Extranodal NK/T-cell lymphoma (NKTCL) is an aggressive EBV-associated lymphoma with poor prognosis, highly prevalent in China. Early-stage NKTCL achieves favorable long-term survival, while advanced disease shows dismal outcomes with no standard therapy. Notably, 10%-20% of patients develop secondary hemophagocytic lymphohistiocytosis (NKTCL-HLH), a life-threatening complication with median survival <2 months and mortality over 90%. Current treatments fail to simultaneously control lymphoma and hyperinflammation, with poor tolerance and high resistance.

The JAK/STAT pathway drives EBV-induced inflammation and tumor progression. Golidocitinib, a selective JAK1 inhibitor, demonstrates potent anti-NKTCL activity and rapid inflammation control. Liposomal mitoxantrone offers targeted efficacy with lower toxicity, while etoposide, methylprednisolone, and pegaspargase provide synergistic anti-tumor and anti-HLH effects.

This study proposes the novel MEPL-G regimen (liposomal mitoxantrone, etoposide, methylprednisolone, pegaspargase, golidocitinib) for NKTCL-HLH. By targeting both HLH and NKTCL, this combination aims to achieve rapid disease control, improve tolerance, and prolong survival, addressing the unmet critical clinical need for this high-risk population.

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.

Inclusion Criteria:

• Histologically confirmed extranodal NK/T-cell lymphoma.
• Meeting the HLH-2004 diagnostic criteria (≥ 5 criteria).
• Age ≥ 18 years, regardless of gender.
• Negative HIV antigen or antibody.
• Left ventricular ejection fraction (LVEF) ≥ 50% on cardiac echocardiography.
• No active visceral bleeding (e.g., gastrointestinal, pulmonary, cerebral).
• No uncontrolled infection (e.g., pulmonary infection, intestinal infection).
• Negative HCV antibody; or positive HCV antibody with negative HCV RNA.
• Negative HBsAg and negative HBcAb. If either is positive, peripheral blood HBV DNA load must be < 1×10³ copies/mL to be eligible.
• Signed written informed consent and ability to understand and comply with all study requirements.

Exclusion Criteria:

• New York Heart Association (NYHA) cardiac function class ≥ II;
• Female patients who are pregnant or breastfeeding;
• Known hypersensitivity to any of the study drugs;
• Presence of other concurrent malignancies (except non-melanoma skin cancer);
• Concurrent central nervous system lymphoma infiltration;
• Severe psychiatric disorders or inability to comply with follow-up;
• Severe renal dysfunction (glomerular filtration rate < 15 mL/min);
• Severe liver cirrhosis (MELD score > 20);
• History of acute or chronic pancreatitis;
• Simultaneous participation in another clinical trial.