Outcomes with itacitinib prophylaxis for cytokine release syndrome: A systematic review

Abstract Introduction: Cytokine release syndrome (CRS) is a common and severe adverse effect reported with many chemotherapeutic agents, cellular therapies, and stem-cell transplantation. JAK-1 plays a crucial role in its pathophysiology. Itacitinib, a JAK-1 inhibitor, is currently under investigation for the prevention of CRS. We aim to explore the outcomes of these studies. Methods: Following PRISMA guidelines, a comprehensive search of PubMed, Cochrane, Embase, Google Scholar, and ClinicalTrials.gov (inception to May 2025) was conducted using MeSH terms for “cytokine release syndrome” and “Itacitinib.” After screening and excluding review articles, meta-analyses, and studies without a patient population of interest, two studies reporting the outcomes of Itacitinib in the prevention of CRS were selected for inclusion from a total of 280 references. Extracted data included patients' demographics, CRS rate, CRS grade, and overall survival (OS). Results: A total of 89 patients from one randomized controlled trial and one pilot study were included in this systematic review. Frigault et al. randomized 47 patients to either Itacitinib (n = 23, 49%, median age 66 years, 65% male) or placebo (n = 24, 51%, median age 64 years, 71% male). Patients were planned to receive axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma (rrLBCL). CRS rate was 65% (n = 12) in the Itacitnib arm and 80% (n = 20) in the placebo arm. The CRS rates for Grades 1 and 2 were 73% (n = 11) and 27% (n = 4), respectively, in the Itacitinib arm. No grade 3 or grade 4 CRS was observed. Immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) occurred in 3 (13%; 95% CI: 3-34) patients in the itacitinib arm and 8 (34.8%; 95% CI: 16-57) patients in the placebo arm. No grade 4 ICANS occurred in either arm. There was no difference in the best overall response rate for lymphoma between the two arms. Abboud et al. treated 42 patients with Itacitinib after haploidentical transplantation. The median age was 60 years. Common underlying conditions included acute myeloid leukemia (AML) (60%) and myelodysplastic syndrome (MDS) (10%). The CRS rates for Grades 1 and 2 were 90% (n = 38) and 10% (n = 4), respectively. No grade 3 or 4 CRS was observed. There were no cases of grade III-IV acute graft-versus-host disease (GVHD). The cumulative incidence of grade II acute GVHD at 1 year was 20.5%. OS at 1 year was 80% (95% CI, 63-90). Conclusion: Itacitinib prophylaxis may prevent high-grade CRS and other immune-mediated adverse events such as ICANS and GVHD without reducing the treatment responses. Future high-quality trials with larger patient populations are required to validate these findings further.