Session: 701. Experimental Transplantation: Basic Biology, Pre-Clinical Models: Poster I
Hematology Disease Topics & Pathways:
AML, Diseases, MDS, Biological Processes, Myeloid Malignancies, genomics, immune mechanism
In order to dissect the immunogenomic mechanisms leading to leukemic immune-evasion, we performed a comprehensive genetic analysis of specimens sequentially collected from a cohort of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) relapsed after aHCT. Specifically, we applied a deep-targeted NGS panel to study HLA region along with 173 genes known to have a role in leukemogenesis and cancer ontogeny. So far, 57 paired/serial biospecimens from 25 transplanted patients have been analyzed (25 samples at AML/MDS diagnosis, 25 at the moment of relapse after aHCT and 7 samples at relapse after chemotherapy)
Overall, we found the acquisition of 8 disruptive HLA somatic mutations in 6 patients at post-transplant relapse (24%), 4 in class I and 4 in class II loci. None of those events were found in samples at diagnosis or at post-chemotherapy relapse, suggesting the possibility of an “immune–escape relapse”. Those somatic hits accounted for 4 intronic indels, 1 frameshift insertion, one splicing site and 2 point mutations in 3` and 5` untranslated regions (UTRs). Median variant allele frequency (VAF) was 17% (range 2-58%). Of note is that all HLA mutant patients received a matched aHCT (4 from related and 2 from a 10/10 matched unrelated donors) suggesting that this mechanism is independent from the deletion and the loss of an immune privileged mismatched allele. Interestingly, median time to relapse was 514 (range 119-935) days for HLA-mutated patients vs 126 (62-543) for HLA wild type cases (p=.00042), consistent with the hypothesis that the establishment of immune-tolerance, and the presence of a GvL effect (less likely in early relapses) are required for the selection of those mutations. When somatic genotype of these patients prior and after transplant was studied, we found that post-aHCT relapses were associated in most cases with a new genomic configuration with either loss of previous events or acquisition of new subclonal mutations in myeloid or cancer related genes (in 17/25 cases). However no difference was seen in terms of number and patterns of new events among the HLA mutated and HLA wild type patients.
Results shown here represent an important proof-of-concept for the role played by somatic mutations in HLA genes in the setting of post-aHCT AML/MDS relapses. These events, in analogy to the deletion or copy neutral LOH, may promote immune escape relapse resistant to immunologic manipulations and may coexist or be an alternative pathway to the progression/relapse characterized by acquisition of myeloid subclonal driver mutations. In that context, HLA mutations would be considered facilitator lesions.
Disclosures: Hsi: CytomX: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Eli Lilly: Research Funding; Abbvie: Research Funding; Miltenyi: Consultancy, Honoraria. Hamilton: Syndax Pharmaceuticals: Consultancy, Honoraria. Carraway: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Takeda: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Majhail: Incyte: Honoraria; Mallinckrodt: Honoraria; Nkarta Therapeutics: Honoraria; Anthem, Inc.: Consultancy. Maciejewski: Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.
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