A Phase II Study of Pembrolizumab+ BEAM before Autologous Stem Cell Transplant (ASCT) Followed By Pembrolizumab Maintenance in Patients with Relapsed/Refractory Classic Hodgkin Lymphoma

Background: Up to 80% of patients with classic Hodgkin lymphoma (cHL) are cured with frontline chemoimmunotherapy. Approximately 5%–10% of patients have primary refractory disease, and 10%–20% of patients ultimately relapse. Prior to advent of novel agents, salvage chemotherapy and autologous stem cell transplant (ASCT) were the standard of care and had cures rates of ~50-60%. Patients with primary refractory disease, relapse within a year of completion of frontline therapy, extranodal disease, requirement of more than 1 line of therapy to achieve best response, and partial response (PR) only at time of ASCT have higher likelihood of relapse after ASCT.

In the last decade, incorporation of novel agents in treatment paradigm of relapsed/refractory cHL (R/R cHL) has improved patient outcomes. Post-ASCT brentuximab vedotin (BV) consolidation has improved progression free survival (PFS) of R/R cHL with high-risk features. Incorporation of PD1inhibitors with salvage regimens has improved rates of complete response (CR) and PFS, including in patients with high-risk R/R cHL. In two large multicenter cohorts, we observed that PD1-inhibitor based salvage regimens before ASCT are associated with significantly higher post-ASCT PFS compared to BV-based and chemotherapy-based salvage regimens. Even in the subgroup of patients who underwent ASCT in CR, PD1-inhibitor based salvage regimens were associated with significantly higher 2-year PFS of ~97.7% compared to chemotherapy-based salvage regimens. Post-ASCT pembrolizumab consolidation, without pre-ASCT PD1-inhibitors, have shown 18-month PFS of ~82%. Mass cytometry and single cell RNA sequencing on peripheral blood mononuclear cells have shown that terminally differentiated and exhausted T cells are associated with loss of response and progression of PD1 inhibitors.

Based on our prior observations, we hypothesize that priming of immune system with pembrolizumab, and subsequent reboot of immune system with BEAM+ASCT may replace exhausted T cells. Post-ASCT maintenance with pembrolizumab then may work on these re-sensitized naïve T cells to improve likelihood of remission. Consequently, administering pembrolizumab before ASCT followed by pembrolizumab maintenance may improve PFS in R/R cHL. To assess this hypothesis, we designed a phase 2 study of pre-ASCT pembrolizumab followed by post-ASCT pembrolizumab maintenance in patients with cHL relapsed or refractory to frontline treatment.

Study Design and Methods:

This investigator-initiated, single-arm, phase 2 study is designed to assess efficacy of pembrolizumab prior to ASCT followed by 1 year of post-ASCT pembrolizumab maintenance in patients with R/R cHL. Adult patients who are relapsed or refractory to frontline treatment will be included. Key inclusion criteria include: 1) Age 18 years or older, 2) Histologically confirmed diagnosis of classical Hodgkin lymphoma that is relapsed after frontline induction chemotherapy, 3) Eligible for ASCT, 4) Karnofsky performance score (KPS) ≥ 70, 5) Adequate organ function within 14 days of study registration. Key exclusion criteria include: 1) Autoimmune illness requiring systemic steroids or biologics, 2) Prior history of autoimmune reaction to PD-1 inhibitors ≥ grade 3 (CTCAE 5.0). Eligible patients will receive two doses of pembrolizumab 200 mg intravenously, one prior to apheresis and another one day before BEAM conditioning, at least 3 weeks apart. Subsequently, patients will undergo ASCT. At day 30 post-ASCT, patients will resume pembrolizumab 200 mg intravenously every 3 weeks for 1 year. Patients will be followed upto 5 years for adverse event monitoring and assessments of study endpoints. Study is approved by local IRB and will be performed in compliance with Declaration of Helsinki.

Total estimated enrollment goal is 28 patients over 2 years. Primary study endpoint is PFS at 1 year. Secondary endpoints are 2-year PFS and OS. Correlative analyses to assess post-ASCT immune reconstitution on pembrolizumab therapy is planned. We estimate that study will open to accrual in August 2024 at University of Minnesota in Minneapolis, Minnesota. Study is registered on clinicaltrials.gov (NCT06377540).