Incidence of Veno-Occlusive Disease with IV in Busulfan Children Is Higher Than Expected: Preliminary Results of the VOD-DF Trial.

Hepatic VOD is a life-threatening complication following SCT with a high incidence in children. Development of VOD is one of the most common causes of early death after SCT. Busulfan (BU), an alkylating agent with a very narrow therapeutic index is a commonly used conditioning agent in pediatric stem cell transplantation (SCT) with a strong correlation between AUC and both efficacy and toxicity. Oral BU (poBU) has significant age-related and interpatient pharmacokinetic differences and was linked with an increased risk for VOD. IV busulfan (ivBU) yielded promising results in some studies to be associated with low toxicity profile, especially with a reduced incidence of VOD.

Patients <18 years with myeloablative SCT were included in a prospective multicenter phase II/III trial to evaluate the efficacy of Defibrotide (DF). Eligibility criteria included conditioning with BU (iv and po) and melphalan (MEL). Pts were prospectively randomized to the control arm or to receive DF. Primary endpoint was the incidence of hepatic VOD by D+30 using modified Seattle criteria (2 or more of the following: bilirubin > 2 mg/dL, hepatomegaly, ascites and/or unexplained weight gain > 5%). VOD was assessed by physical exam; hepatomegaly and ascites were confirmed by ultrasound. A blinded IRC of 3 expert hematologists confirmed the diagnosis of VOD. Although the study was not powered to assess mortality, a composite score was assessed as a secondary endpoint that incorporated VOD-associated toxicity (respiratory failure, renal failure, encephalopathy) and mortality. The additional analysis of the influence of BU on VOD was not planned and is therefore explorative.

360 pts were enrolled between January 2006 and January 2009 by 28 centers in the EU and Israel. An Intent-to-Treat (ITT) analysis was performed on all pts who signed informed consent (n=356). 251 (71%) pts from the ITT population were conditioned with BU (64% ivBU; 36% poBU). 202 (55%) were treated with BU and Melphalan (MEL) (60% ivBU; 40% poBU). In 49 (14%) BU was used without MEL (80% ivBU; 20% poBU). In children <2yrs 44 (12%) were conditioned with BU/MEL (59% ivBU; 41% poBU) and 26 (7%) were conditioned without MEL (85% ivBU; 15% poBU).

The median age of patients with iv BU was 3.65 yrs and 5,13 yrs with poBU; 28% infants, 50% children (ages 2-11 yrs) and 22% adolescents (evenly distributed). 45% female, 55% male (evenly distributed). Allo-SCT was performed in 69% with ivBU and 46% with poBU (remaining with auto-SCT). The diagnoses were evenly distributed between poBU and ivBU. Except in AML 18% were conditioned with ivBU and 32% with poBU. Preexisting liver disease was present in 23% ivBU and 9% poBU pts, of which 46% (17/37) ivBU and 37% (3/8) poBU had elevated transaminases. Overall VOD was experienced by 23% of the infants, 14% of the children and 13% of the adolescents. The overall incidence of VOD in pts treated with BU was 18%. VOD was diagnosed in 24% ivBU vs 8% poBU pts. In pts treated with BU/MEL VOD was diagnosed in 16%. VOD in ivBU/MEL was 21% (26) vs 8% (6) in poBU/MEL. In BU without MEL VOD was diagnosed in 27% (13/49). 31% (12/39) in ivBU pts and 10% (1/10) in poBU pts. In infants treated with BU/MEL the incidence of VOD in the ivBU group was 23% (6/26) and 11% (2/18) in poBU. In BU without MEL in infants the incidences were 41% (9/22) ivBU versus none (0/4) in poBU. The diagnosis of VOD independent of severity was associated with a higher mortality and equaled 24.6% (14/57) compared to 7% in pts without VOD (21/299). Respiratory failure was observed in 10% (16/161) of ivBU vs 2% (2/90) of poBU pts (9% (11/122) vs 1% (1/80) iv vs po BU/MEL); renal failure in 5% (8/161) ivBu vs 1% (1/90) poBU (5% (6/122) vs none in iv vs po BU/MEL). The incidence of multi-organ-failure (MOF) by day +100 was 12% (19/161) in ivBU vs 3% (3/90) in poBU (p=0.022). Compared to all other pts the risk to develop VOD in infants treated with allo-SCT and ivBU is 2.4 times higher (p=0.003).

Although the scope of this trial was not to assess the influence of BU on the incidence of VOD and there was an imbalanced distribution of liver diseases and a potential bias for other risk factors the incidence of VOD in ivBU was unexpectedly high especially in infants. Inasmuch this is due to a high interpatient variability of the AUC should be explored prospectively.

Corbacioglu:Gentium S.p.A.: Consultancy, Research Funding.