Bridging Pediatric B-Cell Acute Lymphoblastic Leukemia (ALL) Patients to CAR-T Cell Therapy: A National Perspective

Introduction:

Bridging therapy (BT) is given between leukapheresis and lymphodepletion to reduce disease burden (DB) or prevent progression. Published guidelines (Mishra et al. 2024 BJH; Feuchtinger et al. 2024 Haematologica) exist, but evidence to guide the choice of BT is scant. High DB before CAR-T has been associated with worse prognosis (Schultz et al. 2022 JCO). The timepoints of disease assessment and the types of BT across institutions vary however, precluding clear guidance. We sought to systematically collect data on DB and bridging therapies given within a large national multicentric cohort with the aim of correlating BT with patient outcome.

Methods:

From August 2016 to July 2024, 144 patients were included. All received systemic BT and 140 (97%) received a CAR-T cell product (tisagenlecleucel: 118 patients, anti-CD19 academic product: 10, anti-CD19 and CD22 dual targeting product: 12). Bone marrow (BM) aspirates were obtained before and after each BT course. High DB was defined by blasts in peripheral blood or ≥5% blasts in the BM detected by flow cytometric or quantitative PCR for leukaemia specific IgH gene rearrangements. Where this was not available, morphological assessment was used. Low DB was defined by disease not meeting high DB criteria. Response was defined as going from high DB to low DB, more than 5% disease reduction, or maintaining low DB between the two timepoints. Resistant disease was defined as high DB with less than 5% reduction, progression was defined as DB going from low to high.

Results:

Of 144 included patients, seventy-four patients (53%) were noted to have been refractory to prior therapy at any point, 13 (9%) had had previous CAR-T cell infusions and 60 (42%) had had a previous hematopoietic stem cell transplant (HSCT).

Ninety-seven patients (67%) received one course of BT, 40 (28%) received two courses (28%), 5 (3.5%) received three courses, and one (0.7%) received five courses. Of a total of 198 bridging courses, escalating intravenous methotrexate with Vincristine (per Capizzi interim maintenance but omitting asparaginase) was the most commonly used [n = 60 (30%)], followed by maintenance [n = 47 (24%)], vincristine and dexamethasone [n = 22 (11%)], Inotuzumab [n = 22 (11%)], high-dose cytarabine [n = 13 (6.5%)], and tyrosine-kinase inhibitor-based therapy [n = 11 (5.5%)]. 23 patients (12%) received a variety of other BT regimens. Capizzi was predominantly used as first line [n = 53/144 (37%)], whereas Inotuzumab was preferred as second-line [n = 15/47 (32%)].

Before BT, 80 patients (56%) had a high DB, with a mean blast percentage of 27%. After completing all courses of BT, 46 patients (32%) remained with high DB before infusion, with a mean blast percentage of 12%. Response to BT was as follows: 98 patients (68%) responded, 12 (8%) had resistant disease, 12 (8%) progressed, and 22 (15%) had no response data available. Of all patients who received Capizzi (n = 60), 38 patients (63%) responded. With Maintenance (n=47), 31 patients (66%) responded. With Inotuzumab (n=22), 12 patients (55%) responded, where 97% of patients started with high DB.

Conclusion:

Patients mostly received low-intensity/outpatient chemotherapy regimens as part of their BT plan. Around 50 – 60% of patients responded to BT. Inotuzumab was often given as a second-line agent, but only 55% responded. Further outcomes which are being analysed currently include toxicity, timeliness of proceeding to CAR-T cell therapy, and finally linking BT and DB to post CAR-T cell outcomes. These additional data will be shared at the congress. Calculating the impact of DB before and after BT and linking it to CAR-T outcomes will aid in dissecting the relative contributions of disease biology and BT choice in outcomes post CAR-T cell therapy.