Despite significant improvements in the treatment of ALL, r/rALL remains an unresolved therapeutic challenge. CAR T-cell therapy and/or a second HSCT may provide a long-term cure, but require an initial bridging therapy. This bridging therapy involves a variety of approaches in different centers and is currently often an approach based on individual trial and error rather than scientific evidence. However, the decades-long development of first-line ALL therapy has shown how successful a common set-up of treatment protocols can be. In order to standardize bridging therapy, we want to join forces of six Bavarian centers for pediatric hematology together with six centers for adult hematology to develop a uniform treatment approach for r/rALL.

Remission induction and bridging therapy remain a challenge in these heavily pre-treated patients when it comes to balancing the risk of toxicity and efficacy. The goal of bridging therapy is to reduce the leukemic burden and maintain the patient in a stable clinical condition without causing high-grade toxicities. In this study group, the current status of bridging therapy in children and young adults with r/rALL will be further developed towards a common protocol that will be evaluated in a clinical trial. Within 18 months, the r/rALL study group will develop a guideline for multimodal bridging therapy prior to CAR T-cell treatment or second HSCT in children and young adults with relapsed/refractory ALL based on existing retrospective data. In addition, a prospective registry for children and young adults with r/rALL in Bavaria and beyond will be established. The analysis of biomarkers for the subsequent response to immunotherapy approaches and the generation of new mechanistic hypotheses with a focus on the leukemia-immune interaction is also planned. The data obtained can then be used to prepare and define a future clinical trial in accordance with GCP and to establish structures for conducting the trial.

Over the next 18 months, the following activities and project measures will be pursued by the r/rALL study group:

Phase 1: Establishment of Bavaria-wide networking structures between all six pediatric and adult hematology centers with quarterly video-based meetings to streamline the currently hypervariable and inconsistent treatment approach towards a future common clinical protocol. Networking also includes an ad hoc clinical panel that provides a cross-center forum for the discussion of individual cases (until the end of 2022).

Phase 2: The ongoing retrospective analysis of bridging therapies will be evaluated to document the status quo for r/rALL (by the end of 2022).

Phase 3: Writing and publishing a guideline for bridging therapy in r/rALL as a consensus paper with expert opinion. (Submission by 06/2023).

Phase 4: Establishment of a prospective registry with BZKF-wide software and e-CRF (by 06/2023).

Phase 5: Preparation of a joint clinical GCP study requires scientific advice (BfArM), preparation of ethics committee approval, selection of a CRO, preparation of a clinical study protocol, IB and IMPD (by end of 2023).

Phase 6: Based on the BZKF's efforts on joint study contracts, data protection, databases and biobanks, we will cryopreserve blood and bone marrow samples from children and young adults with r/rALL to perform biomarker analyses and future hypotheses in terms of back translation into accompanying research projects.

Phase 7: Establish activities for innovative local subprojects, including toxicity management and projects derived from the data collected in phases 2 and 6.