Extranodal NK/T-cell Lymphoma
Conditions
Keywords
Extranodal NK/T-cell lymphoma, Epstein-Barr virus, Sintilimab, Pegaspargase, Anlotinib, Methotrexate, Autologous hematopoietic stem cell transplantation
Brief summary
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.
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.
Interventions
DRUGGELAD 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.
DRUGMEDA 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.
DRUGLEAP 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.
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.
PROCEDUREAutologous Hematopoietic Stem Cell Transplantation
Participants achieving strict complete remission will undergo autologous hematopoietic stem cell transplantation according to institutional transplant procedures if eligible.
Sponsors
Rong Tao
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival Within 24 Months | From randomization to the first protocol-defined EFS event or administrative censoring at 24 months after randomization | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | From randomization to disease progression, relapse, death, or last disease assessment, assessed up to 66 months | 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. |
| Overall Survival | From randomization to death or last confirmed survival status, assessed up to 66 months | 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. |
| Percentage of Participants With at Least One Serious Adverse Event | 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. | 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. |
| Percentage of Participants With at Least One Grade 3 or Higher Adverse Event | 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 | 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. |
| Percentage of Participants Who Permanently Discontinue a Key Component of the Assigned Treatment Strategy Due to Adverse Events | From first dose to permanent discontinuation of assigned protocol treatment, assessed up to 12 months | 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. |
| Strict Complete Remission Rate at Key Response Assessment | At key response assessment after assigned induction treatment, approximately 12-20 weeks after randomization | 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. |
| Percentage of Participants With Treatment-Related Mortality | 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 | 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. |
| Percentage of Baseline Plasma EBV-DNA-Positive Participants With Plasma EBV-DNA Clearance at the Key Response Assessment | At the key response assessment after completion of assigned induction treatment, approximately 12 to 20 weeks after randomization. | 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. |
| Overall Response Rate at Key Response Assessment | At key response assessment after assigned induction treatment, approximately 12-20 weeks after randomization | 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. |
| Percentage of Randomized Participants Who Complete Autologous Hematopoietic Stem Cell Transplantation | From randomization to completion of autologous HSCT, assessed up to 12 months | 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. |
| Cumulative Incidence of Relapse Among Participants Who Achieve Strict Complete Remission | 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. | 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. |
Countries
China
Contacts
CONTACTRong Tao, MD & PhD
CONTACTChuanxu Liu, MD & PhD
STUDY_CHAIRRong Tao, MD & PhD
Shanghai Cancer Center
PRINCIPAL_INVESTIGATORChuanxu Liu, MD & PhD
Shanghai Cancer Center
Outcome results
None listed