International Leukemia Target Board

Improvements in outcome for pediatric hematological malignancies have mainly been driven by the optimization of multi-agent chemotherapy regimens, minimal residual disease monitoring, and risk group stratification based on (cyto)genetic prognostic markers. The prognosis after (multiple) relapse(s) or other new relapsed/refractory (r/r) entities, such as relapse post CAR T-cell therapy in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and persistent MRD after reinduction therapy for relapsed T-cell ALL, remains poor. This is due to the lack of effective salvage therapies. The options for salvage therapies also differ per disease type: limited options exist in r/r acute myeloid leukemia (AML), T-cell acute lymphoid leukemia and lymphoblastic lymphomas (LBL) compared to r/r BCP-ALL. Recently, new ALL relapse categories have been identified for which an umbrella clinical trial is in development with a molecularly stratified approach: the HEM-iSMART protocol. These new categories consist of multiple relapsed BCP-ALL post CART (which frequently means also post-SCT), and T-ALL/LBL which fail reinduction therapy at first relapse. For AML, early phase clinical studies are set up in the context of the so-called PedAL initiative. Typically second or greater relapsed AML is considered an experimental indication.

Molecular profiling of leukemias and lymphomas is performed in many European countries and the results and potential treatment options are discussed in tumor boards of the national groups. However, numbers in each of these national initiatives are limited, especially when focusing on the new ALL relapse categories, whereas the type of actionable events can be numerous and different between disease types.

The international Leukemia Target Board (iLTB) is fostered by the International Berlin-Frankfurt-Muenster (I-BFM) Resistant Disease and AML committees, the European Inter-group for Childhood Non-Hodgkin Lymphoma (EICNHL) and the ITCC (Innovative Therapies for Children with Cancer in Europe), and has been initiated to discuss these national profiling results with experts from diverse disciplines at a European level, with the aim to better understand the nature of these relapses and to facilitate entry in early phase clinical trials. This will ensure that, as patients are scattered across countries, treating physicians receive the best advice about the prioritization of potential treatment options and open trials according to the patient's actionable events prioritization and treatment history when confronted with these specific relapse situations.

Different from (inter)national tumor boards focused on solid tumors, in addition to the discussion of molecular lesions at the DNA/RNA level, the iLTB will discuss immunophenotypic (CD markers)/surface antigen information and if available centralized drug response profiles (DRP) of r/r hemato-oncology patients for whom standard options for cure are very limited. The available information will be integrated by a newly developed prioritization algorithm that has been developed by an international iLTB development team and which will be optimized prospectively. An actionable event is defined in this study as a tumor characteristic for which targeted therapy is approved, or investigated in a clinical trial for any cancer indication, including but not limited to small molecules and immunotherapy.

It is hypothesized that an international platform for discussing the clinical and biological as-pects of children, adolescents, and young adults with relapsed and refractory hematological malignancies to decide the most appropriate treatment for each individual patient can be a way forward to uniform the community and to tackle these challenges.

The ultimate aim of the iLTB is to improve the outcome of patients with r/r hematological malignancies as defined above by prioritizing actionable lesions in a uniform setting through a panel of experts which advises treating physicians about matching trial(s) or the most appropriate alternative when access to a clinical trial is not possible.

The investigators would like to stress that the iLTB is a platform which is meant to timely share, harmonize, and unify the knowledge about actionable lesions and treatment options for only a subset of r/r cases in Europe, i.e., the patients where the national group asks for discussion in the iLTB, and as such the iLTB does not intend to interfere with outcome evaluations linked to national/local tumor board initiatives.

Enrollment of patients will be coordinated by a representative from the national coordinating center (NCC). Informed consent from the patient to share the data in the iLTB is the responsibility of the treating physician/NCC and is needed prior to discussing the patient's data. Results will be fed back to the treating physician via the NCC or directly.

Treatment interventions however, are not part of this study protocol. Any treatment as a result of iLTB advice will be proposed to the patient by the treating physician and will be subject to a separate consent procedure.