Light at the end of the VOD tunnel?

Reduced-intensity allogeneic transplants have become widely used to reduce treatment-related morbidity and mortality (TRM) while maintaining an immunologic (graft versus tumor) response against host tumor cells. These regimens have primarily been used for older patients, those with more indolent diseases, such as chronic lymphocytic leukemia or low-grade lymphoma, and those with underlying organ dysfunction. It is hypothesized that this strategy will make allotransplantation feasible for patients in this latter category who would not be candidates for myeloablative regimens.

This issue contains a report by Hogan and colleagues (page 78) that studied the impact of one reduced-intensity regimen, low-dose total body irradiation (TBI), with or without fludarabine, on hepatic toxicity, the most common cause of fatal regimen-related toxicity after ablative transplant preparation. Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is characterized by fluid retention, painful hepatomegaly, and jaundice. VOD/SOS is more common in patients with active liver inflammation who undergo transplantation, in those who receive more intensive conditioning, and in the setting of active infection during the peritransplantation period.

In their article, Hogan et al describe the incidence, severity, and outcome of hepatic toxicity in 193 consecutive patients prepared for allogeneic transplantation using 200 cGy total body irradiation, with or without fludarabine, and who received cyclosporine and mycophenolate mofetil for postgrafting immunosuppression. Of the patients, 26% developed hyperbilirubinemia (bilirubin levels of 68.4 μM [4 mg/dL] or higher) by day 200 (compared with 48% in a historical group of 1149 patients who underwent transplantation using an ablative regimen), but in none was this due to VOD/SOS. Graft-versus-host disease (GVHD), or cholangitis lenta, was the most common cause of jaundice in these patients. Survival was superior in patients with normal or minimally elevated bilirubin levels and in those whose bilirubin level exceeded 68.4 μM (4 mg/dL) within the first 28 days compared with patients whose bilirubin level reached 68.4 μM (4 mg/dL) after day 28. Among patients with bilirubin levels of 68.4 μM (4 mg/dL) or higher, those with aggressive histologies were more likely to die than those with more indolent disease. Patients who received fludarabine with their preparative regimen were more likely to develop hyperbilirubinemia, although fludarabine was not an independent risk factor for death. There were 3 patients, all with chronic liver disease at the time of transplantation, who died of liver failure.

What does this report show us? First, it shows that allotransplantations can be performed without patients developing VOD/SOS. We must remember, however, that 200 cGy TBI (± fludarabine) is only one of many nonmyeloablative regimens and that VOD/SOS has been reported after conditioning using other reduced-intensity programs. Second, it demonstrates that patients with chronic and pre-existing liver disease remain at high risk for early death and that reduced-intensity preparation does not protect them. It also makes clear that hyperbilirubinemia beyond day 28 is associated with an adverse outcome even in the absence of VOD/SOS and independent of the relative intensity of the regimen. The utility of this marker in predicting overall survival was sufficiently strong to make it both important to look for and discouraging to find in any patient undergoing a reduced intensity allograft. Finally, while Hogan and colleagues have provided important data indicating that this approach significantly reduces regimen-related hepatic toxicity, assessing the effect of nonablative transplantations on long-term outcome will require longer follow-up as well as improved treatment or prevention of other complications such a relapse, GVHD, and infection.