >50 x109/L was 32 days (range 15 to 73). The median time to cessation of immunosuppression was 160 days (91-538).Chimerism studies on day +28 demonstrated 92.3% in whole blood (WB) and 69% in T cells (T) >95%, 5.8% WB and 4.8% T >90-95%, 1.9% WB and 21.4% T >50-89%, 0% WB and 4.8% T <50%; day +90: 83.3% WB and 60.4% T >95%, 4.2% WB and 8.4% T >90-95%, 10.4% WB and 20.8% T >50-89%, 2.1% WB and 10.4% T <50%; day +180: 59.4% WB and 45% T >95%, 19% WB and 17.5% T >90-95%, 16.7% WB and 35% T >50-89%, 4.8% WB and 2.5% T <50%; and day +365: 59.4% WB and 53.4% T >95%, 12.5% WB and 13.3% T >90-95%, 15.6% WB and 20% T >50-89%, 12.5% WB and 13.3% T <50%.In conclusion, FTTA leads to early and sustained engraftment with low rate of graft failure, and minimal occurrence of VOD whilst the incidence of GvHD is low. DisclosuresNo relevant conflicts of interest to declare.

Does defibrotide induce a delay to polymorphonuclear neutrophil engraftment after hematopoietic stem cell transplantation? Observation in a pediatric population.

In recent years, defibrotide (DFT) has emerged as a promising therapy for veno-occlusive disease (VOD). The aim of this study was to investigate whether DFT prophylaxis affects neutrophil engraftment in patients undergoing hematopoietic stem cell transplantation (HSCT). A cohort of 44 consecutive pediatric patients who underwent HSCT was retrospectively analyzed to see the role of DFT on engraftment. Patients were assigned into two groups based on the use or non-use of prophylaxis with DFT. The mean time to engraftment was statistically different between the two groups for both polymorphonuclear neutrophils (PMN) and white blood cells. Our study supports the hypothesis that prophylaxis with DFT for VOD leads to a delay to the engraftment of PMN in pediatric patients that underwent HSCT.

Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Autologous, Non-Purged Peripheral Stem Cell Transplantation for High Risk Neuroblastoma Patients

High-dose chemotherapy (HDC) represents the standard of treatment for high-risk neuroblastoma(NBL), hepatic veno-occlusive disease (VOD) is a common, 10-50% and serious complication of haematological stem cell transplantation (HSCT), with up to 90% mortality rates. We planned study to assess whether the use of prophylactic defibrotide in paediatric patients who were heavily treated with chemo-radiotherapy before transplant, and then underwent autologous HSCT.Seventeen patients who underwent autologous, unpurged peripheral stem cell transplantation PBSC with a high risk of developing VOD, between January 2003-July 2014, were given Defibrotide prophylaxis 25mg/kg/day for 30 days, commencing on -1 of conditioning regimen. All patients were stratified by INSS stage, age, N-MYC status. All were treated with six cycles of induction chemotherapy, myeloablative intensification, surgery for primary site, radiation therapy to the primary tumour site plus metastatic sites i.e bone metastases including skull. Meta-iodobenzylguanidin treatment as targeted radiotherapy was given on -21 prior to myeloablative chemotherapy. Oral 13-cis retinoic acid was employed on day +90 post-transplant. CD34+ cell mobilization and PBSC collection was carreid out after two-four cycles of induction cycles. Conditioning regimen and stem cell infusion was done following four-six weeks of last chemotherapy cycle, in order to reduce the toxicitiy. Conditioning regimen CEM consisted Carboplatin, Etoposide, Melfalan. There were no toxic deaths. All of the patients receieved antimicrobial prophylaxis and total parenteral nutrition support when was needed. Myeloid engraftment on day+13, erythroid engraftment on day+18 and thrombocyte engraftment was achieved on day +23.Defibrotide prophylaxis seems to reduce incidence of VOD and is well tolerated. VOD incidence and severity was reduced in the defibrotide group which suggests that defibrotide might be effective in preventing and treating VOD. Sufficiently powered randomised trials are now required to definitively test the role of defibrotide in this setting. DisclosuresNo relevant conflicts of interest to declare.

Defibrotide for Prevention and Treatment of Veno-Occlusive Disease in Adults: Single-Center Experience

Background: Hepatic veno-occlusive disease (VOD) has been reported at a rate up to 50% following intensive conditioning regimens used in allogeneic hematopoietic stem cell transplantation (AHSCT). Studies on the prophylactic effect of defibrotide to prevent hepatic VOD in adults are rare. Purpose: The research presented here aimed to evaluate whether propylactic defibrotide use can reduce incidence and severity of VOD in adults undergoing AHSCT. Also, we aimed to assess the benefit of defibrotide for treatment of VOD. Methods: Study population comprised 86 consecutive AHSCT patients transplanted between January 2005 and December 2009. 17 of the patients at high risk of developing VOD could have access to defibrotide and received defibrotide prophylaxis. Results: Modified Seattle criteria were used for VOD diagnosis. 14 of 86 patients (10 severe, 3 moderate, 1 mild) were diagnosed with VOD (16.2%). VOD incidence was similar between patients transplanted before December 2004 and after January 2005 (9.3% and 16.2%, respectively; p =0.14, HR =1.88, 95% CI 0.82- 4.29). 13 of 14 patients diagnosed with VOD in the study population were treated with defibrotide whereas only 2 of 12 in the control group received defibrotide for treatment (92.8% and 16.6%, respectively; p =0.0002, HR =65 , 95% CI 5.13-823.1). Mortality rate of VOD in the controls was significantly higher than the study population (66.6% and 21.4%, respectively; p =0.044, HR =0.13, 95% CI 0.02-0.78). Conclusions: Mortality rate related to VOD was lower in the defibrotide group. Therefore, we conclude defibrotide might be beneficial for treatment of VOD in adults.