New X for VEXAS: haploidentical allogeneic haematopoietic cell transplantation in VEXAS syndrome

Extract

Dear Editor, VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic) is a newly identified monogenic disease characterized by somatic mutations in the UBA1 gene in haematopoietic progenitor cells [1]. Besides predominantly autoinflammatory symptoms, it is often associated with myelodysplastic syndromes (MDS) [2]. The disease poses a significant therapeutic challenge due to its refractory nature to standard treatments. To date, the only curative treatment for VEXAS syndrome is allogeneic haematopoietic cell transplantation (HCT). So far, HCT in VEXAS patients has been limited to matched donors [3]. To our knowledge, this is the first report on a haploidentical haematopoietic cell transplantation in VEXAS syndrome.

A 59-year-old male first presented in October 2017 with multiple nodules on both lower legs, accompanied by chills and fever. The patient also experienced sudden swelling and nodules on both arms, along with pain in the ankle joints, which impaired mobility. Later, bilateral V. saphena parva and left V. cephalica thrombosis were detected. Arthralgias, which were intermittent and varied in location, and mild lymphadenopathy persisted over months. Symptoms fluctuated in waves from 2017 to 2024, particularly when steroid doses were reduced. Under the initially suspected diagnosis of adult-onset Still’s disease, anti-inflammatory therapy consisted of steroids and azathioprine (1 month, 2 × 75mg/day); later the treatment history included methotrexate (6 months oral, 10 mg/day; 8 months s.c., 15 mg/week), colchicine (3 months, 2 × 0.5 mg/day), anakinra (1 month, 100 mg/day), ciclosporin A (3 months, 2 × 75mg/day), tocilizumab (2 months, 162 mg/week) canakinumab (30 months, 150 mg/month), adalimumab (2 months, 40 mg biweekly), upadacitinib (1 month, 15 mg/day), and tofacitinib (4 months, 2 × 5mg/day). All mentioned therapies were discontinued due to insufficient effect or side effects (anakinra). This led to long-term use of high-dose steroid, inducing osteoporosis with vertebral fractures. Under immunosuppression the patient developed a severe Listeria meningitis. Besides steroid-induced and infectious complications, we discovered pulmonary involvement with sterile infiltrates and moderately reduced diffusion capacity.