A study analyzing the genetic mutations of blood cells in VEXAS syndrome shows how distinctly different VEXAS-associated myelodysplastic syndromes (MDS) is from classical MDS and sheds light on what might put some patients with VEXAS syndrome at a higher risk of worse outcomes than others. The findings were published in Blood.
VEXAS – an acronym for vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic – is a syndrome first reported in 2020. It is a systemic autoinflammatory disease seen mainly in older men, brought on by somatic mutations in the UBA1 gene, a gene located on the X chromosome that encodes the major E1-enzyme needed for ubiquitination. Patients commonly present with treatment-refractory inflammatory symptoms, such as ear chondritis and neutrophilic dermatitis. Based on evolving data, the incidence of VEXAS-associated MDS is estimated to be between 25% and 55%, generally associated with lower-risk MDS, with rare transformation to acute myeloid leukemia.
In this study, researchers set out to describe clonal hematopoiesis (CH), the process of reproduction of mutated blood cells, specifically as it relates to VEXAS syndrome and the incidence of MDS.
“This is the first study dedicated to characterizing the CH landscape and the clinical impact it has in VEXAS,” said Bhavisha Patel, MD, of the National Institutes of Health (NIH) in Bethesda, Maryland.
Eighty patients with VEXAS syndrome – 16 from Mayo Clinic and 64 from NIH – had CH screenings, including 13 who were evaluated prospectively. The median age was 69 years, and study participants had a median disease duration of 3.7 years (range = 0.1-20.6 years). Fever, fatigue, and unintentional weight loss were the most common inflammatory symptoms, followed by skin involvement. Venous thromboembolism and cytopenia were the most common hematologic findings.
UBA1 mutations were the most common, researchers found. They also found that 60% of the patients had at least one typical CH mutation, mutations to known myeloid-related genes: 35% with one mutation and 25% with two or more. This incidence is much higher than what was seen in healthy, age-matched controls over the age of 40, of whom 18% had these mutations.
Most of these mutations involved the DNMT3A and TET2 genes, including 21 with single or multiple mutations in either one – 14 to DNMT3A and seven to TET2 – and seven with mutations to both. These are also the most commonly mutated genes in healthy individuals and people with “benign” diseases.
“Therefore, the clonal landscape of VEXAS is more representative of an inflammatory disease, typically enriched in DNMT3A/TET2 mutations, as opposed to myeloid neoplasms, where somatic mutations in prognostically adverse genes are common,” researchers stated.
This underscores the key role of UBA1 mutations in the clinical manifestations of VEXAS syndrome, both inflammatory and hematologic, Dr. Patel said. “UBA1 is a driver clone for progressive marrow failure and likely development of myeloid neoplasm because we didn’t identify high frequency or burden of mutations observed in classical myeloid neoplasms.”
Overall survival in this group at 10 years was 60%, with the cause of death attributed primarily to infections and uncontrolled inflammation. Transfusion-dependent anemia and thrombocytopenia with an associated MDS diagnosis were associated with poor outcomes, including increased mortality, researchers found.
Having typical CH mutations (DNMT3A, TET2, UBA1, VAF), brought a seven-fold risk of mortality, the study found, with differences in groups carrying one or more of these mutations. The presence of either DNMT3A or TET2 mutations (n=19) nearly doubled that risk. Having both DNMT3A and TET2 mutations (n=7), or having other mutations (n=20), was linked with only a modest increase in mortality, and not significantly so. These estimates are limited by the very small sample size.
The underlying biology of why either DNMT3A or TET2, but not both, was linked with significantly higher mortality is “difficult to understand with such few patients,” Dr. Patel said. “We are exploring this further, but our methylation data with epigenetic age acceleration would indicate that there may be some compensatory effects when these co-exist.”
The findings could help guide treatment, Dr. Patel noted. “Ultimately, these findings have to be confirmed in prospective studies, but patients with VEXAS syndrome with cytopenia or coexisting CH mutations have higher risk of poor outcomes,” she said. “Therefore, these could be used to risk stratify for treatment. Treatments include biologics that target inflammation, agents that may target the clone” – such as hypomethylating drugs – “and bone marrow transplantation, each with a different efficacy and safety profile.”
Any conflicts of interest declared by the authors can be found in the original article.
Gutierrez-Rodrigues F, Kusne Y, Fernandez J, et al. Spectrum of clonal hematopoiesis in VEXAS syndrome [published online ahead of print, 2023 Apr 21]. Blood. doi: 10.1182/blood.2022018774.