Clinical Efficacy of Erythroid Stimulating Agent (ESA) and Luspatercept (LUSPA) in Vexas Syndrome with or without Myelodysplastic Syndrome (MDS) : A Multicenter Retrospective Study By the Frenvex Group

Background:

VEXAS syndrome is caused by the clonal expansion of hematopoietic stem or progenitor cells with somatically acquired mutation of UBA1, a key enzyme of the ubiquitylation proteasome system. The disease is characterized by heterogeneous inflammatory manifestations, cytopenia, and high frequency of concomitant myelodysplastic syndrome (MDS). While its pathophysiology is not fully characterized, anemia is the most frequent, often difficult to treat cytopenia in VEXAS. Besides red blood cell (RBC) transfusions, no standard therapeutic options for anemia of VEXAS exist.

Methods: In this multicenter study, we retrospectively evaluated erythroid response (HI-E, evaluated according to IWG 2018 response criteria) in anemic (Hb <10g/dl) VEXAS patients treated with an ESA or LUSPA in 7 centers of the French Vexas (FRENVEX) group. MDS was defined according to WHO 2016. To be evaluable for ESA and LUSPA response , patients should have received at least 16 weeks of the respective treatments. ESA failure was defined as absence of HI-E at optimal ESA dose.

Results:

Overall, 45 VEXAS patients received ESA as first line treatment for at least 16 weeks , 8 of whom were switched to LUSPA after ESA failure. Median age at ESA onset was 73.3 (range: 49.7-80). Regarding UBA1 variants, 11 (24.4%), 12 (26.6%), 5 (11.1%) and 9 (20%) harbored p.Met41Thr, pMet41Leu, p.Met41Val and alternative variants (S56, active adenylation domain, splice) mutations respectively. Thirty seven (82.2%) patients had concomitant MDS (IPSS-R very low, low, intermediate and high risk in 5.4, 59.4, 27 and 8.1% patients, respectively; IPSS-M very low, low, moderate low, moderate high and high in 5.4, 45.9, 32.4, 8.1 and 8.1% respectively). Fourteen patients (31%) were non RBC transfusion dependent (NTD), 13 (29%) had high transfusion dependence (HTD), and 16 (40%) low TD (LTD).

Overall, HI-E was 38.8% at week 16 (43.7%, 25.6% and 23% in NTD, LTB and HTB respectively (p=0.31)). Only 2 responders (both HTB at baseline) relapsed after 6.3 and 9.2 months, while the remaining responders were still responding after 4.3 to 96 months (median 35.2 months). Median baseline sEPO level was 33 UI/mL in responders vs 300 UI/mL in non-responders (p=0.01). In MDS patients, IPSS-M very low-low was associated with a trend for higher response (42.1 vs 16.6% in IPSS-M moderate low-high, p=0.09). Patient with alternative UBA1 (54.4%) variants had higher HI-E than classical Met41 variants (23.5%, p=0.01), while association with concomitant MDS did not influence HI-E. In multivariate analysis, only higher ANC at ESA onset (continuous variable, OR=1.58, p=0.014) and alternative variants (OR=5.05, p=0.05) had an independent favorable impact on HI-E probability at week 16, while transfusion burden and baseline EPO levels lost their prognostic value.

After ESA failure, 8 patients (1NTD, 3LTB, 4HTB) were treated with LUSPA using the approved schedule. 7/8 had MDS but none had SF3B1 mutation. At week 16, 4/8 (50%) reached HI-E, including the NTD and the 3 LTB, but no HTB patient. Three of the 4 responders continued LUSPA and were still responders after 15,16 and 10 months. while the last responders discontinued LUSPA after 6 months, requiring other therapeutic interventions for severe inflammation

With a median follow-up of 24.4 months, median overall survival (OS) from ESA onset was 44.2 months, and it was not reached, 74.4 and 30.3 months for NTD, LTB and HTB patients respectively (p<0.001). Reaching HI-E did not improve OS compared to non-responders. Venous thrombotic events were observed in 3/18 patients during EPO treatment, but not during LUSPA exposition.

Summary/Conclusion: In this retrospective study, to our knowledge the first of ESA and luspatercept treatment in VEXAS patients with anemia, with or without MDS, HI-E was achieved in 38.8% with ESA and 50% with Luspatercept, with a reasonable safety profile in those patients prone to clinical events. Patients with alternative UBA1 variants responded better than those with Met41 variants. We also confirm that RBC transfusion requirement is associated with reduced survival in VEXAS patients. Prospective studies with those drugs in anemic VEXAS patients are warranted.