Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation.

PURPOSE: Hepatic venoocclusive disease (VOD) is a common complication of cytoreductive therapy for marrow transplantation. Only 25% of patients who develop VOD have severe disease. We tested the hypothesis that early clinical signs of VOD would predict which patients would recover and which would die. PATIENTS AND METHODS: We evaluated 355 consecutive patients who had transplants between August 6, 1987 and July 21, 1988 for occurrence of VOD and whether it was reversible within 100 days of transplant. Total serum bilirubin and weight gain from day -7 through day +16 posttransplant were compared among patients with no, severe, or nonsevere VOD. Logistic regression models were developed to estimate probabilities of severe VOD at each of six time intervals. The accuracy of these models was tested by applying them to 392 consecutive patients who underwent transplantation between July 22, 1988 and July 20, 1989. RESULTS: As early as day -1, bilirubin and weight gain were significantly different between patients whose VOD proved to be severe and patients with reversible VOD or no disease. Regression models were used to generate coefficients (beta 0, beta 1, beta 2) for the equation P = 1/(1 + e-z), where P is the probability of severe VOD and z = beta 0 + beta 1 (In total serum bilirubin [mg/dL]) + beta 2 (percent weight gain). Application of this equation to the next 392 patients allowed us to calculate sensitivity, specificity, and positive predictive value for a range of probabilities. CONCLUSION: The course of VOD after cytoreductive therapy can be predicted by knowing the serum bilirubin and weight gained within 1 to 2 weeks of transplantation. Probability estimates derived from patient data are highly specific and moderately sensitive. Such probability estimates may be useful when considering potentially risky interventions to treat VOD, such as recombinant human tissue plasminogen activator.

Association of pulmonary function testing abnormalities and severe veno-occlusive disease of the liver after marrow transplantation.

We investigated an association between pulmonary function testing (PFT) before bone marrow transplantation and the development of severe veno-occlusive disease (VOD) of the liver. We previously noted that reductions in diffusing capacity of the lung for carbon monoxide (corrected for hemoglobin) (D(L)COc) were associated with mortality after transplantation, but this was not caused by respiratory failure. We performed a case-series review of prospectively collected data from 307 marrow recipients who underwent PFT within 2 weeks of transplantation. Of these, 170 (56%) developed VOD; 39 (13%) mild, 81 (26%) moderate, and 50 (16%) severe or fatal. Both total lung capacity (TLC) and D(L)COc were associated with severe VOD in univariate analysis (P = 0.006 for each). However, D(L)COc entered logistic regression models that contained variables for all known risk factors for severe VOD, while TLC did not contribute additional predictive information. The odds ratio (OR) associated with a D(L)COc below the lower limits of normal (70% of predicted) was 2.4 (95 % CI, 1.0 to 5.4; P = 0.04). We conclude that reduced diffusion capacity of the lung measured before marrow transplantation is an independent risk for severe hepatic VOD. We speculate that the decreased D(l)COc indicates pre-existing systemic endothelial cell damage and a susceptibility to severe hepatic injury from chemotherapy.

A pilot study of continuous infusion heparin for the prevention of hepatic veno-occlusive disease after bone marrow transplantation.

Twenty-eight patients undergoing marrow transplantation participated in a pilot study to determine the safety of continuous infusion heparin for the prevention of veno-occlusive disease (VOD) of the liver. Four doses of continuous infusion heparin were administered, ranging from a dose prolonging the partial thromboplastin time (PTT) to 1.5-2.0 times the patients' baseline value, to a dose prolonging the PTT to less than 1.2 times the patients' baseline value. Seven patients (25%) received a full course of heparin, beginning from the day the preparative therapy started through day 14 post-transplant (range 20-26 days on heparin). In 21 patients infusions were ended before day 14 post-transplant, a median of 16 days on heparin (range 1-26 days). Of these, 14 patients were withdrawn from heparin because of bleeding and seven were withdrawn because of anticipated bleeding. Bleeding was observed in 27 patients and was minor in 25. Two patients developed major bleeding in the gastrointestinal tract which was not fatal. Minor bleeding was observed in 27 of 28 case control patients who did not receive heparin. The sites of bleeding were similar in control and heparin treated patients. VOD developed in 20 patients (71%) and was sever or fatal in four (14%). The prevalence of VOD was not influenced by the dosage of heparin or the duration of its administration. We conclude that low dose heparin resulting in marginal prolongation of the PTT may be infused into patients undergoing marrow transplantation with a low risk of serious bleeding. Further studies are needed to evaluate its efficacy.

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.

A phase I/II study of prostaglandin E1 for the prevention of hepatic venocclusive disease after bone marrow transplantation.

We conducted a phase I/II trial of prostaglandin E1 (PGE1) for the prevention of hepatic venocclusive disease (VOD). Twenty-four patients at high risk for VOD received PGE1 at four dose levels ranging from 1.25 to 10 ng/kg/min. Severe toxicity was experienced at all dose levels and was manifested as cutaneous erythema and desquamation, severe pain in dependent extremities, fluid retention and grade 4 oedema, or hypotension. In 12/24 patients, PGE1 administration was stopped prior to day 15 due to severe toxicity attributed to the drug. Three of 12 patients who received PGE1 for the entire course of treatment and 9/12 patients whose PGE1 was stopped prior to day 15 developed severe toxicity which was attributed to PGE1 (P = 0.039). Severe toxicity attributed to PGE1 was not related to either PGE1 concentration or PGE1 clearance. Six of 12 patients whose PGE1 infusion was stopped prior to day 15 and 2/12 patients who received PGE1 for the full course of treatment developed severe VOD (P = 0.19). We conclude that PGE1 causes significant toxicity in patients undergoing marrow transplantation. The ability of PGE1 to prevent severe VOD in patients at high risk remains unproven.

Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.

OBJECTIVE: To determine the incidence and clinical course of veno-occlusive disease of the liver (VOD) after bone marrow transplantation and to analyze risk factors for severe VOD. DESIGN: Cohort study of 355 consecutive patients. SETTING: A bone marrow transplantation center. MEASUREMENTS: Each patient was prospectively evaluated for VOD, and many risk factors for severe VOD were analyzed using logistic regression models. The relation of VOD to renal and cardiopulmonary failure was analyzed using time-dependent proportional hazards models. RESULTS: Veno-occlusive disease developed in 190 of 355 patients (54%; 95% CI, 48% to 59%): Fifty-four patients had severe VOD and 136 had mild or moderate VOD. Independent variables derived from a multivariate model for predicting severe VOD included elevated transaminase values before transplantation (relative risk, 4.6; P < 0.0001); vancomycin therapy during cytoreductive therapy (relative risk, 2.9; P = 0.003); cytoreductive therapy with a high-dose regimen (relative risk, 2.8; P = 0.01); acyclovir therapy before transplantation (relative risk, 4.8; P = 0.02); mismatched or unrelated donor marrow (relative risk, 2.4; P = 0.02); and previous radiation therapy to the abdomen (relative risk, 2.2; P = 0.04). Vancomycin therapy was a marker for persistent fever. Multiorgan failure was more frequent among patients with VOD and usually followed the onset of liver disease. CONCLUSIONS: Veno-occlusive disease, which developed in 54% of bone marrow transplant recipients, is frequently associated with renal and cardiopulmonary failure. Pretransplant transaminase elevations, use of high-dose cytoreductive therapy, and persistent fever during cytoreductive therapy are independent predictors of severe VOD.