{"doi":"10.1002/hon.70094_189","title":"189 | THERAPY‐DRIVEN EVOLUTION AND INTRATUMORAL GENETIC HETEROGENEITY IN CNS LYMPHOMAS","abstract":"D. A. Solomon and H. Geng equally contributing author. Introduction: There remains a significant gap in our understanding of the molecular pathways that mediate therapeutic resistance and disease progression in CNS lymphoma (CNSL). CNSL generally exhibit multifocal dissemination as an end-stage manifestation. Methods: To elucidate key genetic and pathophysiologic pathways of CNS lymphoma that mediate resistance, we combined molecular histopathologic analyses, MRI, and next generation sequencing to compare the genetic features of PCNSL and SCNSL at the time of diagnosis with multifocal lesions isolated from relapsed, treatment-refractory disease from matched patient specimens at final progression, isolated from whole brain autopsy specimens. Pathways were evaluated in a patient-derived xenograft model of CNSL. Whole-exome sequencing from diagnostic specimens (4 brain and 1 retinal biopsy) were compared with matched whole brain autopsy specimens in 5 patients: 4 with PCNSL and 1 with SCNSL. A median of 6 distinct anatomical CNS lymphoma-containing brain regions were analyzed/whole brain autopsy specimen. Median age was 57 (range 51–81 yrs). Two patients died after primary refractory disease to methotrexate-based induction and three died after median of four progressions including after lenalidomide and pomalidomide. Results: CNS lymphoma progression in autopsy specimens was consistently detected in non-enhancing lesions, often with caudal progression. While intratumoral Ki67 and PAX5 expression did not exhibit intralesional heterogeneity, phylogenetic trees revealed significant mutational evolution from germline to biopsy and autopsies, with shared and autopsy-specific mutations and copy number aberrations in individual lesions. HLA-A mutations, 6p21–6p22 loss (HLA genes) and acquired high-level focal PD-L1 (9p24.1) amplification were detected in autopsy specimens. While CD163+ macrophage expression was stable, CD8+ T cells were significantly reduced in autopsy lesions compared to paired and an external set of 22 diagnostic specimens of PCNSL. Ch7 gains were reproducibly detected in autopsy specimens, and intratumoral expression of candidate Ch7 genes was confirmed, including MET and IKZF1. Distinct from PAX5 whose expression was uniform, IKZF1 expression at progression was highest at the edge of lymphomatous lesions, invading into normal brain. Mutations in the IKZF1 pathway were selectively enriched in patients treated with lenalidomide. Acquired cereblon loss in autopsy lesions was also reproducibly detected in patients treated with lenalidomide. Preclinical PDX models of CNSL confirmed a correlation between cereblon expression, IKZF1 degradation, transcriptional regulation of IKZF1 target genes, and lenalidomide response. Conclusions: CNSL exhibit significant intralesional genomic heterogeneity at progression. Acquired genomic alterations likely contribute to immunosuppresion and the IKZF1 pathway may contribute to CNSL invasion and therapeutic resistance. Research funding declaration: Supported by a grant from the Leukemia and Lymphoma Society and by NIH R01CA139-83-01A1 Keywords: genomics, epigenomics, and other -omics; pathology and classification of lymphomas; aggressive B-cell non-Hodgkin lymphoma No potential sources of conflict of interest.","journal":"Hematological Oncology","year":2025,"id":568551,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9447,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":272482,"name":"Huimin Geng","orcid":"0000-0001-5339-5446","position":1,"is_corresponding":false},{"id":1057212,"name":"Michael P. Randall","orcid":"0000-0002-8687-1514","position":2,"is_corresponding":false},{"id":1472827,"name":"Rachel E. Sobel","orcid":"0000-0002-4492-9562","position":3,"is_corresponding":false},{"id":377506,"name":"Joseph C. Cleveland","orcid":null,"position":4,"is_corresponding":false},{"id":1271930,"name":"Aishwarya Ballapuram","orcid":null,"position":5,"is_corresponding":false},{"id":1472828,"name":"L. Chen","orcid":"0000-0002-4471-1256","position":6,"is_corresponding":false},{"id":1013565,"name":"Ming‐Chi Lu","orcid":"0000-0001-9051-0351","position":7,"is_corresponding":false},{"id":297412,"name":"Soonmee Cha","orcid":"0000-0002-5924-5876","position":8,"is_corresponding":false},{"id":322389,"name":"Clifford A. Lowell","orcid":"0000-0002-0467-7073","position":9,"is_corresponding":false},{"id":266945,"name":"W. Patrick Devine","orcid":"0000-0003-4634-8830","position":10,"is_corresponding":false},{"id":564639,"name":"James L. Rubenstein","orcid":"0000-0002-9062-2449","position":11,"is_corresponding":false},{"id":236611,"name":"David A. Solomon","orcid":"0000-0003-4571-7999","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:56:52.212268Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}