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2541 Clonal Hematopoiesis in Vexas Syndrome

Program: Oral and Poster Abstracts
Session: 503. Clonal Hematopoiesis, Aging and Inflammation: Poster II
Hematology Disease Topics & Pathways:
Research, autoimmune disorders, Translational Research, Genetic Disorders, genomics, hematopoiesis, Diseases, Immune Disorders, Biological Processes, molecular biology
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Bhavisha A. Patel, MD1, Fernanda Gutierrez-Rodrigues, PhD2, Yael Kusne, MD, PhD3, Jenna A. Fernandez, PhD4*, Terra L. Lasho, PhD4, Ruba Shalhoub, MS5*, Xiaoyang Ma, MS5*, Hugh Alessi6*, Christy Finke, BS4*, Matthew Koster, MD7*, Abhishek A. Mangaonkar, MBBS4, Kenneth Warrington, MD7*, Kebede H. Begna, MD8, Zhuoer Xie, MD, MS9, Amanda Ombrello, MD10*, David S. Viswanatha, MD11, Marcela Ferrada, MD12*, Lorena Wilson, NP, PhD13*, Ronald Go, MD4, Taxiarchis Kourelis, MD4, Kaaren K. Reichard, MD14*, Horatiu Olteanu, MD, PhD15*, Emma M. Groarke, MD1, Ivana Darden, RN1*, Dalton Hironaka, BA16*, Sofia Rosenzweig, BS13*, Daniel L. Kastner, MD PhD13*, Katherine R. Calvo, MD, PhD17, Colin O. Wu, PhD5*, Peter C. Grayson, MD, Msc12*, David B. Beck, MD, PhD18*, Mrinal M. M. Patnaik, MD, MBBS4 and Neal S. Young, MD1

1Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
2Hematology Branch, National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, MD
3Department of Hematology and Oncology, Mayo Clinic, Phoenix, AZ
4Division of Hematology, Mayo Clinic, Rochester, MN
5Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
6National Institutes of Health, Bethesda, MD
7Division of Rheumatology, Mayo Clinic, Rochester, MN
8Divison of Hematology, Mayo Clinic, Rochester, MN
9Division of Hematology, Mayo Clinic, Lutz, FL
10National Human Genome Research Institute, NIH, National Institutes of Health, Bethesda, MD
11Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
12Vasculitis Translational Research Program, National Institute of Arthritis, Musculoskeletal, and Skin Diseases. National Institutes of Health, Bethesda, MD
13Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
14Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
15Mayo Clinic, Rochester, MN
16Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD
17Hematology Section, Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD
18National Institutes of Heath, Bethesda, MD

Background

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described systemic inflammatory disease of older men, due to somatic mutations in UBA1 (UBA1mut). VEXAS predisposes to myelodysplastic syndrome (MDS) and plasma cell dyscrasia (PCD). A few studies have reported concomitant somatic mutations in genes associated with myeloid neoplasia but their true prevalence and the clonal landscape is unknown in UBA1mut cases. We hypothesized that clonal hematopoiesis in myeloid-related genes (typical CH) may be linked to heterogenous clinical phenotypes and progression to MDS seen in VEXAS.

Methods

We performed error-corrected DNA sequencing (ECS) in 80 VEXAS patients and correlated findings with clinical outcomes in 77 patients. Targeted single-cell proteogenomic sequencing (scDNA) was performed on three patients to define clonal architectures. DNA methylation was also investigated in 38 cases.

Results

UBA1mut p.M41T c.122T>C (n=52; 65%) was most frequent followed by p.M41V c.121A>G (n=15;18%), p.M41L c.121A>C (n=10,12%), and three (4%) splice site mutations (c.118-1G>C); one patient had two UBA1mut in independent clones: a p.M41T and c.118-2A>C. Median variant allele frequency (VAF) of UBA1 mut variant was 75%. Forty-eight patients (60%) had one (n=28; 35%) or ≥2 typical CH mutations (n=20; 23%) concomitant with UBA1mut, a frequency much higher than in healthy age-matched controls (>50% in VEXAS patients ³40 years vs. 18% in controls). Mutations in DNMT3A and TET2 were most frequent, DNMT3A mutations at high VAF (median 27%), in contrast to TET2 (median 1.5%; Figure 1).

Patients with typical CH were divided into 4 subgroups: with DNMT3A or TET2 mutations alone (D/T, n=19), concomitant DNMT3A and TET2 mutations (D&T; n=7), mutations in other genes regardless of DNMT3A/TET2 mutations (Others; n=20), and no typical CH mutations (n=31). UBA1mut genotype and co-occurring CH mutations did not predict inflammatory or hematologic manifestations (MDS, PCD, thrombosis, cytopenia). An MDS diagnosis was only associated with transfusion-dependent anemia and thrombocytopenia but not with typical CH mutation subgroups, UBA1 VAF or abnormal karyotype. Overall survival was 60% at 10 years. MDS diagnosis did not confer poorer prognosis but transfusion-dependent anemia, thrombocytopenia, and the presence of typical CH mutation at VAF>2% (particularly DNMT3A/TET2) increased the risk of mortality (Figure 2). VEXAS patients had marked epigenetic age acceleration with a median of 11 years (range 7-23), especially in those with DNMT3A or TET2 mutations.

By scDNA, >90% of myeloid but not lymphoid cells were UBA1mut. The majority (60-90%) of HSPC in the marrow were also UBA1mut. There was a shift towards increased neutrophils (with typically high CD16/CD62L/CD10 expression), plasmacytoid DC and classical monocytes in PB, compared to a healthy control. In UPN1, a TET2 and DNMT3A mutations preceded UBA1mut in the same clone, resulting in striking clonal expansion after acquisition of UBA1mut; all variants were at VAF >45% by ECS. In UPN2, UBA1mut was a driver of a clone that dominated the clonal landscape; subclones with SF3B1 and TET2 mutations in the same cell remained stable at lower VAF by ECS (<5%). In UPN3, UBA1mut itself resulted in clonal expansion of mutated cells.

Conclusions

In VEXAS, UBA1mut cells are the primary cause of inflammatory and hematological manifestations, defining a new molecularly defined somatic entity that is associated with MDS. scDNA data demonstrate that UBA1mut clones have competitive proliferative advantage, therefore, the expansion of clones with typical CH mutations is dependent on co-occurrence with UBA1mut. In VEXAS, typical CH mutations may serve as a biomarker of shortened overall survival, without an increased rate of myeloid neoplastic transformation.

Disclosures: Mangaonkar: Bristol Myers Squibb: Research Funding. Warrington: Eli Lilly: Other: Clinical Trial Support; GSK: Other: Clinical Trial Support; Kiniksa: Other: Clinical Trial Support; Chemocentryx: Consultancy. Begna: ImmunoGen: Research Funding; Novartis: Honoraria. Kourelis: Novartis: Research Funding. Patnaik: Kura Oncology, Stemline Therapeutics: Research Funding.

*signifies non-member of ASH