Monday, September 25, 2023
|
Characteristic |
Total |
UBA1 genotype |
Typical CH |
Typical CH subgroup |
Typical CH VAF |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
M41T |
M41V |
M41L |
c.118–1 G>C |
P value |
Yes |
No |
P value |
D/T |
D&T |
Others with or without D/T |
No typical CH |
P value |
VAF <10% |
VAF ≥10% |
P Value |
||
| Number (n) | 77 | 49 | 16 | 9 | 3 | 46 | 31 | 19 | 7 | 20 | 31 | 54 | 23 | ||||
| Median UBA1 VAF, % (range) | 74.3 (8.7, 97.3) | 75.3 (24.0, 97.3) | 71.6 (8.7, 93.3) | 80.5 (47.5, 86.4) | 64.7 (59.3, 65.7) | .3 | 7.2 (8.7, 97.3) | 75.1 (24.0, 89.3) | 1 | 81.9 (35.0, 97.3) | 57.3 (28.4, 94.7) | 74.0 (8.7, 93.3) | 75.1 (24.0, 89.3) | .2 | 74.2 (8.7, 93.3) | 76.1 (28.4, 97.3) | .4 |
| Median age, years (range)* | 69.3 (48.4, 88.7) | 71.0 (48.4, 88.7) | 62.8 (55.9, 78.0) | 69.0 (62.5, 75.7) | 62.8 (61.0, 71.3) | .06 | 70.0 (55.0, 83.0) | 68.0 (48.0, 89.0) | .2 | 70.8 (57.6, 82.7) | 71.0 (58.0, 80.4) | 69.4 (55.4, 78.7) | 68.0 (48.4, 88.7) | .6 | 69.1 (48.4, 88.7) | 70.8 (55.4, 82.7) | .4 |
| Median follow-up from symptom onset, years (range) | 3.7 (0.1, 20.6) | 3.2 (0.2, 0.6) | 3.3 (0.1, 11.2) | 5.5 (1.8, 6.8) | 3.7 (3.0, 4.6) | .5 | 3.2 (0.1, 20.6) | 4.4 (0.2, 9.0) | .6 | 2.8 (0.5, 15.5) | 3.2 (0.9, 6.4) | 4.4 (0.1, 20.6) | 4.4 (0.2, 9.0) | .5 | 4.0 (0.1, 13.8) | 2.9 (0.5, 20.6) | .6 |
| Median time to follow-up from sequencing, years (range) | 0.8 (0.05, 6.3) | 0.8 (0.05, 2.9) | 0.8 (0.1, 6.3) | 1.2 (0.1, 2.0) | 0.9. (0.5, 0.9) | .5 | 0.9 (0.05, 6.3) | 0.8 (0.07, 2.8) | .7 | 0.8 (0.05, 6.3) | 0.9 (0.2, 2.9) | 0.8 (0.1, 2.3) | 0.8 (0.1, 2.8) | .8 | 0.8 (0.05, 6.3) | 0.8 (0.2, 2.3) | .9 |
| Hematologic manifestations and diagnoses | |||||||||||||||||
| Cytopenias, no (%) | |||||||||||||||||
| Tranfusion-dependent anemia | 18 (23) | 10 (20) | 4 (25) | 4 (44) | 0 (0) | .5 | 9 (20) | 9 (29) | .5 | 4 (21) | 3 (43) | 2 (10) | 9 (29) | .3 | 13 (24) | 5 (22) | 1 |
| Thrombocytopenia (<100 × 103/μL) | 19 (25) | 11 (22) | 5 (31) | 2 (22) | 0 (0) | .9 | 11 (24) | 7 (23) | 1 | 5 (26) | 1 (14) | 5 (25) | 7 (23) | .9 | 12 (22) | 6 (26) | 1 |
| Presumed MDS, n (%)† | 14 (18) | 7 (14) | 3 (19) | 4 (44) | 0 (0) | .2 | 8 (17) | 6 (19) | 1 | 4 (21) | 2 (29) | 2 (10) | 6 (19) | .5 | 9 (17) | 5 (22) | .7 |
| Plasma cell disorder, n (%) | |||||||||||||||||
| MGUS | 15 (19) | 10 (20) | 4 (25) | 0 (0) | 1 (33) | .4 | 11 (24) | 4 (13) | .4 | 3 (16) | 3 (43) | 5 (25) | 4 (13) | .3 | 8 (15) | 7 (30) | .2 |
| Multiple myeloma | 2 (3) | 1 (2) | 0 (0) | 1 (11) | 0 (0) | .3 | 1 (2) | 1 (3) | 1 | 0 (0) | 0 (0) | 1 (5) | 1 (3) | 1 | 2 (4) | 0 (0) | 1 |
| Venous thromboembolism, n (%) | 44 (57) | 28 (57) | 10 (63) | 6 (67) | 0 (0) | .3 | 28 (61) | 16 (52) | .7 | 11 (58) | 4 (57) | 13 (65) | 16 (52) | .9 | 30 (56) | 14 (61) | .9 |
| Inflammatory manifestations and diagnosis | |||||||||||||||||
| Relapsing polychondritis n (%) | 46 (59) | 31 (63) | 6 (38) | 6 (67) | 3 (100) | .1 | 25 (54) | 21 (68) | .3 | 10 (53) | 5 (71) | 10 (50) | 21 (68) | .5 | 34 (63) | 12 (52) | .4 |
| Sweet syndrome, n (%) | 16 (21) | 8 (16) | 3 (19) | 3 (33) | 2 (67) | .1 | 8 (17) | 8 (26) | .5 | 3 (16) | 1 (14) | 4 (20) | 8 (26) | .9 | 12 (22) | 4 (17) | .8 |
| Symptom based | |||||||||||||||||
| Systemic symptoms‡ | 71 (92) | 45 (92) | 15 (94) | 8 (89) | 3 (100) | 1 | 42 (91) | 29 (94) | 1 | 18 (95) | 6 (86) | 18 (90) | 29 (94) | .7 | 51 (94) | 20 (87) | .4 |
| Skin involvement | 62 (81) | 38 (78) | 14 (88) | 7 (78) | 3 (100) | .8 | 37 (80) | 25 (81) | 1 | 16 (84) | 3 (43) | 18 (90) | 25 (81) | .1 | 46 (85) | 16 (73) | .1 |
| Periorbital edema | 25 (32) | 13 (27) | 11 (24) | 0 (0) | 1 (33) | <.01 | 21 (46) | 4 (13) | <.01 | 8 (42) | 3 (43) | 10 (50) | 4 (13) | .02 | 16 (30) | 9 (39) | .4 |
| Inflammatory eye disease | 8 (10) | 1 (2) | 4 (25) | 3 (33) | 0 (0) | .7 | 14 (30) | 10 (32) | 1 | 9 (47) | 1 (14) | 4 (20) | 10 (32) | .3 | 19 (35) | 5 (22) | .3 |
| Inner ear involvement§ | 39 (51) | 23 (47) | 9 (56) | 5 (55) | 2 (67) | .8 | 22 (48) | 17 (55) | .7 | 8 (42) | 5 (71) | 9 (45) | 17 (55) | .6 | 29 (54) | 10 (43) | .5 |
| Chondritis (ear/nose) | 42 (55) | 29 (59) | 5 (31) | 5 (55) | 3 (100) | .1 | 25 (54) | 17 (55) | 1 | 10 (53) | 5 (71) | 10 (50) | 17 (55) | .8 | 29 (54) | 13 (57) | 1 |
| Cardiac manifestations | 9 (12) | 5 (10) | 2 (13) | 2 (22) | 0 (0) | .7 | 4 (9) | 5 (16) | .5 | 2 (10) | 0 (0) | 2 (10) | 5 (16) | .8 | 6 (11) | 3 (13) | 1 |
| Pulmonary/pleural issues | 43 (56) | 29 (59) | 9 (56) | 5 (55) | 0 (0) | .3 | 26 (57) | 17 (55) | 1 | 11 (58) | 6 (86) | 9 (55) | 17 (55) | .3 | 27 (50) | 16 (70) | .1 |
| Musculoskeletal|| | 56 (73) | 35 (71) | 12 (75) | 7 (78) | 2 (67) | 1 | 35 (76) | 21 (68) | .6 | 15 (79) | 6 (86) | 14 (70) | 21 (68) | .8 | 36 (67) | 20 (87) | .1 |
Table 1. Clinical characteristics of 77 patients with VEXAS stratified based on UBA1 genotype and typical CH mutations
P values obtained using Wilcoxon rank sum test or Kruskal-Wallis test for continuous variables, and χ2 test or Fisher exact test for discrete variables. P values <.05 are shown in bold.
D/T, DNMT3A or TET2 mutations; D&T, DNMT3A and TET2 mutations; MPN, myeloproliferative neoplasm; MGUS, monoclonal gammopathy of unknown significance.
*A reported age is at the time of sequencing for CH.
†Patients without a BM evaluation is clinically justified because preserved blood counts were counted as not having MDS (n = 10).
‡Systemic symptoms included at least having one of the following: fatigue, fever, or unintentional weight loss.
§Inner ear involvement includes at least having one of the following: vestibular symptoms, hearing loss, tinnitus, or vertigo.
||Musculoskeletal includes at least having one of the following: joint pain, arthritis, or tenosynovitis.
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
This activity is intended for hematologists, rheumatologists, dermatologists, internists, and other physicians caring for patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome.
The goal of this activity is for learners to be better able to describe the landscape of clonal hematopoiesis (CH) and its impact in a large cohort of 80 patients with VEXAS, using error-corrected and single-cell DNA sequencing (scDNA), and correlations of these findings with clinical outcomes, according to a retrospective study.
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Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1 mut) and characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 patients with VEXAS for CH in their peripheral blood (PB) and correlated the findings with clinical outcomes in 77 of them. UBA1 mut were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1 mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1 mut was the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed 2 major patterns: with either typical CH preceding UBA1 mut selection in a clone (pattern 1) or occurring as an UBA1 mut subclone or in independent clones (pattern 2). VAF in the PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1 mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a systemic autoinflammatory disease seen primarily in older men secondary to acquired somatic mutations in UBA1 (UBA1mut ), an X-linked gene that encodes the major E1-activating enzyme required for ubiquitylation.[1]UBA1mut occur at the hematopoietic stem and progenitor cell level but are restricted to the myeloid lineage in the blood, triggering the activation of inflammatory pathways in these cells.[1,2]
Patients with VEXAS present with adult-onset treatment-refractory inflammatory symptoms (eg, ear chondritis and neutrophilic dermatitis) and have a predisposition for myelodysplastic syndrome (MDS) and plasma cell dyscrasias.[1,3,4] MDS is reported at a high frequency in VEXAS (25%-55%), but progression to acute myeloid leukemia (AML) has only been reported in a single case.[1,2,5,6] Most MDS cases are stratified as being low risk based on the revised international prognostic scoring system (IPSS-R) and normal karyotypes. Atypia, in addition to the characteristic vacuolated myeloid and erythroid progenitor cells, is a common but nonspecific bone marrow (BM) morphologic finding in VEXAS.[3]
Clonal hematopoiesis (CH) in known myeloid-related genes (referred to in this article as "typical CH") occurs at higher frequencies in many autoimmune/inflammatory diseases.[7–9] A few studies have reported concomitant somatic mutations in typical CH genes with UBA1mut .[4,10–13] However, the true prevalence and clinical impact of coexisting CH mutations with UBA1mut in VEXAS remain to be defined; a higher frequency is expected because of advanced age, severe and chronic inflammation, and predisposition to hematologic malignancies (MDS and plasma cell dyscrasia). We performed the current study to define the CH landscape and its impact in a large cohort of patients with VEXAS using error-corrected and single-cell DNA sequencing and correlated these findings with clinical outcomes.
