Pilot Prospective Study of Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Vexas Syndrome

Introduction VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory condition due to UBA1 mutations with limited therapeutic options. Previously, we reported preliminary outcomes on a series of 5 patients with VEXAS treated with allogeneic hematopoietic stem cell transplantation (alloHCT, Mangaonkar A et al. Am J Hematol 2023). In this abstract, we present long-term, prospective follow-up data on an expanded cohort of 10 VEXAS patients [including 1 with a haploidentical donor (haploHCT)] treated with alloHCT. Methods After discussions with multidisciplinary experts, we drafted a clinical consensus document to pursue alloHCT in VEXAS. UBA1 mutations were detected either through Sanger or next generation sequencing (NGS). Primary indications for alloHCT were steroid-refractory inflammation, bone marrow failure or emerging myeloid neoplasm. Results From year 2021 to 2023, 10 patients (all men) with a median age of 63 (range: 49-74) years and median HCT-CI score of 4 (0-6) underwent alloHCT (Table 1). UBA1 mutations were detected in all patients prior to alloHCT; p.Met41Val (n=5), p.Met41Thr (n=3), and c.118-1G>C (splice variants, n=2). Graft was T-cell replete peripheral blood stem cell in matched sibling (n=4) and unrelated (n=5) donors, and bone marrow in haploHCT. Reduced intensity conditioning (RIC) was used in all patients with Fludarabine/Melphalan (Flu/Mel, n=7), Flu/Busulfan (Bu, n=2), and Thiotepa/Bu/Flu (in haploHCT) followed by post-transplant cyclophosphamide-based (PTCY/tacrolimus/MMF) graft-versus-host disease (GVHD) prophylaxis (n=9, except 1 due to cardiac dysfunction). At a median follow-up (since alloHCT) of 9 (95% CI 1-20) months, there were no deaths and median GVHD-free, relapse-free survival (GRFS) was not reached. Frequent complications included infections (n=6), late acute skin GVHD (n=2, grade 3 in 1, none with gut/liver or chronic GVHD), mixed (≥10% recipient) chimerism at day 100 (myeloid n=4, lymphoid n=5, none associated with relapse). Among patients with >12 months of follow-up (n=5), there was no evidence of disease (absence of clinical features, normalization of bone marrow morphology and inflammatory markers, UBA1 mutation clearance was demonstrated in 4 patients). Mixed chimerism (in either lymphoid or myeloid fraction) was not associated with disease relapse or graft failure, and resolved after withdrawal of immunosuppression. Thus far, 5 patients have been weaned off steroids after a median of 3.5 (2-14) months from alloHCT. Conclusions RIC alloHCT with PTCY/Tacrolimus/MMF is a feasible and successful treatment strategy for patients with VEXAS syndrome.