Efficacy of erythroid‐stimulating agent and luspatercept in VEXAS syndrome: A multicenter retrospective study by the FRENVEX group

VEXAS syndrome (for Vacuoles in myeloid progenitors, E1 ubiquitin activating enzyme, X‐linked, Autoinflammatory manifestations, and Somatic) is due to somatically acquired UBA1 mutations within hematopoietic stem/progenitor cells. ¹ It is characterized clinically by a variety of autoinflammatory manifestations and biologically by marked cytopenia and more specifically macrocytic anemia. ² Anemia in VEXAS is usually non‐regenerative and red blood cell (RBC) transfusion dependency is observed in 23%–83% of cases. ³ , ⁴ Precise mechanisms underlying anemia in VEXAS are not completely elucidated. Chronic inflammation certainly contributes, as RBC transfusion independency (TI) might be reached by controlling inflammatory burden. ⁵ Besides RBC transfusion, there is no validated therapeutic option regarding anemia management. Erythroid‐stimulating agents (ESA) and more recently luspatercept (LUSPA) have been approved for the treatment of anemia in MDS. ⁶ The aim of this multicenter retrospective study was to evaluate erythroid response to those drugs (HI‐E according to IWG‐2018 criteria) in VEXAS patients with anemia treated with ESA and LUSPA.

Anemic (Hb<10 g/dL) VEXAS patients, with or without MDS, who were treated with ESA and/or LUSPA between 2020 and 2024 in eight centers of the French Vexas (FRENVEX) group (Lyon Sud, Clermont‐Ferrant, Toulouse, Paris Saint‐Antoine, Paris Saint‐Louis, Bourg‐en‐Bresse, Centre Alpes‐Léman, and Angers) ⁷ were included. Definitions and responses criteria are defined in Supporting Information.

Overall, 45 VEXAS patients received ESA (N = 26 darbepoietin, N = 15 epoietin‐alfa, N = 3 epoietin‐beta) as the first‐line treatment, 8 of whom were switched to LUSPA after ESA failure. Regarding delay between UBA1 molecular diagnosis and ESA initiation, 33% (15/45) of patients started ESA before a formal VEXAS diagnosis (median time before diagnosis: 11.1 months) (95% CI: 0.95–85.1), while the others (30/45) initiated ESA with a median time of 6.6 months (95% CI: 0.31–121.1) after VEXAS diagnosis. Median age at ESA initiation was 73.3 (range: 49–87.7). Regarding UBA1 variants, 14 (31%), 14 (31%), 6 (13%), and 11 (24%) harbored p.Met41Thr, pMet41Leu, p.Met41Val, and alternative variants (seven splice, three S56, and one active adenylation domain) mutations, respectively (Figure S1A). Sixteen patients (35.5%) were non‐RBC transfusion dependent (NTD), 13 (29%) had high transfusion burden (HTB), and 16 (35.5%) low TB (LTB) before ESA initiation according to IWG 2018 criteria. Clinical and biological characteristics of patients with and without RBC transfusion dependency were similar (Table S1). Thirty seven (82%) patients had associated MDS (IPSS‐R/M characteristics are reported in Figure S1A). Detailed hematological features are reported in Table S2. While MDS patients were more prone to have RBC transfusion dependency (RBC_TD) (Figure S1B), IPSS‐R and IPSS‐M was not associated with baseline RBC_TD (Figure S1C). Regarding UBA1 variant impact on TD, p.Met41Val and pMet41Leu have higher transfusion burden compared to p.Met41Thr and alternative variants (Table S3).

HI‐E was achieved in 14/45 patients (31%) at week 16 (44%, 26%, and 23% in NTD, LTB, and HTB, respectively [p = 0.31]) (Figure 1A). HI‐E was associated with lower baseline endogenous EPO (sEPO) level (median 33 UI/L in responders vs. 300 UI/L in non‐responders, p = 0.01) (Figure 1B), alternative UBA1 variants (HI‐E 54.4% vs. 23.5% in classical Met41 variants, p = 0.01), and higher ANC (Figure 1C). In patients with sEPO > 200 UI/L, only 2/18 (11%) reached HI‐E. HI‐E in MDS and non‐MDS at week 16 (w16) were 29.7 (11/37) and 37.5% (3/8), respectively (RR = 0.7, 95% CI: 0.15–3.90) (Figure 1C). In MDS patients, very low to low IPSS‐M was associated with a trend for higher response (42 vs. 17% in IPSS‐M moderate low to high, p = 0.09) at w16. Co‐mutational burden did not influence HI‐E probability at w16. However, patients with splicing genes mutations were enriched in non‐responders (Table 1). VEXAS disease activity (response vs. absence of inflammation control) at w16 did not influence probability of response (8/25 [32%] vs. 5/18 [28%], p = 0.68). Concomitant use of glucocorticoids sparing agents (ruxolitinib vs. other) did not influence response rate at w16 (4/13 [31%] vs. 10/32 [31%]). After a median follow‐up of 24.4 months (5.2–104.2), cumulative incidence of ESA loss of response was 19 (3/16) and 38% (5/13) at 1 and 2 years of treatment, respectively (Figure 1D). Median overall survival (OS) from ESA initiation was 44.2 months, and it was not reached, 74.4 months and 30.3 months for NTD, LTB (p = 0.044), and HTB (p = 0.003) patients, respectively (Figure 1E).

Figure 1.

Erythroid hematological improvement: (A) at 16 week and (B) 24 weeks. (C) Serum endogenous erythropoietin (EPO) levels at erythropoietin‐stimulating agent (ESA) according to HI‐E response at week 16. (D) Cumulative incidence of ESA failure in responding patients. (E) Baseline predictive factors of HI‐E response at week 16 on ESA. (F) Overall survival according to baseline red blood cell transfusion burden before ESA initiation.

Table 1.

Patient characteristics.

Baseline patient characteristics	Overall N = 45	ESA responders at week 16 N = 14	ESA non‐responders at week 16 N = 31	P value (responders vs. non‐responders)
Age, median (range)	73.3 (46.7−87.7)	73.9 (46.9−87.6)	72.6 (46.7−87.7)	0.86
UBA1 type of mutation, n (%)
p.Met41Leu	14/45 (31)	2/14 (14)	3/31 (10)	0.64
p.Met41Thr	14/45 (31)	3/14 (21)	11/31 (35)	0.34
p.Met41Val	6/45 (13)	3/14 (21)	12/31 (39)	0.25
Othera	11/45 (25)	6/14 (44)	5/31 (16.1)	0.05
UBA1 myeloid co‐mutations, n (%)
Splicing genes (U2AF1, ZRSR2, SF3B1, SRSF2)	11/43	2/11	9/11	0.002
TET2	8/43	3/8	5/8	0.31
DNMT3A	7/43	1/4	3/4	‐b
Other chromatin remodeling (ASXL1, SETBP1)	3/43	1/3	2/3	‐b
Associated MDS according to 2016 WHO, n (%)	37/45 (82)	11/14 (79)	26/31 (84)	0.67
SLD	4/37 (11)	1/11 (9)	3/26 (11)	0.91
MLD	21/37 (57)	5/11 (46)	16/26 (61)	0.44
RARS	3/37 (8)	2/11 (18)	2/26 (8)	0.39
EBI	7/37 (19)	1/11 (9)	5/26 (20)	0.34
MDS/MPN	2/37 (5)	2/11 (18)	0/26	0.37
RBC transfusion dependence, n (%)	30/45 (67)	7/14 (50)	23/31 (74)	0.11
Median number of RBC units 16 weeks before ESA onset, median (range)	4 (1−16)	2 (1−16)	4 (1−16)	0.45
Thrombotic history, n (%)	7/45 (15.5)	4/14 (28.5)	6/31 (19)	0.23
Baseline blood parameters, median (range)
Hemoglobin (g/dL)	8.3 (6.1−9.9)	8.9 (6.1−9.5)	8.2 (6.2−9.5)	0.4
Reticulocytes (G/L)	33 (16−132)	33 (16−71)	38 (10−132)	0.74
Platelets (G/L)	106 (14−407)	93 (14−302)	106 (15−407)	0.45
ANC (G/L)	2,4 (0.9−6.3)	3.4 (0.9−5.6)	1.7 (0.7−5)	0.02
Monocytes (G/L)	0.24 (0.1−1.6)	0.33 (0.1−1.6)	0.21 (0.06−0.87)	0.51
CRP (mg/L)	24.2 (1−144)	24.4 (5−55.8)	21 (3−113)	0.75
Endogeneous EPO (UI/mL)	171 (9−2227)	33 (9−130)	329 (64−2227)	0.01
Serum Ferritin (ng/mL)	719.5 (196−300)	644.5 (196−1306)	763 (213−300)	0.44
Concomittant treatment, n (%)
GC alone	23/45 (51)	7/14 (50)	16/31 (64.4)	0.92
Ruxolitinibc	13/45 (29)	5/14 (36)	8/31 (26)	0.46
Tocilizumabc	3/45 (7)	2/14 (14)	1/31 (3.2)	0.16
Colchicinec	2/45 (10)	0/14	2/31 (6.4)	0.32

Abbreviations: ANC, absolute neutrophil counts; CRP, C‐reactive protein; EBI, MDS with excess blasts type 1; ESA, erythropoietin‐stimulating agents; GC, glucocorticoids; MDS, myelodysplastic syndrome; MLD, multilineage dysplasia; MPN, myeloproliferative neoplasm; RARS, refractory anemia with ring sideroblasts; RBC, red blood cell; SLD, single lineage dysplasia; VAF, variant allelic frequency; WHO, World Health Organization.

^a Other UBA1 mutations are S56, splice, and active adenylation domain variants.

^b Sample too small for statistics.

^c +/− glucocorticoids.

After ESA failure (primary refractory or relapse), eight patients (1NTD, 3LTB, and 4HTB) were treated with LUSPA using the approved schedule. Seven of them had MDS but none had SF3B1 mutation. At week 16, four (50%) reached HI‐E, including the NTD and the three LTB, but no HTB patient (while the only patient without MDS did not respond). Three of the four responders continued LUSPA and were still responders after 15, 16, and 10 months, while the last responders relapsed on anemia and discontinued LUSPA after 6 months.

With a median follow‐up of 24.4 months, median OS from ESA initiation was 44.2 months, and it was not reached, 74.4 months and 30.3 months for NTD, LTB, and HTB (p = 0.019) patients, respectively. Venous thrombotic events (VTE) were observed in 3/18 patients during EPO treatment, but not during LUSPA exposure. No other significant adverse events were reported during follow‐up. Main causes of death were infections (n = 5) and MDS progression (n = 3). No transformation to acute myeloid leukemia was observed during follow‐up.

This retrospective multicenter study shows that EPO and LUSPA (although the number of patients was small for the latter drug) are effective in about a 1/3 of patients and safe therapeutic options to treat anemia in VEXAS syndrome. While exact mechanism underlying anemia is unclear, it has been recently shown that UBA1 ^mut was absent in patient erythroblasts, as UBA1 variants lead to massive cell death at the early stages of erythroid differentiation with erythroblastopenia. As in Diamond Blackfan anemia, and in MDS with 5q deletion, p53 seems to be a key player in this early erythropoiesis abortion through an aberrant p53 cytoplasmic ubiquitylation leading to its expression downregulation and dysfunction. ⁸

The response rate to ESA was similar to that reported in lower risk MDS patients, and similar in patients with or without associated MDS. ⁹ , ¹⁰ , ¹¹ , ¹² Main prognostic factors of response to ESA (baseline serum EPO level, and RBC‐TD) were also similar to those described in lower risk MDS. ¹³ For unclear reasons, UBA1 alternative variants were associated with better HI‐E. Notably, the relapse rate was low (36.3% at 2 years), and the response to ESA was long‐lasting, whereas the median ESA response duration is generally 18–24 months in MDS.

LUSPA is currently used in Europe as the second‐line treatment of anemia of lower risk MDS with ringed sideroblasts (RS‐MDS). Used here off label in eight patients, it yielded HI‐E in 4, with still limited follow up. While first evidences suggest that anemia might be related to early erythropoiesis dysfunction in VEXAS, LUSPA, is thought to be more efficient on late erythropoiesis deficiency such as thalassemia or RS‐MDS. ¹⁴ However, LUSPA also modulates bone marrow inflammation with downregulation of inflammatory pathways (i.e., IL6) that might explain its efficacy in VEXAS. ¹⁵ Thrombotic events during ESA and LUSPA exposure were moderate. VTE are frequent in VEXAS natural disease history, but did not seem to be increased by ESA and LUSPA.

Our study is the first assessing the efficacy of ESA and LUSPA in VEXAS with anemia and confirms that RBC transfusion requirement is associated with reduced survival in VEXAS patients. Our preliminary results suggest that ESA and LUSPA may lead to erythroid improvement and RBC transfusion independency, with a good safety profile. Prospective studies with those drugs in anemic VEXAS patients will be needed.

AUTHOR CONTRIBUTIONS

Maël Heiblig performed research, analyzed the data, and wrote the article. Vincent Jachiet, Jérôme Hadjadj, Lin Pierre Zhao, Thibault Comont, Hervé Lobbes, Valentin Lacombe, Anne Blandine Boutin, Joris Galland, Benjamin Terrier, and Sophie Georgin‐Lavialle treated patients. Pierre Fenaux and Arsène Mekinian reviewed the manuscript and gave the final approval.

CONFLICT OF INTEREST STATEMENT

The authors do not have any conflicts of interest to declare for this study.

ETHICS STATEMENT

This study was conducted in accordance with the Good Clinical Practice protocol and the tenets of the Declaration of Helsinki principles and was approved by the local Institutional Review Board (Ethics Committee of the Research [CER] Paris Nord—IRB 00006477—of HUPNVS, Paris 7 University, AP‐HP; No. CER‐2022‐194).

FUNDING

This study was not funded by any specific grant.

Supporting information

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DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.