Smart start with tislelizumab as frontline treatment in advanced-stage classical Hodgkin lymphoma：a PET-adapted, chemotherapy-sparing phase 2 study

Abstract Background Around 10-30% of classical Hodgkin's lymphoma(cHL) will relapse or refract after treatment with traditional cytotoxic drug-based chemotherapy, meanwhile the short and long-term chemotherapy-related toxicity cannot be ignored. In order to balance efficacy and toxicity, we use the concept of “Smart Start” to explore the efficacy and safety of tislelizumab sequentially combined with AVD regimen in the first-line treatment of cHL in phase II study (NCT04843267). Methods The study included untreated cHL patients with advanced-stage (Ⅲ to Ⅳ and ⅡB with unfavorable risk factors). All patients first received 2 cycles of tislelizumab monotherapy, followed by PET-CT evaluation (PET-2). PET-2–defined complete response (CR) patients continued to receive 4 cycles of tislelizumab monotherapy; partial response (PR) patients received 4 cycles of tislelizumab and AVD combination therapy; progression disease (PD)/ stable disease (SD) patients withdrew from the study. After 6 cycles of treatment, the patients who still maintained PR according to the PET-CT evaluation (PET-3), could receive 2 additional cycles of tislelizumab and AVD combination therapy. The primary endpoint is PET-2 CR rate, and the secondary endpoints include overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. CRR and ORR were analyzed via Clopper-Pearson exact method, Survival curves were estimated via Kaplan-Meier method and compared using log-rank tests, while safety followed NCI CTCAE v5.0 and MedDRA coding standards. Results 32 patients were enrolled in the study from August 2021 to July 2023, with one exclude following pathological review as peripheral T-cell lymphoma. The remaining 31 patients had a median age of 32years (range 21-68), including >45year-old 25.8%, male 59.4% (19/31), and stage IV 64.5% (20/31). All 31 patients completed at least two cycles of tislelizumab monotherapy and PET-2 efficacy evaluation. PET-2 CR rate was 32.3% (10/31), the overall response rate (ORR) was 96.8% (30/31), and one patient developed PD (3.6%) during treatment. Up to the last dose of the study, 28 patients (90.3%,28/31) achieved CR, and three (9.7%) had PD during the treatment. After a median follow-up of 36 months, 6 of the 10 CR patients in PET-2 had maintained CR without chemotherapy, while 14 patients received only 4 cycles of chemotherapy with maintained CR, reducing chemotherapy exposure. The 3-year PFS was 70.5%, with 1- and 2-year PFS rate of 80.5% and 73.8%, respectively. Overall survival (OS) remained 96.7% at 1, 2 and 3 years. Univariate analysis revealed significant PFS advantages for females and patients aged <45 years. Females achieved 100% PFS at 1, 2 and 3 years, whereas males had PFS of 73.3%, 66.7% and 51.0%, respectively (P = 0.0169). Patients <45 years demonstrated 1-, 2- and 3-year PFS of 86.7%, 82.2% and 82.2%, respectively, compared with 62.5%, 46.9% and 37.5% for those ≥45 years (P = 0.0172). The treatment regimen was well tolerated, with no treatment-related SAE or death observed. Immune-related AE were predominantly grade 1/2, while grade 3/4 hematological toxicities mainly ocurred during combination treatment. Conclusions The study demonstrated that tislelizumab sequentially combined with AVD regimen achieved high CR rates while enabling chemotherapy reduction in 64% of patients. The findings show that cytotoxic drugs could be reduced or even omitted in some of advanced-stage cHL patients, particularly among female and younger patients. These results support further investigation of this treatment approach in cHL management.