P1232: PRINCIPLES OF PRECISION ONCOLOGY IN PRIMARY REFRACTORY HIGH-GRADE B-CELL LYMPHOMA WITH MYC-, BCL2 AND/OR BCL6 REARRANGEMENTS (HGBL-DH/TH)

Abstract

Background: The optimal treatment strategy in primary refractory high-grade B-cell lymphomas with MYC-, BCL2 and/or BCL6rearrangements (prHGBL-DH/TH) remains insufficiently addressed in the light of unfavorable prognosis and recent findings concerning the mutational pathogenesis of this provisional entity. Although there is growing evidence supporting multidisciplinary molecular tumor-boards (MTB) in solid tumors, only a minor subset of MTB recommendations affects hematologic malignancies. Aims: In the present study, we aimed to emphasize the potential of MTB recommendations in HGBL-DH/TH patients (n=19) based on previously published whole exome sequencing (WES) data. Methods: For the annotation of genomic alterations, the institutional MTB pipeline (University Cancer Center Schleswig-Holstein: UCCSH), certified for routine clinical diagnostics, was employed. Consecutive data-base research and annotation according to NCT/DKTK MASTER evidence levels was performed in order to identify molecularly stratified treatment strategies. Results: Median age was 72 (range 35-79) and 68.4% (n=13) were male. Cytogenetically 7/19 cases presented with MYC/BCL2, 5/19 with MYC/BCL6 double-hit-constellation and 7/19 triple-hit lymphomas were included. The standard turn-around time for the MTB pipeline after sampling was 21 days. The applied LymphGen algorithm proposed by Wright et al.revealed the majority of cases (n=13) to correspond to the C3/EZB cluster whereas three cases corresponded to the C1/BN2 cluster and the remaining three cases were not classifiable. Our virtual institutional MTB pipeline identified molecular stratified treatment approaches in 16/19 HGBL-DH/TH cases with NCT/DKTK evidence level of m2A or higher. As proposed by Horak et al., we classified significant mutations in accordance with biomarker/treatment baskets and detected four targetable cell cycle (CC) alterations, two targetable tyrosine kinases (TK) and five others (OTH). Noticeable, 14 mutations affecting chromatin and/or epigenetic modifiers such as EZH2 or IDH1 were annotated as promising therapeutic targets. Moreover, one case presented with relevant BRCAness features suggesting the administration of a PARP-inhibitor such as Olaparib. Each recommended drug was either approved by the FDA and/or EMA or at least designated for FDA/EMA fast track development. Image:Summary/Conclusion: The applied virtual MTB approach revealed molecularly stratified treatment options alongside targetable genomic signatures in the majority of primary refractory HGBL-DH/TH patients. The present results underline the potential relevance of MTB consultations in this difficult-to-treat entity.