The Importance of Harmonizing Transplantation Procedures in Children with ALL: ALL-SCT-BFM 2003, a Prospective Multicenter Trial.

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.