Allogeneic Hematopoetic Stem Cell Transplantation (SCT) In Children with ALL: Outcome of Matched Sibling Donor SCT (MSD-SCT) Is Equivalent to Unrelated Well Matched Donor HSCT (MD-HSCT) A Report From the Prospective International Multicenter Trial ALL-SCT-BFM 2003
Authors: Schrauder AndrÉ , von Stackelberg Arend , Schrappe Martin , Klingebiel Thomas , Bader Peter , Ebell Wolfram , Handgretinger Rupert , Sykora Karl-Walter , Schrum Johanna , Kremens Bernhard , Ehlert Karoline , Albert Michael , Meisel Roland , Tayfun Güungör , Holter Wolfgang , Strahm Brigitte , Gruhn Bernd , Schulz Ansgar S , Zimmermann Martin , Pötschger Ulrike , Peters Christina 
Published: October 2019

Abstract
Abstract 530
In 2003 the Berlin-Frankfurt-M ünster (BFM)-Study group initiated a prospective international multicenter trial (ALL-SCT-BFM 2003) for allogeneic hematopoetic stem cell transplantation (HSCT) in children with ALL. Main goals were 1. to answer the question, whether HSCT from a matched sibling donor (MSD) was equivalent to HSCT from a 9/10 or 10/10 HLA matched donor (MD) and 2. to standardize and harmonize the HSCT procedure. Another intention was to determine the efficacy of HSCT from HLA-mismatched donors (MMD) compared to HSCT from MD/MSD as well as the incidence of acute and chronic graft-versus-host disease (GvHD) and the antileukemic efficacy of the procedure.
Between September 2003 and September 2009, 387 patients (188 in CR1, 199 ≥ CR2) were transplanted in 27 participating HSCT centers in Austria, Germany and Switzerland. Mean age of the patients at HSCT was 10 years (range 0.5 to 18). Indications for HSCT were poor response to induction treatment, either detected by morphology on day 33 or by minimal residual disease load measured after 12 weeks of treatment, cytogenetic aberrations [t(9;22), t(4;11)], early bone marrow relapse, or any subsequent ALL relapse. 97 patients received a MSD-HSCT, 251 patients a MD-HSCT, and 39 patients a MMD-HSCT. Median follow-up was 2.4 years. The compliance with HLA-typing procedures according to the trial guidelines (high resolution typing of HLA A, B, C, DRB1 and DQB1) improved over time to 100% since 2007. Unmanipulated bone marrow was used in 81% of MSD-HSCT and in 65% of MD-HSCT as determined by the protocol. The conditioning regimens consisted of TBI+VP16 for MSD, TBI+VP16+ATG for MD, and TBI+Flu+VP16+ATG for MMD; TBI was substituted by BU+Cy in children younger than 2 years). GvHD prophylaxis (CSA for MSD, and CSA plus MTX on day 1, 3 and 6 for MD) were given in the vast majority of patients according to the trial guidelines. Protocol deviations were mostly due to clinical reasons.

Results:
Acute GvHD (Grade III and IV) occurred in 10% of all patients, the 2-year cumulative incidence of extensive chronic GvHD was 15% after MSD and 12 % after MD HSCT. The 4-year probability of event-free survival (pEFS) after MSD-HSCT was equivalent to MD-HSCT (70% vs. 68%; p=0.37). The cumulative incidence of treatment related mortality (TRM) after 1 year was 5% for MSD and 8% for MD HSCT (n.s.). The 2-years cumulative incidence of relapse was 18% after MSD-HSCT and 20% after MD-HSCT (n.s.) For patients with very high risk of relapse the results for MD/MSD HSCT (n=187) and MMD HSCT (n=39) differed significantly (2-year pEFS 68% vs. 28%; p<0.001). The 2-year incidence of relapse was 23% after MSD/MD HSCT and 37% after MMD-HSCT (n.s.). The 1-year incidence of TRM was 8% after MSD/MD-HSCT and 22% after MMD-SCT (p=0.04). Overall, MMD HSCT showed a significant worse result with higher TRM and higher relapse rates. For patients beyond CR1 (n=25) transplanted from a MMD, the 2-year pEFS was 19% only.
The results from this ALL-SCT-BFM 2003 trial, which is the largest prospective, international and multicenter HSCT trial ever performed in childhood ALL, demonstrate the feasibility of a harmonized HSCT approach across multiple international centers. We demonstrate that allogeneic HSCT from well HLA-matched unrelated donors or geno-identical sibling donors is an effective treatment option with acceptable toxicity in children with high risk ALL. Precise HLA typing and matching and ATG resulted in a low incidence of extensive chronic GvHD which is an important achievement for the quality of life in children and adolescents. These data will form a solid basis for subsequent ALL-HSCT trials, focussing on controlled modifications and interventions in patients at highest risk for relapse after HSCT.

Disclosures:
No relevant conflicts of interest to declare.