Dual anti-HLH and antitumor efficacy of golidocitinib in relapsed/refractory PTCL-associated hemophagocytic lymphohistiocytosis: A retrospective safety and activity analysis

Abstract Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome driven by cytokine storms (e.g., IFN-γ, IL-6, IL-10). Lymphoma-associated HLH (LA-HLH), particularly linked to aggressive T/NK-cell neoplasms, demonstrates dismal prognosis and mandates urgent suppression of both hyperinflammation and malignancy. While JAK inhibitors (e.g., ruxolitinib) target the JAK-STAT pathway central to HLH cytokine signaling, their utility in PTCL-associated HLH is limited by substantial hematologic toxicity and lack of proven antitumor efficacy in PTCL. Golidocitinib, a potent and selective JAK1 inhibitor, has shown promising anti-tumor activity with favorable safety profile in relapsed/refractory (r/r) peripheral T-cell lymphoma (PTCL), representing a mechanistically rational strategy to disrupt pathogenic signaling in high-risk LA-HLH. This was a retrospective study of patients with PTCL-associated HLH treated with golidocitinib monotherapy or combination therapy. Methods: In this single-center study, sixteen patients with relapsed/refractory PTCL-associated HLH meeting HLH-2004 criteria were enrolled between July 1, 2024, and June 26, 2025, receiving golidocitinib-based therapy (8 monotherapy, 8 combined with chemotherapy). Lymphoma response was assessed per Lugano 2014 criteria, and HLH response was evaluated according to the response criteria defined in the Histiocyte Society HLH-2004 protocol. Results: Baseline characteristics included a median age of 56 years (range 28–61), 9 males; lymphoma subtypes comprised extranodal NK/T-cell lymphoma (n=6), angioimmunoblastic T-cell lymphoma (n=5), NK-cell leukemia (n=2), hepatosplenic T-cell lymphoma (n=2), and PTCL-NOS (n=1). 87.5% patients (14/16) had Ann Arbor stage III–IV disease; median prior lines of anti-lymphoma therapy were 2 (range 1–4); 10 patients (62.5%) had ECOG PS ≥2. Systemic HLH manifestations included fever (≥38.5°C) in all patients, cytopenia in 8 (50%) patients, hepatic impairment in 7 (43.8%) patients; elevated biomarkers included EBV-DNA in 10 patients (62.5%) and elevated sCD25 in 11/11 tested patients (100%). Anti-lymphoma efficacy demonstrated an ORR of 46.7% (7/15) and CR rate of 13.3% (2/15) with a median time to response of 2 months (1-3). Among 10 patients with elevated EBV-DNA, 60% (6/10) achieved undetectable levels post-treatment. Rapid anti-HLH activity was observed, HLH response rate was 85.7% (6/7) and 77.8% (7/9) at week 2 and week 4 respectively. Clinical improvements included resolution of fever, hematologic recovery (7 patients at both timepoints), and hepatic function normalization (7 patients at both timepoints). Significant reductions in inflammatory markers were observed, including neutrophil to lymphocyte ratio (NLR), IL-6, CRP, TNF-α, ferritin, and triglycerides. At data cutoff (median follow-up: 3.1 months, range 0.8–6.3), 62.5% of patients (10/16) remained on treatment, with median PFS and OS were not reached. Treatment-related adverse events (TRAEs) were manageable, with the most common being thrombocytopenia (42.8%), CMV reactivation (28.6%), abnormal liver function (14.3%). Grade ≥3 TRAEs lung infection (14.3%) and CMV reactivation (14.3%); serious TRAEs comprised CMV reactivation (28.6%), lung infection (14.3%), and thrombocytopenia (14.3%). No treatment-related deaths occurred. Conclusion： This study demonstrates that golidocitinib-based regimens provide dual anti-HLH and antitumor efficacy in relapsed/refractory PTCL-associated HLH, with rapid clinical improvement (e.g., fever resolution, biomarker normalization) and an ORR of 46.7%. Most patients achieved systemic and hematologic recovery with a manageable safety profile and no treatment-related deaths. These findings highlight the potential of JAK1 inhibition in this high-risk cohort, warranting prospective validation to confirm efficacy and optimize therapeutic strategies.