Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia: Why Do Adolescents and Young Adults Outcomes Differ from Those of Children? a Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)
Authors: Grain Audrey , Rialland Fanny , Chevallier Patrice , Blin Nicolas , Dalle Jean-Hugues , Michel Gerard , Dhedin Nathalie , Peffault De Latour Regis , Pochon Cecile , yakoub Agha Ibrahim , Bertrand Yves , Sirvent Anne , Jubert Charlotte , Forcade Edouard , Berceanu Anna , Gandemer Virginie , Schneider Pascale , Bay Jacques-Olivier , Rohrlich Pierre Simon , Brissot Eolia , Paillard Catherine , Plantaz Dominique , Nguyen Quoc Stephanie , Gonzales Fanny , Maillard Natacha , Planche Lucie , Baruchel Andre 
Published: November 2021

Abstract
Introduction:
Adolescents and Young Adults (AYA) represent a specific population in the Acute Lymphoblastic Leukemia (ALL) landscape, often presenting high-risk diseases and increased chemotherapy-related toxicities. Indications of Hematopoietic Stem Cell Transplantation for pediatric patients (HSCT) have been restricted to those with early poor response to chemotherapy. The same trend has led to a decrease of HSCT indications in AYAs, which are nevertheless still more frequent than in younger counterpart. Outcomes of AYAs after HSCT seemed to be worse than the ones of children in two previous studies published in 2013 and 2014. In Minneapolis, the decrease of overall survival in AYA was attributed to an excess of Treatment Related mortality (TRM) (28% versus 14%; p=0.04), but because of small numbers, factors influencing TRM were not identified. Our study aimed to compare, in a large cohort, the outcomes of children and AYA with ALL after HSCT and to determine factors influencing potential differences.
Material and Methods:
All patients aged between 1 and 25 years, reported in the SFGM-TC (Francophone Society of bone marrow transplantation and cellular therapy) registry, who received a first HSCT in treatment for ALL between 2005 and 2012 were included. The AYA group was defined by age range between 15 and 25 years old, according to European studies and the SFGM-TC. Data about diagnosis and transplantation procedure were prospectively collected in the registry. Before transplant procedure, patients or their parents/guardians provide a signed consent in order to be included in the registry.
Results:
891 patients were included, 494 children and 397 AYA. Median time of follow up was 45.6 months (0 to 114). HSCT was performed in first CR for 56.8% of the AYAs, whereas 57.5% of children received HSCT in second CR or more advanced phase (p&lt;0.001). HSCT procedures mainly included a Myelo-Ablative Conditioning (MAC) regimen. TBI was used more frequently in AYAs than in children (90.1% versus 83.1%, p=0.003). Bone Marrow (BM) or Cord-Blood (CB) were often used in children 60.2% and 29.4% versus 55.6% and 16.4% in AYA group respectively (p &lt; 0.0001) . Peripheral Blood Stem Cells (PBSC) were more frequently used for AYA (28%) than for children 10.3% (p &lt; 0.0001). Moreover, when being transplanted in an adult center, PBSC were more commonly used for AYA (30% of AYA's HSCT in adult centers versus 21.2% of AYA's HSCT in pediatric centers, p=0.051). BM and PBSC cells were provided by a match sibling donor (MSD) in 40.2% of children and 43.4% of AYAs and from a MUD in 57.2% and 55.1% of cases respectively (p = 0.474). Anti-thymoglobulins (ATG) were used for 336 patients (48% of children and 26% of AYA patients, p&lt;0.001). See patient's characteristics in Table.
Five-year OS was lower in AYA 53.1% versus 64% (p = 0.0012) and we confirmed higher 5-years TRM in AYA 19% versus 13% (p=0.04). TRM incidence markedly rose after 10 years of age (from 9% before 10 years old to 20% between 10 and 15 years, and 17% after 15 years).
Graft versus host disease and Relapse Free Survival probability (GRFS) was lower in AYA: 36% versus 47% (p=0.007), while Cumulative Incidence of Relapse (CIR) and acute Graft versus Host Disease (GvHD) incidence were both similar in our two groups: 32% and 61% in AYAs versus 27% and 59% in children, (p=0.19 and p=0.62), respectively. Thus, chronic GvHD, which occurred more frequently in AYA than in children (32% versus 19%, p&lt;0.001), mainly impact post-HSCT morbi-mortality in AYA (Figure 1 and 2).
In our multivariate analysis, two factors were associated with higher risk of cGvHD: use of PBSC as stem cell source (HR 1.41 [0.96-2.07], p=0.083), and absence of ATG use (HR associated with use of ATG: 0.62 [0.42-0.92], p=0.017) (Figure 3). Of note a subgroup analysis in patients who received a bone marrow transplant after a MAC, showed no TRM difference between AYA and children.
Conclusion:
AYA or patients aged more than 10 years, compared to ones aged less than 10 years have a worse outcome after HSCT for ALL. Excess of death in this specific population is mainly due cGvHD. Transplantation practices in those patients, particularly choice of stem cells source and GvHD prophylaxis, should be discussed. Their treatment adherence should also be questioned and reinforced by development of multidisciplinary teams.
Figure 1 Figure 1.

Disclosures
Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Forcade: Novartis: Other: travel grant.