Low-Dose Nivolumab Offers Novel Strategy for Hodgkin Lymphoma Treatment

Low-dose nivolumab (Opdivo) plus lenalidomide (Revlimid) yielded a promising response with a favorable safety profile in patients with classical Hodgkin lymphoma (cHL), according to a single-arm phase 2 study (CTRI/2022/04/042179) published in Blood Immunology & Cellular Therapy, offering a potential chemotherapy-free management option.¹

A fixed dose of 40 mg of nivolumab, well below the standard 14-day dosing frequency of a 240 mg flat dose or 3 mg/kg and the 28-day 480 mg flat dose, plus 10 mg of lenalidomide led to an overall response rate of 90% (n =18; 95% CI, 68%–98%) in 20 patients; 60% (n = 12) achieved a complete response, and 30% (n = 6) achieved a partial response. At a median follow-up of 15 months (range, 10.5–22.4), the progression-free survival rate was 83.5% (95% CI, 56.8%–94.4%), and the relapse-free survival rate for patients who underwent transplant was 92.9% (95% CI, 56.6%–98.8%).

Looking at flow cytometry, the single 40 mg dose of nivolumab was adequate to achieve complete PD-1 receptor occupancy on T cells, which persisted for the entire 14-day dosing interval, suggesting that the standard dosing frequency may be excessive.

Regarding safety, only 1 patient (5%) experienced a grade 2 immune-related adverse event of acute demyelinating polyneuropathy that required treatment discontinuation. Three patients had grade 1 anemia. No cases of thrombocytopenia or neutropenia were reported, and no lenalidomide dose reductions for cytopenia were required. The treatment did not adversely impact stem cell mobilization for the 15 patients who proceeded to subsequent autologous transplant.

“Through the efficacy and receptor occupancy data shown here, we propose an alternative model of scheduling and dosing for nivolumab, based on PD-1 receptor occupancy rather than plasma drug levels. In regions where flow cytometry is available, this will prove to be a useful tool to personalize nivolumab dosing and extend the duration between infusions, using PD-1 receptor occupancy in individual cases to rationalize therapy,” wrote Anu Korula, MD, et al, Christian Medical College, Vellore, India.

“In regions with resource constraints where flow cytometry is not available, the duration of infusion could be extended, based on available data to 4 [to] 6 weekly infusions, with resultant cost-savings that will significantly improve medication access,” the authors added.

The findings challenge the conventional pharmacokinetic-based dosing models for monoclonal antibodies. The study strongly advocates for using pharmacodynamic biomarkers, such as PD-1 receptor occupancy, to guide personalized and more cost-effective dosing schedules, potentially and significantly improving medication access globally.

What Was the Rationale for the Study?

The advent of immune checkpoint inhibitors (ICIs) has transformed oncology, but critical questions remain regarding the minimum effective dose and optimal scheduling. Current approved doses for ICIs like nivolumab are often extrapolated from phase 1/2 trials focused on maximum tolerated dose rather than the lowest effective dose, a methodology better suited to conventional chemotherapy.

This approach is particularly problematic for ICIs, where a clear dose-response relationship has not been established. The high cost and accessibility issues associated with standard dosing are significant barriers to care, especially in lower- and middle-income countries.²

Based on emerging real-world evidence of low-dose nivolumab's efficacy, this phase 2 trial was designed to formally investigate a chemotherapy-free, immunomodulatory regimen for relapsed/refractory cHL.¹ The study aimed to:

• Evaluate the clinical efficacy of a low, fixed 40-mg dose of nivolumab combined with lenalidomide.
• Use flow cytometry to measure PD-1 receptor occupancy as a direct biological marker of drug adequacy and persistence on target cells.
• Propose a more rational, evidence-based model for ICI dosing that balances efficacy with cost and accessibility.

What Are the Next Steps?

Based on these promising results, the researchers have initiated a phase 3 randomized controlled trial to compare a short-course, low-dose nivolumab regimen with the standard doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) regimen in newly diagnosed, advanced-stage Hodgkin lymphoma.

REFERENCES:

1. Korula A, Kulkarni U, Arunahalam AK, et al. Low-dose Nivolumab and Lenalidomide in Relapsed/Refractory Hodgkin Lymphoma - A Single Arm Phase II Trial. Blood Immun & Cell Ther. 2025; 100011. doi: 10.1016/j.bict.2025.100011.

2. Ravikrishna M, Abraham G, Patil VM, et al. Checkpoint inhibitor accessibility in 15,000+ Indian patients. J Clin Oncol. 2022