Extranodal NK/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with particularly high incidence in Asia, especially in southern China where it accounts for 10%-15% of all malignant lymphomas. Early-stage NKTCL can achieve an 80% long-term survival rate with radiotherapy combined with pegaspargase-based chemotherapy. However, advanced and relapsed/refractory NKTCL carries a dismal prognosis, with long-term survival below 40%. A severe complication is hemophagocytic lymphohistiocytosis (HLH), which develops in 10%-20% of patients and leads to an extremely aggressive clinical course, with median survival less than 2 months and 6-month overall survival of only 23%.
Pathogenically, EBV infection induces abnormal immune activation through the JAK/STAT and NF-κB pathways, triggering a cytokine storm characterized by elevated IFN-γ, TNF-α, IL-6, and IL-10. This immune dysregulation, combined with impaired cytotoxic function, drives both lymphomagenesis and HLH progression. Current treatments remain unsatisfactory. Traditional HLH-directed regimens fail to control underlying lymphoma, while conventional lymphoma chemotherapy shows limited efficacy and poor tolerance due to multi-drug resistance and organ dysfunction.
Recently, targeted agents have emerged as promising strategies. Golidocitinib, a highly selective JAK1 inhibitor, effectively blocks JAK1-STAT3 signaling, suppresses EBV-driven tumor growth, and mitigates cytokine storms. It has demonstrated encouraging anti-tumor activity in relapsed/refractory NKTCL. Meanwhile, liposomal mitoxantrone improves tumor targeting and reduces cardiotoxicity, with objective response rates of 50%-60% in NKTCL. Etoposide, methylprednisolone, and pegaspargase further provide synergistic anti-lymphoma and anti-inflammatory effects.
Our research group has accumulated extensive experience in NKTCL and NKTCL-HLH, validating effective combination regimens and supporting the rationale of combining anti-lymphoma and anti-HLH strategies. Therefore, this study designed the innovative MEPL-G regimen (liposomal mitoxantrone, etoposide, methylprednisolone, pegaspargase, golidocitinib) for NKTCL-HLH patients. This regimen aims to rapidly control HLH, eradicate lymphoma, improve safety and tolerance, and ultimately prolong survival, addressing the urgent unmet medical need for this high-risk population.
