PD-1 Blockade after Epigenetic Therapy in Patients with Relapsed or Refractory Hodgkin Lymphoma: Higher-Than-Expected Rate of Complete Responses

Background: Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) after brentuximab vedotin (Bv) and autologous stem cell transplantation (ASCT) represent an unmet medical need. Allogeneic SCT can be curative, but is burdened with significant morbidity and mortality. Nivolumab and pembrolizumab are anti-programmed death (PD)-1 monoclonal antibodies and are referred to as immune checkpoint inhibitors (ICI). These agents have shown remarkable activity in patients with R/R cHL, but rarely induce complete response (CR). Studies on ovarian cancer cell lines have shown that exposure of tumor cells to the hypomethylating agent (HMA) 5-azacitidine, may induce transcription of latent endogenous retroviral genes, which then trigger a T-cell-mediated immune response. Therefore, HMA can act as "immunologic primers" and enhance the efficacy of ICI. We reviewed our experience with ICI in patients with R/R cHL, and compared responses between those who had been previously exposed to 5-azacitidine to those who had not.

Methods: Twelve 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 = 3). Response was assessed by positron emission tomography/computerized tomography. For patients who were transplant candidate, ICI were used as a bridge to the procedure.

Results: The patient median age was 35 years [range 25-79]. The median number of prior treatments was 11 [range 3-16] and 75% of patients had had ≥ 7 lines of therapy. All patients had received ASCT and Bv. Six had been exposed to 5-azacitidine for a median of 2.5 months [range 2-16] as part of a phase 1 study (NCT01998035). Four of them had received it immediately prior to ICI, the other two within 14 months of starting ICI. A total of 141 patient-courses were completed, with a median of 7 courses per patient [range 1-39]. There were 6 grade ≥ 3 adverse events (AE): infusion reaction (N = 1), thrombocytopenia (N = 1), grade-5 respiratory failure (N = 1), myelodysplastic syndrome, (N = 2, one of which pre-existent, both evolved into fatal acute myeloid leukemia (AML)), and acute kidney injury (N = 1, pre-existent). Grade 1-2 AE included infusion reaction (5), elevated thyroid stimulating hormone levels (3), diarrhea (2), fatigue (1). Ten patients are evaluable for response: 7 (70%) achieved CR, one partial response, one a reduction of tumor burden and one stable disease. Five of the 6 patients who received 5-azacitidine prior to ICI achieved CR, while only 2 of 4 who did not receive prior 5-azacitidine achieved CR. One patient's evaluation is pending at this time. At a median follow-up of 14.2 months [range 0.5-17.7], 9 patients are alive and 7 are still receiving treatment. Two patients with radiographic progression continue to be treated given sustained clinical benefit. One patient transitioned to allogeneic SCT while in complete remission and one discontinued due to symptomatic progression. The median progression-free survival has not been reached as of this writing (7.9+ months).

Conclusions: We report the largest cohort of patients treated with ICI after being exposed to HMA. In these patients with very heavily pretreated cHL we observed a higher-than-expected CRR. Most serious AE were not related to ICI therapy. The finding that most CR clustered in patients previously exposed to 5-azacitidine may reflect synergism between HMA and ICI and support the notion of HMA-mediated "immunologic priming". This hypothesis is being tested in prospective clinical trials at our institution.