P316: prioritizing precision medicines in pediatric blood cancer: experience of the dutch individualized therapy (ither) study’s molecular tumor board

Background: Institutional and national molecular tumor boards have been implemented for relapsed or refractory pediatric cancer to prioritize targeted drugs for individualized treatment based on actionable oncogenic lesions. Patients with hematological malignancies form a minority in pan-pediatric cancer precision medicine programs. In the Netherlands, the individualized THERapy (iTHER) study ran from 2017 to 2022 as a prospective non-interventional study. Aims: We report on the results for 56 iTHER patients with hematological malignancies, for which we considered lineage-specific surface markers and ex vivo drug sensitivity in addition to molecular aberrations as targetable events. Methods: Tumor DNA/RNA were isolated from biopsies with ≥20% tumor. For cases enrolled till March 2020, profiling was performed by INFORM in Germany (Van Tilburg et al. Cancer Discov 2021), for later cases at the Princess Máxima Center (Langenberg et al. EJC 2022). Oncogenic lesions were prioritized using the INFORM decision tree (Worst et al. EJC 2016). Flow cytometry data with disease-specific flow panels was performed conform EuroFlow. Patients’ leukemic cells, either fresh-frozen mononuclear cells or cells harvested from patient-derived xenografts, were exposed for 3-4 days to several drugs, depending on cell availability and genetic targets. Results: The median age at inclusion was 13 years (range 0.9-23). Disease entities included 25 acute lymphoblastic leukemia (ALL), 18 acute myeloid leukemia (AML), 10 non-Hodgkin lymphoma (NHL), two Hodgkin lymphoma (HL) and one stem cell leukemia/lymphoma (SCLL). All T-ALL and lymphoma cases were included at first relapse, primary refractory, or primary high risk, while 39% of AML (7/18) and 50% of BCP-ALL (10/20) cases were included at second or further relapse. Prior to iTHER tumor board discussion, 34% of the patients had undergone allogenic stem cell transplantation, 50% had received anti-CD marker immunotherapy (including CAR-T in 11 patients), and 12.5% had received targeted treatment. For 51 of 56 patients (91.1%), material with sufficient tumor percentage (≥20%) was available for molecular analyses. The median time between study registration and discussion in the iTHER tumor board was 40 days for iTHER1 (sample shipment and profiling at INFORM) and 25 days for iTHER2 (profiling at the Princess Máxima Center). Targetable oncogenic alterations across 55 genes were identified in 49/51 cases (median 3, rang 1-10 alterations per case) with at least an intermediate priority target in all these cases. Targeted treatment based on the iTHER advice was given to 29% (14/51) of the profiled patients; the targeted drug matched a genetic aberration in a tumor driver in 13 patients and was chosen based on ex vivo drug sensitivity in 1/15 patients with available DRP data. Six patients identified with very high priority tyrosine kinase gene fusions received the recommended inhibitor. Targeted therapy was combined with cytarabine or azacitidine in AML patients and with dexamethasone or other induction therapy drugs in ALL patients. Immunotherapy treatment after iTHER advice was given to 41% (21/51) of the profiled patients, 8 of which had not previously been treated with immunotherapy. Summary/Conclusion: The presence of intermediate and higher priority genetic targets in addition to targetable cell surface markers in all profiled relapsed/refractory pediatric hemato-oncology cases indicates multiple opportunities for targeted and immunotherapy treatment. These results warrant international collaboration to combine expertise for this rare, heavily pre-treated, pediatric population.Keywords: Hematological malignancy, relapsed/refractory, Targeted therapy, Pediatric