Sintilimab, pegaspargase, and anlotinib as induction therapy for advanced-stage NKTCL: a multicenter phase II study

Extranodal natural killer/T-cell lymphoma is an aggressive Epstein-Barr virus-associated lymphoma with poor outcomes in advanced-stage disease. High-dose methotrexate-containing, asparaginase-based regimens induce responses but are limited by toxicity, and lower-intensity alternatives show suboptimal durability. We conducted a prospective, multicenter, single-arm phase II trial of the LEAP regimen in newly diagnosed stage IV disease. Eligible patients had ECOG 0-3 and were >65 years or ≤65 years with contraindications to high-dose methotrexate. Treatment comprised up to eight 21-day cycles of sintilimab 200 mg (day 1), pegaspargase 2500 IU/m2 (day 1), and anlotinib 8 mg (days 1-14), with autologous hematopoietic stem cell transplantation (auto-HSCT) allowed for complete responders at the investigator's discretion and patient's preference. Thirty-seven patients were enrolled (median age 64; range, 32-78). At week 24, the complete remission (CR) was 72.9% (27/37), surpassing the prespecified 55% threshold. With a median follow-up of 48 months, estimated 4-year progression-free survival (PFS) and overall survival (OS) were 56.6% and 75.2%, respectively. Seventeen patients underwent auto-HSCT after achieving CR and had lower relapse (17.6% vs 60.0%) and improved PFS (Hazard Ratio=0.23; p<0.05) versus observation. Grade ≥3 adverse events were limited to neutropenia (10.8%) and hyperbilirubinemia (10.8%), with no treatment discontinuations for toxicity or treatment-related deaths. LEAP regimen produced high CR rates and durable survival with manageable toxicity in advanced-stage disease unsuitable for HD-MTX induction and may enable curative-intent therapy; randomized validation is warranted. The study was registered at ClinicalTrials.gov (NCT04004572).