Summary:The original definition of hepatic veno-occlusive disease (VOD), which is still widely accepted, includes onset of the clinical syndrome before day +20 following highdose chemotherapy (HDC) and stem cell transplantation (SCT). We retrospectively identified four patients following HDC and SCT presenting with late onset VOD occurring at day +24, day +27, day +34 and day +42 post SCT. All patients had moderate VOD, with successful resolution of the VOD before day +100 with optimal supportive therapy. Common risk factors for VOD shared by all four patients included an older age (median age: 60 years), and use of a busulphan-containing regimen. Mean and maximum bilirubin levels for all patients during the VOD syndrome were 2.02, 1.76, 5.09, 2.87 mg/dl and 2.5, 2.2, 8.9 and 4.1 mg/dl, respectively, which correlated well with duration of VOD. All patients encountered platelet transfusion-dependent thrombocytopenia during VOD. Ursodeoxycholic acid was used as VOD prophylaxis beginning at a mean of 33 days prior to onset of VOD. As the cellular target of hepatic VOD is as yet unidentified, it is uncertain whether ursodiol or other common characteristics of patients with late onset VOD influence the pathogenesis and natural history of this disease. We believe that the uncommon clinical entity of late onset VOD, a potentially fatal regimen-related toxicity, should not be ignored as a diagnosis of liver disease after 3 or more weeks following HDC and SCT. Keywords: late onset VOD; high-dose chemotherapy; peripheral blood stem cell transplantation; ursodeoxycholic acid; VOD risk factors Hepatic veno-occlusive disease (VOD) is the leading cause of regimen-related morbidity and mortality in the first 2 months following high-dose chemotherapy (HDC) and bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) 1 with an incidence ranging from 0% to 70%. 2 VOD was originally defined as a clinical syndrome occurring by day +20 following SCT with at least two of the following features: jaundice, tender hepatomegaly and ascites or unexplained weight gain. 3 In the absence of histological confirmation, the combination of all three clinical features has been reported to have a specificity of 92% and sensitivity of 56%. 2,4 It is now clear that VOD can develop in patients beyond day +20, thus necessitating that a time limit be omitted from the diagnostic criteria for VOD. 1,2,5 The entity of late onset VOD is not well described. Beyond the third and fourth weeks post SCT, the main differential diagnoses of liver injury include infective causes, acute GVHD, drug-related insults and recurrent disease. 6 Given that severe VOD is associated with a mortality approaching 100% by day +100 with no truly effective therapeutic options, 1,3,5,7 early detection and institution of appropriate supportive measures are vital. VOD must not be ignored as a diagnostic consideration beyond 3 to 4 weeks post SCT in patients with clinical or biochemical liver dysfunction and/or weight gain. Here, we review the clinical ...

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Summary:While high-dose chemotherapy and stem cell transplantation is associated with higher complete response rates than conventional chemotherapy in patients with metastatic breast cancer (MBC), its role in conferring a survival advantage is unproven. We report the results of a prospective phase II trial of 33 patients accrued between 1996 to 1998 with chemosensitive MBC, who received cyclophosphamide (Cy) 2000 mg/m 2 /day and carboplatin (Cb) 600 mg/m 2 /day for 3 consecutive days, followed by infusion of peripheral blood stem cells cultured in IL-2 for 24 h on day 0 as adoptive immunotherapy. Low-dose interleukin-2 (IL-2) was administered from day 0 to ؉4 and/or ؉7 to ؉11, ؉14 to ؉18, ؉21 to ؉25, then 5 days per month for 11 months to augment a graft-versus-tumor effect. The results of this study were compared to those of a historical control group treated with an identical high-dose Cb ؉ Cy regimen with SCT but without IL-2 treatment. Only gastrointestinal (GI) toxicity was more frequent in the IL-2 cohort (P = 0.0031). At a median follow-up of 18.6 months, the median progression-free survival (PFS) is 9 months (2.4-40) and the median OS has not been reached yet. The Kaplan-Meier estimated 2 year PFS is 35%, compared with 17% in the control arm (P = 0.73), and the estimated 2 year OS is 78%, compared with 61% in the control arm (P = 0.22). Multivariate analysis showed that ER status was an independent predictor for OS and PFS, and less chemotherapy prior to HDCSCT predicted for a better PFS. These results show that augmenting HDC with IL-2 activated SCT is well-tolerated. Whether a therapeutic advantage is achievable in patients with MBC remains to be determined. Bone Marrow Transplantation (2000) 25, 19-24.