Incidence Of Hepatic Veno-occlusive Disease Research Articles

Low incidence of hepatic veno-occlusive disease (VOD) in patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with inotuzumab ozogamicin (INO) followed by allogeneic stem cell transplantation (allo-SCT).

e19024 Background: Hepatic VOD is an uncommon, but often fatal complication of allo-SCT. The risk is increased after INO, an anti-CD22 antibody conjugated to calicheamicin with high remission rates in relapsed CD22-positive B-ALL. Previous reports have described VOD rates as high as 19% in INO-treated patients who then received allo-SCT. We report our safety experience using INO followed by allo-SCT. Methods: We identified patients >18 yrs with B-ALL treated with allo-SCT and INO in the University of Chicago IRB-approved SCT database. We reviewed the EMR for patient details, toxicities (CTCAE v5.0), and outcomes. Hepatic VOD was defined according to EBMT criteria. Overall survival (OS) was from time of allo-SCT to death or last follow-up. Results: Between 2010-2021, 72 adult patients with B-ALL received allo-SCT, and 17 also received INO as salvage therapy (Table). Median follow-up was 19 months (1-110). All received ursodiol prophylaxis and 15/17 received an azole for antifungal prophylaxis. They had median 2 cycles (1-3) of INO with median of 1.9 months (1-14) from the last dose of INO to allo-SCT. For cycle 1, 13/17 (77%) received 0.8 mg/m2 on D1 and 0.5 mg/m2 on D8 and D15. Of these, 11 had a subsequent cycle (5 with same dosing and 7 had 0.5 mg/m2 on D1, D8, and D15). 1 patient had 0.5 mg/m2 on D1, D8, and D15 for 2 cycles. 3 patients received 0.8 mg/m2 on D1 and 0.4 mg/m2 on D8 and D15 for 2 cycles. After INO, 10 patients achieved CR and 3 had CRi for ORR of 13/17 (76%). The 4 patients with persistent disease despite INO went into remission with a different salvage therapy prior to allo-SCT. Conditioning regimens are listed in Table 1. No patients developed VOD after allo-SCT. Within 2 yrs of allo-SCT, 3/17 (18%) relapsed and 7/17 (41%) died. The median OS was 21.2 months [18 - NR]. Conclusions: Limiting the number of INO cycles (median 2) prior to allo-SCT, delaying allo-SCT for 2 months after INO exposure, and avoiding dual alkylating agent conditioning may have contributed to the absence of VOD in our patients. Larger data sets will be useful to validate these important safety observations.[Table: see text]

Prophylactic Danshen Injection Combined with Prostaglandin E1 and Low-dose Heparin may prevent Hepatic Veno-occlusive Disease after Hematopoietic Stem Cell Transplantation: A Single-center Study in China

Objective: To investigate the effect of Danshen injection combined with prostaglandin E1 and low-dose heparinon prevention of hepatic veno-occlusive disease (HVOD) after hematopoietic stem cell transplantation (HSCT). Methods: A total of 126 patients undergoing HSCT between January 2008 and June 2015, received a combined prophylactic regimen of intravenous Danshen 20-30 ml/day, prostaglandin E 120-30 μg/d, and subcutaneous injection of low-dose heparin (100 U/kg/day) for prevention of HVOD. The incidence of HVOD and adverse events associated with this prophylactic regimen were observed. Results: Among 126 patients, 65 received autologous peripheral blood stem cell transplant, 34 received HLAidentical sibling HSCT, six received HLA mismatched siblingHSCT, seven received HLA-matched unrelated HSCT, and 14 received HLA-mismatched unrelated HSCT. No adverse reaction or coagulation disorder associated with this prophylactic regimen was observed. Only one case with acute myeloid leukemia (CR2) developed HVOD seven days after receiving myeloablative chemotherapy with oral busulfan and cyclophosphamide followed by HLAmismatched unrelated peripheral blood stem cell transplantation. This patient died of HVOD. Conclusion: Danshen injection combined with prostaglandin E1 and low-dose heparin is a safe and effective regimen for the prevention of HVOD after HSCT.

Research progress of long noncoding RNAs in the proliferation, apoptosis and metastasis of hepatic cell

Long noncoding RNAs(lncRNAs) are a novel class of RNA molecules defined as transcripts longer than 200 nucleotides. LncRNAs may participate in the regulation of gene expression.The hepatic veno-occlusive disease(HVOD) is one of complications of hematopoietic stem cells transplantation(HSCT). Hepatocyte injury is the main feature of HVOD induced by HSCT. As the liver is an important organ in functional metabolism and energy conversion, and the severe liver function damage is one of the direct causes of death after HSCT. LncRNAs can promote the repair of injured hepatocyte, which may help to reduce the incidence of HVOD caused by HSCT.The authors summriz the research progress of lncRNAs in the proliferation, apoptosis and metastasis of liver cells. Key words: RNA; Hepatocyte; Hepatic veno-occlusive disease

Effect of FOXP3 polymorphism on the clinical outcomes after allogeneic hematopoietic stem cell transplantation in pediatric acute leukemia patients

Forkhead BOX P3 (FOXP3) polymorphisms have recently been investigated as candidate risk factors in several tumors and autoimmune diseases. This study aims to evaluate the potential influence of FOXP3 rs3761548 polymorphism in the donor on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 171 patients were enrolled for this study and genotyped using direct sequencing. Patients with rs3761548 CC genotype had higher incidence of hepatic veno-occlusive disease (HVOD) and cytomegalovirus (CMV) infection than that of the individuals with AA or AC genotype (P=0.011, P=0.023). Treatment-related mortality (TRM) rate of patients with AA or AC genotype was lower than that of the patients with CC genotype (P=0.044) resulting in a difference in overall survival (OS). However, there was no difference in graft-versus-host disease (GVHD) relapse or blood stream infection (BSI), depending on the genotype at rs3761548 locus. In multivariate analysis, CC genotype showed as a risk factor in the development of HVOD and CMV infection, with low OS. In conclusion, this is the first report on FOXP3 rs3761548 SNP in allo-HSCT and we suggest that this SNP be considered a candidate marker for predicting the development of HVOD and CMV infection after allo-HSCT.

Clinical analysis of acute heart failure's risk factor for chronic myelogenous leukemia patient during the early stage of allogeneic hematopoietic stem cell transplantation

The study was to analyze the acute heart failure's risk factors and clinical characteristics for the patient with chronic myelogenous leukemia (CML) during the early stage (within 100 d) of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 106 cases of CML received allo-HSCT were retrospectively studied in Nanfang Hospital from May 2003 to May 2013. On the basis of existence or absence of acute heart failure during early stage of allo-HSCT (100 d), the patients were divided into heart failure (15 cases) and control group (91 cases). Using Logistic univariate analysis, Fisher' exact test and Pearson X(2) test, the acute heart failure's risk factors and clinical characteristics of both groups were analyzed. The median occurrence time of acute heart failure was 3 d (1 d before transplantation to 84 d after transplantation). Logistic univariate analysis indicated that the imatinib treatment history and time, and the prophylaxis regimens for GVHD with anti-thymocyte globulin (ATG) were all the poor prognostic factors for acute heart failure. Incidence of hepatic veno-occlusive disease (HVOD), bacterial infection and adverse prognostic events including death in the heart failure group patients were statistically higher than that in control group (P < 0.05). Acute heart failure mostly happened in the early stage after allo-HSCT, imatinib treatment and GVHD prophylaxis regimens with ATG are the poor prognostic factors for acute heart failure. The patients of heart failure group seem to have higher incidence of hepatic veno-occlusive disease (HVOD), bacterial infection and deaths.

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

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

High‐dose busulfan–thiotepa with autologous stem cell transplantation followed by posterior fossa irradiation in young children with classical or incompletely resected medulloblastoma

The aim of the study is to evaluate the outcome of young children with high risk localized medulloblastomas (newly diagnosed classical or incompletely resected) treated by high-dose busulfan-thiotepa with autologous stem cell rescue (ASCT) followed by focal radiation therapy (RT). Between September 1994 and January 2010, 19 children younger than 5 years old at diagnosis fulfilling the above inclusion criteria were treated at the Institute Gustave Roussy. After conventional chemotherapy, they received busulfan at a dose of 600 mg/m(2) and thiotepa at a dose of 900 mg/m(2) followed by ASCT. Focal RT was delivered at least 70 days after ASCT. The median follow-up was 40.5 months (range, 14.5-191.2 months). The 3-year event-free survival (EFS) and OS were 68% (95% CI 45-84%) and 84% (95% CI 61-94%), respectively. Acute toxicity consisted mainly in hepatic veno-occlusive disease (6/19 patients) and bone marrow aplasia (all patients). No toxic death occurred. The Full Scale Intellectual Quotient tended to decrease over time at a mean rate of 0.9 point per year from the date of diagnosis. This intensive treatment resulted in a high overall survival rate in young children with newly diagnosed non-metastatic classic or incompletely resected MB. In spite of a high incidence of hepatic veno-occlusive disease (32%), the acute toxicity was manageable. Delayed neuropsychological side effects remain main concerns. These results should to be confirmed in a larger cohort.

Putative Prophylaxes Updated of Placenta Extract and Aloe vera as Biogenic Stimulants

Placental tissue has been discarded post partum, but it is now becoming recognized as a potential source of stems and progenitor cells. Updated findings were shown in the present review that this tissue holds visible promise as a source of stem cells which have widespread clinical applications. Defibrotide (a polydeoxyribonucleotide fraction) from human placental extract could reduce incidence of hepatic veno-occlusive disease which is a leading morbidity and mortality after haemopoietic stem-cell transplantation. KiSS-1 is a human metastasis suppressor gene that inhibits the metastasis of human melanomas and breast carcinomas, without affecting tumorigenicity. KiSS-1 encodes a carboxy-terminally amidated peptide with 54 amino-acid residues. The peptide was isolated from human placenta as the endogeneous ligand of an orphan G-protein- coupled receptor and termed ‘metastin’. Metastin has potential as a suitable biomarker and novel effective therapy for cancer metastasis. JBP485, a novel dipeptide isolated from human placental hydrolysate, was recognized as a target reagent in drug-drug interaction and to restore liver function in vivo study. Cognitive decline in elderly people often derives from the interaction between aging-related changes and age-related diseases, such as diabetes, and covers a large spectrum of clinical manifestations, from intact cognition through mild cognitive impairment and dementia. Aloe vera supplementation may provide the efficacy of hypoglycemic activity as well as lowering lipid oxidation, and the possible putative prophylaxes to optimize cognitive decline in older adults with pre-diabetes symptom. Because of the diversities of placental extract and Aloe vera as biogenic stimulants, present review introduced the briefly selected authors’ intentions in each topical subject. Specially, the influence of gut microbiota to host is astonishing and highlighting that the consequence of our behaviours affect not only the environment without, but also that within us. Based on geriatric and neurological viewpoint, present review highlights current therapeutic strategies of placenta extract and Aloe vera as the so-called “biogenic stimulants”, aimed at producing a biological rejuvenator in placental extract and improving cognitive function via modifying the brain’s insulin sensitivity in Aloe vera.

Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation

AbstractWe conducted a prospective cohort study testing the noninferiority of survival of ablative intravenous busulfan (IV-BU) vs ablative total body irradiation (TBI)-based regimens in myeloid malignancies. A total of 1483 patients undergoing transplantation for myeloid malignancies (IV-BU, N = 1025; TBI, N = 458) were enrolled. Cohorts were similar with respect to age, gender, race, performance score, disease, and disease stage at transplantation. Most patients had acute myeloid leukemia (68% IV-BU, 78% TBI). Grafts were primarily peripheral blood (77%) from HLA-matched siblings (40%) or well-matched unrelated donors (48%). Two-year probabilities of survival (95% confidence interval [CI]), were 56% (95% CI, 53%-60%) and 48% (95% CI, 43%-54%, P = .019) for IV-BU (relative risk, 0.82; 95% CI, 0.68-0.98, P = .03) and TBI, respectively. Corresponding incidences of transplant-related mortality (TRM) were 18% (95% CI, 16%-21%) and 19% (95% CI, 15%-23%, P = .75) and disease progression were 34% (95% CI, 31%-37%) and 39% (95% CI, 34%-44%, P = .08). The incidence of hepatic veno-occlusive disease (VOD) was 5% for IV-BU and 1% with TBI (P < .001). There were no differences in progression-free survival and graft-versus-host disease. Compared with TBI, IV-BU resulted in superior survival with no increased risk for relapse or TRM. These results support the use of myeloablative IV-BU vs TBI-based conditioning regimens for treatment of myeloid malignancies.

Hepatic veno-occlusive disease related to tacrolimus after pancreas transplantation

Hepatic veno-occlusive disease (HVOD) describes the nonthrombotic, fibrous obliteration of the small centrilobular hepatic veins by connective tissue and centrilobular necrosis in zone 3 of the acini. Occlusion of the terminal venules of the liver might result in HVOD with the characteristic clinical findings of painful hepatomegaly, ascites, jaundice, and weight gain for more than 5% of patients. It is mainly observed after hematopoietic stem cell transplantation (SCT) and is responsible for significant morbidity and mortality. The incidence of HVOD is much lower after solid organ transplantation than after SCT and seems to differ from one organ to another. It has been sporadically reported after lung, renal, and liver transplantation, but has never been reported after pancreas transplantation. In general, HVOD is presumably attributed to azathioprine or tacrolimus used in solid organ transplantation. Here we describe a case of HVOD occurring after pancreas transplantation, in which tacrolimus might have played a causative role because complete recovery was observed after discontinuation of tacrolimus. Pancreas transplantation physicians should raise the suspicion of HVOD when a recipient presents with hepatomegaly, ascites, or jaundice.

Safety of PK-Guided IV Bu Cy VP-16 Preparative Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation for Lymphoma: Findings From a Multi-Center Phase II Study in North America

AbstractAbstract ▪813▪This icon denotes a clinically relevant abstract Background:Published reports indicate that oral or intravenous (IV) busulfan in combination with cyclophosphamide and VP-16 (BuCyVP-16) is an effective conditioning regimen with acceptable safety profile for lymphoma patients prior to autologous hematopoietic stem cell transplantation (ASCT). Since the therapeutic window of Bu is narrow, it is important to standardize the systemic exposure during conditioning. Although the IV formulation of Bu eliminates the problem of variable drug absorption, unpredictable systemic exposure can still occur due to interpatient differences in Bu clearance. Therefore, tighter control of systemic Bu exposure using pharmacokinetics (PK) may lead to improved efficacy and further decrease in toxicity. The aim of this multi-center, single-arm, Phase II study was to prospectively evaluate the safety and efficacy of IV BuCyVP-16 regimen in lymphoma patients undergoing ASCT, after optimizing Bu exposure using PK-directed dosing. Methods:Patients with chemosensitive, relapsed or primary-refractory Hodgkin and B-cell non-Hodgkin lymphoma undergoing the first ASCT received a test dose of IV Bu (0.8 mg/kg) given as a 2-hour infusion 11 to 14 days before transplant. Bu exposure was determined as area under the concentration-time curve (AUC) using six serial blood samples after the test dose administration. Doses for the conditioning regimen were then calculated to result in total AUC (conditioning + test) of 20,000 mM*min. One-fourth of the resulting calculated Bu dose was given as a 3-hour infusion on Day -8, followed by a second, confirmatory PK analysis. The same daily Bu dose was administered on the next 3 days, unless the confirmatory PK analysis showed that this would result in total AUC outside the target range (>24,000 mM*min or <16,000 mM*min), in which case the subsequent dosing was further adjusted. VP-16 (1.4 g/m2) was administered on Day -4, followed by 2.5 g/m2/day of Cy on Days -3 and -2. Transplant-related mortality (TRM), defined by death from any cause other than disease progression, was monitored throughout the trial. After median 2 years of follow-up, the outcomes will be compared with a BEAM regimen control group from the CIBMTR registry, using pre-specified matching criteria. Results:A total of 202 subjects with Hodgkin (n=65) and non-Hodgkin lymphoma (n=137) were enrolled from 32 centers in the US and Canada.196 subjects had both test PK and confirmatory PK results. Test PK demonstrated that 36.2% (n=71) of the patients had exposure outside of expected range (1,250 μM*min ± 20%): higher AUC (>1,500 μM*min) in five patients (2.6 %) and lower AUC (<1,000 μM*min) in 66 (33.7%). These would have been dosed outside the total target AUC range if dose was not individualized based on test PK. Mean Bu clearances were comparable between test and Day -8 PK, 3.04 ± 0.48 ml/min/kg and 3.03 ± 0.49 ml/min/kg, respectively. Accordingly, 94.9 % of patients (n=186) fell within the target range (AUC, 20,000 μM*min ± 20%), using consistent doses on Days -8 through -5. The other ten patients (5.1%) required dose alteration for the last two days of conditioning due to clearance changes between test PK and confirmatory PK (Day -8): a dose reduction in eight patients (4.1%) and a dose increase in two (1.0%).An early subset-analysis by age in June 2011 revealed that 4 of 18 subjects older than 65 years suffered TRM. Consequently, the protocol was amended to lower the inclusion age limit to 65. The final TRM at day 100 was 4/18 (22.2% [95%CI; 6.4–47.6%]) for patients older than 65 years and 5/184 (2.7% [95%CI; 0.9–6.2%]) for those 65 years old or younger. PK results indicated no extraordinary Bu exposure in TRM cases. The most frequently observed grade ≥ 3 adverse events (CTCAE ver. 3.0) were febrile neutropenia 55.1 % (Grade 3: 52.2%; Grade 4: 2.9%; no Grade 5), stomatitis 37.7% (all Grade 3 events) and nausea 9.7% (all Grade 3 events). No case of hepatic veno-occlusive disease (HVOD) meeting Baltimore criteria was reported. Conclusions:A pre-conditioning test dose estimated individual PK parameters and accurately predicted Day-8 PK in 95% of the subjects. This strategy personalized the dosing for optimal Bu exposure preventing the Bu overexposure or underexposure that would have occurred in over a third of patients. The toxicity of PK-guided IV BuCyVP-16 preparative regimen was low for patients younger than 66 years of age. This approach resulted in no incidence of HVOD. Disclosures:Costa:Otsuka: Research Funding. Off Label Use: Off label use of busulfan in non hodgkin and hodgkin lymphoma. Waller:Outsuka: Research Funding. Freytes:Otsuka Pharmaceuticals: Research Funding. Shea:Otsuka : Research Funding. Rodriguez:Otsuka: Consultancy, Research Funding, Speakers Bureau; Millennium: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; SOBI: Consultancy, Speakers Bureau. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka: Employment. Smith:Otsuka America Pharmaceuticals Inc: Consultancy. Elekes:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Vaughan:Pierre Fabre: Honoraria.

Development and Validation of a Test Dose Strategy for Once-Daily i.v. Busulfan: Importance of Fixed Infusion Rate Dosing

Intravenous (i.v.) busulfan (Bu) administered once daily in myeloablative transplant regimens is convenient, effective, and relatively well tolerated. Therapeutic drug monitoring is recommended as nonrelapse mortality increases when daily exposure, as determined by the area under the plasma concentration versus time curve (AUC), exceeds 6000 μM·min. We describe sequential studies to achieve accurate prediction of treatment doses of Bu based on the kinetics of a smaller test dose. A total of 335 patients with hematologic malignancies were given daily i.v. Bu 3.2 mg/kg × 4 and fludarabine 50 mg/m(2) × 5. Pharmacokinetic monitoring was conducted for both the test dose and first treatment dose of Bu (day -5). Three different test dose schedules were evaluated: 12 mg Bu administered over 20 minutes, 0.8 mg/kg over 3 hours, and 0.8 mg/kg infused at 80 mg/h. The 3.2 mg/kg treatment doses were infused over a fixed time of 3 hours for the first 2 test dose trials and at a fixed rate of 80 mg/h for the final protocol. All test dose infusions were on day -7. In the first 2schedules, Bu administered over a fixed time had significantly higher clearance for the test dose compared with the treatment dose. However, when both the test and the treatment doses were administered at the same infusion rate, clearance of the drug between the 2 dosing days was equivalent. Predicted day -5 AUC (AUC(-5)) showed a high linear correlation (r(2) = 0.74) to the actual AUC(-5). The error of these predictions was <20% in 98% of patients and <10% in 80%. In 24 individuals, the test dose predicted an AUC >5500μM·min; therefore, the first Bu treatment dose was reduced to a desired target AUC. All adjusted doses fell within 20% of the targeted exposure. We conclude that a test dose strategy for therapeutic drug monitoring of daily i.v. Bu is accurate if the test and treatment doses are infused at the same rate. This approach allows targeting of therapeutic doses of Bu to desired levels and the potential for improved safety and efficacy.

Weight‐based strategy of dose administration in children using intravenous busulfan: Clinical and pharmacokinetic results

A prospective clinical trial was performed in order to validate the pharmacokinetic (PK) and clinical benefits of a new dosing schedule of intravenous busulfan (IV Bu) in children. IV Bu was administered as a 2-hr infusion every 6 hr for 4 days. Five dose levels were given according to body-weight strata. The 67 children aged from 4 months to 17.2 years were followed up over 50 months after autologous or allogeneic stem-cell transplantation. Reduced PK variability was seen after IV Bu administration enabling efficient targeting with 78% of patients within the 900-1,500 µM · min therapeutic window and reproducible exposures across administrations. No neurological complications occurred. The low incidence of hepatic veno-occlusive disease (VOD) recorded was not correlated with high area under the curve (AUC). Only stomatitis was correlated with high AUC in the autologous group. The 4-year overall survival was 59% in the autologous group and 82% in the allogeneic group. The new dosing schedule using IV Bu provides adequate therapeutic targeting from the first administration, with low toxicity and good disease control in high-risk children. The choice of this formulation of Bu should be considered because of its low morbidity and good outcome.

Low incidence of hepatic veno-occlusive disease in pediatric patients undergoing hematopoietic stem cell transplantation attributed to a combination of intravenous heparin, oral glutamine, and ursodiol at a single transplant institution

We report the low incidence of hepatic VOD in pediatric patients with various diagnoses including hematologic malignancies and non-malignant conditions transplanted at our institution. Retrospective review of 188 patients who underwent HSCT and received a combined prophylactic regimen of intravenous heparin, oral glutamine, and ursodiol was undertaken. Analysis of the outcome of VOD revealed only one clinical case with acute myeloid leukemia; the patient developed hepatic VOD 10 days after receiving myeloablative chemotherapy with busulfan and CTX followed by HLA-matched related peripheral blood stem cell transplantation. The low incidence of hepatic VOD in an otherwise high-risk pediatric transplant population is an important observation, which may be partly attributed to this prophylactic regimen, and warrants further randomized clinical trials for confirmation.

Defibrotide (DF) for the Prevention of Hepatic Veno-Occlusive Disease (VOD) in Pediatric Stem Cell Transplantion: Results of a Prospective Phase II/III Randomized, Multicenter Study.

Abstract 653 Background:Hepatic VOD is a life-threatening complication following SCT with a particularly high incidence in children. Development of VOD is one of the most common causes of early death after SCT. DF (Gentium SpA), a polydisperse oligonucleotide, demonstrates a protective effect on vascular endothelial cells in vitro. Small non-randomized trials to assess DF for the prophylaxis of VOD were promising without significant anticoagulant effects. Methods:Eligibility criteria included pts <18 years with myeloablative SCT and at least 1 of the following high risk criteria for VOD: conditioning with busulfan and melphalan, pre-existing liver disease, 2nd myeloablative transplant, allo-SCT for leukemia in 2nd relapse, macrophage activating syndromes, prior abdominal irradiation, prior gemtuzumab, osteopetrosis, and adrenoleukodystrophy. Pts were prospectively randomized to the control arm (no prophylactic DF) or to receive DF 25mg/kg/day IV from the start of conditioning until D+30 post SCT. All pts diagnosed with VOD received DF for treatment. Primary endpoint: incidence of hepatic VOD by D+30 using modified Seattle criteria (2 or more of the following: bilirubin > 2 mg/dL, hepatomegaly, ascites and/or unexplained weight gain > 5%). VOD was assessed by physical exam; hepatomegaly and ascites were confirmed by abdominal ultrasound. A blinded independent review committee of 3 expert hematologists confirmed the diagnosis of VOD. Although the study was not powered to assess mortality, a composite score was assessed as a secondary endpoint that incorporated VOD-associated toxicity (respiratory failure, renal failure, encephalopathy) and mortality. Incidence and severity of graft versus host disease (GvHD) was assessed. As the true incidence of VOD in this population was unknown, the trial incorporated a planned adaptive interim analysis to be reviewed by an independent DSMB. Results:Based on the recommendations of the DSMB, 360 pts were enrolled between January 2006 and January 2009 by 28 centers in the EU and Israel. An Intent-to-Treat (ITT) analysis was performed on all randomized pts who signed informed consent (DF: 180; control: 176). Median age was 4.8 years; 24% infants, 52% children (ages 2-11 years) and 23% adolescents. 41% were female, 59% male. 68% were allo-, 31% auto-SCT. There were no significant differences between the two arms in disease types or risk factors. Ninety-three percent (93%) of the patients completed the primary endpoint at day +30. In the ITT analysis, 12% (22/180) of the pts of the DF arm and 20% (35/176) of the control group developed VOD by D+30 (P=0.054); in the PP analysis, the VOD incidence was 12% (20/164) vs 21% (35/169) (P=0.037). VOD was experienced by 23% of the infants, 14% of the children and 13% of the adolescents. The composite score (assessing VOD morbidity and mortality) was significantly in favor of the DF arm (P=0.034). Significantly less acute GvHD by D+100 was reported in the DF pts (32% (57/180) vs 43% (75/176); P=0.023 by Wilcoxon test). Observation of VOD in either arm led to a higher mortality: mortality of pts with VOD equaled 24.6% (14/57) compared to 7% in pts without VOD (21/299). Renal failure was observed in 1% (2/180 pts) of DF pts vs 6% (10/176) of the control (P=0.017); respiratory failure was observed in 7% vs 9% (NS); and encephalopathy in 1% vs 2% (NS). SAEs were experienced by 58% of the DF pts vs 59% of the control, including infections (24% vs 27%) and respiratory disorders (12% vs 9%); 9 hemorrhagic events were seen in the DF arm compared to 21 in the control. Conclusions:This Phase II/III randomized study demonstrates the efficacy and safety of DF in preventing VOD in pediatric pts at high risk of VOD. Use of prophylactic DF results in a 40% reduction in the incidence of VOD. Consistent with the role of DF in endothelial protection, both renal failure and acute GvHD were significantly lower in the DF arm. Safety of DF was confirmed by lack of significant toxicity (including hemorrhage). DF can be recommended for the prevention of VOD in this high risk population. Disclosures:Corbacioglu:Gentium S.p.A.: Consultancy, Research Funding. Massaro:Gentium S.p.A.: Consultancy. D'Agostino:Gentium S.p.A.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hoyle:Gentium S.p.A.: Employment. Iacobelli:Gentium: Employment.

Risk factors for hepatic veno-occlusive disease: a retrospective unicentric study in 116 children autografted after a high-dose BU-thiotepa regimen

At our Institute, during the last decade, the incidence of hepatic veno-occlusive disease (HVOD) appears to be on the increase among pediatric patients treated with BU-thiotepa (BU-TTP)-conditioning regimen. We thus performed a retrospective analysis to identify the risk factors for HVOD, which could explain such a change. In total, 116 patients treated at Institut Gustave Roussy, between May 1998 and December 2005 were eligible for this study having received BU-TTP as their first high-dose chemotherapy regimen, followed by autologous hematopoietic SCT (AHSCT). According to McDonald's clinical criteria, HVOD was diagnosed in 31% of these children. Demographic, clinical, biological and therapeutic parameters were evaluated in uni- and multivariate analyses that showed a significant correlation between previous carboplatin therapy and risk of developing post transplant HVOD (P=0.028). Comparable results were found for etoposide (P=0.048). In addition, a correlation between HVOD and risk of post transplant death was linked to its association with other types of organ failure (P=0.029). This study demonstrates that previous VPCARBO administration in conventional chemotherapy significantly increases the risk of HVOD among brain tumor patients later consolidated with BU-TTP followed by AHSCT.

Glutathione S‐transferase A1 polymorphisms and acute graft‐vs.‐host disease in HLA‐matched sibling allogeneic hematopoietic stem cell transplantation

Busulfan and the metabolites of cyclophosphamide are conjugated with glutathione and catabolized by enzymes of the cytosolic glutathione S-transferases family. There are clearly linked single nucleotide polymorphisms in the promoter region of the glutathione S-transferase A1 gene (i.e., GSTA1*A, -567T, -69C and -52G; GSTA1*B, -567G, -69T and -52A). We assessed whether the clinical outcomes, including acute graft-vs.-host disease, of 61 patients with hematological malignancies, following HLA-matched sibling allogeneic stem cell transplantation using busulfan/cyclophosphamide conditioning are altered by glutathione S-transferase A1 genotypes. Globally, grade II-IV acute graft-vs.-host disease developed in 13 patients (21%). Grade II-IV acute graft-vs.-host disease developed in 15.2% of 46 patients with GSTA1*A/*A diplotype and in 40.0% of 15 patients with GSTA1*A/*B or GSTA1*B/*B diplotype (p = 0.04). Moreover, this relationship between GSTA1*A/*A diplotypes and lower incidence of acute graft-vs.-host disease was independent of the age, gender, stem cell source, and disease status. The incidences of acute skin graft-vs.-host disease were 7% (3/46) in patients with GSTA1*A/*A and 27% (4/15) in patients without GSTA1*A/*A (p = 0.009, univariate; p = 0.01, multivariate). Acute hepatic graft-vs.-host disease developed in 6 (13%) of 46 patients with the GSTA1*A/*A diplotype and in 4 (27%) of 15 patients without this diplotype (p = 0.09, univariate; p = 0.12, multivariate). Ten patients (16%) developed hepatic veno-occlusive disease. No significant difference was found in the incidence of hepatic veno-occlusive disease between patients with and without the GSTA1*A/*A diplotype (19.6% vs. 6.7%; p = 0.24). We conclude that the GSTA1*A/*A diplotype is an independent protective factor against acute graft-vs.-host disease, especially for skin graft-vs.-host disease, and probably for hepatic graft-vs.-host disease, in patients using busulfan/cyclophosphamide conditioning. The identification of glutathione S-transferase A1 genotypes prior to allogeneic stem cell transplantation could allow conditioning regimens and graft-vs.-host disease prophylaxis to be modified to improve outcome.

Allogeneic Stem Cell Transplantation for Patients with Advanced Hematological Malignancies: Comparison of Fludarabine-based Reduced Intensity Conditioning versus Myeloablative Conditioning

We compared the outcomes of allogeneic hematopoietic stem cell transplantation using reduced intensity and myeloablative conditioning for the treatment of patients with advanced hematological malignancies. A total of 75 adult patients received transplants from human leukocyte antigen-matched donors, coupled with either reduced intensity (n=40; fludarabine/melphalan, 28; fludarabine/cyclophosphamide, 12) or myeloablative conditioning (n=35, busufan/cyclophosphamide). The patients receiving reduced intensity conditioning were elderly, or exhibited contraindications for myeloablative conditioning. Neutrophil and platelet engraftment occurred more rapidly in the reduced intensity group (median, 9 days vs. 18 days in the myeloablative group, p<0.0001; median 12 days vs. 22 days in the myeloablative group, p=0.0001, respectively). Acute graft-versus-host disease (≥grade II) occurred at comparable frequencies in both groups, while the incidence of hepatic veno-occlusive disease was lower in the reduced intensity group (3% vs. 20% in the myeloablative group, p=0.02). The overall 1-yr survival rates of the reduced intensity and myeloablative group patients were 44% and 15%, respectively (p=0.16). The results of present study indicate that patients with advanced hematological malignancies, even the elderly and those with major organ dysfunctions, might benefit from reduced intensity transplantation.

Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide

Malignant infantile osteopetrosis (MIOP) is a rare hereditary disorder of osteoclast function, which can be reversed by hematopoietic stem cell transplantation (SCT). We observed a high incidence of hepatic veno-occlusive disease (VOD) in transplanted patients and explored the prevention of this complication by using defibrotide (DF) as a prophylaxis. Twenty children with MIOP were consecutively transplanted in our center between 1996 and 2005. Eleven of these patients were transplanted between 1996 and 2001 and experienced an overall incidence of VOD of 63.6% (7/11). VOD was severe in three patients and one patient succumbed to VOD-related multi-organ failure. Owing to this very high incidence of VOD, DF prophylaxis was initiated in nine patients consecutively transplanted between 2001 and 2005. In this group, only one patient (11.1%) was diagnosed with moderate VOD. We report here a very high risk in patients with MIOP to develop VOD after transplantation. Prophylactic DF was implemented in our current transplant protocol and reduced the VOD rate significantly in this high-risk population.

Treatment with Granulocyte Colony-Stimulating Factor after Allogeneic Transplantation Increases the Risk of Hepatic Veno-Occlusive Disease and Death: A Retrospective Analysis of 440 Cases at a Single Center.

Hepatic veno-occlusive disease (VOD) is one of the most serious complications of hematopoietic stem cell transplantation (HSCT). Various factors have been identified as increasing the risk of hepatic VOD; history of liver dysfunction, elevated AST level, transplant from an HLA-mismatched or unrelated donor, and abdominal irradiation, but few of them have been associated with a significantly increased risk. A recent study showed a newly association between the use of granulocyte colony-stimulating factor (G-CSF) and subsequent higher incidence of VOD. The present analysis was performed to elucidate the clinical effects of G-CSF on the incidence of hepatic VOD and survival after HSCT in a large group of patients at a single institution. We retrospectively reviewed 440 patients (264 males, 176 females; median age 35, range 0–67) with hematological diseases who underwent allogeneic transplantation between September 1986 and December 2003. G-CSF was given basically according to the primary diseases and type of transplant, and a total of 230 patients with lymphoid malignancy received G-CSF shortly after transplantation, while G-CSF was not administered in remaining 210 patients with myeloid malignancy. A diagnosis of VOD was made according to the McDonald's criteria and 47 patients (11.0%) were eventually diagnosed with VOD. Hepatic VOD occurred in 33 of 230 patients (14%) in the patients with G-CSF versus 14 of 210 patients (6%) in the non G-CSF group. Several possible risk factors based on the previous studies, including the use of G-CSF, were counted on an initial univariate analysis and cumulated significant factors further analyzed for their potential value for VOD development in multivariate analysis. By univariate analysis, the HLA disparity, performance status before transplantation, febrile episode during conditioning therapy and the use of G-CSF were significantly related to the incidence of VOD. A multivariate analysis with logistic regression again identified the use of G-CSF as the factor that significantly influenced the occurrence of VOD, in addition to the former three independent variables. Our analysis of risk factors in this series confirmed some other published studies but differed for other factors. Surprisingly,the administration of G-CSF may have an adverse impact on the subsequent survival after transplantation. Patient survival probability was statistically different (p=0.0063) between two groups, as analyzed by the Kaplan-Meier plot: the ten year survival rate was 50±4% in the G-CSF group and 64±4% in the non G-CSF group (p=0.0063). There were a total of 98 deaths in the G-CSF group compared with 70 deaths in the non G-CSF group. Although relapse and GVHD were the most common cause of death in both groups, death due to hepatic failure/VOD/TMA was observed 10% in the G-CSF group versus 4% in the non G-CSF group. Our data based on retrospective analysis should be interpreted with some caution, but they have suggested that G-CSF might be involved in VOD development and also adversely affected the outcome. Although underlying mechanism how G-CSF adversely effect on survival should be multifactorial, it is possible that G-CSF could activate the coagulation system and therefore induce thrombotic events including VOD. Thus, this putative mechanism of G-CSF towards a prothrombotic tendency warrants a further clarification, and the use of G-CSF should be carefully assessed in transplant recipients.