Don't GO to VOD

Hepatic veno-occlusive disease (VOD) is one of several regimen-related toxicities that results from high-dose cytotoxic therapy used to prepare patients for stem cell transplantation. Injury to sinusoidal endothelial cells is the initiating event in the pathogenesis of VOD and leads to sinusoidal obstruction, necrosis of hepatocytes in zone 3 of the liver acinus, and narrowing and fibrosis of central veins. Because of the primary role of sinusoidal obstruction in the clinical manifestations of VOD (hepatomegaly, jaundice, and fluid retention), it has been proposed that sinusoidal obstruction syndrome (SOS) is a more appropriate label for this syndrome (see DeLeve et al, Semin Liver Dis. 2002;22:27-42).

In this issue of Blood, Wadleigh and colleagues (page 1578) report that VOD/SOS is more common in patients who had previously received gemtuzumab ozogamicin (GO) than in patients who had not. Nine of 14 (64%) patients who had received GO prior to transplantation developed VOD/SOS, whereas only 4 of 48 (8%) patients who had not received prior GO developed VOD/SOS. Other groups have reported similar findings. What is different about Wadleigh et al's data is that VOD/SOS occurred only in patients who had received GO within 3.5 months of transplantation.

How should these data influence clinical practice? They suggest that patients should not receive transplants within 3.5 months of GO administration. The numbers are too small to say with confidence whether patients could safely receive transplants more than 3.5 months after GO. The most conservative approach would be to offer transplantation only to patients who have not received any GO. If GO must be given prior to transplantation, strong consideration should be given to using a reduced-intensity preparative regimen. Although no data are available regarding the use of GO prior to reduced-intensity allografts, it seems prudent to minimize the cytotoxicity in such patients. It is hoped that registry studies will indicate whether there is a safe interval beyond which transplantation can be performed in patients treated with GO and whether this is a concern at all in reduced-intensity allograft recipients.

What don't we know? We don't know whether GO can be safely administered for relapse after transplantation. One study reported that 11 of 23 patients who were treated with GO for relapse after transplantation developed VOD and 7 of these patients died of liver failure (see Rajvanshi et al, Blood. 2002;99:2310-2314). Registry studies will be important in this circumstance as well. We also don't know what the risk of VOD/SOS is in autologous transplant recipients who receive GO before transplantation. All reports of VOD/SOS and GO in the context of transplantation have been in allograft recipients. We must not forget that autograft recipients also develop VOD/SOS.