Low-Dose Nivolumab Plus AVD As Front-Line Therapy for Classical Hodgkin's Lymphoma: Preliminary Results of a Phase 2 Trial

Introduction: The treatment landscape for newly diagnosed Hodgkin lymphoma (HL) has improved in recent years with the addition of novel agents to the first line. The use of immune checkpoint inhibitors targeting the programmed death cell protein1 (PD-1) has demonstrated impressive response rates and favorable safety profiles. However, the high cost of these drugs at the standard doses is a big barrier for implementation worldwide, making them practically inaccessible to most patients in low- to middle-income countries (LMICs).

Objective: We aimed to evaluate the safety and efficacy of low-dose nivolumab in combination with AVD (doxorubicin, vinblastine and dacarbazine) as a first-line treatment for cHL.

Methods: We conducted a single-center, phase 2 open-label clinical trial (NCT05772624). Eligible patients were diagnosed with classical HL and no prior therapy, >16 years of age, at any stage, with adequate organ function and measurable disease (>1.5 cm). Early unfavorable disease was determined according to NCCN criteria. The treatment consisted of two initial cycles of low-N-AVD (flat-dose nivolumab 40 mg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2, IV, days 1 and 15 of a 28-day cycle, IV). Response was assessed with FDG PET/CT after two cycles of N-AVD and at the end of the treatment. Upon intermediate assessment, partial responders received 4 more cycles of low-N-AVD, and complete responders (D1-D3) received 2-4 more cycles of AVD regimen without nivolumab (2 for favorable early stages and 4 for advanced and unfavorable early stage). Responses were defined according to the 2014 Lugano criteria. The primary endpoint was the overall response rate (ORR), including complete remission (CR) and partial remission (PR). Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.03).

Results: A total of 20 patients have been included. The median age was 27 years (range, 18-72); 12 (60%) were female and 8 (40%) male. Most of them corresponded to a disease stage III-IV (n=12, 60%) . Median nivolumab dose per kilogram was 0.61 (range, 0.44-0.90). After two cycles of low-N-AVD, the objective response rate was 100%, with 10 (50%) achieving a complete response (CR) and 10 (50%) showing a partial response (PR). 16 patients have concluded the study. Upon PET-CT assessment at the end of therapy, 13 (65%) achieved CR, and 2 patients (10%) PR (only one had measurable disease >1.5 cm). 3 patients are still on treatment, 1 patient (5%) abandoned the study after achieving CR at the interim evaluation, and 1 (5%) presented progressive disease (PD). The latter only received two cycles of low-N-AVD and they achieved complete metabolic response after the two initial cycles. In total, 11 (55%) of patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (n=9 45%), and hypothyroidism (20%). None presented febrile neutropenia. Cost was reduced from 13,000 USD with standard N-AVD to 1,700 USD per cycle, generating savings of up to 77% per cycle.

Conclusion: In this single-center phase 2 trial, low-dose nivolumab combined with AVD as first-line therapy for classical Hodgkin's lymphoma (HL) demonstrated promising results. After two cycles, all patients achieved an objective response, with most attaining a complete metabolic response and continuing with AVD alone. This approach presents a potential strategy for improved treatment efficacy while mitigating financial and biological toxicity, especially in LMICs.