The Search for Effective Treatments
Dr. Beck pointed out that VEXAS is a progressive disease that often leads to worsening anemia and macrocytosis, a sign of bone marrow failure. For this reason, finding effective treatments for the condition has been high on the list of priorities for researchers. In a multicenter retrospective study from Hadjadj et al., the authors looked at 110 patients with VEXAS who received a total of 194 courses of targeted therapy. At three months, the overall response rate (complete or partial) was 24% for patients who were treated with Janus kinase (JAK) inhibitors, 32% for those treated with interleukin-6 (IL-6) inhibitors, 9% for those on IL-1 inhibitors and 0% for tumor necrosis factor alpha (TNFα) inhibitors or other targeted agents.5 At six months, response rates were 30% for JAK inhibitors and 26% for IL-6 inhibitors. Although the authors of the study conclude that JAK inhibitor and IL-6 inhibitor therapies show some benefit, Dr. Beck noted that these treatments are still insufficient for a large number of patients with VEXAS.
On that topic, Dr. Beck discussed research on azacitidine, a cytosine analogue and antineoplastic agent used in the therapy of myelodysplastic syndromes, as a treatment for VEXAS. In a multicenter retrospective study of 88 patients with VEXAS, most of whom (80%) met criteria for MDS, inflammatory response rates to azacitidine were 41% at six months and 54% at 12 months, regardless of MDS status. Among responders, relapse-free survival was 90% at one year and 85% at five years, although relapse was common after discontinuation. A molecular response, which was defined as a ≥25% reduction in UBA1 variant allele frequency (VAF), was seen in 65% of patients and correlated with clinical response. This last finding was highlighted by Dr. Beck, who said such results imply that UBA1 mutation burden could potentially be used as a biomarker of response to azacitidine in patients with VEXAS.
Somatic Mosaicism
The second speaker in the session was Michelle Robinette, MD, PhD, instructor in medicine at Brigham and Women’s Hospital, Boston, and a postdoctoral fellow at Dana Farber Cancer Institute, Boston. Dr. Robinette began her talk by discussing the general topic of somatic mosaicism, a state in which two or more groups of cells possess different genetic compositions. This phenomenon can, at times, manifest quite visibly. Proteus syndrome, for example, is a disease in which a gene mutates in some—but not all—cells, leading to overgrowth of portions of the body. (It is believed that Joseph Merrick, the 19th-century Englishman who became known as the Elephant Man due to his pachydermatous deformities, suffered from this condition.)6
