Background: Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) after brentuximab vedotin (Bv) and autologous stem cell transplantation (ASCT) have limited treatment options. Immune checkpoint inhibitors (ICI) are active in this population, but rarely induce complete response (CR). Evidence suggests that exposure of tumor cells to 5-azacitidine may activate a T-cell-mediated immune responses, thus enhancing the efficacy of ICI. We reviewed our experience with ICI in patients with R/R cHL, and compared responses between those who had been exposed to 5-azacitidine to those not previously esposed to a hypomethylating agent.
Methods: Eleven patients with R/R cHL received pembrolizumab at the dose of 2 mg/kg every 3 weeks (N = 9), or nivolumab at the dose of 3 mg/kg every 2 weeks (N = 2). Response was assessed by positron emission tomography/computerized tomography (PET/CT).
Results: The patient population was very heavily treated, with a median of 12 [3-16] prior treatments. All had received ASCT and Bv. Six had been exposed to 5-azacitidine on a Phase 1 study. Four of them had received it immediately prior to ICI, all of them within 14 months. Grade ≥3 adverse events (AE) included: infusion reaction (N = 1) thrombocytopenia (N = 1), grade-5 respiratory failure (N = 1), myelodysplastic syndrome (N = 2, one pre-existent), and acute kidney injury (N = 1, pre-existent). Nine patients were evaluable for response: 7 (78%) achieved CR, one PR, and one a reduction of tumor burden. All five evaluable patients who received 5-azacitidine prior to ICI achieved CR (one is pending evaluation and will be reported), while only 2 of 4 who did not receive prior 5-azacytidine achieved CR. At a median follow-up of 9.0 months [0.5-14.3], 9 patients are alive and 6 are still receiving treatment.
Conclusions: We documented an unprecedented rate of CR to ICI in patients with heavily pre-treated R/R cHL. The most serious AE’s were unrelated to ICI therapy. We believe this experience supports the notion of epigenetic priming, as shown in lung cancer studies, and is now being studied in the context of a clinical trial.