R/R ALL

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and young adults. An unsolved challenge remains relapsed/refractory ALL (r/rALL). Currently, there is no standard treatment for r/rALL and new approaches are urgently needed. Therefore the setup of bridging therapy und analysis of ALL immune interaction as biomarkers for response is this studies subject.

Concept

Initial Situation
Despite significant improvements in the treatment of ALL,¹ r/rALL remain an unsolved therapeutic challenge. CAR T-cell therapy and/or a second HSCT can facilitate long term cure, ^2,3 but require initial bridging therapy. This bridging therapy includes a broad variety of approaches across centres and is currently often an approach of individual trial-and-error, rather than of scientific evidence. However, decades of development in ALL first-line treatment have shown how successful a collaborative set-up of joint treatment protocols can be. To standardise bridging therapy, we want to join forces across six bavarian centres for pediatric hematology together with six centres for adult hematology, to develop a standard treatment approach for r/rALL.

Study Objectives
The remission induction and bridging therapy remains a challenge in balancing risk of toxicity and efficacy in these heavily pretreated patients. The aim of bridging therapy is to reduce leukemia burden and keep the patient in a stable clinical condition without causing high-grade toxicities. This study group is going to advance the current status of bridging therapy in children and young adults with r/rALL towards a collaborative protocol, evaluated in a clinical study. Within 18 months, the study group r/rALL will develop a guidance for multimodal bridging therapy before CAR T-cell treatment or 2nd HSCT in children and young adults with relapsed / refractory ALL based on existing retrospective data. Furthermore a prospective registry for children and young adults with r/rALL in Bavaria and beyond will be set-up. Analysis of biomarkers for later response to immunotherapy approaches and for the generation of novel mechanistic hypotheses, focusing on leukemia-immune-interaction is also planned. Through the achieved data preparing and defining a future GCP clinical trial and set-up of structures for the conduction of the trial is then possible.

Milestones

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

Phase 1: Set-up of networking structures across Bavaria between all six pediatric and adult

hematology centres with quarterly video-based meetings to streamline the currently

hypervariable and inconsistent treatment approach towards a future joint clinical protocol.

Networking will also include an ad-hoc clinical board to provide a multi-centre forum for

the discussion of individual cases (until end of 2022).

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

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

Phase 4: Set-up of a prospective registry using BZKF-wide software and e-CRF (until 06/2023).

Phase 5: The preparation of a joint clinical GCP trial require Scientific Advice (BfArM), preparation of ethical review board approval, selection of a CRO, preparation of a clinical trial protocol, IB and IMPD (until end of 2023).

Phase 6: Based on the BZKF efforts in joint study contracts, data protection, databases and

biobanking, we will cryopreserve blood and bone marrow samples from children and

young adults with r/rALL for biomarker analyses and generation of future hypotheses in

terms of reverse translation in accompanying research projects.

Phase 7: Set-up of activities for innovative local sub-projects, including toxicity management and projects derived from data assembled in 2 & 6.

Long-term goals

» Advance the current status of bridging therapy in children and young adults with r/rALL towards a collaborative protocol, evaluated in a clinical study.

» Establishing the network and promote further collaboration
» Defining and publish therapy guidelines
» Preparing and defining a future clinical trials and set-up of structures for the conduction