Abstract Introduction: The last decade has seen the deep genomic characterization of childhood leukemia, but the clinical implementation of these discoveries remains to be tested. Our Regional Leukemia Genomics Study aimed at expanding access to genomic profiling and interpretation via multidisciplinary tumor boards to pediatric oncology centers in the Northeast, and to assess its impact on diagnosis, prognosis and treatment selection in patients with leukemia. Study Design 100 patients with leukemia were enrolled between November 1, 2021 and December 16, 2024 across six institutions (Albany, Connecticut Children’s, Dartmouth-Hitchcock, Hasbro Children’s, Maine and University of Vermont Medical Centers). Leukemia samples were profiled using targeted DNA-based panel (RHP) for mutations and copy number changes, and an RNA-based fusion panel, without germline matching. Profiling results were returned to clinicians and reviewed at monthly tumor boards for selected cases. Results: Median age at enrolment was 9 years (0–22 years) with 91% of patients having newly diagnosed leukemia. The most common diagnoses were B and T-cell acute lymphoblastic leukemia (B-ALL n=72; T-ALL n=12). 243 sequence variants were identified by RHP in 83 patients, of which 189 were classified as pathogenic. The most frequent mutations (31%, 59/189) involved the RAS pathway, 73% of which were oncogenic per OncoKB. Fourteen samples had cryptic rearrangements identified by our panel, including nine rare fusions (ETV6: : BCL2L14, ETV6: : LMBR1, PAX5: : FBRLS1, RNF38: : PAX5, SET: : MLLT10, KAT6A: : NCOA2, KMT2A: : AFDN, KMT2A: : USP2, KMT2A: : BCAT1) with potential diagnostic and prognostic relevance. Germline predisposition was considered in 11 cases for selected genes (ETV6, IKZF1, ATRX, GATA2, PAX5, TERT, TP53) based on variant allele frequency (VAF) and tumor board review. One PTPN11 variant (E258K, VAF 42. 7%) associated with Noonan syndrome was confirmed to be germline. Twenty-two targeted therapy possibilities were discussed at tumor boards, with FLT3-ITD (gilteritinib/sorafenib), ABL-class fusions (tyrosine kinase inhibitors (TKI) ), RAS pathway mutations (MEK and RAS-inhibitors), CRLF2 (ruxolitinib) or KMT2A rearrangements (menin inhibitors) as most frequent, potentially actionable events. Detection of cryptic fusions led to treatment changes for three patients, including ones with NUP98-rearranged relapsed acute myeloid leukemia (AML), KMT2A: : BCAT1 AML and NUP214: : ABL1 relapsed B-ALL. Matched diagnostic and relapse samples were collected for four patients, including one patient with leukemia lineage switch after first relapse treatment with blinatumomab. TP53 mutations were acquired at relapse in three of the four relapsed leukemias. Conclusion: Our study gave pediatric patients with leukemia from Northeast centers access to state-of-the-art clinical genomic profiling. We demonstrated the feasibility and early impact of integrated sequencing and tumor board approach to inform diagnosis, prognosis, therapy choices and referrals for genetic counseling. Citation Format: Sabrina Testa, Nathan Hope, Catherine F. Seaman, Victoria Koch, Shanna L. Richard, Jessica Geaney, Natalie S. Bezler, Angela M. Ricci, Jennifer J. G. Welch, Sei-Gyung Sze, Jessica Heath, Trevor Coles, Melissa Burns, Marian H. Harris, Harrison K. Tsai, Andrew E. Place, Jessica A. Pollard, Yana Pikman. Expanded genomic profiling informs clinical management of pediatric patients with leukemia treated at Northeast pediatric cancer programs abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₂): Abstract nr B001.
Testa et al. (Thu,) studied this question.