Impact of Salvage and Bridging Therapy in Adult Patients with Refractory B-Cell Acute Lymphoblastic Leukemia (B-ALL) Referred for Anti-CD19 CAR T-Cell Therapy: An Intention to Treat Analysis
Authors: Ortiz-Maldonado Valentin , Martinez-Cibrian Nuria , Del Campo Balguerías Gonzalo , Español-Rego Marta , Navarro Sergio , Brillembourg Helena , Alserawan Leticia , Castella Maria , Benitez-Ribas Daniel , Magnano Laura , Correa Juan Gonzalo , Rivero Andrea , Mozas Pablo , Oliver-Caldes Aina , Gine Eva , Rodríguez-Lobato Luis Gerardo , Martínez-Roca Alexandra , Montoro-Lorite Mercedes , Ayora Pilar , Fernández de Larrea Carlos , Pascal Mariona , Esteve Reyner Jordi , Urbano-Ispizua Alvaro , Juan Manel , Delgado Julio 
Published: December 2023

Background: Prognosis of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) is poor, particularly after allogeneic hematopoietic cell transplantation (alloHCT). In this setting, several CAR T-cell products targeting CD19 (CART19) have been able to achieve complete response (CR) rates of 70 to 90%. However, a significant proportion of these patients still relapse. Several studies focus on the effect of the CART19 product on efficacy, however, information on how salvage therapy (ST) and bridging therapy (BT) can modulate the outcomes of CART19 therapy is scarce.

Methods: We report the outcomes of all adult patients with R/R B-ALL intended for treatment (aphaeresis performed) with available CART19 products in a single institution from Jul 2017 to Jul 2023. This includes patients intended to receive the academic varnimcabtagene autoleucel (var-cel) in the CART19-BE-01 trial and the consecutive compassionate use and hospital exemption programs, as well as with commercially available tisagenleuceucel (tisa-cel). Lymphodepletion was performed with fludarabine (90 or 120 mg/m 2) and cyclophosphamide (900 or 1000 mg/m 2), followed by the infusion var-cel or tisa-cel, respectively. We analyzed all ST (treatment administered after last relapse before CART19-apheresis) and BT (treatment administered after apheresis and before CART19 infusion) performed, and analyzed the impact of BT on PFS and OS after apheresis.

Results: A total of 74 adult B-ALL patients underwent leukapheresis and CART19 (var-cel/tisa-cel) production. At screening patients had a median age of 34 years (19-78), 45% were females, with a median of 3 prior lines of therapy (2-7) including inotuzumab (69%), blinatumomab (27%) and allo-HCT (84%). After last relapse, 92% of patients received ST with a median of 1 (0-3) treatment line, including inotuzumab (48%), high-dose chemotherapy (28%), low-dose chemotherapy (21%), TKIs (12%), blinatumomab (9%), radiotherapy (7%) and DLIs (4%). The overall response to ST prior apheresis was MRD-negative CR (28%), MRD-positive CR (22%), partial response (4%) and progressive disease (PD) in 46%. After apheresis was secured, BT was performed in 76% of patients with a median of 1 (0-2) bridging line, including low-dose chemotherapy (44%), intrathecal therapy (23%), high-dose chemotherapy (15%), TKIs (15%), inotuzumab (14%), radiotherapy (3.5%), blinatumomab (1.8%) and DLIs (1.8%). BT was not administered in 24% (8/74) of patients mainly due to morphological remission at screening (83%) and frailty (11%). The overall response to BT prior CART19 infusion was MRD-negative CR (31%), MRD-positive CR (12%), partial response (7%) and progressive disease (47%), with a 3% treatment related mortality (TRM) events attributed to BT. Inotuzumab administration occurred either as ST or BT to CART19 in 86% of patients (the remaining 14% was previouly given as bridge to allo-HCT), and was able to achieve MRD-negative CR in 42% of patients. The overall control of the disease after BT either worsened (51%), remained similar (14%), or improved (35%). After this, 12% (n=9) of CART19 treatments were not performed due to progressive disease (33%), TRM (22%), therapeutic alternative (22%), and production failure (11%). Infused patients achieved an MRD-negative CRR of 90% with a median PFS of 11,2 months. There were no differences in OS between patients with ≥5% or &lt;5% bone marrow (BM) blast counts either before apheresis (ITT, figure 1) or after BT prior to CART19 infusion. However, despite the lack of apparent impact of this disease burden categorization on the OS at both timepoints, a statistically significant difference was observed after categorizing patients regarding the response to BT (figure 2), with a median PFS of 6.6 vs 18.6 months if the overall disease status of the patients either worsened or remained stable/improved after BT (p=0.0002).

Conclusions: To the best of our knowledge this could be one of the first studies focusing on the impact of ST and BT in adult patients with R/R B-ALL referred for CART19 therapy. These results suggest that the potentially synergistic impact of bridging therapy may be mediated more by the modulation exerted by BT on the proliferative kinetics of the disease rather than on the absolute tumour burden of the patient. More detailed results on the independent impact of each type of BT will be provided in the final presentation.