Overview

This is a randomized, open-label, prospective, multicenter phase III superiority study in patients with newly diagnosed stage IV extranodal NK/T-cell lymphoma. The study compares two frontline induction strategies followed by consolidation with autologous hematopoietic stem cell transplantation in patients who achieve a protocol-defined strict complete remission.

Eligible participants will be randomized 1:1 to Arm A or Arm B, stratified by three-level PINK-E risk category. Arm A consists of one cycle of GELAD induction followed by three cycles of MEDA chemotherapy. Participants who achieve strict complete remission after key response assessment will proceed to autologous hematopoietic stem cell transplantation consolidation. Arm B consists of four cycles of LEAP induction with sintilimab, pegaspargase, and anlotinib. Participants who achieve strict complete remission will receive high-dose methotrexate CNS-directed consolidation followed by autologous hematopoietic stem cell transplantation consolidation if eligible.

The primary endpoint is event-free survival within 24 months after randomization. Secondary endpoints include progression-free survival, overall survival, overall response rate, complete remission rate, strict complete remission rate, autologous hematopoietic stem cell transplantation completion rate, cumulative incidence of relapse, grade 3 or higher adverse events, treatment discontinuation, treatment-related mortality, and plasma EBV-DNA clearance dynamics.

Eligibility

Inclusion Criteria:

• Age 18 to 70 years at the time of signing informed consent.
• Histologically confirmed extranodal NK/T-cell lymphoma according to the current classification criteria, with tumor tissue confirmed to be EBER positive. Central pathology review is recommended.
• Stage IV disease according to Lugano 2014 staging criteria, with baseline staging including PET/CT and bone marrow evaluation.
• Previously untreated disease, with no prior systemic anti-lymphoma therapy, radiotherapy, or other anti-tumor treatment for NKTCL.
• At least one evaluable lesion assessable by PET/CT and/or contrast-enhanced CT/MRI.
• Eastern Cooperative Oncology Group performance status score of 0 to 3.
• Adequate hematologic function during screening, defined as absolute neutrophil count ≥1.0 × 10\^9/L, hemoglobin \>80 g/L, and platelet count \>50 × 10\^9/L.
• Adequate hepatic and renal function during screening, defined as alanine aminotransferase and aspartate aminotransferase ≤2 × upper limit of normal, total bilirubin ≤2 × upper limit of normal, and creatinine clearance ≥60 mL/min.
• No severe uncontrolled coagulation disorder, and judged by the investigator to be able to receive pegaspargase-containing therapy.
• Judged by the investigator to have no absolute contraindication to key components of the assigned treatment strategy, including irreversible contraindication to high-dose methotrexate, severe organ dysfunction precluding transplant evaluation, or other conditions clearly preventing completion of the protocol-defined strategy.
• Written informed consent provided by the participant or legally authorized representative.

Exclusion Criteria:

• Prior systemic anti-lymphoma therapy, radiotherapy, or investigational anti-tumor therapy.
• Active central nervous system lymphoma involvement, including active brain parenchymal, meningeal, cerebrospinal fluid, or intraocular involvement.
• Active infection requiring intensive care support, or infection judged by the investigator to be uncontrolled and likely to significantly interfere with protocol treatment.
• Known history of acute or chronic pancreatitis, or any condition judged by the investigator to be an absolute contraindication to pegaspargase.

Fulminant disseminated intravascular coagulation, or severe coagulation disorder judged by the investigator to be uncorrectable in the short term and to substantially increase treatment risk.

• Severe cardiac, pulmonary, hepatic, renal, or other major organ dysfunction that, in the investigator's judgment, would significantly interfere with protocol treatment.
• Irreversible contraindication to high-dose methotrexate, including but not limited to marked renal failure, inability to receive standardized hydration, alkalization, leucovorin rescue, or methotrexate clearance monitoring, or any condition judged by the investigator to prevent safe administration of methotrexate within the protocol-defined strategy.
• Active hepatitis C virus infection, human immunodeficiency virus infection, or active uncontrolled hepatitis B virus replication.
• Uncontrolled severe hypertension, active bleeding, recent major thromboembolic event, or vascular high-risk condition judged by the investigator to preclude safe administration of anlotinib.
• Pregnant or breastfeeding women, or participants of reproductive potential unwilling to use effective contraception during the study.
• Any other medical, psychological, social, or compliance-related condition that, in the investigator's judgment, makes the participant unsuitable for this study.