Ursodiol Prophylaxis against Hepatic Complications of Allogeneic Bone Marrow Transplantation

A Randomized, Double-Blind, Placebo-Controlled Trial

  1. James H. Essell, MD;
  2. Mark T. Schroeder, MD;
  3. Glenn S. Harman, MD;
  4. Ronald Halvorson, MD;
  5. Vernon Lew, RPh;
  6. Natalie Callander, MD;
  7. Michael Snyder, MD;
  8. Stacey K. Lewis, MD;
  9. Jeffrey P. Allerton, MD; and
  10. James M. Thompson, DO
  1. From Wilford Hall Medical Center, Lackland Air Force Base, Texas. Disclaimer: The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Department of Defense or other Departments of the U.S. Government. Grant Support: Summit Pharmaceuticals supplied the study drug and placebo. No financial assistance was provided. Requests for Reprints: James H. Essell, MD, Oncology-Hematology Care, Inc., 199 William H. Taft Road, Cincinnati, OH 45219. Current Author Addresses: Dr. Essell: Oncology-Hematology Care, Inc., 199 William H. Taft Road, Cincinnati, OH 45219.
     
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    Abstract

    Background: Hepatic complications are a major cause of illness and death after bone marrow transplantation.

    Objective: To confirm the results of a pilot study that indicated that ursodiol prophylaxis could reduce the incidence of veno-occlusive disease of the liver.

    Design: Randomized, double-blind, placebo-controlled study.

    Setting: Tertiary care teaching hospital.

    Patients: 67 consecutive patients undergoing transplantation with allogeneic bone marrow (donated by a relative) in whom busulfan plus cyclophosphamide was used as the preparative regimen and cyclosporine plus methotrexate was used to prevent graft-versus-host disease.

    Intervention: Before the preparative regimen was started, patients were randomly assigned to receive ursodiol, 300 mg twice daily (or 300 mg in the morning and 600 mg in the evening if body weight was > 90 kg), or placebo.

    Measurements: Patients were prospectively evaluated for the clinical diagnosis of veno-occlusive disease, the occurrence of acute graft-versus-host disease, and survival.

    Results: The incidence of veno-occlusive disease was 40% (13 of 32 patients) in placebo recipients and 15% (5 of 34 patients) in ursodiol recipients (P = 0.03). Assignment to placebo was the only pretransplantation characteristic that predicted the development of veno-occlusive disease. The most significant predictor of 100-day mortality was the diagnosis of veno-occlusive disease. The difference in actuarial risk for hematologic relapse in patients with chronic myelogenous leukemia and nonhepatic toxicities between the two groups was not statistically significant (13% in the ursodiol group and 20% in the placebo group; P > 0.2).

    Conclusion: Ursodiol prophylaxis seemed to decrease the incidence of hepatic complications after allogeneic bone marrow transplantation in patients who received a preparative regimen with busulfan plus cyclophosphamide.

    Veno-occlusive disease of the liver is a common regimen-related toxicity in patients undergoing allogeneic bone marrow transplantation [1-4]. The risk for developing veno-occlusive disease after bone marrow transplantation depends on many factors, including a history of liver disease, elevated liver enzyme levels before bone marrow transplantation, conditioning regimen, patient age, presence of acute graft-versus-host disease, and type of prophylaxis against graft-versus-host disease [1-5]. No safe, proven therapy for established veno-occlusive disease has been developed. Prophylactic regimens involving heparin or prostaglandin E1 have met with mixed success [6-9].

    Ursodiol is a naturally occurring hydrophilic bile salt that makes up 1% of the total bile salt pool in humans [10-12] and has shown efficacy in the treatment of some hepatic disorders [13-15]. Because it is relatively nontoxic and inexpensive (average wholesale price of 600 mg/d for 90 days is $408.00) [16], ursodiol would be an attractive prophylactic agent if its efficacy could be demonstrated. We did a randomized, double-blind, placebo-controlled study to confirm the reduction in hepatic complications seen with ursodiol prophylaxis in a pilot trial [17].

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    Methods

    All patients entered into our study gave written informed consent. The Wilford Hall Medical Center Institutional Review Board reviewed and approved the protocol and the informed consent document.

    Eligibility and Randomization

    The study was open to enrollment between 24 February 1992 and 4 August 1994. Eligibility criteria included imminent transplantation with allogeneic bone marrow from a related donor and a preparative regimen with busulfan plus cyclophosphamide. Exclusion criteria were impaired creatinine clearance (<50 mL/min), pregnancy, lactation, failure to give informed consent, and allergy to bile acids.

    At the start of the study, equal numbers of cards labeled “ursodiol” and “placebo” were placed individually in opaque envelopes that were then sealed. These envelopes were randomized and given consecutive numbers. At registration, each patient received the next envelope. The pharmacist unsealed the envelopes, distributed the study drug, and maintained a blinded record of the assignment. The pharmacist was not involved in the clinical care of patients or in the determination of veno-occlusive disease. The study was unblinded 45 days after the final patient underwent transplantation.

    Administration of Study Drug

    Patients received identical-appearing capsules that contained ursodiol, 300 mg, or placebo. Patients weighing less than 90 kg received one capsule twice daily. Those weighing more than 90 kg received one capsule each morning and two capsules each evening. The ursodiol dose was derived from Podda and colleagues' data for patients with primary biliary cirrhosis and chronic hepatitis [18]. Administration of the study drug was started before the preparative regimen and was continued until 80 days after transplantation. If mucositis prohibited the swallowing of capsules, the powders from the study drug capsules were mixed with soft food for administration. The powders for ursodiol and placebo were identical in appearance.

    Preparative Regimen

    All patients received preparation with busulfan plus cyclophosphamide, as described by Tutschka and colleagues [19]. Four patients with multiple myeloma (two in the ursodiol group and two in the placebo group) received busulfan, 0.75 to 0.875 mg/kg of body weight every 6 hours for 4 consecutive days [20]. Dosages were based on actual body weight. For patients weighing more than 120% of ideal body weight, dosages were based on adjusted actual body weight, as described elsewhere [17].

    Prophylaxis against Graft-versus-Host Disease

    All patients received a 96-hour infusion of cyclosporine, 5 mg/kg per day, starting on the day before transplantation. Thereafter, the dose was adjusted to maintain a level in the range of 200 to 400 ng/mL. For patients without graft-versus-host disease, the cyclosporine dose was slowly tapered and therapy was discontinued 180 days after transplantation. All patients were scheduled to receive methotrexate, 10 mg/m2 intravenously, 1, 3, and 6 days after transplantation [21]. Methotrexate doses were maintained if the serum bilirubin level exceeded 34.21 µmol/L or if the serum creatinine level was greater than 176.80 µmol/L [5].

    Supportive Therapy

    Seventeen patients (7 ursodiol recipients and 10 placebo recipients) were isolated in laminar air-flow rooms. The remaining 50 patients were treated in private rooms with hepafiltration systems. All patients except those with myelogenous leukemia or myelodysplasia received filgrastim. The first 5 patients in the protocol did not receive antibiotic prophylaxis with quinolone; all others received ciprofloxacin or ofloxin. Patients received prophylaxis with intravenous immunoglobulin, trimethoprim-sulfamethoxazole, and acyclovir, as described elsewhere [17]. Only patients who developed grade II to IV acute graft-versus-host disease received specific ganciclovir prophylaxis against cytomegalovirus [22]. Fungal prophylaxis was limited to oral clotrimazole; prophylaxis with fluconazole or amphotericin was not used.

    Data Collection

    For each patient, a history, physical examination, and laboratory studies were done daily while the patient was an inpatient and as clinically indicated while the patient was an outpatient (not less than weekly until 100 days after transplantation). Patients with hepatic dysfunction had abdominal ultrasonography to screen for structural abnormalities of the hepatobiliary system and ascites. Veno-occlusive disease was considered possible when at least two of the following conditions occurred concomitantly within 30 days after transplantation: jaundice (bilirubin level > 51.31 µmol/L), painful hepatomegaly, and fluid accumulation evidenced by ascites or unexplained weight gain (>5% above baseline weight). The staff transplantation physicians, who were blinded to study group assignment, prospectively diagnosed veno-occlusive disease when these criteria were met and when no other clinically evident problem (such as heart failure, primary renal failure, sepsis, or drug toxicity) explained the abnormalities. Acute graft-versus-host disease was assessed according to the grading system described in the literature [23]. All surviving patients have been followed for at least 1 year.

    Statistical Analysis

    The primary end point was the diagnosis of veno-occlusive disease. Secondary end points included overall survival and the incidence of hepatic graft-versus-host disease. In the pilot study, the incidence of veno-occlusive disease in the control group was 64% [17]. On the basis of this incidence, the current study was sized so that at an α level of 0.05, there would be at least an 80% chance (β = 0.20) of detecting an absolute reduction in the incidence of veno-occlusive disease of 35% between the groups. The required sample size per group according to binomial sample-size formulas was 34.

    We compared categorical variables by using the Fisher exact test, and we compared continuous variables by using the Student t-test. We used Kaplan-Meier methods to estimate survival probabilities and used the log-rank test to compare these probabilities [24].

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    Results

    During this study, 80 patients underwent allogeneic bone marrow transplantation at Wilford Hall Medical Center, lackland Air Force Base, Texas. Thirteen patients were ineligible because they received preparative regimens other than busulfan plus cyclophosphamide. The remaining 67 patients were randomly assigned (35 to the ursodiol group and 32 to the placebo group). The patient characteristics of the two groups (Table 1) were similar except for diagnosis and donor-recipient ABO mismatches. All 67 patients received transplants from an HLA-identical or single-antigen-mismatched relative. No patient had an active systemic fungal infection within a week of starting the preparative regimen or was receiving therapeutic vancomycin, acyclovir, or amphotericin B when the preparative regimen was started. All patients had a bilirubin level less than 34.21 µmol/L before initiation of the preparative regimen. The patients with chronic myelogenous leukemia in the first chronic phase had transplantation within 1 year of diagnosis; none had received busulfan before transplantation. One patient in the placebo group withdrew from the trial 2 days after transplantation; all others continued to receive the study drug until death or 80 days after transplantation. Early hyperbilirubinemia (bilirubin level > 34.21 µmol/L within 6 days after transplantation) resulted in truncated methotrexate courses in 6 placebo recipients and 1 ursodiol recipient (P = 0.048).

    View this table:
    Table 1. Patient Characteristics

    The incidence of veno-occlusive disease was lower in the ursodiol group than in the placebo group (5 of 34 patients compared with 13 of 32 patients; P = 0.03). Individual clinical variables used to diagnose veno-occlusive disease are shown in Table 2. Compared with the placebo group, the ursodiol group tended to have lower bilirubin levels, fewer cases of ascites, and less painful hepatomegaly. To assess the differences in bilirubin level and weight as a function of time, a one-way analysis of variance was done on even-numbered days between 4 days before transplantation and 24 days after transplantation. Patients in the ursodiol group had significantly lower mean bilirubin levels from days 4 through 16 after transplantation. Mean daily weights did not differ significantly between the two groups.

    View this table:
    Table 2. Study Findings

    The statistical analysis of the relation of the incidence of veno-occlusive disease and ursodiol use, controlling for initial diagnosis (chronic myelogenous leukemia compared with other diagnoses), showed that the relation was consistent and significant across both strata. The pooled Mantel-Haenszel odds ratio estimate showed that in the placebo group, the relative risk for veno-occlusive disease was 2.57 (95% CI, 1.08 to 6.10) compared with the ursodiol group. The estimated odds ratios based on the initial diagnosis did not significantly differ between groups.

    Of the 18 patients in whom veno-occlusive disease was diagnosed (5 in the ursodiol group and 13 in the placebo group), 17 met all three clinical criteria for veno-occlusive disease. The 1 patient who met only two diagnostic criteria had a total bilirubin level greater than 51.31 µmol/L, weight gain of 4% from baseline, and painful hepatomegaly. In all 18 patients, veno-occlusive disease was diagnosed before day 21; 16 patients had a total bilirubin level greater than 51.31 µmol/L within 14 days after transplantation. Fourteen of the 18 patients in whom veno-occlusive disease was diagnosed (78%) died by day 100 compared with 7 of the 49 patients (14%) in whom the disease was not diagnosed (P < 0.001). In the ursodiol group, nonbilirubin criteria for veno-occlusive disease were uncommon in patients without this diagnosis: None had ascites, 1 had painful hepatomegaly, and 7 had weight gain greater than 5% from baseline. Two patients met two of three criteria for veno-occlusive disease but did not prospectively receive this diagnosis. One (ursodiol group) of these 2 patients developed hyperbilirubinemia with painful hepatomegaly and died of sepsis 21 days after transplantation. These abnormalities were prospectively coded as cholangitis lenta. Autopsy did not show hepatic findings consistent with veno-occlusive disease. The other patient had weight gain associated with renal failure and nonpainful hepatomegaly that resolved after treatment of sepsis.

    The strongest predictor of 100-day survival was the diagnosis of veno-occlusive disease. As shown in the Figure 1, 100-day survival rates in the ursodiol group seemed to improve. The diagnosis of chronic myelogenous leukemia was associated with favorable 100-day survival rates (85% compared with 59% for other diagnoses; P = 0.03).

    Figure 1. Survival rate at 100 days was 0.77 for patients receiving ursodiol and 0.59 for those receiving placebo ( = 0.19).
    View larger version:
      Figure 1. Survival rate at 100 days was 0.77 for patients receiving ursodiol and 0.59 for those receiving placebo ( = 0.19). Survival rates.P

      In our study, chronic myelogenous leukemia in the first chronic phase was the most common disease. During a mean follow-up of 42 months, the actuarial 3-year rate of hematologic relapse for these patients did not significantly differ between the two groups (13% in the ursodiol group and 20% in the placebo group; P > 0.2).

      Table 2 shows other toxic events that occurred after transplantation. The ursodiol group showed a trend toward a decreased incidence of overall graft-versus-host disease but not of graft-versus-host disease of the liver. After ursodiol therapy was discontinued 80 days after transplantation, liver enzyme levels did not significantly increase and cyclosporine levels did not change. Severity of mucositis and incidence of severe renal toxicity were similar in placebo and ursodiol recipients. No meaningful difference in antibiotic requirements or documented infections was noted between the groups. We found no adverse effects attributable to ursodiol.

      The causes of death among patients who died within 100 days after transplantation are shown in Table 2. In the ursodiol group, fewer deaths were attributed to veno-occlusive disease; otherwise, the causes of death were similar in the two groups.

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      Discussion

      Our study provides evidence that prophylaxis with ursodiol reduces hepatic complications after allogeneic bone marrow transplantation. Hepatic dysfunction was attributed to veno-occlusive disease on the basis of clinical criteria that reflect common practice; 94% of patients in whom veno-occlusive disease was diagnosed met all three clinical criteria. The specificity of the clinical diagnosis of veno-occlusive disease is generally poor. However, a 90% correlation between the presence of all three clinical criteria and histologic findings on liver biopsy has been reported [25]. The observed 22% survival rate 100 days after transplantation in patients with a diagnosis of veno-occlusive disease is consistent with a severe hepatic disorder, such as veno-occlusive disease; it is inconsistent with steatosis, drug toxicity, cyclosporine toxicity, or hemolysis from an ABO-mismatched graft [26, 27]. Cholangitis lenta and acute graft-versus-host disease are potentially morbid conditions with hepatic manifestations. The equivalence between the two ursodiol and placebo groups in infectious complications, deaths attributed to infections, incidence of hepatic graft-versus-host disease, and deaths from graft-versus-host disease suggests that the decrease in the incidence of veno-occlusive disease in the ursodiol group was not solely related to reallocation of nonspecific liver toxicity. The lower incidence of ascites, painful hepatomegaly, and weight gain in the ursodiol group suggests that an ursodiol-induced decrease in bilirubin levels was not the only reason for the decrease in the incidence of veno-occlusive disease.

      The International Bone Marrow Transplant Registry has reported that busulfan-containing preparative regimens, omission of intravenous immunoglobulin therapy, Karnofsky performance status score less than 90%, fungal infections within 1 week of beginning transplantation, previous liver disease, and age older than 20 years are independent risk factors for veno-occlusive disease. Neither the diagnosis of chronic myelogenous leukemia nor the presence of an ABO donor-recipient mismatch was found to be a risk factor [28]. Our analysis indicated that only assignment to placebo was predictive of veno-occlusive disease. Increased pharmacologic levels of busulfan, as measured by the area under the concentration-versus-time curve, have been correlated with an increased risk [29]. Twenty-one patients in this trial were also enrolled in a concurrent trial of busulfan pharmacokinetics: The distribution, clearance, and area under the curve were not affected by ursodiol administration [30]. These pharmacokinetics data, the similar intensity of mucositis in the two groups, and the equivalent relapse rate in the two groups for patients with chronic myelogenous leukemia in the first chronic phase all suggest a similarly intensive preparative regimen in both groups.

      The incidence of veno-occlusive disease in the placebo group is within the range reported elsewhere but is higher than the incidence reported in many series [27]. Nevertheless, the 59% incidence of a maximum bilirubin level greater than 51.31 µmol/L and the 50% incidence of weight gain greater than 5% in the placebo group of our trial are similar to the 54% and 53% respective rates seen in the busulfan-cyclophosphamide group of a recently reported trial from the Seattle group [31].

      The mechanism by which ursodiol may reduce post-transplantation hepatic complications is not clear. Although the exact pathogenesis of veno-occlusive disease is unknown, endothelial damage is an early event; damage to zone 3 hepatocytes is also pivotal. The damage to hepatocytes may result from cytoreductive agents or from ischemia caused by decreased sinusoidal blood flow [27]. For patients with primary biliary cirrhosis, the improvement in survival seen with ursodiol suggests an actual cytoprotective effect [15]. The mechanism of this effect is postulated to be a replacement of endogenous, toxic, hydrophobic bile acids in the liver with nontoxic, hydrophilic bile acids [32-35]. The increased stability of hepatocyte cell membranes in ursodiol-rich bile [36, 37] provides a hypothesis for the mechanism by which ursodiol could interrupt the pathogenesis of veno-occlusive disease. Theoretically, increased membrane stability could result in decreased hepatocyte necrosis from damage caused by high-dose alkylator therapy or ischemia. The effect of ursodiol on endothelial cell membranes has not been characterized.

      Our study had insufficient power to detect a difference in survival, and a statistically significant survival advantage was not seen with ursodiol. However, the reduction in hepatic complications attributed to veno-occlusive disease (the single strongest predictor of 100-day mortality) in the ursodiol group suggests that a larger study could show a survival advantage. The statistically nonsignificant relapse rate in the subgroup with chronic myelogenous leukemia and the lower rate of acute graft-versus-host disease in all patients indicate that substantial, long-term, ursodiol-related toxicities are unlikely.

      In our study, the prophylactic use of ursodiol reduced acute hepatic complications after allogeneic bone marrow transplantation in which a preparative regimen with busulfan plus cyclophosphamide was used. Administration of ursodiol does not seem to increase the risk for primary disease relapse or nonhepatic complications. Thus, ursodiol seems to be a potentially effective method of reducing regimen-related hepatotoxicity. The mechanism of ursodiol cytoprotection, the optimal ursodiol dosing, and the applicability of ursodiol to other preparative regimens require further elucidation.

      Dr. Thompson: Indiana Blood and Marrow Transplantation, 1633 North Capitol Avenue, Suite 300, Indianapolis, IN 46202.

      Drs. Schroeder, Lewis, and Allerton and Mr. Lew: 59 MDW, 2200 Bergquist Drive, Suite 1, Lackland Air Force Base, TX 78236-5300.

      Dr. Harman: Dubuque Internal Medicine, 1515 Delhi Street, Suite 100, Dubuque, IA 52001.

      Dr. Halvorson: Dakota Midwest Cancer Institute, 1000 East 21st Street, Suite 2000, Sioux Falls, SD 57105-1002.

      Dr. Callander: Division of Hematology, University of Texas Health Sciences Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7880.

      Dr. Snyder: Missoula Oncology and Infectious Disease, 615 West Alder, Missoula, MT 59802.

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      References

      1. 1.↵
        Bearman SI, Appelbaum FR, Buckner CD, Peterson FB, Fisher LD, Clift RA, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol. 1988; 6:1562-8.
      2. 2.↵
        Rollins BJ. Hepatic veno-occlusive disease. Am J Med. 1986; 81:297-306.
      3. 3.↵
        McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venoocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984; 4:116-22.
      4. 4.↵
        Atkinson K, Biggs J, Noble G, Ashby M, Concannon A, Dodds A. Preparative regimens for marrow transplantation containing busulfan are associated with haemorrhagic cystitis and hepatic veno-occlusive disease but a short duration of leucopenia and little oro-pharyngeal mucositis. Bone Marrow Transplant. 1987; 2:385-94.
      5. 5.↵
        Essell JH, Thompson JM, Harman GS, Halvorson RD, Snyder MJ, Johnson RA, et al. Marked increase in veno-occlusive disease of the liver associated with methotrexate use for graft-versus-host disease prophylaxis in patients receiving busulfan/cyclophosphamide. Blood. 1992; 79:2784-8.
      6. 6.↵
        Bearman SI, Shen DD, Hinds MS, Hill HA, McDonald GB. A phase I/II study of prostaglandin E1 for the prevention of hepatic veno-occlusive disease after bone marrow transplantation. Br J Haematol. 1993; 84:724-30.
      7. 7.↵
        Attal M, Huguet F, Rubie H, Huynh A, Charlet JP, Payen JL, et al. Prevention of hepatic veno-occlusive disease after bone marrow transplantation by continuous infusion of low-dose heparin: a prospective, randomized trial. Blood. 1992; 79:2834-40.
      8. 8.↵
        Gluckman E, Jolivet I, Scrobohaci ML, Devergie A, Trainequ R, Bourdeau-Esperou H, et al. Use of prostaglandin E1 for prevention of liver veno-occlusive disease in leukaemic patients treated by allogeneic bone marrow transplantation. Br J Haematol. 1990; 74:277-81.
      9. 9.↵
        Bearman SI, Hinds MS, Wolford JL, Peterson FB, Nugent DC, Slichter SJ, et al. A pilot study of continuous infusion heparin for the prevention of hepatic veno-occlusive disease after bone marrow transplantation. Bone Marrow Transplant. 1990; 5:407-11.
      10. 10.↵
        Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Ursodeoxycholic acid: a review of its pharmacological properties and therapeutic efficacy. Drugs. 1984; 27:95-131.
      11. 11.↵
        Bachrach WH, Hofmann AF. Ursodeoxcholic acid in the treatment of cholesterol cholilithiasis. Part I. Dig Dis Sci. 1982; 27:737-61.
      12. 12.↵
        Parquet M, Metman EH, Raizman A, Rambaud JC, Berthaux N, Infante R. Bioavailability, gastrointestinal transit, solubilization and faecal excretion of ursodeoxycholic acid in man. Eur J Clin Invest. 1985; 15:171-8.
      13. 13.↵
        Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med. 1991; 324:1548-54.
      14. 14.↵
        Combes B, Carithers RL Jr, Maddrey WC, Lin D, McDonald MF, Wheeler DE, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycolic acid in primary biliary cirrhosis. Hepatology. 1995; 22:759-66.
      15. 15.↵
        Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Dickson ER. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology. 1996; 110:1515-8.
      16. 16.↵
        Red Book. Montvale, NJ: Medical Economics; 1997.
      17. 17.↵
        Essell JH, Thompson JM, Harman GS, Halvorson RD, Snyder MJ, Callander NS, et al. Pilot trial of prophylactic ursodiol to decrease the incidence of veno-occlusive disease of the liver in allogeneic bone marrow transplant patients. Bone Marrow Transplant. 1992; 10:367-72.
      18. 18.↵
        Podda M, Ghezzi C, Battezzati PM, Bertolini E, Crosignani A, Petroni ML, et al. Effect of different doses of ursodeoxycholic acid in chronic liver disease. Dig Dis Sci. 1989; 34(12 Suppl):59S-65S.
      19. 19.↵
        Tutschka PJ, Copeland EA, Klein JP. Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood. 1987; 70:1382-8.
      20. 20.↵
        Raybon K, Thomas A, Schroeder M, Lewis S, Christman K, Wilks S, et al. Bone marrow transplantation in multiple myeloma with busulfan and cyclophosphamide: unacceptable toxicity with standard dose in heavily pretreated patients [Abstract]. Blood. 1995; 86(Suppl 1):961a.
      21. 21.↵
        Deeg JH, Spitzer TR, Cottler-Fox M, Cahill R, Pickle LW. Conditioning-related toxicity and acute graft-versus-host disease in patients given methotrexate/cyclosporine prophylaxis. Bone Marrow Transplant. 1991; 7:193-8.
      22. 22.↵
        Schroeder M, Essell J, Harman G, Halvorson R, Dolan M, Callander N, et al. Directed ganciclovir prophylaxis against cytomegalovirus pneumonitis in patients undergoing allogeneic bone marrow transplantation [Abstract]. Blood. 1993; 82(Suppl 1):425a.
      23. 23.↵
        Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation. 1974; 18:295-304.
      24. 24.↵
        Matthews DE, Farewell VT. Using and Understanding Medical Statistics. 2d ed. New York: Karger; 1988.
      25. 25.↵
        Carreras E, Granena A, Navasa M, Bruguera M, Marco V, Sierra J, et al. On the reliability of clinical criteria for the diagnosis of hepatic veno-occlusive disease. Ann Hematol. 1993; 66:77-80.
      26. 26.↵
        Mehta J, Powles R, Horton C, Milan S, Singhal S, Treleaven J. Relationship between donor-recipient blood group incompatibility and serum bilirubin after allogeneic bone marrow transplantation from HLA-identical siblings. Bone Marrow Transplant. 1995; 15:853-8.
      27. 27.↵
        Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995; 85:3005-20.
      28. 28.↵
        Rozman C, Carreras E, Qian C, Gale R, Bortin MM, Rowlings PA, et al. Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia. Bone Marrow Transplant. 1996; 17:75-80.
      29. 29.↵
        Grochow LB, Jones RJ, Brundrett RB, Braine HG, Chen TL, Saral R, et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol. 1989; 25:55-61.
      30. 30.↵
        Schroeder M, Jaslowski A, Thomas A, Warren T, Lewis S, Essell J, et al. Busulfan pharmacokinetics in patients undergoing allogeneic bone marrow transplant: an analysis of the effects of ursodiol [Abstract]. Blood. 1996; 88(Suppl 1):259b.
      31. 31.↵
        Clift RA, Buckner CD, Thomas ED, Bensinger WI, Bowden R, Bryant E, et al. Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood. 1994; 84:2036-43.
      32. 32.↵
        Batta AK, Salen G, Arora R, Shefer S, Tint GS, Abroon J, et al. Effect of ursodeoxycholic acid on bile acid metabolism in primary biliary cirrhosis. Hepatology. 1989; 10:414-9.
      33. 33.↵
        Podda M, Ghezzi C, Battezzati PM, Bertolini E, Crosignani A, Petroni ML, et al. Ursodeoxycholic acid for chronic liver diseases. J Clin Gastroenterol. 1988; 10(Suppl 2):S25-S31.
      34. 34.↵
        Chretien Y, Poupon R, Gherardt MF, Chazouilleres O, Labbe D, Myera A, et al. Bile acid glycine and taurine conjugates in serum of patients with primary biliary cirrhosis: effect of ursodeoxycholic treatment. Gut. 1989; 30:1110-5.
      35. 35.↵
        Podda M, Ghezzi C, Battezzati PM, Crosignani A, Zuin M, Roda A. Effects of ursodeoxycholic acid and taurine on serum liver enzymes and bile acids in chronic hepatitis. Gastroenterology. 1990; 98:1044-50.
      36. 36.↵
        Guldutuna S, Zimmer G, Imhof M, Bhatti S, You T, Leuschner U. Molecular aspects of membrane stabilization by ursodeoxycholate. Gastroenterology. 1993; 104:1736-44.
      37. 37.↵
        Bellentani S, Chao YC, Ferretti I, Panini R, Tiribelli C. Chronic administration of ursodeoxycholic and tauroursodeoxycholic acid changes microsomal membrane lipid content and fatty acid compositions in rats. Biochem Biophys Res Commun. 1996; 220:479-83.
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