Checkpoint Blockade Treatment May Sensitize Hodgkin Lymphoma to Subsequent Therapy

Abstract

Background. Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. Materials and Methods. Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progressionfree survival (PFS), duration of response, and overall survival (OS). Results. Eighty-one patients were included. Seventy-two percent had stage III-IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. Conclusion. In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials.

Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

“…93 Finally, checkpoint blockade may sensitize lymphoma to subsequent therapy. Carreau and colleagues showed that the overall response to subsequent therapy after checkpoint inhibition was 62% in 81 patients with relapsed refractory Hodgkin lymphoma 94 and 51% in 59 patients with relapsed refractory non-Hodgkin lymphoma. 95 With further studies, we are hopeful that biomarkers including PD-L1 expression, TMB, and MSI status will be used to best-select patients with hematologic malignancies for treatment with checkpoint blockade who are most likely to benefit.…”

Addition of chemotherapy to nivolumab after PD-1 inhibitor failure as bridge to allogeneic stem cell transplantation in classical Hodgkin’s lymphoma: report on three cases and literature review

“…PD-1 inhibitors improved the duration of response to the next therapy (169 days) compared with the most recent prior treatment before PD-1 blocker (84 days). 16 PD-1 inhibitors and CT are believed to act synergistically and bidirectionally: on one side, PD-1 inhibitors remove the ‘brakes’ on T-cell immune responses and induce changes into tumor microenvironment by impairing the function of immunosuppressive cells. This combinatory effect allows tumor cells to become more sensitive not only to immunogenic cell death but also to direct DNA damage of several CT. On the other side, although CT can diminish the total number of immune cells, it enhances the antitumor activity of PD-1 blockers through the selective activation of effectors cells (T-helper type 1 cells, cytotoxic T-lymphocytes, γ/δ T-cells, and dendritic cells) and the repression of immunosuppressive cells (regulatory T-cells and myeloid-derived suppressor cells).…”

“…This synergetic effect has been further explained by the influence of PD-1 inhibitors on several immunologic signaling pathways and surface molecules implicated in the cHL clinical course (such as STAT6, HLA I, or PD-L2). 16 – 19 …”

“…16 This synergetic effect has been further explained by the influence of PD-1 inhibitors on several immunologic signaling pathways and surface molecules implicated in the cHL clinical course (such as STAT6, HLA I, or PD-L2). [16][17][18][19] Allo-SCT has a relevant role as consolidation therapy for R/R cHL, but it is still controversial whether previous anti-PD-1 therapy can increase the risk of immune-mediated events after allo-SCT, like GVHD, as seen in murine models. 20 The Spanish group GELTAMO reported its experience in the treatment of R/R cHL with nivolumab in a series of 74 cases.…”

“…PD-1 inhibitors improved the duration of response to the next therapy (169 days) compared with the most recent prior treatment before PD-1 blocker (84 days). 16 This synergetic effect has been further explained by the influence of PD-1 inhibitors on several immunologic signaling pathways and surface molecules implicated in the cHL clinical course (such as STAT6, HLA I, or PD-L2). [16][17][18][19] Allo-SCT has a relevant role as consolidation therapy for R/R cHL, but it is still controversial whether previous anti-PD-1 therapy can increase the risk of immune-mediated events after allo-SCT, like GVHD, as seen in murine models.…”