Naturally occurring anticoagulants and bone marrow transplantation: plasma protein C predicts the development of venocclusive disease of the liver

Venocclusive disease (VOD) of the liver is the major dose-limiting complication of pretransplant regimens for bone marrow transplantation. Recent reports from different groups point to the involvement of the hemostatic mechanism in the development of VOD. We measured the naturally occurring anticoagulants protein C, antithrombin III, and protein S in 45 patients undergoing bone marrow transplantation for hematologic malignancies before cytoreductive therapy and after transplant. The aim of this prospective study was both to evaluate the status of the naturally occurring anticoagulant pathway in patients who develop VOD compared with patients who do not, and to find a predictive marker of VOD. In transplant patients, protein C decreased from before cytoreductive therapy to posttransplant, whereas protein S and antithrombin III did not. In a multivariate analysis, protein C was the only variable that could independently discriminate between VOD and non- VOD patients at all times. Discriminant function analysis established that low protein C levels before cytoreductive therapy predicted the occurrence of VOD with good sensitivity and specificity.     

Hepatic veno-occlusive disease--liver toxicity syndrome after bone marrow transplantation.

Hepatic veno-occlusive disease (VOD) is the most common life threatening complication of preparative-regimen-related toxicity for bone marrow transplantation (BMT). The frequency of VOD varies greatly, from 1-2% in centers performing pediatric BMT for thalassemia to over 50% in some centers doing BMT for hematologic malignancy. The term liver toxicity syndrome is a clinicopathologic definition which encompasses the range of histopathology within the hepatic venules and surrounding sinusoids and hepatocytes. These histologic abnormalities are statistically associated with a clinical syndrome of jaundice, ascites, and painful hepatomegaly developing early post-transplant. Newer modalities which may aid accuracy are transvenous liver biopsy along with determination of the gradient between the wedged and free hepatic venous pressures, and measurement of blood coagulatory components, particularly protein C levels. Analyses of clinical risk factors for VOD are confounded by lack of a clear hierarchy of risk when comparing heterogeneous patient populations, the methods of patient selection and choice of controls, and whether analysis is univariate or multivariate. Prospective multivariate analyses indicate that the risk of developing liver toxicity is independently correlated with intensity of conditioning therapy, pre-transplant viral hepatitis, use of antimicrobial therapy with acyclovir, amphotericin, or vancomycin (reflecting fever), and mismatched or unrelated allogeneic marrow grafts. These analyses plus morphologic and biochemical data support the hypothesis that VOD is caused by cytoreductive injury to hepatocytes and endothelium in zone three of the liver acinus, and in turn strongly influenced by factors which induce the release of tumor necrosis factor-alpha (TNF-alpha) leading to enhancement or activation of coagulation with obstruction of hepatic sinusoids and venules. Pharmacokinetic measurements of busulfan as a conditioning agent demonstrate a correlation between high steady-state busulfan levels and liver toxicity and suggest that safer and/or more efficacious plasma busulfan concentrations can be obtained by making individual dose adjustments and by changing the schedule of administration. Conservative therapy of severe VOD, including the use of peritoneal-pleural shunts for relief of ascites, is unsatisfactory. Results from prophylactic studies aimed at preventing VOD by heparin or prostaglandin E1 indicate considerable differences with toxicity and efficacy. Use of the TNF-alpha blocker, pentoxifylline, has also shown promise in lessening VOD. A statistical model which predicts patients likely to have an unfavorable outcome from VOD has been used to select premorbid patients for promising new therapeutic modalities, such as recombinant tissue plasminogen activator.     

High-dose busulphan alone as cytoreduction before allogeneic or autologous stem cell transplantation for chronic myeloid leukaemia: a single-centre experience

Transplant-related morbidity and mortality remain a major problem following stem cell transplantation (SCT). The use of high-dose single-agent busulphan before allogeneic or autologous SCT may be a reasonable compromise between maintaining cytoreductive efficacy and minimizing toxicity in patients with chronic myeloid leukaemia (CML). Seventy patients with CML have received busulphan as the only cytoreductive therapy before SCT on 79 occasions. The probability of survival of the 14 allogeneic recipients (all of whom were undergoing a second transplant from the original donor) was 78% at 5 years. Sixty-five autologous SCT were performed in 56 patients, of whom 40 were in late chronic phase. The actuarial 3-year post-autograft survival was 54% for these 56 first autografts. For patients in chronic phase, the 3-year survival was 76% compared with 30% at 2 years for those with advanced phase disease. Busulphan therapy was well tolerated, and except for mild mucositis little toxicity was experienced. None of these patients developed hepatic veno-occlusive disease (VOD). Nine patients (one allogeneic and eight autologous recipients) received several doses of an intravenous formulation of busulphan with very low toxicity. High-dose busulphan alone appears sufficient to provide adequate cytoreduction and immunosuppression in second allogeneic transplants and is also effective as cytoreduction before autologous SCT in patients with CML.     

Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment

Hepatic veno-occlusive disease (HVOD) following bone marrow transplantation is potentially fatal. Criteria for diagnosis and starting treatment are mainly based on adult studies. Recombinant tissue plasminogen activator (rtPA) has been used with variable success. rtPA and heparin were given to 12 children (nine with immunodeficiency, two malignancy, one thalassaemia) with moderate to severe HVOD. Of the 12, 10 responded with a fall in bilirubin concentration; eight survived with complete resolution of HVOD. Four of the five patients with associated multiorgan failure (MOF) died despite rtPA treatment. One child suffered significant, and one minor, bleeding during rtPA treatment. A scoring system for quantifying the severity of HVOD in children is proposed, incorporating the criteria used to diagnose HVOD, risk factors for its development and also parameters reflective of the patient's general condition. This will facilitate early diagnosis and management of those cases which, if not treated promptly, are likely to deteriorate with an adverse outcome. Our experience suggests rtPA and heparin are an effective treatment for HVOD in children, with relatively little toxicity provided therapy is started before MOF develops.     

Incidence,survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients

The incidence, risk factors and mortality of veno-occlusive disease (VOD) were identified for 142 pediatric hematopoietic stem cell (HSC) transplant recipients with hematological malignancies (83), solid tumors (41) and nonmalignant diseases (18). This historical cohort of 142 HSC transplant patients, from January 1993 through June 2000, was assessed by chart review. Risk factors for the development of VOD and mortality were assessed by multiple logistic regression and Kaplan-Meier survival curves respectively. The incidence of VOD was 18.3% (26/142 transplants). Multivariate analysis reconfirmed the known pretransplant risk factors of induction therapy with busulfan and transplantation with matched unrelated donor cells as significant risk factors for the development of VOD. In addition, two new risk factors, positive CMV serology in the recipient and TPN provided in the 30 days prior to transplant, were identified. Mortality in transplant patients at 100 days was greater in the VOD-positive group (10/26 (38.5%)) compared to the VOD-negative group (11/116 (9.5%) (P=0.001)). The risk of death was 4.97 times higher with 95% CIs (2.11, 11.71) for the VOD-positive group. Decreasing the risk factors for VOD may decrease mortality in this patient population.     

前列腺素E脂质微球联合小剂量肝素及丹参预防60例异基因造血干细胞移植后肝静脉闭塞病

目的:探讨前列腺素E脂质微球联合小剂量肝素及复方丹参预防肝静脉闭塞病(VOD)的效果.方法:59例急、慢性白血病患者及1例T细胞淋巴瘤患者接受移植治疗.移植患者中3例曾有乙型肝炎病史,1例有轻度脂肪肝病史.移植前所有患者肝功能均正常.采用CyTBI加Ara-C/VP-16或改良BuCy2方案预处理.VOD预防方案:移植前8 d至移植后28 d,采用前列腺素E脂质微球(凯时)30～40vg/d联合小剂量肝素(100U/kg·d-1)及复方丹参30～40 ml/d,发生VOD后继续上述治疗,加用去纤苷10 mg/kg·d-1.结果:59例均获得植入,1例植入失败.2例出现重症VOD,其中1例为接受单倍型半相合外周血干细胞移植的复发ALL患者,1例患者有轻度脂肪肝,接受非血缘外周血干细胞移植.2例均采用较强的清髓性预处理方案,最终死于多脏器功能衰竭.结论:本研究采用的VOD预防方案,VOD发生率低于文献报道,提示前列腺素E脂质微球联合小剂量肝素及复方丹参方案对预防VOD的发生可能有一定效果.     

A comparison of clinical criteria for the diagnosis of veno-occlusive disease of the liver after bone marrow transplantation.

Two major studies have established clinical criteria for the diagnosis of veno-occlusive disease of the liver (VOD) after bone marrow transplantation (BMT). McDonald and co-workers defined VOD as the onset of two of the following occurring before day 30 post-BMT: (a) jaundice (bilirubin > 27 mmol/l), (b) tender hepatomegaly, and (c) ascites or weight gain. In contrast, Jones and co-workers defined VOD as the onset, before day 21 post-BMT, of hyperbilirubinemia (bilirubin > 34 mmol/l) as well as two of the following: (a) hepatomegaly, (b) ascites, and (c) weight gain. We retrospectively reviewed the occurrence of VOD in 101 patients transplanted primarily for hematologic malignancies between 1979 and 1990, applying both sets of criteria. Of the 101 patients, eight (7.9%) fulfilled the Jones criteria whereas 32 (31.7%) had VOD according to the McDonald criteria (p < 0.001). Early mortality (prior to 50 days post-BMT) was 75% (6/8) in patients who fulfilled the Jones criteria but only 28.1% (9/32) in the McDonald group (p < 0.005). Overall, mortality in each group was 75% (6/8) and 65.6% (21/32), respectively. All of the six patients with VOD according to the Jones criteria who died had evidence of hepatic failure. Of the 32 patients who fulfilled the McDonald criteria, eight have also fulfilled the Jones criteria and are described above. Of the remaining 24 patients, 22 had complete resolution of VOD as defined by these criteria within 50 days of BMT, none developed hepatic failure, and 15 died.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pilot trial of prophylactic ursodiol to decrease the incidence of veno-occlusive disease of the liver in allogeneic bone marrow transplant patients.

Ursodiol is a hydrophilic, non-hepatotoxic bile salt indicated for the medical treatment of cholesterol gallstones. This pilot study explored the use of prophylactic ursodiol in an attempt to decrease the incidence and severity of veno-occlusive disease (VOD) of the liver following allogeneic bone marrow transplantation (BMT). Between February 1991 and January 1992, 22 consecutive patients undergoing BMT for hematologic malignancies received the BU(4)/CY(2) preparative regimen and CSA/MTX for GVHD prophylaxis. Ursodiol, 600-900 mg daily by mouth was begun at least 1 day prior to beginning the preparative regimen. Results for this pilot group were compared to a control group of 28 consecutive patients transplanted between June 1989 and January 1991 with the same regimen without ursodiol. There were no significant differences in disease or clinical status between the groups pretransplant. However, mean baseline AST levels were significantly higher in the ursodiol group, 28.0 U/l vs 18.1 U/l in the control group (p = 0.001). The median maximum bilirubin observed post-transplant was 2.35 mg/dl (range 0.9-45) in the ursodiol group, and 5.05 mg/dl (range 0.7-29.4) in controls. The incidence of VOD was 2/22 (9.1%) in the ursodiol group and 18/28 (64.3%) in controls (p = 0.0001). Death due to VOD occurred in 1/22 patients (4.5%) in the ursodiol group and in 6/28 (21.4%) controls (p = 0.12). Our data suggest that ursodiol may decrease the incidence of VOD in allogeneic BMT patients.     

Risk factors for hepatic veno-occlusive disease after high-dose busulfan-containing regimens followed by autologous bone marrow transplantation: a study in 136 children.

Risk factors for hepatic veno-occlusive disease (HVOD) were analysed in a population of 136 autografted children who received high-dose busulfan (BU) as part of a conditioning regimen. HVOD was diagnosed according to McDonald's clinical criteria. The incidence of HVOD was particularly high in this series (22%) compared with series with other conditioning regimens but the outcome was favorable in 26 patients (87%). Four deaths occurred (13%), one of which was HVOD related. The clinical presentation of HVOD was similar to that described in previous reports. Although statistical analysis failed to demonstrate any factors predictive of outcome, it did identify risk factors for the occurrence of HVOD: these were (1) a total dose of BU exceeding the standard 16 mg/kg dose; (2) the use of three as opposed to two alkylating agents; (3) the sequence of BU administration when given in the conditioning regimen containing three alkylating agents; and (4) concomitant ketoconazole therapy.     

A randomized trial of heparin plus ursodiol vs. heparin alone to prevent hepatic veno-occlusive disease after hematopoietic stem cell transplantation

Hepatic veno-occlusive disease (VOD) is a common and serious regimen-related toxicity after hematopoietic stem cell transplantation (HSCT). There is no safe and proven therapy for established VOD, and focus has been on its prevention. Previous studies have shown that a continuous infusion of unfractionated heparin or ursodiol may reduce the incidence of VOD. In order to compare the efficacy of heparin plus ursodiol with that of heparin alone, we conducted a prospective, randomized study involving 165 consecutive patients who underwent HSCT for a variety of disorders. Eighty-two patients were assigned to receive heparin plus ursodiol, and 83 were assigned to receive heparin alone. Thirteen and 16 patients were diagnosed as having VOD in the heparin plus ursodiol group and the heparin alone group, respectively (15.9% vs 19.3%; P = 0.348). Eighty-nine percent of the heparin plus ursodiol group and 89.2% of the heparin alone group were surviving at day 100 post-HSCT (P = 0.298). The only independent variable associated with an increased risk of VOD was an allogeneic type of HSCT (P = 0.018). In conclusion, this study shows that there is no difference in efficacy between heparin plus ursodiol and heparin alone for the prevention of hepatic VOD.     

Improved results of allogeneic bone marrow transplantation for advanced hematologic malignancy using busulfan, cyclophosphamide and etoposide as cytoreductive and immunosuppressive therapy.

Twenty-four patients between the ages of 8 and 48 years (median 27.5) with high-risk for relapse hematologic malignancy received a marrow transplant from an HLA and MLC compatible sibling donor after chemotherapy with busulfan, 4 mg/kg/day for 4 days by mouth, cyclophosphamide 60 mg/kg/day i.v. for 2 days, and etoposide 60 mg/kg i.v. over 4 h on the first day of cyclophosphamide treatment (BU/CY/VP). Toxicity consisted of mucositis, skin rash, and nausea and vomiting in all patients, transient fever thought to be due to etoposide administration in 16/24 (67%) patients, and clinical veno-occlusive disease (VOD) of the liver in 4/24 (17%). There were nine deaths from causes other than recurrent disease in the first 100 days after transplant and two deaths after day 100, a total transplant mortality of 11/24 (46%). Three patients relapsed, but 10/24 (40%) remain alive and disease free 26-182 weeks (median 60 weeks) from transplant. These results compare favorably with results in a group of 12 similar risk patients treated with total body irradiation (TBI) containing regimens during an overlapping time period. Six of the TBI patients have had persistent or recurrent disease and only two (17%) are currently alive and disease free. The probability of disease persistence or relapse is 67% in the TBI group and 20% in the BU/CY/VP group (p less than 0.02).     

Use of prostaglandin E1 for prevention of liver veno-occlusive disease in leukaemic patients treated by allogeneic bone marrow transplantation

Prostaglandin E1 (PGE₁) was used to prevent veno-occlusive disease (VOD) of the liver after allogeneic bone marrow transplantation (BMT) for leukaemia. It was given in continuous i.v. infusion from day – 8 to day 30 after BMT at a dose of 0.3 μg/kg/h. The patients were studied according to the risk factors for VOD: diagnosis, intensification of the conditioning and previous liver abnormalities. The diagnosis of VOD was made on at least two of the following factors: weight gain, hepatomegaly, jaundice, ascitis, pain of the right upper quadrant, increased platelet consumption. 109 patients were studied, 50 were treated by PGE₁ and 59 did not receive it. The actuarial incidence of VOD was 12.2% in the PGE₁ group and 25.5% in the non PGE₁ group ( P =0.05). In acute leukaemia, the incidence was 39.1% in the non-treated group and 12.8% in the PGE₁ treated group (P=0.02). Patients with previous hepatitis had an incidence of 62.5% in the non treated group and 15.5% in the treated group ( P =0.05). A positive cytomegalovirus (CMV) serology seemed to increase the risk of VOD: the incidence of VOD was 31.4% in non-treated patients and 22% in PGE₁ treated patients. The multivariate analysis of the risk factors for VOD shows that unfavourable factors were: recipient positive CMV serology ( P =0.06), hepatic disease prior to transplant ( P =0.02) and the absence of PGE₁ treatment ( P =0.02). This study suggests that prophylactic PGE₁ treatment may decrease the incidence of VOD in patients treated for leukaemia by allogeneic bone marrow transplantation.     

Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study

Severe hepatic veno-occlusive disease (VOD) is a recognized complication of autologous and allogeneic stem cell transplantation (SCT) that is often fatal. Defibrotide (DF) is a polydeoxyribonucleotide that has been found to have anti-thrombotic, anti-ischaemic and thrombolytic properties without causing significant anticoagulation. Preliminary studies have demonstrated activity for DF in the treatment of VOD, with minimal associated toxicity. In the present study, 40 patients who fulfilled established criteria for VOD were treated with DF on compassionate grounds in 19 European centres; 28 patients met risk criteria predicting progression of VOD and fatality or had evidence of multiorgan failure (MOF), and were defined as 'poor-risk'. DF was commenced intravenously at a median of 14 d (range, -2 d to 53 d) post SCT at doses ranging from 10 to 40 mg/kg. The median duration of therapy was 18 d (range, 2--71 d). Twenty-two patients showed a complete response (CR) (bilirubin < 34.2 micromol/l and resolution of signs/symptoms of VOD and end-organ dysfunction) [CR = 55%, confidence interval (CI) 40--70%] and 17 patients (43%) are alive beyond d +100. Ten poor-risk patients showed a complete response (CR = 36%, CI 21--51%). These results demonstrate that DF is an active treatment for VOD following SCT and a randomized trial is now underway in order to further evaluate its role.     

17例肝小静脉闭塞病患者的诊断和治疗

目的 总结肝小静脉闭塞病(HVOD)的诊断和治疗方法.方法 回顾性分析17例肝小静脉闭塞病的临床和病理资料. 结果根据影像学检查结果和临床及病理学资料,将肝小静脉闭塞病分为急性进展型和慢性型.其中急性进展型11例,经内科保守治疗,5例临床治愈,2例好转,2例死亡,手术治疗2例死亡,慢性型6例,经内科保守治疗1例,手术治疗5例,均达到临床治愈.结论 病理活组织检查是确诊肝小静脉闭塞病的有效方法.急性进展型的肝小静脉闭塞病宜内科保守治疗,慢性型在内科治疗无效的情况下可行手术治疗.     

Charcoal hemofiltration for hepatic veno-occlusive disease after hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (HVOD) after hematopoietic stem cell transplantation (HSCT) results in considerable morbidity and mortality. No therapy has been shown to be uniformly effective. Several studies have highlighted the pivotal role of endothelial injury and the hemostatic system in the pathogenesis of HVOD. Charcoal hemofiltration has been shown to be effective for adsorbing circulating bilirubin and other protein-bound toxins and for supporting patients in hepatic failure. We describe two adult patients with severe, biopsy-proven HVOD (peak bilirubin levels, more than 50 mg/dl in both cases) after HSCT who were successfully treated with charcoal hemofiltration after other treatments failed (including defibrotide in one patient). Both patients were heavily treated before they underwent either autologous (melphalan and total body irradiation conditioning) or allogeneic (cyclophosphamide and total body irradiation conditioning) HSCT. Additional studies are warranted to confirm this preliminary observation and investigate the mechanism of action.     

Recombinant human tissue plasminogen activator for the treatment of established severe venocclusive disease of the liver after bone marrow transplantation.

Seven patients were treated with recombinant human tissue plasminogen activator (tPA) for severe hepatic venocclusive disease (VOD) that developed after bone marrow transplantation for hematologic malignancy. Recombinant human tPA (10 mg/d x 2 days) and heparin (1,000 U bolus followed by continuous intravenous infusion of 150 U/kg/d x 10 days) were begun a median of 9 days (range, 4 to 18 days) posttransplant. The median total serum bilirubin and percent weight gain from baseline were 19.4 mg/dL (range, 14.6 to 34.9 mg/dL) and 9.1% (range, 1% to 18.5%), respectively, at the start of tPA administration. Five patients responded to therapy with prompt reduction in total serum bilirubin within 96 hours of starting tPA. Three patients are alive 178 to 379 days posttransplant without evidence of VOD. No patient had significant hemorrhagic complications with tPA. We conclude that recombinant human tPA can be administered to patients with severe VOD at the dosage described. Whereas preliminary data suggests that recombinant human tPA can alter the natural history of severe VOD, further study is necessary to determine its efficacy.     

Serum hyaluronic acid in patients with veno-occlusive disease following bone marrow transplantation

The development of hepatic veno-occlusive disease following bone marrow transplantation is associated with high-dose combination cytoreductive therapy. Experimental models have suggested that drug-induced injury to hepatic sinusoidal endothelial cells is involved in the pathogenesis of this syndrome. Hyaluronic acid is a polysaccharide that is metabolized, almost exclusively, by hepatic sinusoidal endothelial cells. The aim of the present study was to evaluate serum hyaluronic acid as a marker for endothelial cell injury in patients with veno-occlusive disease following bone marrow transplantation. Hyaluronic acid was measured in sera from patients with and without veno-occlusive disease using an enzyme-linked protein binding assay. Mean peak serum hyaluronic acid levels were significantly greater in patients who had a diagnosis of VOD compared to those transplant patients who did not, 1173.4 +/- 982.9 vs 444.9 +/- 735.6 ng/ml (P = 0.01). Serial serum samples obtained from a separate cohort of patients also demonstrated that serum hyaluronic acid levels were higher in patients with moderate or severe veno-occlusive disease compared to those with none or mild disease at days 7, 17 and 25 following transplantation (greatest difference at day 25: 366 +/- 327 vs 126 +/- 151, P = 0.01). Serum hyaluronic acid levels are increased in veno-occlusive disease and increase over time in patients with severe disease. Further studies are required to determine if elevated serum hyaluronic acid levels are due to decreased clearance by injured hepatic sinusoidal endothelial cells or increased production from early hepatic fibrogenesis associated with the acute liver injury.     

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 M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation

Hepatic venoocclusive disease (HVOD) in bone marrow transplantation (BMT) is attributed to toxicity of cytoreductive agents, especially busulfan and cyclophosphamide, in the conditioning therapy. Busulfan, as well as the metabolites of cyclophosphamide, are conjugated with glutathione (GSH), catalyzed by enzymes of the glutathione S-transferase (GST) family. To assess the impact of polymorphisms of the GST genes, GSTM1 and GSTT1, on the risk of HVOD, we evaluated 114 consecutive patients with beta-thalassemia major undergoing BMT. There was a significantly increased incidence of HVOD in patients with the GSTM1-null genotype compared with those with the GSTM1-positive genotype (46.5% vs 18.3%; P =.001). Pharmacokinetic analysis in these patients showed that the clearance of busulfan was higher and first-dose steady-state concentration was lower among those with HVOD (0.403 +/- 0.06 vs 0.33 +/- 0.071 L/h/kg, Student t test P value =.000 01; and 508 +/- 125 vs 656 +/- 255 ng/mL, t test P value =.001, respectively). We conclude that the GSTM1-null genotype predisposes to HVOD, and the sinusoidal endothelial cells and hepatocyte damage may be mediated by metabolites of busulfan through depletion of the cellular GSH pool.     

Cytomegalovirus seroconversion in patients receiving intensive induction therapy prior to allogeneic bone marrow transplantation

Cytomegalovirus (CMV) seropositivity in recipients of an allogeneic bone marrow transplant (BMT) is a major risk factor for development of post-transplant CMV infection. CMV serology was assessed in 98 patients during intensive chemotherapy for haematological malignancy prior to allogeneic BMT. Thirty-seven patients eventually received a BMT; the remaining 61 patients were treated with chemotherapy alone. The proportion of seropositive patients in the BMT group increased from 36% to 48% between presentation and transplantation. This represents an increase in recipient seropositivity of 33% as a direct result of pre-transplant therapy. Mean time to seroconversion was 186 days. Seropositivity in patients receiving chemotherapy only increased from 43% to 56% during treatment and follow-up. The most likely source of the CMV acquired by these patients is CMV-infected blood products. We suggest that, wherever possible, CMV-negative blood products should be used exclusively from presentation to support all patients receiving chemotherapy in whom BMT is a therapeutic option.