Incidence, Clinical Associations, and Co-Mutation Patterns of UBA1 Mutations in MDS

Background Mutations in UBA1 are associated with VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, an adult-onset inflammatory disorder (Beck DB et al. NEJM 2020). Approximately 40% of VEXAS patients are also diagnosed with myelodysplastic syndromes (MDS). However, the prevalence and characteristics of UBA1 mutations in MDS are unknown. We hypothesize that UBA1 mutations underlie a proportion of MDS cases with systemic inflammation.

Methods Molecular data were reviewed from a representative diagnostic and treatment-naive MDS cohort (n= 3,328) ascertained through the International Working Group for MDS (Bernard E et al NEJM Evid 2022). We prioritized 375 cases for UBA1 genotyping based on: 1) male gender; and 2) no identified driver mutations or few mutations, enriched in DTA (DNMT3A, TET2, ASXL1) genes; or 3) unclassifiable (MDS-U or MDS/MPN-U) per 2016 WHO Classification. We identified UBA1 hotspot mutations (M41T/V/L) with digital droplet PCR. Resulting UBA1 status was integrated with cytogenetic and sequencing data from 121 genes involved in myeloid pathogenesis to identify patterns of co-mutation. Clinical associations of UBA1 mutations were evaluated and where available, clinical history was reviewed for inflammatory conditions.

Results We identified 30 UBA1 M41T/V/L mutations (median number mutant droplets: 1301; range: 4-12166) in 8% of the cohort (n=28 of 375 patients). This included 15 patients with M41T (c.122T>C), 7 with M41V (c.121A>G), 4 with M41L (c.121A>C), and 2 patients with more than one mutation (1 with M41V/T, and 1 with M41L/V).

In 79% of UBA1-mutant cases (22/28), the karyotype was normal. Loss of the Y chromosome was observed in 6 cases. Three cases had MDS-associated cytogenetic abnormalities: del(11q), del(13q) and focal del(20q).

In 43% of UBA1-mutant cases (12/28), UBA1 mutations were the sole genetic abnormalities. For a further 43% we observed co-mutation with DTA genes (DNMT3A, TET2, ASXL1) with median variant allele fraction (VAF) of 0.21 (0.02-0.56). SF3B1 co-mutations with VAF >30% were observed in 3 cases.

Most UBA1-mutant cases were classified per 2016 WHO as MDS-SLD/MLD (n=18), but two cases were MDS with excess blasts 1, and one case was CMML-1 with 9% blasts. The median age at diagnosis was 72 years (44-89). No significant difference was found when comparing clinical parameters (blast counts, complete blood counts, age) between UBA1 mutant and wildtype MDS MDS.

Clinical history was readily available for 4 UBA1-mutant patients. Inflammatory symptoms were reported in 3 patients, localized in the lungs (n=2), skin (n=2) and cartilage (n=1). Two patients also had a diagnosis of inflammatory/rheumatological disease (vasculitis and relapsing polychondritis), two patients had thrombosis, one had a history of monoclonal gammopathy of undetermined significance. The 4th patient, without inflammatory symptoms, had a prior diagnosis of T-cell large granular lymphocytic leukemia.

Follow-up for transformation to acute myeloid leukemia (AML) and overall survival was available for 310 and 339 patients, respectively. No UBA1-mutant patients transformed to AML (n=24; median follow-up 2.6 years). There was no difference in overall survival between UBA1-mutant (n=27) and wildtype (n=312) patients (log-rank test p = 0.7), however, when subsetting for patients with no mutations detected by targeted DNA sequencing (UBA1-mutant n=7; wildtype n=45), UBA1-mutant patients had worse overall survival (median 5.2 vs 7.3 years; log-rank test p = 0.03).

ConclusionUBA1 mutation in isolation or in combination with other mutations implicated in myeloid pathogenesis account for a significant proportion (8%) of patients diagnosed and treated as MDS but without established disease classification. Ongoing work includes 1) clinical review of inflammatory symptoms for the remaining UBA1-mutant cases and 2) profiling a larger cross-section of MDS by a UBA1 targeted panel to characterize mutations beyond the M41 locus.

Bernard:Pfizer: Honoraria. Germing:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Sanz:La Hoffman Roche Ltd.: Other: Advisor or review panel participant; takeda: Honoraria; Celgene Corporation: Consultancy; Novartis Oncology: Consultancy; Janssen Pharmaceuticals, Inc.: Other: Teaching and Speaking; Abbvie Pharmaceuticals: Other: Advisor or review panel participant; Helsinn: Honoraria, Other: Advisor or review panel participant; Takeda Pharmaceuticals Ltd: Other: Advisor or review panel participant. van de Loosdrecht:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thol:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Palomo:Janssen: Consultancy. Fenaux:Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Savona:Taiho Pharmaceutical: Consultancy; Ryvu Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Incyte Corporation: Research Funding; TG Therapeutics: Consultancy, Other: Travel expenses, Research Funding; Astex Pharmaceuticals: Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; AbbVie: Consultancy, Other: travel expenses; ALX Oncology: Research Funding; Geron: Consultancy; Karyopharm Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy, Other: travel expenses. Santos:Janssen-Cilag: Speakers Bureau; BMS: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Speakers Bureau. Kotsianidis:Celgene: Research Funding; Genesis Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Hellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Hellas: Research Funding. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Silence Therapeutics: Honoraria; Geron: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Jazz: Honoraria; BMS/Celgene: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Heuser:PinotBio: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Kura Oncology: Consultancy; Glycostem: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BMS: Consultancy; Agios: Consultancy, Research Funding; Takeda: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Eurocept: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Tolremo: Consultancy; Astellas: Research Funding; Bayer Pharma AG: Research Funding; BergenBio: Research Funding; Loxo Oncology: Research Funding. Valent:Incyte: Honoraria; Celgene: Honoraria, Research Funding; Blueprint Medicines: Honoraria; Novartis: Consultancy, Honoraria. Finelli:Takeda: Consultancy. Voso:Astellas: Speakers Bureau; jazz: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Shih:BMS (Taiwan): Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis (Taiwan): Consultancy, Membership on an entity's Board of Directors or advisory committees. Ogawa:Clinical Research Support Center Kyushu: Research Funding; 15/353395 (US03): Patents & Royalties; The Chemo-Sero-Therapeutic Research Institute: Speakers Bureau; 2013-096582 (JP01): Patents & Royalties; Astrazeneca: Speakers Bureau; Pfaizer: Speakers Bureau; DaiichiSankyo: Speakers Bureau; 2013-526957 (JP02): Patents & Royalties; PCT/JP2014/062112 (WO01): Patents & Royalties; Esai Pharmatheutical: Consultancy; Novartis: Honoraria, Speakers Bureau; Chordia Threapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding; The Mitsubishi foundation: Honoraria; Astellas: Speakers Bureau; Otsuka Pharmatheutical: Research Funding; 2015-239547: Patents & Royalties; Sysmex: Honoraria; Nanpu Hospital: Research Funding; ASAHI Genomics: Current equity holder in publicly-traded company; MSD: Speakers Bureau; Kirin/Chugai: Speakers Bureau; 62/187386 (US01): Patents & Royalties; 2014-191287: Patents & Royalties. Ebert:TenSixteen Bio: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; GRAIL: Consultancy; Skyhawk Therapeutics: Membership on an entity's Board of Directors or advisory committees; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Deerfield: Research Funding; Celgene: Research Funding. Bejar:Aptose Biosciences: Current Employment, Current equity holder in publicly-traded company; Gilead: Other: data safety monitoring committees chair; Epizyme: Other: data safety monitoring committee chair; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Gattermann:Novartis: Honoraria; Takeda: Research Funding; Celgene: Honoraria; BMS: Honoraria. Papaemmanuil:Isabl Inc.: Current equity holder in private company, Current holder of stock options in a privately-held company, Other: CEO, Patents & Royalties: Whole genome cancer analysis; TenSixteen Bio: Current equity holder in private company.