JAK Inhibitors Show Promise in Concurrent Myeloid Disorders, IADs

Treatment with Janus kinase (JAK) inhibitors has the potential to fill an unmet need for patients with concurrent myeloid disorders and adult-onset inflammatory syndromes, according to new research published in Leukemia Research.¹

In recent years, it’s been estimated that 10% to 28% of patients with myeloid disorders, such as myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), develop adult onset inflammatory and autoimmune disorders (IADs), complicating treatment.

“Recently, adult-onset inflammatory syndromes, with somatic mutation in UBA1 gene on X-chromosome, have been identified and termed VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome,” explained the researchers of the new analysis. “The clinical features in patients with VEXAS syndrome include recurrent fever, cutaneous and pulmonary involvement, ear and nose chondritis, venous thromboembolism, hematopoietic dysplasia, and bone marrow vacuolization restricted to myeloid and erythroid precursor cells.”

It’s been estimated that 10% to 28% of patients with myeloid disorders, such as myelodysplastic syndromes and chronic myelomonocytic leukemia, develop adult onset inflammatory and autoimmune disorders, complicating their treatment.

Image credit: ARMMY PICCA - stock.adobe.com

With data pointing to 5-year survival at as low as 50%, the researchers of the analysis highlighted the importance of early diagnosis and management of VEXAS syndrome. Data have shown that more than half of patient with VEXAS syndrome become dependent on glucocorticoids and while steroids have shown efficacy, side effects are common.²

With a need for novel treatment approaches outside of conventional strategies for the management of myeloid disorders, few studies have shown promise of JAK inhibitor use in these patients with IADs.

For example, in one small study of 30 patients with VEXAS, 15 achieved a clinical response (CR) after 1 month of treatment, and 20 had a greater than 50% reduction in C-reactive protein (CRP) level—considered a biological response (BR). More than half of patients achieved a CR (57.1%) or BR (53.6%) after 6 months of treatment. Subgroup data showed the highest response rates with ruxolitinib compared with other JAK inhibitors.

In the current analysis, the researchers also outlined the success of JAK inhibitor treatment among 3 case studies from patients aged over 60 years with myeloid disorders presenting with inflammatory and autoimmune features and refractory to traditional treatment. Patient features included erythema nodosum, Raynaud’s phenomenon, Sjögren syndrome, and refractory pruritis.

In the case studies included in the analysis, JAK1 inhibitor upadacitinib significantly improved inflammatory symptoms and allowed for tapering of steroids among 2 patients. The treatment also improved hemoglobin and reduced levels of serum CRP. Following loss of response in one patient stopped, subsequent ruxolitinib treatment showed efficacy.

Amidst growing evidence that JAK inhibitors may be promising for treating myeloid disorders with IADs, the researchers noted that the mechanisms underlying IADs in patients with MDS remains unknown. Proposed mechanisms include Th17/Treg imbalance in low risk MDS and increased secretion of TNF-α and IL-6 in CMML.

“There is growing interest in studying bidirectional relationships between IADs and MDS/CMML at the molecular level in search for potential therapeutic options in targeting specific pathways,” detailed the researchers. “In some patients with IAD-AH monogenic mutations, either germline (GATA2) or somatic (UBA1), have been identified. The somatic mutations in UBA1 genes, recently described in VEXAS syndrome, are associated with adult-onset inflammation, and a high prevalence (24 %-55%) of MDS. Our cases, although did not have any of the recognized mutations in UBA1 gene, phenotypically had VEXAS-like features, as reported earlier. Alternatively, other genes than UBA1 or undefined mutations in UBA1 that are not routinely detected on genetic probes, could contribute to such VEXAS-like phenotypes.”

References

1. Mishra R, Calabrese C, Jain AG, Singh A. Association between myeloid disorders and adult onset-inflammatory syndromes, successful treatment with JAK-inhibitors: Case series and literature review. Leuk Res. Published online September 4, 2024. doi:10.1016/j.leukres.2024.107584
2. Alcedo PE, Gutierrez-Rodrigues F, Patel BA. Somatic mutations in VEXAS Syndrome and Erdheim-Chester disease: Inflammatory myeloid diseases. Semin Hematol. 2022;59(3):156-166.