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As results of frontline and relapse protocols for children with acute lymphoblastic leukaemia (ALL) are improving over time, there is a strong need for prospective haematopietic stem cell transplantation (SCT) trials, ensuring well standardized procedures for all relevant components which are potentially responsible for heterogeneity in post-SCT outcome. Therefore, in 2003 the Berlin-Frankfurt-Münster (BFM)-Study Group initiated a prospective international multicenter trial (ALL-SCT-BFM 2003). Main goals are the standardization and harmonisation of the SCT procedure and the question, if nowadays SCT from a matched sibling donor (MSD) is equivalent to SCT from a very well matched donor (MD). Further, we want to determine the efficacy of a SCT from HLA-mismatched donors (MMD) compared to SCT from MD/MSD as well as the incidence of acute and chronic graft versus host disease (GvHD) after SCT. Between September 2003 and June 2007, 381 patients (185 in CR1, 196 in CR2 or after subsequent relapse) were recruited by 27 participating SCT centers in Austria, Germany and Switzerland. Indications for SCT were poor response to induction treatment, either detected by morphology on day 33 or by minimal residual disease load measured after 11 weeks of treatment, cytogenetic aberrations [t(9;22), t(4;11)], early bone marrow relapses of ALL, or any subsequent ALL relapse. 76 patients had an indication for a MSD, 131 patients for a MD, and 174 patients for a MMD. Compliance with HLA-typing procedures according to the trial guidelines (high resolution typing of HLA A, B, C, DRB1 and DQB1) improved over time: 54% in 2004, 83% in 2005, 90% in 2006, and so far 100% in 2007. Unmanipulated bone marrow was used in 73% of MSD- and MD-SCT as recommended by the protocol. The recommended conditioning regimens (TBI+VP16 for MSD, TBI+VP16+ATG for MD, and TBI+Flu+VP16+ATG for MMD; in children younger than 2 years, TBI was substituted by BU+Cy) were used in 80% of all patients. GvHD prophylaxis (cyclosporine A for MSD, and cyclosporine A plus “short methotrexate” for MD) was given in 83% of all patients according to the trial guidelines. In most cases, deviations were due to clinical reasons. As the trial ALL-SCT-BFM 2003 is ongoing till 2009, interim results regarding outcome will not be presented. Nevertheless, treatment-related mortality is still very low (7%) and has improved over time since the very early beginning. Final results will be a very stable basis for subsequent ALL-SCT trials, focussing on controlled modifications and interventions in those patients being at highest risk for relapse subsequent to SCT.

Viral infections remain a major cause for transplant related mortality. The introduction of PCR-based assays permits rapid, specific and highly sensitive detection of various viral infections prior to clinical symptoms and thus facilitates preemtive treatment strategies. However a broad routine screening by PCR during the early post-transplant period is cost-intensive. Clinical benefit of broad vs restriced viral screening by PCR was evaluated in total of 98 consecutive pediatric SCT-patients(pts). The first 56 consecutive pts underwent broad viral screening including CMV, ADV, EBV, HSV, VZV, HHV6, HHV7, HHV8, PVB19, RSV, BKV, Enterovirus, Influenza A and B, and Parainfluenza 1–3. PCR-screening was performed twice weekly until day +28 and once weekly until day +100 in peripheral blood (PB), stool, urine and mouth wash. A total of 15675 samples were analyzed. HSV-IgG positive pts. received prophylactic acyclovir. All pts. received preemptive treatment for CMV viremia (gancyclovir) and ADV viremia (cidofovir). Pts with EBV-viremia exceeding 103 copies per ml PB received gancyclovir. In pts. undergoing the broad screening 50/56 pts were positive for at least one virus. The overall incidence of viremia was 61%. HHV6 was detectable in 66% (39% in PB), HHV7 in 16% (11% in PB), CMV in 36% (all in PB, in 23% additionally positive in other sites), EBV in 39% (35% in PB), ADV in 27% (5% in PB), BKV in 13% (all in urine) and PVB19 in one pts. Although the first detection of a viral infection occured before day +120 in all children, PCR positivity persisted throughout the first year post-transplant in many cases. There was no significant difference in the incidence of overall viral infection, viremia or multiple viremia between pts. with T-cell depleted grafts and those with unmanipulated grafts. However T-cell depletion was associated with significantly more lethal viral infections (32% vs 6%, p=0,0127). There was no significant difference in the incidence of viral infections, viremia and lethal viral disease between pts receiving myeloablative conditioning and those receiving reduced intensity conditioning. Isolated HHV6 or HHV7 viremia was not associated with any clinical symptoms and there was no difference concerning the incidence of CMV viremia, lethal viral disease or TRM between pts with and without HHV6 viremia. Of the 20 pts with CMV viremia, 6 pts had lethal CMV disease. 10% of the patients with EBV viremia were symptomatic, the disease being lethal in one case. The three pts who developed ADV viremia had previously been ADV positive in stool. All three pts died from disseminated ADV disease despite treatment with cidofovir. All pts with BKV positive urine had hemorrhagic cystitis. On the basis of these results, the viral screening for the subsequent 42 pts PCR screening was restricted to ADV, CMV and EBV in PB, ADV in stool and BKV in urine once weekly until day +28 and every two weeks thereafter, reducing the cost of the viral screening to 13%. For the patients undergoing restricted screening there was no difference concerning the incidence of CMV, EBV, ADV viremia and the incidence of lethal viral disease (18% vs 14%). We conclude that broad and cost intensive PCR screening for viral infections is of no clinical benefit.