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My paper of the month - Allogeneic hematopoietic cell transplantation for VEXAS syndrome: results of a multicenter study of the EBMT

WP/Committee not specified

Jose Aspa-Cilleruelo* and John Snowden* comment on the publication entitled “Allogeneic hematopoietic cell transplantation for VEXAS syndrome: results of a multicenter study of the EBMT” published in Blood Advances.  

* Dr Jose Aspa-Cilleruelo, Haematology Senior Clinical Fellow, Sheffield Teaching Hospitals NHS Foundation Trust, UK

* Prof John Snowden, Consultant & Director of BMT & Cellular Therapy, Sheffield Teaching Hospitals NHS Foundation Trust, UK

Allogeneic hematopoietic cell transplantation for VEXAS syndrome: results of a multicenter study of the EBMT

Carmelo Gurnari et al. Blood Adv. 2024 Mar 26;8(6):1444-1448. doi: 10.1182/bloodadvances.2023012478.

VEXAS syndrome is a relatively new and uncommon condition that encompasses autoinflammatory manifestations alongside myelodysplastic or myeloproliferative features. Its genetic ‘signature’ is the mutation of the UBA1 gene.       

Since it was first described in 2020, the treatment of these patients has been directed towards the clinical manifestations, mainly rheumatological and dermatological, although there is also published experience with azacitidine in these patients. Alongside there is specialised management of the ‘autoinflammatory’ aspects. However, the only curative treatment is allogeneic haematopoietic transplantation (alloSCT), although the experience in these patients is limited.

In this article, Gurnari et al. present the experience reported by the EBMT in alloSCT in patients with VEXAS. The cohort consists of 19 patients, all male, with a median age of 59 years. All of them presented with macrocytic anaemia (median Hb 9 g/dL), with a median platelet count of 149 x10^9/L and a neutrophil count of 4.4 x10^9/L. Additionally, 68% of the patients had concomitant MDS and 5% had MPN. Of the 12 cases of MDS, the majority classified as low or intermediate risk on the IPSS-R scale.

The alloSCT was performed at different times in the evolution depending on the patient, with a median of 41 months from the onset of the syndrome. Prior to the transplant, the patients had received different treatments depending on the investigator and the clinical expressions. Eight patients received azacitidine with an approximate CR incidence of 38%, while 5 patients received ESAs. Regarding rheumatological treatment, the options were varied, including classical antirheumatic agents such as methotrexate or hydroxychloroquine, and other biological agents such as tocilizumab. Remarkably, 4 patients received ruxolitinib, with a 50% CR, and 2 patients received baricitinib, achieving PR. Regarding the pre-transplant condition, 44% of the patients had a Karnofsky score <80% and 26% had an HCT-CI ≥ 3. The main donor was the MUD (63%), with MRD and MMRD both equally represented (16%), and MMUD (5%). The majority source of progenitors was peripheral blood. Regarding conditioning, the main drug was fludarabine in combination with various alkylating agents. One patient received TBI, and in 2 patients a sequential scheme such as FLAMSA/BuCY was applied. Concerning GVHD prevention, 68% of the patients were treated with serotherapy (ATG or Alemtuzumab) and the rest with PTCy, in combination with an antiproliferative drug (MTX or MMF).

The incidence of primary graft failure was 5% (n=1). The median neutrophil engraftment was 16 days and platelets 15 days. The median follow-up of the cohort was 14 months, with an estimated 2-year OS of 74%. The TRM during follow-up was 21% (3 bacterial infections and 1 CNS toxicity). The incidence of aGVHD was 58%, and grade II-IV was 26%. Twenty-one per cent of the patients presented cGVHD, with a median to event of 4.6 months.

All patients with follow-up over one year, 58% (n=11) of the total cohort, did not show any relapse and immunosuppression could be suspended in all of them. Regarding the mutational profile, the most frequent co-mutations were in the DAT group as well as KRAS. The post-transplant mutational profile was not reported, however, given the origin of these mutations, they are not expected to disappear. Nonetheless, of the 6 patients with post-transplant molecular studies, all presented eradication of the specific UBA1 mutation between 3 and 6 months post-alloSCT.

This study presents the largest series of transplanted VEXAS patients to date. Despite the small cohort, the results provide acceptable outcomes as a basis of developing and refining this approach in this condition affecting a predominantly older age group. Currently, there is an ongoing phase 2 clinical trial from which more relevant information can be obtained to determine the best timing and strategy for transplanting these patients.