Risk Factors Affecting Outcome of Transplantation in Pediatric Acute Lymphoblastic Leukemia: Results of the International BFM ALL SCT Study
Authors: Balduzzi Adriana , Dalle Jean-Hugues , Lankester Arjan C , Yaniv Isaac , Yesilipek Akif , Sedlacek Petr , Ifversen Marianne , Sufliarska Sabina , Bierings Marc B , Wachowiak Jacek , Toporski Jacek , Poetschger Ulrike , Glogova Evgenia , Hirsch Ingeborg , Peters Christina 
Published: October 2019

Abstract
BACKGROUND. Allogeneic hematopoietic stem cell transplantation (HSCT) is of benefit in pediatric patients with high-risk acute lymphoblastic leukemia (ALL) in first or further remission. Whether transplantation from unrelated donors could yield similar results to transplantation from HLA identical siblings is still to be assessed within countries running different frontline and relapse protocols.
AIM OF THE STUDY. A prospective study was initiated within the International BFM Study Group, in order to assess whether the outcome of HSCT from a 9 or 10 out of 10 HLA allelic matched compatible donor (MD) was inferior to the outcome of HSCT from a matched sibling donor (MSD) in children or young adults with ALL carrying very high risk eligibility criteria for transplantation. Primary endpoint was event-free survival (EFS) and secondary endpoints were non-relapse mortality (NRM) and incidence of acute and chronic graft-versus-host disease (aGVHD, cGVHD).
PATIENTS AND METHODS. Between 2007 and 2013, 10 countries (Czech Republic, Denmark, France, Israel, Italy, The Netherlands, Poland, Sweden, Slovakia, Turkey) participated into the ALL SCT I-BFM Study, coordinated by Peters in Vienna. 298 consecutive patients, 18 years old or younger (70% male, median age 9 years), affected with VHR ALL in complete remission (CR), were enrolled in the core arm of the Study (MD vs MSD). Of 298, 107 patients were transplanted from a MSD (50% in CR1, 47% in CR2, 4% >CR2) and 191 from a MD (44% in CR1, 48% CR2, 9% >CR2), either related (5%) or unrelated (95%), at a median of 189 and 197 days, respectively, after diagnosis/relapse. As per protocol, conditioning regimen consisted of TBI-etoposide, in patients older than 2 years, or busulfan-cyclophosphamide-melphalan, in patients 2 years or younger, and GVHD-prophylaxis consisted of cyclosporine (CSA) only for MSD and CSA/methotrexate/ATG for MD recipients. Median follow-up for alive patients was 3.1 years.
RESULTS. Three-year EFS was 67% (SE 5%) for MSD vs 61% (SE 4%) for MD recipients (p-value 0.254), overall survival (OS) 76% (SE 4%) vs 69% (SE 4%) (p-value 0.207), cumulative incidence of relapse (CIR) 24% (SE 4%) vs 22% (SE 3%) (p-value 0.935) and NRM 8% (SE 3%) vs 16% (SE 3%) (p-value 0.094), respectively. There was a trend for a higher risk NRM for MD patients, although no statistical significance was reached (HR 1.94, CI 0.85-4.41; p=0.114), after adjusting for risk profile and donor type. Being transplanted in CR2 was associated with lower EFS and higher NRM (p=0.001).
Grade II-IV acute GVHD occurred in 37% and grade III-IV in 16% of MSD vs 42% and 15% of MD recipients; 39% of the evaluable MSD and 19% of the MD recipients experienced chronic GVHD, which was severe in 24% and 10%, respectively. Cumulative incidence of developing chronic GVHD was 39% (SE 5%) and 17% (SE 3%), for patients grafted from MSD and MD, respectively (p=0.001). Being transplanted from a MD, compared with a MSD, was significantly associated with a reduced risk of developing chronic GVHD (HR 0.31, CI 0.18-0.54, p <0.001), despite a similar risk of relapse (HR 0.81, CI 0.47-1.39; p=0.440). Acute GVHD grade 3 or 4 had statistically significant impact on NRM (HR 4.76, CI 2.33-9.74; <0.001) and OS (HR 1.97, CI 1.14-3.42; p=0.016), after adjusting for risk profile and donor type.
CONCLUSIONS. Outcome of transplantation of MD pediatric recipients with VHR ALL in CR was not inferior to the outcome of MSD recipients in terms of EFS, OS, and CIR, with probability of chronic GVHD being lower for MD versus MSD recipients, which suggests the crucial role of serotherapy, and severe acute GVHD being associated with increased NRM and lower OS but similar CIR.

Disclosures
Dalle: Gilead: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Macopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Peters:Medac: Research Funding; Fresenius: Research Funding; Amgen: Research Funding; Jazz: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanovi: Research Funding; Pierre-Fabre: Research Funding.