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1421 Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: From Recapitulation/Acquisition of Leukemogenic Hits to Immune Escape Due to Somatic Class I/ II HLA Mutations

Program: Oral and Poster Abstracts
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
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Simona Pagliuca, MD1,2, Carmelo Gurnari, MD2,3*, Sanghee Hong, MD4, Cassandra M Kerr, MS2*, Sunisa Kongkiatkamon, MD2,5*, Hassan Awada, MD2, Ashwin Kishtagari, MBBS2, Misam Zawit, MBBS2*, Laila Terkawi2*, Valeria Visconte, PhD2, Eric D. Hsi, MD6, Betty K. Hamilton, MD7, Hetty E. Carraway, MD, MBA7, Navneet S. Majhail, MD, MS7 and Jaroslaw P. Maciejewski, MD, PhD8

1Université de Paris, Paris, France
2Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
3Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
4University Hospitals/ Case Western Reserve University, Cleveland, OH
5Department of hematology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
6Department of Laboratory Medicine, Cleveland Clinic Foundation, Cleveland, OH
7Department of Hematology and Medical Oncology, Leukemia Program, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
8Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH

Curative potential of allogeneic hematopoietic cell transplantation (aHCT) in myeloid malignancies is principally related to the graft versus leukemia (GvL) effect exerted by donor-derived immune effectors on leukemic cells. However, different pathways may drive post-transplant relapse, including perturbation/attenuation of T cell-mediated GvL responses. For example, decreased expression of HLA alleles has been described in post-aHCT relapse.1 This could be due to down-regulation of HLA or 6p HLA locus deletion. However, the occurrence of chromosome 6p uniparental disomy (UPD) along with del6p (first described by our group in the context of aplastic anemia)2 suggests that HLA loss of heterozygosity (LOH) and inherent loss of one allele (presenting immunodominant peptides) may be a significant contributor to leukemic relapse either directly, causing decreased HLA expression or as additive effect to HLA down-regulation. In relapses after haploidentical or mismatched aHCT, LOH of mismatched allele has been described.3 Here, we hypothesize that not only copy neutral LOH or haploinsufficient HLA expression but also defective function due to HLA mutations may lead to immune escape from GvL. Such a mechanism would involve the loss of an allele responsible for the presentation of an immunodominant antigenic peptide. Moreover, unlike relapse due to the acquisition of additional myeloid mutations, HLA mutant relapse would also acquire resistance to donor lymphocyte infusion (DLI) therapy.

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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