GELAD-Based Response-Adapted Treatment for Early-Stage Extranodal NK/T-Cell Lymphoma

A Prospective Multicenter Response-Adapted Treatment Study Based on Early Response Assessment After GELAD Induction Chemotherapy in Early-Stage Extranodal NK/T-Cell Lymphoma

This prospective, multicenter study evaluates a response-adapted treatment strategy for previously untreated patients with early-stage extranodal NK/T-cell lymphoma of the upper aerodigestive tract.

All participants receive two cycles of GELAD induction chemotherapy, followed by early response assessment using positron emission tomography/computed tomography (PET/CT) and plasma Epstein-Barr virus (EBV) DNA. Subsequent treatment is determined by the early response.

Participants with complete metabolic response and negative EBV DNA enter PART A and are randomized 1:1 to standard-dose radiotherapy (50 Gy) or reduced-dose radiotherapy (40 Gy); both groups subsequently receive two additional cycles of GELAD. Participants with partial response and negative EBV DNA enter PART B and receive standard 50 Gy radiotherapy followed by two additional cycles of GELAD. Participants with stable disease, local or regional progressive disease that remains amenable to curative radiotherapy, or partial response with positive EBV DNA enter PART C and receive 50 Gy radiotherapy followed by response-adapted sintilimab consolidation.

The primary objective of PART A is to determine whether reduced-dose radiotherapy is noninferior to standard-dose radiotherapy with respect to the 24-month progression-free survival rate. The primary objective of PART C is to evaluate the 24-month progression-free survival rate with response-adapted sintilimab consolidation in patients with a high-risk early response.

Inclusion Criteria:

• Age 18 to 75 years, inclusive.

• Histologically confirmed extranodal NK/T-cell lymphoma, nasal type, according to the 2022 World Health Organization classification.

• Diagnosis confirmed by institutional or central pathological review. Tumor tissue must be adequate for morphological assessment, immunohistochemistry, and Epstein-Barr virus-encoded RNA in situ hybridization.

• Lugano 2014 stage IE or IIE disease with a primary site in the upper aerodigestive tract, including but not limited to the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, or oral cavity.

• At least one disease lesion evaluable by PET/CT at baseline.

• No previous chemotherapy, radiotherapy, immunotherapy, or other antitumor biological therapy for lymphoma.

• Eastern Cooperative Oncology Group performance status of 0 to 2.

• Adequate organ function, including:

  • Absolute neutrophil count at least 1.0 x 10^9/L.
  • Platelet count at least 75 x 10^9/L.
  • Hemoglobin at least 90 g/L.
  • No granulocyte colony-stimulating factor, platelet transfusion, or red blood cell transfusion within 14 days before enrollment.
  • Total bilirubin no greater than 1.5 times the upper limit of normal.
  • Alanine aminotransferase and aspartate aminotransferase no greater than 2 times the upper limit of normal.
  • Serum creatinine no greater than 1.5 times the upper limit of normal.
  • Fibrinogen at least 1.5 g/L.
  • Left ventricular ejection fraction at least 50%.

• Ability to understand the study and provide written informed consent.

• Willingness to comply with protocol treatment, follow-up, laboratory testing, imaging assessments, and biospecimen collection.

Exclusion Criteria:

• Diagnosis not meeting the 2022 World Health Organization criteria for extranodal NK/T-cell lymphoma or not confirmed after pathological review.
• Lugano stage III or IV disease or distant organ involvement inconsistent with localized early-stage disease.
• Primary disease outside the upper aerodigestive tract or predominantly systemic or widespread extranodal disease.
• Previous lymphoma-directed chemotherapy, radiotherapy, immunotherapy, or other systemic antitumor treatment.
• Human immunodeficiency virus infection, active hepatitis C virus infection, or hepatitis B virus infection with HBV DNA greater than 10^3/mL.
• History of pancreatitis or pancreatic disease considered unsuitable for pegaspargase treatment.
• Acute or systemic infection requiring intravenous anti-infective treatment.
• Severe complications including hemophagocytic lymphohistiocytosis or disseminated intravascular coagulation.
• Significant organ dysfunction, including respiratory failure, chronic congestive heart failure of New York Heart Association class II or higher, decompensated hepatic or renal dysfunction, uncontrolled hypertension or diabetes despite appropriate treatment, or cardiovascular or cerebrovascular thrombosis or bleeding within the previous 6 months.
• Active autoimmune disease or another condition considered by the investigator to make immune checkpoint inhibitor treatment unsuitable.
• Pregnancy or breastfeeding.
• Participants of reproductive potential who are unwilling to use adequate contraception.
• Known severe hypersensitivity to any study drug or its excipients.
• Another active malignancy within the previous 6 months requiring surgery, radiotherapy, or systemic anticancer therapy.
• Severe psychiatric disorder, poor adherence, or another condition that, in the investigator's judgment, would prevent completion of protocol treatment or follow-up.
• Current use of another investigational drug or participation in another interventional clinical trial within 4 weeks before enrollment.