Treatment with Janus kinase (JAK) inhibitors, especially ruxolitinib, was an effective therapeutic option for patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, according to a retrospective analysis published in Blood.
VEXAS syndrome is caused by mutations in the UBA1 gene of blood cells and causes inflammatory and hematologic manifestations. Previous retrospective studies and case reports have shown poor response to a variety of therapeutic strategies for this condition, except in a few patients who were treated with JAK inhibitors, according to Pierre Sujobert, MD, PhD, of Hôpital Lyon Sud in France.
For the present study, Dr. Sujobert and colleagues conducted an international, multicenter, retrospective analysis to look at the outcomes of patients with VEXAS syndrome who were treated with different JAK inhibitors to better characterize the safety and efficacy of these drugs. The study included 30 patients with genetically proven VEXAS syndrome who were treated with ruxolitinib (n=12), tofacitinib (n=11), baricitinib (n=4), or upadacitinib (n=3) from April 2018 to February 2022. Fourteen patients had concomitant myeloid neoplasia, most commonly myelodysplastic syndromes (MDS).
Half of the patients had a clinical response (CR) after one month of treatment with a JAK inhibitor. Twenty patients had a biological response (BR), defined as >50% reduction of C-reactive protein level, and 11 patients had complete BR.
After three months of JAK inhibitor treatment, the CR and BR rates were 57.1% and 53.6%, respectively. The median duration of CR was not reached.
The researchers examined outcomes further, conducting a subgroup analysis by JAK inhibitor. Patients treated with ruxolitinib had higher response rates compared with other JAK inhibitors. Rates were numerically higher at one month (CR=67% vs. 38%; p=0.13) and significantly higher at three months (CR=83% vs. 18%; p=0.001) and six months (CR=87% vs. 11%; p=0.002).
Additionally, ruxolitinib efficacy was similar in patients with or without myeloid neoplasia. Since ruxolitinib is not curative, Dr. Sujobert said further research is being done on alternative treatment options or treatments given after JAK inhibition.
With a median follow-up of 6.9 months (range = 1-41), 75% of patients treated with ruxolitinib were still receiving treatment compared with only 28% of patients assigned to other JAK inhibitors. Nine patients discontinued JAK inhibitors other than ruxolitinib because of lack of efficacy (four before one month, and five before three months). The most common adverse events were infections (36.7%) and thromboembolic complications (20%). Worsening of cytopenias, especially anemia, was not uncommon during the first weeks of treatment, according to the researchers.
“Our study shows that ruxolitinib is a good option to control the inflammatory burden in VEXAS, allowing [patients] to decrease (and even stop) corticosteroids, and these effects are sustained over time,” Dr. Sujobert said. “However, even if the inflammatory burden is controlled, patients still present complications linked to VEXAS such as infections and thrombosis, and the UBA1-mutated clone seems to persist [and] expand.”
“Given the high doses of cortico-dependance of VEXAS patients (20-30 mg/day), [steroids] are associated with well-known morbidity and mortality,” Dr. Sujobert said. “Ruxolitinib was mostly well tolerated, except for some patients with hematologic toxicities at the beginning of the treatment.”
MDS progression was observed in two patients treated with ruxolitinib. Three patients (10%) died during the study: one from legionellosis (treated with tofacitinib), one from colon cancer progression (treated with ruxolitinib), and one from an undetermined cause (treated with ruxolitinib).
Among patients still being treated at six months, median steroid dose reduction was 83.6% for patients treated with ruxolitinib and 75% for patients on other JAK inhibitors. There was a significant increase in hemoglobin (p=0.031) and platelet counts (p=0.028) in patients treated with ruxolitinib compared with other JAK inhibitors.
Since ruxolitinib is not curative, Dr. Sujobert said further research is being done on alternative treatment options or treatments given after JAK inhibition. Other therapeutic options for patients with VEXAS syndrome are drugs targeting interleukin (IL)-1 or IL-6, which Dr. Sujobert said “might also be interesting to control the inflammatory burden but are not expected to be curative.”
Any conflicts of interest declared by the authors can be found in the original article.
Heibling M, Ferrada M, Koster M, et al. Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome: a retrospective multicenter study [published online ahead of print, 2022 May 24]. Blood. doi: 10.1182/blood.2022016642.