BRIDGE-NK: Immunotherapy Versus Chemotherapy Induction Followed by Autologous HSCT in Advanced NKTCL (BRIDGE-NK)

BRIDGE-NK: A Randomized, Open-Label, Prospective Phase III Study of Immunotherapy Induction Versus Chemotherapy Induction Followed by Autologous Hematopoietic Stem Cell Transplantation Consolidation in Newly Diagnosed Advanced Extranodal NK/T-Cell Lymphoma

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Extranodal NK/T-cell Lymphoma
• Intervention / Treatment: Drug: GELAD regimen; Drug: MEDA regimen; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Drug: LEAP regimen; Drug: High-dose methotrexate

Detailed Description

Extranodal NK/T-cell lymphoma is an aggressive Epstein-Barr virus-associated lymphoma with poor outcomes in advanced-stage disease. High-dose methotrexate-containing asparaginase-based chemotherapy can induce responses but is limited by early toxicity, organ dysfunction, infection risk, and incomplete treatment delivery in patients with high tumor burden. PD-1 antibody-based immunotherapy combinations have shown promising activity and tolerability in advanced-stage disease, but randomized evidence comparing immunotherapy induction with chemotherapy induction in a frontline curative-intent strategy remains lacking.

This study is designed to evaluate whether immunotherapy induction followed by CNS-directed high-dose methotrexate consolidation and autologous hematopoietic stem cell transplantation can improve event-free survival compared with a conventional chemotherapy induction strategy followed by autologous hematopoietic stem cell transplantation. The comparison focuses on the entire treatment strategy, including induction depth, feasibility of subsequent consolidation, and early strategy failure, rather than isolated response to a single regimen.

Strict complete remission is defined as all of the following: complete metabolic remission on PET/CT according to Lugano 2014 criteria, negative plasma EBV-DNA, and negative EBER staining on repeat bone marrow biopsy for participants with baseline bone marrow involvement.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Rong Tao, MD & PhD; Phone Number: 660103 008621-64175590; Email: hkutao@hotmail.com
• Study Contact Backup: Name: Chuanxu Liu, MD & PhD; Phone Number: 660103 008621-64175590; Email: liuchaunxu@shca.or.cn

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200433
      • Fudan University Shanghai Cancer Center,
      • Contact: Rong Tao, MD & PhD; Phone Number: 660103 008621-64175590; Email: hkutao@hotmail.com
      • Contact: Chuanxu Liu, MD& PhD; Phone Number: 660103 008621-64175590; Email: liuchaunxu@shca.or.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: Chemotherapy Induction Followed by Autologous HSCT Consolidation; Participants randomized to Arm A will receive one 21-day cycle of GELAD induction followed by three 21-day cycles of MEDA chemotherapy. After completion of GELAD ×1 plus MEDA ×3, participants will undergo key response assessment with PET/CT, plasma EBV-DNA testing, and repeat bone marrow biopsy with EBER staining if bone marrow was involved at baseline. Participants who achieve strict complete remission will proceed to autologous hematopoietic stem cell transplantation consolidation if eligible. Participants who do not achieve strict complete remission and require non-protocol anti-tumor therapy will be managed according to the protocol-defined event rules.	Drug: GELAD regimen; Gemcitabine 1.0 g/m² on day 1, etoposide 60 mg/m² on days 1-3, pegaspargase 2000 IU/m² on day 4, and dexamethasone 40 mg on days 1-4, repeated every 21 days for 1 cycle.; Drug: MEDA regimen; Methotrexate 3.0 g/m² on day 1 as a 3-hour intravenous infusion, etoposide 100 mg/m² on days 2-4, dexamethasone 40 mg on days 1-4, and pegaspargase 2500 IU/m² on day 4, repeated every 21 days for 3 cycles.; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Participants achieving strict complete remission will undergo autologous hematopoietic stem cell transplantation according to institutional transplant procedures if eligible.
Experimental: Arm B: Immunotherapy Induction Followed by HD-MTX and Autologous HSCT Consolidation; Participants randomized to Arm B will receive four 21-day cycles of LEAP induction with sintilimab, pegaspargase, and anlotinib. After completion of LEAP ×4, participants will undergo key response assessment with PET/CT, plasma EBV-DNA testing, and repeat bone marrow biopsy with EBER staining if bone marrow was involved at baseline. Participants who achieve strict complete remission will receive high-dose methotrexate CNS-directed consolidation for up to 3 doses, followed by autologous hematopoietic stem cell transplantation consolidation if eligible.	Procedure: Autologous Hematopoietic Stem Cell Transplantation; Participants achieving strict complete remission will undergo autologous hematopoietic stem cell transplantation according to institutional transplant procedures if eligible.; Drug: LEAP regimen; Sintilimab 200 mg intravenously on day 1, pegaspargase 2500 IU/m² on day 1 with a maximum single dose of 3750 IU, and anlotinib 8 mg orally on days 1-14, repeated every 21 days for 4 cycles.; Drug: High-dose methotrexate; Participants who achieve strict complete remission after LEAP induction will receive methotrexate 3.0 g/m² as a 3-hour intravenous infusion every 2 weeks for up to 3 doses, with hydration, urine alkalization, leucovorin rescue, and methotrexate concentration monitoring.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival Within 24 Months	Event-free survival is defined as the time from the date of randomization to the first occurrence of any of the following events: disease progression; death from any cause; inability to complete the assigned protocol-defined treatment strategy due to severe adverse events, persistent organ toxicity, treatment-related complications, or other unacceptable toxicity; or failure to achieve strict complete remission at the key response assessment followed by initiation of non-protocol anti-tumor therapy. Participants without an EFS event at 24 months after randomization will be administratively censored at 24 months.	From randomization to the first protocol-defined EFS event or administrative censoring at 24 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival	Progression-free survival is defined as the time from randomization to documented disease progression, relapse after response, or death from any cause, whichever occurs first. Participants without an event will be censored at the date of the last valid disease assessment.	From randomization to disease progression, relapse, death, or last disease assessment, assessed up to 66 months
Overall Survival	Overall survival is defined as the time from randomization to death from any cause. Participants who are alive will be censored at the last date they are known to be alive.	From randomization to death or last confirmed survival status, assessed up to 66 months
Percentage of Participants With at Least One Serious Adverse Event	The percentage of participants who experience at least one serious adverse event, as defined in the study protocol, during the specified assessment period. Each participant will be counted once regardless of the number of serious adverse events experienced. Serious adverse events will be assessed by the investigator for relationship to protocol treatment.	From the first dose of protocol treatment through 30 days after the last protocol treatment, and through Day +90 after autologous HSCT for transplanted participants, assessed up to 12 months.
Percentage of Participants With at Least One Grade 3 or Higher Adverse Event	The percentage of participants who experience at least one grade 3 or higher adverse event, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Each participant will be counted once according to the highest adverse event grade experienced during the assessment period.	From first dose of protocol treatment through 30 days after the last protocol treatment, and through Day +90 after autologous HSCT for transplanted participants, assessed up to 12 months
Percentage of Participants Who Permanently Discontinue a Key Component of the Assigned Treatment Strategy Due to Adverse Events	The percentage of participants who permanently discontinue at least one key component of the assigned protocol-defined treatment strategy because of an adverse event, treatment-related toxicity, or treatment-related complication. Each participant will be counted once.	From first dose to permanent discontinuation of assigned protocol treatment, assessed up to 12 months
Strict Complete Remission Rate at Key Response Assessment	Strict complete remission rate is defined as the proportion of participants who meet all of the following criteria: complete metabolic remission on PET/CT, negative plasma EBV-DNA, and negative EBER staining on repeat bone marrow biopsy among participants with baseline bone marrow involvement.	At key response assessment after assigned induction treatment, approximately 12-20 weeks after randomization
Percentage of Participants With Treatment-Related Mortality	The percentage of participants who die from an adverse event or complication judged by the investigator to be related to protocol treatment, treatment-related supportive procedures, or autologous hematopoietic stem cell transplantation.	From first dose through 30 days after the last protocol treatment, and through Day +90 after autologous HSCT for transplanted participants, assessed up to 12 months
Percentage of Baseline Plasma EBV-DNA-Positive Participants With Plasma EBV-DNA Clearance at the Key Response Assessment	The percentage of participants with detectable plasma Epstein-Barr virus DNA at baseline who achieve plasma EBV-DNA clearance at the key response assessment. Plasma EBV-DNA will be measured using quantitative real-time polymerase chain reaction and reported in copies/mL. Plasma EBV-DNA clearance is defined as a decrease from a detectable baseline value to less than 500 copies/mL or below the lower limit of quantification of the assay. The denominator will include baseline plasma EBV-DNA-positive participants with an evaluable plasma EBV-DNA result at the key response assessment.	At the key response assessment after completion of assigned induction treatment, approximately 12 to 20 weeks after randomization.
Overall Response Rate at Key Response Assessment	Overall response rate is defined as the proportion of participants achieving complete remission or partial remission according to Lugano 2014 criteria at the key response assessment.	At key response assessment after assigned induction treatment, approximately 12-20 weeks after randomization
Percentage of Randomized Participants Who Complete Autologous Hematopoietic Stem Cell Transplantation	The percentage of all randomized participants who complete autologous hematopoietic stem cell transplantation after achieving protocol-defined strict complete remission and meeting transplant eligibility criteria. The denominator will include all randomized participants in each treatment arm.	From randomization to completion of autologous HSCT, assessed up to 12 months
Cumulative Incidence of Relapse Among Participants Who Achieve Strict Complete Remission	The cumulative incidence, expressed as a percentage, of first lymphoma relapse among participants who achieve protocol-defined strict complete remission at the key response assessment. Relapse will be assessed according to Lugano 2014 criteria using PET/CT and, where clinically indicated, contrast-enhanced CT or MRI, bone marrow evaluation, and plasma EBV-DNA testing. Death without documented relapse will be treated as a competing event.	From the date of first documented strict complete remission to relapse, death, or the last valid disease assessment, assessed up to 66 months after randomization.

Collaborators and Investigators

• Sponsor: Rong Tao
• Investigators: Study Chair: Rong Tao, MD & PhD, Shanghai Cancer Center; Principal Investigator: Chuanxu Liu, MD & PhD, Shanghai Cancer Center

Publications and helpful links

General Publications

• Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.
• Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Araujo IBO, Berti E, Bhagat G, Borges AM, Boyer D, Calaminici M, Chadburn A, Chan JKC, Cheuk W, Chng WJ, Choi JK, Chuang SS, Coupland SE, Czader M, Dave SS, de Jong D, Du MQ, Elenitoba-Johnson KS, Ferry J, Geyer J, Gratzinger D, Guitart J, Gujral S, Harris M, Harrison CJ, Hartmann S, Hochhaus A, Jansen PM, Karube K, Kempf W, Khoury J, Kimura H, Klapper W, Kovach AE, Kumar S, Lazar AJ, Lazzi S, Leoncini L, Leung N, Leventaki V, Li XQ, Lim MS, Liu WP, Louissaint A Jr, Marcogliese A, Medeiros LJ, Michal M, Miranda RN, Mitteldorf C, Montes-Moreno S, Morice W, Nardi V, Naresh KN, Natkunam Y, Ng SB, Oschlies I, Ott G, Parrens M, Pulitzer M, Rajkumar SV, Rawstron AC, Rech K, Rosenwald A, Said J, Sarkozy C, Sayed S, Saygin C, Schuh A, Sewell W, Siebert R, Sohani AR, Tooze R, Traverse-Glehen A, Vega F, Vergier B, Wechalekar AD, Wood B, Xerri L, Xiao W. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022 Jul;36(7):1720-1748. doi: 10.1038/s41375-022-01620-2. Epub 2022 Jun 22.
• Li D, Liu C, Wan J, Zhang W, Ma Y, Zhu Y, Ma L, Tian S, Ding H, Tao R. Sintilimab, pegaspargase, and anlotinib as induction therapy for advanced-stage NKTCL: a multicenter phase II study. Blood Adv. 2026 Mar 3:bloodadvances.2025018720. doi: 10.1182/bloodadvances.2025018720. Online ahead of print.
• Zhu Y, Tian S, Xu L, Ma Y, Zhang W, Wang L, Jin L, Liu C, Zhu C, Li Z, Hao S, Zhong H, Ding H, Tao R. GELAD chemotherapy with sandwiched radiotherapy for patients with newly diagnosed stage IE/IIE natural killer/T-cell lymphoma: a prospective multicentre study. Br J Haematol. 2022 Feb;196(4):939-946. doi: 10.1111/bjh.17960. Epub 2021 Nov 21.
• Liu C, Ding H, Zhu Q, Liu P, Zhu Y, Wang L, Ma Y, Zhang W, Tian S, Zhang X, Jin L, Liu L, Li Z, Hao S, Tao R. Induction with MEDA regimen and consolidation with Auto-HSCT for stage IV NKTCL patients: A prospective multicenter study. Int J Cancer. 2022 Sep 1;151(5):752-763. doi: 10.1002/ijc.34055. Epub 2022 Jun 9.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: June 16, 2026
• First Submitted That Met QC Criteria: June 24, 2026
• First Posted (Actual): July 1, 2026

Study Record Updates

• Last Update Posted (Actual): July 1, 2026
• Last Update Submitted That Met QC Criteria: June 24, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Methotrexate; Pegaspargase; Sintilimab; Autologous hematopoietic stem cell transplantation; Anlotinib; Epstein-Barr virus; Extranodal NK/T-cell lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Infections; Virus Diseases; Neoplasms by Histologic Type; DNA Virus Infections; Lymphoma, Non-Hodgkin; Lymphoma; Herpesviridae Infections; Tumor Virus Infections; Lymphoma, T-Cell; Epstein-Barr Virus Infections; Lymphoma, Extranodal NK-T-Cell; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pterins; Pteridines; Aminopterin; Methotrexate
• Other Study ID Numbers: SHCA-NKT-Bridge26

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: IPD sharing is currently undecided. The study team will determine whether de-identified participant-level data can be shared after study completion in accordance with institutional policy, participant consent, and applicable regulations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No