Multinational Retrospective Analysis of Bridging Therapy Prior to Chimeric Antigen Receptor T Cells for Relapsed/Refractory Acute Lymphoblastic Leukemia in Children and Young Adults

Background: Chimeric antigen receptor (CAR) T cells targeting CD19 are a well-established treatment option for children and young adults suffering from relapsed and/or refractory B-lineage acute lymphoblastic leukemia. Nonetheless, there is still insufficient data about the proper management of bridging therapy between eligibility for therapy and administration of CAR T cells taking into consideration that most of the patients are heavily pretreated. Bridging therapy has been designed to achieve a low leukemia burden prior to CAR T cell infusion. However, systematic data of bridging therapy are still limited and the effect of bridging therapy on outcome, side effects and response to CAR T cell therapy is still poorly understood. With this retrospective, multinational, large-scale study, we strive to understand the impact of low- and high-intensity bridging regimens on a variety of outcome parameters in order to improve the basis for clinical decision making in bridging therapy prior to CAR T cell administration.

Methods: Real-world data were collected from 83 patients receiving 88 CAR T cell therapies from twelve different sites in Germany, Austria and Switzerland. Data were collected anonymously via paper case report forms and subsequently analyzed. Performed treatments were classified into the categories 1) no systemic therapy, 2) low-intensity therapy and 3) high-intensity therapy. Bridging therapies were defined as high-intensity if at least one chemotherapeutic agent of the following was given: cyclophosphamide/ifosfamide, etoposide, anthracyclines or other agents with high toxicity potential (intravenous methotrexate, platinum-based antineoplastic drugs, thiotepa, high-dose cytarabine, fludarabine). Low-intensity bridging therapies comprised the administration of steroids, vincristine, low-dose cytarabine, PEG-asparaginase/Erwinia asparaginase and oral maintenance therapy (mercaptopurine, thioguanine, oral methotrexate, hydroxyurea). The administration of specific chemotherapeutic agents as well as immunotherapies and targeted therapies was assessed. CAR therapies comprised CD19 2 ^nd generation CAR T cell products from commercial and academic providers. We then analyzed the impact of different bridging regimens on several outcome parameters such as overall and disease-free survival, adverse events, tumor burden and performance status at defined time points (eligibility, leukapheresis if performed, lymphodepletion/CAR T cell infusion).

Results: 33 of 88 treatments were classified as high-intensity and 34 as low-intensity bridging regimens. Prior to 13 CAR T cell administrations no systemic bridging therapy was given, 8 of 88 bridging regimens could not be stratified due to incomplete data (Figure 1). Between eligibility and apheresis, mostly low-intensity therapy or no systemic therapy was given. Within the period between apheresis and CAR T cell infusion, treatment diversified due to the heterogeneity of the cohort. Patient characteristics are listed in Table 1. Patients receiving a high-intensity bridging therapy had a significantly higher tumor burden at time point of eligibility defined by blasts in bone marrow and by measurement of minimal residual disease (MRD) compared to patients treated with a low-intensity or no systemic bridging therapy. Tumor burden within the two groups converged over the time of bridging therapy. However, at time of lymphodepletion, patients in the high-intensity group showed a significantly lower performance status indicated by Karnofsky/Lansky score than patients in the low-intensity/no systemic therapy group, reflecting the higher toxicity potential. Furthermore, these patients suffered significantly more often from bacterial adverse events and mucositis. Neither overall nor disease-free survival differed significantly between the two bridging regimen groups.

Conclusion: In this retrospective cohort data, a high-intensity bridging therapy has not improved the outcome of CAR T cell therapy in terms of overall and disease-free survival. Yet high-intensity bridging therapy has caused more mucositis, bacterial adverse events and worsened the performance status. Our study suggests that a low-intensity bridging regimen may be preferred whenever tumor burden and disease kinetics allow this treatment strategy.