Veno-occlusive Disease of the Liver and Multiorgan Failure after Bone Marrow Transplantation: A Cohort Study of 355 Patients

Survival after bone marrow transplantation depends on recovery from the effects of cytoreductive therapy, successful engraftment, prevention of infections and graft-versus-host disease, and eradication of the underlying disease [1]. Liver damage, a common complication of cytoreductive therapy, develops in 20% to 40% of patients who undergo bone marrow transplantation for malignancy [2-5]. The most prominent site of liver damage after cytoreductive therapy is the terminal hepatic venule [6, 7]. In addition to causing vascular changes, cytoreductive therapy may result in necrosis of hepatocytes in zone 3 of the liver acinus, engorgement of sinusoids with hepatocytes and red blood cells, and perivenular fibrosis [3, 6, 7]. The clinical syndrome resulting from this hepatic damage is commonly called veno-occlusive disease of the liver (VOD). In 1980, we reported that patients receiving high-dose cytoreductive therapy had a higher incidence of VOD than did those receiving low-dose therapy [7]. In recent years, the trend has been to give even greater doses of cytoreductive therapy to patients at increased risk for relapse of malignancy after marrow grafting [5, 8-10]. High-dose regimens reduce the incidence of tumor relapse but are associated with liver, renal, cardiac, and pulmonary complications [8-12]. Our clinical impression is that the current incidence of VOD at our institution is much higher than the 21% rate we reported 9 years ago [2] and that more patients have severe liver disease. Factors other than high-dose cytoreductive therapy must be involved in the pathogenesis of VOD, because not all patients receiving identical high-dose regimens develop this complication. In three studies, patients with hepatitis at the time of cytoreductive therapy were significantly more likely to develop VOD than patients with normal serum liver enzyme levels [2-4]. Other factors that have been reported to increase the risk for VOD include increasing age, certain diagnoses, estrogen-progestin therapy, amphotericin therapy during cytoreductive therapy, methotrexate therapy after transplantation, and seropositivity for cytomegalovirus [2-5, 13, 14]. In addition to increases in cytoreductive therapy dosing, several other changes in the technique of bone marrow grafting occurred in the last decade: These include the use of cyclosporine for graft-versus-host disease prophylaxis; the more extensive use of antibiotics, antifungal agents, and antiviral drugs during periods of profound immunodeficiency; and the wider use of bone marrow from unrelated and HLA-mismatched donors [15-17]. To determine the incidence of VOD after bone marrow transplantation, we prospectively followed 355 consecutive patients who underwent transplantation in Seattle, Washington. We were particularly interested in analyzing risk factors for VOD in order to explain the apparent increased incidence and severity of this complication. We also examined the relation between VOD and the failure of other organs because we have noted that multiorgan failure tends to follow the development of liver disease. Methods Patient Selection We evaluated all patients referred to the Fred Hutchinson Cancer Research Center for bone marrow transplantation between August 1987 and August 1988. Three hundred and sixty patients received cytoreductive therapy in preparation for bone marrow grafting. Five patients who died before bone marrow infusion were excluded from the analysis. Thus, 355 patients were prospectively studied for the development of liver toxicity and organ failure in the early post-transplant period. Four patients received a second marrow graft within the year, but only data from the first transplant were analyzed. Underlying diseases for which transplantation was done included acute myelocytic leukemia (n = 98), acute lymphocytic leukemia (n = 61), chronic myelogenous leukemia (n = 94), lymphoma (n = 65), other malignant conditions (n = 16), and other hematologic disorders (n = 21). Bone Marrow Transplant Techniques The methods used at our institution have been previously reported [8, 9, 15, 18]. Briefly, patients receive chemotherapy or chemoradiation therapy before infusion of bone marrow. By convention, the day of bone marrow infusion is considered day zero and all post-transplant events are dated from this day. Patients who receive allogeneic marrow are given prophylactic therapy, usually with cyclosporine and methotrexate, for graft-versus-host disease [15]. Definition of Veno-occlusive Disease A diagnosis of VOD was made according to the criterion we proposed in 1984, that is, the occurrence of two of the following events within 20 days of transplantation: hyperbilirubinemia (total serum bilirubin > 34.2 mol/L [2 mg/dL]), hepatomegaly or right upper quadrant pain of liver origin, and sudden weight gain (> 2% of baseline body weight) because of fluid accumulation [2, 19]. No other explanation for these signs and symptoms could be present at the time of diagnosis. Patients were classified as having liver disease of uncertain cause if liver disease developed that could be explained by graft-versus-host disease, sepsis syndrome (fever and hypotension), cardiac failure, or tumor infiltration. Patients who developed both mild hyperbilirubinemia (total serum bilirubin < 34.2 mol/L [2 mg/dL]) and weight gain below the threshold criterion of 2% were also placed in the uncertain cause category. Patients who died before day 5 were also classified as having disease of uncertain cause because they did not live long enough for liver disease to become clinically apparent. Patients were classified as showing no liver disease if no liver abnormalities were observed within 20 days of marrow infusion. Clinical Course and Outcome of Veno-occlusive Disease Patients who met criteria for the diagnosis of VOD were evaluated for severity as follows: Patients were classified as having mild disease if they showed no apparent adverse effect from liver disease; required no medications for diuresis of excessive fluid or for hepatic pain; and had completely reversible signs, symptoms, and laboratory abnormalities. Patients were classified as having moderate VOD if they had an adverse effect from liver disease; required sodium restriction and diuretics to minimize signs of fluid excess (edema, ascites, cardiopulmonary congestion) or medication to alleviate pain from hepatomegaly; and eventually showed a complete resolution of all signs of liver damage (a return of weight to baseline, a decrease in liver size, and a decrease in total serum bilirubin to < 34.2 mol/L [2 mg/dL]). Patients were classified as having severe VOD if they showed an adverse effect from liver disease, and signs, symptoms, and laboratory values did not resolve before day 100 or the patient died, whichever occurred first. Death was not a requirement for assignment to the severe VOD category. Risk Factors for the Development of Veno-occlusive Disease Appendix Table 1 summarizes all risk factors analyzed for the development of VOD. Appendix Table 1. Individual Risk Factors Analyzed for the Development of Veno-occlusive Disease of the Liver One of us reviewed referral correspondence and interviewed and examined each patient at his or her arrival to the center. Medications given before the start of cytoreductive therapy were recorded. Then, starting with day 1 of cytoreductive therapy, each patient's signs, symptoms, medications, laboratory and radiologic results, and clinical findings were noted on a daily basis until day 20 after transplantation. We analyzed three categories of factors that could be related to the development of VOD: pretransplant factors, transplant decision factors, and clinical course factors. Pretransplant factors were those present before the start of cytoreductive therapy. Included in this category were demographic variables and variables derived from a detailed medical history, including information about individual chemotherapy agents as well as combination chemotherapy delivered before patients arrived at our center. Transplant decision factors were those decided on for each patient before the start of cytoreductive therapy. Such factors included the dose and type of cytoreductive therapy, the type of transplant, and the HLA match between donor and recipient. The dose rate of total body irradiation for most patients (271 of 277) was 6 to 7 cGy/min using opposing cobalt sources. Six patients received total body irradiation at 12 cGy/min using a linear accelerator. For patients receiving a total body irradiation dose of more than 12 Gy, we analyzed whether radiation delivered in divided daily doses (fractionated) or in multiple doses per day (hyperfractionated) had an effect on the incidence of VOD. Clinical course factors were those occurring after the start of cytoreductive therapy but before the clinical appearance of liver disease. Such factors included all medications received by each patient and the occurrence of fever. Evaluation of Renal, Cardiac, Pulmonary and Neurologic Events Organ dysfunction was scored on a daily basis (to day 20 after transplantation). We noted the day of onset of organ dysfunction and its severity, using the following definitions: Renal insufficiency was defined by a doubling of the baseline creatinine level (that is, the lowest serum level 1 to 3 days before bone marrow infusion). Renal failure was defined by a creatinine level of 265 mol/L (3 mg/dL), a blood urea nitrogen level 28.6 mmol/L (80 mg/dL), or the need for hemodialysis. Cardiac failure was defined by radiographic evidence of an increased cardiac size or the development of pulmonary vascular congestion that was not present at baseline. Pleural effusions were defined by radiographic evidence in the pleural space, and pulmonary infiltrates by radiographic evidence of diffuse interstitial infiltrates that were not present at baseline. The need for oxygen support was based on documentation of hypoxemia by arteri