A novel combination therapy of lenalidomide and PD-1 inhibitor has demonstrated remarkable efficacy in a heavily pretreated patient with relapsed classical Hodgkin lymphoma (cHL), offering new hope for patients who have exhausted standard treatment options.
Case Demonstrates Sustained Response After Multiple Treatment Failures
The case involves a 68-year-old male initially diagnosed with stage IV B classical Hodgkin lymphoma (nodular sclerosis type) with bone marrow involvement in 2019. Despite receiving multiple lines of therapy over five years, including standard ABVD chemotherapy, second-line GDP regimen, PD-1 monoclonal antibody (sintilimab), CD30-targeted therapy (brentuximab vedotin), and combination approaches, the patient experienced repeated disease progression.
The breakthrough came when physicians switched to a combination of lenalidomide (25mg daily for 21 days followed by a one-week break) plus tislelizumab (200mg every 3 weeks) in June 2024. After 10 cycles of this combination therapy, the patient achieved sustained disease stability with resolution of B symptoms, weight gain, and reduction in lymph node and spleen size.
Mechanistic Rationale for Combination Approach
The therapeutic rationale for combining lenalidomide with PD-1 inhibition stems from the unique pathophysiology of classical Hodgkin lymphoma. The disease is characterized by rare malignant Reed-Sternberg cells surrounded by a prominent but dysfunctional immune-reactive infiltrate, which plays a critical role in disease pathogenesis.
Lenalidomide, as an immunomodulatory drug, enhances tumor recognition and immune response through multiple mechanisms. It increases NK cell numbers and activity, lowers NK cell activation thresholds, and modulates chemokine levels within the tumor microenvironment. Simultaneously, PD-1 monoclonal antibodies block the PD-1/PD-L1 pathway, significantly augmenting the tumoricidal effects of autologous T lymphocytes, NK cells, and monocytes/macrophages.
Clinical Evidence Supporting Combination Strategy
The selection of this combination was inspired by research in multiple myeloma, where lenalidomide was shown to reduce PD-1 expression in various effector cells and decrease PD-L1 expression in tumor cells. A study by Fehniger et al. in relapsed/refractory cHL patients demonstrated a median overall survival of 23.7 months with lenalidomide treatment, with CCL17 levels declining in responding patients.
Ma et al. reported a clinical benefit rate of 47% with continuous low-dose lenalidomide administration in patients with relapsed Hodgkin lymphoma after autologous stem cell transplantation. These data suggested that patients with relapsed/refractory cHL could benefit from lenalidomide treatment.
Treatment Course and Response
The patient's treatment journey illustrates the challenges faced in managing relapsed/refractory cHL. Initial ABVD therapy from December 2019 to April 2020 provided temporary improvement, but disease progression occurred by June 2020. Subsequent GDP chemotherapy caused severe grade 4 myelosuppression with platelet counts dropping to 10×10E9/L, leading to treatment discontinuation due to the patient's rare Rh-negative blood type and bleeding risk concerns.
Sintilimab monotherapy provided 18 cycles of disease control before progression in October 2021. Eight courses of brentuximab vedotin followed by combination therapy with brentuximab vedotin plus tislelizumab also eventually failed, with disease progression documented by May 2024.
The lenalidomide-tislelizumab combination achieved rapid symptom resolution, with the patient's fatigue and night sweats disappearing, weight increasing, and no fever episodes occurring. Ultrasonography showed partial reduction in superficial and deep enlarged lymph nodes and decreased spleen enlargement.
Safety Profile and Tolerability
The combination therapy demonstrated excellent tolerability. The patient developed only a grade 1 rash following treatment initiation, which completely resolved with corticosteroid therapy. No further adverse reactions were observed during the 10-month treatment period, allowing the patient to return to normal daily activities.
Clinical Implications and Future Directions
This case represents the first reported successful use of lenalidomide combined with PD-1 inhibitor in relapsed/refractory classical Hodgkin lymphoma. The sustained response after 10 cycles suggests potential synergistic therapeutic effects through enhanced immune-mediated cytotoxicity.
The authors acknowledge limitations including the single-case nature of the report and economic constraints preventing PET/CT follow-up evaluation. They emphasize that while this combination achieved good efficacy in this case, further clinical trials are needed to determine broader applicability to all patients with relapsed/refractory cHL.
The success of this combination therapy offers a new treatment paradigm for heavily pretreated patients with relapsed/refractory classical Hodgkin lymphoma, particularly those who cannot tolerate intensive chemotherapy or are ineligible for autologous stem cell transplantation. The findings warrant prospective clinical investigation to validate this approach in larger patient cohorts.
