Immune reconstitution following high-dose chemotherapy and autologous stem cell transplantation with and without pembrolizumab maintenance therapy in patients with lymphoma

Abstract Background : Autologous stem cell transplantation (ASCT) is a standard of care for patients with chemosensitive, relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). While the clinical benefit of ASCT has traditionally been attributed solely to cytoreduction from intensive chemotherapy, ASCT has important immunogenic effects which may contribute to its anti-tumor efficacy and could provide a favorable immune environment for post-ASCT immune-based maintenance treatments. We previously reported clinical results of a phase II trial (NCT02362997) testing 8 doses of pembrolizumab maintenance therapy after ASCT for patients with R/R cHL or DLBCL. To clarify the impact of pembrolizumab on immune reconstitution, we compared the kinetics of peripheral blood immune cell recovery after ASCT for trial patients receiving pembrolizumab maintenance to those of a contemporaneous control cohort of similar patients undergoing ASCT without pembrolizumab maintenance. Objective : To characterize the impact of post-ASCT pembrolizumab maintenance therapy on immune reconstitution for patients with R/R DLBCL and cHL and to identify candidate biomarkers of efficacy and immune-related adverse events (irAEs). Study design : Peripheral blood mononuclear cell (PBMC) samples were prospectively collected 1-18 months after ASCT and analyzed by flow cytometry using a panel of fluorophore-conjugated monoclonal antibodies to identify B cells, natural killer (NK) cells, and various dendritic cell (DC) and T cell subsets. Results : A median of 5 (range 1-8) post-ASCT PB samples were collected from 144 patients (59 pembrolizumab, 85 control). Clinical characteristics of the two cohorts were similar. Compared to cHL patients, DLBCL patients (who all received anti-CD20 monoclonal antibody therapy before ASCT) had delayed CD19+ cell reconstitution which persisted for at least 18-month after ASCT. No other differences in immune reconstitution were observed based on lymphoma subtype. Post-ASCT pembrolizumab maintenance therapy was associated with 1) an elevation in circulating DCs (driven by higher levels of plasmacytoid and immature DCs) which persisted for the duration of pembrolizumab treatment, and 2) a significant reduction in PD-1+ T cells which persisted for 6-12 months after completion of pembrolizumab therapy. Despite the key role of T cells in mediating the effects of PD-1 blockade, pembrolizumab maintenance did not affect recovery of any T cell subsets. In an exploratory analysis, a higher baseline CD4+ TEMRA cell count (defined as CD3+ CD4+ CD45RA+ CD62L-) was associated with inferior PFS, but only among patients who received pembrolizumab maintenance (p=0.003). As continuous variables, lower absolute levels of NK cells (p=0.009), PD-1+ CD4+ T cells (p=0.005), and PD-1+ CD8+ T cells (p=0.005) before pembrolizumab initiation were each associated with a higher risk of grade 2+ irAEs. Conclusion : Post-ACST pembrolizumab maintenance therapy is associated with a persistent elevation in circulating DCs, but its impact on the reconstitution of other immune cells in peripheral blood appears limited. Our study suggests that early features of post-ASCT immune reconstitution could be associated with PFS and risk of irAE and warrant additional investigation.