Retrospective and Observational Study on CAR-T 19 Bridge Therapies in Pediatric, Adolescents and Young Adults &lt;24 Years with B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Experience of the Spanish Hematopoietic Stem Cell Trasplantation and Cellular Therapy Group (GETH-TC)
Authors: Galán-Gómez Víctor , González-Martínez Berta , Alonso-Saladrigues Anna , Rives Susana , Molinos Quintana Agueda , Perez Simon Jose Antonio , Herrero-Velasco Blanca , Kwon Mi , Barba Pere , Sánchez-Salinas Mario , López-Corral Lucía , Torrent Anna , Hernani Rafael , Leon Triana Odelaisy , Pérez-Martínez Antonio 
Published: December 2023

INTRODUCTION
CAR-T therapy has revolutionized the treatment of B-ALL.
The development of CAR-T therapy is a long and delicate process where once apheresis is done, a bridge period that least until CAR-T cells are infused starts. Meanwhile, the objective will be to maintain disease control, decrease tumor burden (TB) and prevent disease progression with no severe comorbidities by the administration of a bridge chemotherapy. That will decrease the risk of severe (grade 3-4 ASTCT) Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) with an improvement of event free survival.
Nevertheless, there is no consensus nor standard guidelines about bridge chemotherapy type, especially in pediatric patients.
In this way, the main objective of this study is to identify CAR-T outcomes in pediatric, adolescents and young adults (AYA) diagnosed of BCP-ALL based on bridge chemotherapy.
MATHERIAL AND METHODS
An observational, retrospective and non-interventional study of Spanish pediatric and AYA under 24 years old diagnosed with BCP-ALL treated with tisagenlecleucel that have been registered by the Spanish Hematopoietic Stem Cell Transplantation and Cellular Therapy (GETH-TC) CAR-T clinical database from years 2017 to 2022. Data have been collected from nine centers members of GETH-TC CAR-T workgroup: La Paz University Hospital, Sant Joan de Déu University Hospital, Virgen del Rocío University Hospital, Niño Jesús Pediatric University Hospital, Gregorio Marañón General University Hospital, Vall d'Hebron University Hospital, Salamanca Clinic University Hospital, Germans Trials i Pujol University Hospital and Valencia Clinic Hospital.
General, pre-CAR-T, CAR-T-related and post-CAR-T variables have been analysed from GET-TC CAR-T database, highlighting those related to bridge therapy and related outcomes.
Bridging chemotherapy was analyzed considering whether the patients had received high (myelosuppression ≥7 days) or low (myelosuppression ≤7 days) intensity schemes, or in contrast, immunotherapy.
Fisher's Exact Test for count data and Log Rank test for Overall Survival (OS), Relapse Free Survival (RFS) and Duration of Response (DOR). Variables with p&lt;0.05 value have been considered of statistical significance.
RESULTS
Baseline characteristics of the 103 patients are summarized in Table 1.
CRS after infusion was presented in 86 (83.5%) patients. Grade 3-4 was developed in 4/29 (13.8%) with low pre infusion TB in contrast to 18/55 (32.7%) with high TB (p=0.001).
Complete remission (CR) was achieved 87 (85.3%) patients. All patients (100%) with a low TB were in CR VS 78.2% in the high TB arm (p=0.015). Otherwise, 91.9% of those patients that received low intensity bridge chemotherapy or immunotherapy were in CR VS 71% of those where high intensity bridge was administered (p=0.027).
With a median of 23.75 months, OS at 12 months was 62.23% (CI95% 51.71-74.89). No statistical significance was found between bridge chemotherapy groups, although it was higher in low intensity and immunotherapy group (68.33% CI95% 55.41-84.27) VS (57.89% CI95% 40.43-82.89) (p=0.11).
With a median of 9.26 months, RFS at 12 months was 41.7% (CI95% 31.71-54.85). No statistical significance was found between bridge chemotherapy groups, but was higher in low intensity group and immunotherapy (51.8% CI95% 39.45-68.01) VS (34.69% CI95% 18.59-64.74) (p=0.089).
With a median of 8.28 months, DOR at 12 months was 41.7% (CI95% 31.71-54.85). No statistical significance was found between bridge chemotherapy groups, with an increasing tendency in low intensity group and immunotherapy (51.8% CI95% 39.45-68.01) VS (34.69% CI95% 18.59-64.74) (p=0.089).
In the multivariate analysis, grade 3-4 CRS HR 8.7 (CI95% 0.82-92) (p = 0.072) and high TB HR 4.7 (CI95% 1.1-20) (p = 0.038) were related with a decreased OS.
CONCLUSIONS
Receiving low intensity bridge or immunotherapy is related with high rates of CR. In the same way, in this group of patients there is tendency to achieve higher OS, RFS and DOR. This is the reason because its use should be prioritized avoiding those of high intensity bridge chemotherapy.
High TB is an important risk factor related with a poor response and high grade CRS development, so it is essential to reduce TB previous CAR-T infusion in order to improve outcomes and reduce toxicities.