Risk Of Hepatic Veno-occlusive Disease Research Articles

Treosulfan in combination with fludarabine as part of conditioning treatment prior to allogeneic hematopoietic stem cell transplantation

The combination of treosulfan with fludarabine (Treo-Flu) is one of the new megatherapies prior to hematopoietic stem cell transplantation. Preclinical studies have documented the myeloablative and myelosuppressive effects of treosulfan, in addition to its immunosuppressive and antimalignant activities. Treosulfan pharmacokinetics involves nonenzymatic activation and generation of epoxides as active compounds. In the clinical studies, the most common adverse effects of Treo-Flu were grade 4 hematologic toxicities with leukopenia, neutropenia and thrombocytopenia. Among the most common nonhematologic toxicities, grade 2 or lower mucositis was usually reported. One of the advantages of treosulfan-based conditioning regimens is their good safety profile, especially the low risk of hepatic venoocclusive disease. Additional drugs reported in combination with the Treo-Flu backbone are thiotepa and melphalan. Treo-Flu alone and in multiple drug combinations can be successfully and safely combined with posttransplant cyclophosphamide immunosuppression for unma¬nipulated haploidentical transplantations. On the basis of chimerism studies, the Treo-Flu megatherapy lacks full myeloablative potential, but the profound myelosuppression with donor cell-mediated alloreactivity can result in full donor chimerism in the majority of transplant recipients. The clinical studies of allogeneic hematopoietic stem cell transplantation show high heterogeneity, but the safety and feasibility of the Treo-Flu regimen are evident and support its place among reduced-intensity protocols.

Pharmacokinetics and Safety of a Novel Conditioning Regimen, Individualized Once-Daily Intravenous Busulfan with Bortezomib, in Relapsed Multiple Myeloma Patients Undergoing a Second Autologous Hematopoietic Stem Cell Transplantation

Abstract 4509 BACKGROUND:Once multiple myeloma (MM) relapses after a first autologous hematopoietic stem cell transplantation (HSCT), long-term disease control is challenging because of limited therapeutic options. A second autologous HSCT is one of the options although the choice of conditioning regimens has not been thoroughly investigated. Past studies demonstrated that adding oral busulfan (Bu) to melphalan for conditioning regimen prior to a first HSCT resulted in better disease control of MM than melphalan single administration [Lahuerta et al, Haematologica. 2010;95:1913]. Nonetheless, the risk of hepatic veno-occlusive disease (VOD) hinders the use of oral Bu as a part of the conditioning regimen. Intravenous (IV) Bu eliminates the unpredictable bioavailability of the oral drug, whereas pharmacokinetic (PK)-directed dose optimization reduces inter-individual variability in the metabolism of Bu, resulting in decreased incidence of VOD and improvement in the control of hematologic malignancies [Andersson et al, Biol Blood Marrow Transplant 2002;8:477]. In addition, a proteasome inhibitor like bortezomib may have synergy with an alkylating agent for conditioning prior to HSCT in myeloma [Lonial et al, Clin Cancer Res 2010; 16: 5079], but the safety of a combination with Bu has not been investigated to date. Here we report results from a multicenter, prospective Phase 2 study to examine the pharmacokinetics of IV Bu and safety with bortezomib as a conditioning regimen for a second autologous HSCT. METHODS:30 patients with relapsed MM who had a first autologous HSCT ≥1 year prior to the planned HSCT were enrolled from eleven centers in the US and Canada. Patients received a test dose of IV Bu (0.8 mg/kg) over 2 hours between days 12 and 9 prior to HSCT. Serial blood samples were drawn up to 360 min after the start of the infusion. A central laboratory measured Bu concentrations, determined Bu exposure as area under the concentration-time curve (AUC) using WinNonlin software, and recommended individualized PK-directed dosing in order to achieve a total regimen AUC of 20,000 μM·min. Using the patient-specific PK-directed dose, IV Bu was administered over 3 hours once daily from Day -5 to Day -2. In all patients, a second PK analysis was conducted on Day -5 to confirm the PK-directed dose. Bu doses were adjusted on Day -3 and Day -2, if needed. Bortezomib (1.3 mg/m2 QD) was administered as an IV bolus injection on Day -1. RESULTS:All 30 patients who enrolled in this study had been treated with high dose melphalan before a first HSCT. The median time from the first to second HSCT was 31.4 months (range 12.0 – 119.2 months). Disease status prior to the second HSCT was VGPR (n=6), PR (n=12), SD (n=2), and PD (n=10). Test PK revealed that 40.0 % (n=12/30) of the patients had doses outside of target range (1,250 μM·min +/− 20%), based on expected exposure using a fixed dose of 0.8 mg/kg. Specifically, infusion of the test dose resulted in 1,500 μM·min or higher AUC in 3.3% (n=1/30) and 1,000 μM·min or lower AUC in 36.7% (n=11/30) of patients. In order to achieve the target AUC, daily PK-directed dose of IV Bu when conditioning started on Day -5 ranged between 1.99 mg/kg and 4.73 mg/kg: lower than 3.2 mg/kg in 12 subjects and higher than 3.2 mg/kg in the remaining 18. Confirmatory PK on Day -5 demonstrated that mean Bu clearances were comparable to that from test PK: 3.03 ml/min/kg for test dose and 2.93 ml/min/kg for Day - 5. Consequently, using a test dose followed by PK-directed Bu dosing, 93.3% of patients (n=28/30) fell within the target range (AUC, 20,000 μM·min +/−20%). Only two patients (6.7%) needed subsequent daily dose adjustment on Day -3 and Day -2. No instances of VOD, seizure, or worsening neuropathy have been reported to date. One death was reported by Day 30 after transplant in a patient with Parkinsonism who died of pulmonary complications. CONCLUSION:This multicenter, prospective study reveals that a pre-transplant test dose PK allows accurate targeting of busulfan dosing. The conditioning regimen of bortezomib and IV busulfan with PK-directed dose optimization is well tolerated in patients with relapsed MM who undergo second autologous HSCT. Disclosures:Freytes:Otsuka Pharmaceuticals: Research Funding. Off Label Use: Busulfex and bortezomib as conditioning regimen for autologous transplant in patients with multiple myeloma. Yeh:Otsuka Pharmaceutical Development & Commercialization, Inc.: Research Funding. Shaughnessy:Otsuka: Consultancy, Honoraria, Speakers Bureau. White:Otsuka: Consultancy, Honoraria. Rodriguez:Millennium: Research Funding, Speakers Bureau; Otsuka: Research Funding. Yu:Otsuka Pharmaceutical Development & Commercialization, Inc.: Research Funding. Sun:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Armstrong:Otsuka Pharmaceutical Development and Commercialization, Inc.: Employment. Elekes:Otsuka Pharmaceutical: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Reece:Novartis: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Johnson & Johnson: Research Funding.

Use of Prophylactic Anticoagulation and the Risk of Hepatic Veno-Occlusive Disease in Patients Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Use of Prophylactic Anticoagulation and the Risk of Hepatic Veno-Occlusive Disease in Patients Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Use of prophylactic anticoagulation and the risk of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis

Hepatic veno-occlusive disease is a serious regimen-related toxicity in patients undergoing hematopoietic stem cell transplantation. We performed a systematic review and meta-analysis of the literature on the effect of anticoagulation in preventing veno-occlusive disease. Several databases and online journals were searched for randomized controlled trials and cohort studies. Twelve studies (2782 patients) were eligible. Anticoagulation prophylaxis was associated with a statistically nonsignificant decrease in risk of veno-occlusive disease (pooled relative risk (RR), 0.90; 95% confidence interval (CI), 0.62-1.29). Results of one of three randomized controlled trials may have been affected by delayed introduction of anticoagulation. A second trial enrolled patients who received conventional chemoradiotherapy for early-stage disease (RR, 0.18; 95% CI, 0.04-0.78). The third trial was a pilot study with a small sample size (RR, 0.74; 95% CI, 0.53-1.04). Significant heterogeneity and methodologic weaknesses preclude drawing a meaningful conclusion from the pooled analysis. Despite some limitations, results of two of three eligible randomized controlled trials suggest that prophylactic anticoagulation may help prevent veno-occlusive disease. However, a large randomized controlled trial is needed for confirmation. Additionally, in future studies, owing to the wide spectrum of severity of veno-occlusive disease, outcomes such as 100-day mortality should strongly be considered.

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.

Platelet Transfusion Containing ABO-Incompatible Plasma and Hepatic Veno-occlusive Disease after Hematopoietic Transplantation in Young Children

Hepatic veno-occlusive disease is a major limiting factor of high-dose chemotherapy in children. The cells lining the hepatic vascular endothelium express blood group A and/or B antigens according to the patient's blood group. We designed a study evaluating the impact of platelet concentrates containing ABO-incompatible plasma transfused to young children with a high risk of hepatic veno-occlusive disease. In all, 186 consecutive children (median age: 4 years, range: 0.75-17 years), treated with high-dose chemotherapy containing busulfan followed by hematopoietic stem cell transplantation for neuroblastoma (n=112) or brain tumor (n=74) between 1988 and 1998, were investigated. The main endpoint was the occurrence of hepatic veno-occlusive disease. Multivariate analysis was performed using a Cox's regression model with transfusion of platelet concentrates containing ABO-incompatible plasma as a time-dependent covariate. We found that 73 out of 186 (39%) children developed hepatic veno-occlusive disease after transplantation. Multivariate analysis demonstrated that two factors significantly increased the risk of hepatic veno-occlusive disease occurrence: transfusion of platelet concentrates containing ABO-incompatible plasma (P=0.003) and use of melphalan in the conditioning regimen (P=0.006). Conversely, the number of platelet concentrates transfusions per week, child's age, weight, sex, and use of cyclophosphamide in the conditioning regimen had no effect. Transfusion of platelet concentrates containing ABO-incompatible plasma increases the risk of hepatic veno-occlusive disease in young children treated with a busulfan-containing regimen. Binding of A and/or B antigens expressed on the surface of hepatic endothelial cells may promote this complication. Transfusion of platelet concentrates containing ABO-incompatible plasma should be avoided in these children.

Gemtuzumab ozogamicin: increased risk of hepatic veno-occlusive disease

Gemtuzumab ozogamicin: increased risk of hepatic veno-occlusive disease

Plasma concentration monitoring of busulfan: does it improve clinical outcome?

High dosage busulfan (1 mg/kg orally every 6 hours x 16 doses) is frequently used in preparative regimens for haemopoietic stem cell transplantation (HSCT). Busulfan is well absorbed after oral administration, exhibits low protein binding and is metabolised through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as area under the plasma concentration-time curve (AUC) or average concentration at steady state (Css). Relative to that in adolescents and adults, patients less than 4 years of age have an increased apparent oral clearance (CL/F) of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte. Several investigators have identified relationships between busulfan Css and outcome in patients undergoing HSCT. Busulfan concentration-response relationships are regimen-, age- and disease-dependent. The busulfan/cyclophosphamide (BU/CY) regimen is the only regimen for which substantial concentration-outcome data exist. Generally, the risk of hepatic veno-occlusive disease is increased with busulfan Css > 900 microg/L. The impact of busulfan Css on veno-occlusive disease may be influenced by the age of the patient and the dose of cyclophosphamide. Lower rates of relapse in chronic myelogenous leukaemia occur in patients with a busulfan Css > 917 microg/L without an increased risk of toxicity. Busulfan Css is also related to the engraftment rate in children, and escalating busulfan doses to achieve a target Css > 600 microg/L improves graft retention. Therapeutic drug monitoring of busulfan should be performed to maximise the likelihood of engraftment and minimise the risk of toxicity and relapse in HSCT patients receiving the BU/CY preparative regimen.

Intravenous immunoglobulin and the risk of hepatic veno-occlusive disease after bone marrow transplantation.

Recent reports using historical controls or registry cohorts suggest, respectively, either an increase in the mortality or a decrease in the incidence of hepatic veno-occlusive disease (VOD) with the administration of intravenous immunoglobulin (i.v.Ig) after bone marrow transplantation. These divergent results prompted us to conduct a retrospective analysis of two randomized clinical trials conducted at our center to determine the effect of i.v.Ig infusions on the development and severity of VOD. Patients were randomized to receive (n=318) or not to receive (n=315) i.v.Ig prophylaxis after human leukocyte antigen-identical sibling (n=414), mismatched or unrelated (n=178), or autologous or syngeneic (n=41) marrow transplantation. To determine the relationship of i.v.Ig to the development and severity of VOD, a single observer reviewed data displays created for each patient for grading VOD without knowledge of patient i.v.Ig use. In this analysis, VOD was defined as hyperbilirubinemia > or =2.0 mg/dL before day 20 and abrupt weight gain > or =2% before day 14 posttransplant in the absence of other causes of liver disease. Hepatic VOD developed in 235 (37%) of the 633 randomized patients. No evidence for VOD was found in 230 (36%) patients. The remaining 168 (27%) patients were classified as having liver disease of uncertain etiology. Hepatic VOD was judged to be severe in 63 (10%) and mild or moderate in 172 (27%) patients. The number of patients developing any VOD or severe VOD was similar between those randomized to i.v.Ig prophylaxis and untreated controls (115 vs. 120 and 32 vs. 31, respectively). Logistic regression models identified several covariates as significant (p < 0.01) factors associated with the development of severe VOD. Increased risk occurred with elevated pretransplant serum aspartate aminotransferase (odds ratio [OR] = 2.64) and earlier year of transplant (OR = 3.73); decreased risk occurred with autologous or twin donors (OR = 0.09) and acute myeloid leukemia (OR = 0.39). The development of any VOD was associated with an elevated pretransplant alkaline phosphatase (OR = 4.1), pretransplant use of vancomycin (OR = 1.6) or amphotericin (OR = 3.0), posttransplant use of cyclosporine (OR = 2.5), older patient age (OR = 1.03), and obesity (OR = 0.78). We concluded from the controlled trials of 633 patients that the administration of i.v.Ig did not influence the development or severity of VOD after bone marrow transplantation.