Lung-Predominant Hyperinflammatory Syndrome in Therapy-Related Myelodysplastic Syndrome Responsive to Interleukin-1 Blockade

Background/Objectives: In myelodysplastic neoplasms, autoinflammatory syndromes result from dysregulated innate immunity and cause severe, organ-dominant inflammation. Interleukin-1 signaling through the NLRP3 inflammasome is implicated in the pathogenesis of myelodysplastic disease and related inflammatory complications, especially in the context of RAS-pathway activation. Reports describing therapy-related myelodysplastic syndrome with pulmonary autoinflammatory syndromes are rare, and the efficacy of interleukin-1 blockade in this setting has not been previously documented. Results: A man in his 60s with therapy-related myelodysplastic syndrome (del 5q) following rectal chemoradiation developed a recurrent, lung-predominant autoinflammatory syndrome refractory to corticosteroids and Janus kinase inhibition. Next-generation sequencing identified gain-of-function mutations in NRAS, PTPN11, SF3B1, and ASXL1. On two separate occasions, anakinra produced rapid clinical improvement with normalization of inflammatory biomarkers and radiographic resolution; on both occasions, discontinuation of anakinra led to prompt relapse within days, with ferritin rising to above 5500 ng/mL and C-reactive protein exceeding 300 mg/L. Conclusions: This case demonstrates that interleukin-1-mediated inflammation can drive pulmonary complications in therapy-related myelodysplastic syndrome. Targeted cytokine blockade with anakinra produced reproducible and measurable clinical improvement when conventional therapies were insufficient. The recurrence of symptoms following anakinra withdrawal, and rapid improvement upon re-administration, underscores the functional link between interleukin-1-driven inflammation and clinical outcomes. The RAS/MAPK mutational context and the observed on–off response to anakinra further support an interleukin-1-driven mechanism that merits further investigation.