Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma
Table 1
Synopsis of current evidence and evolving role of checkpoint inhibitors in selected subtypes of B-cell NHL.
Histologic subtype
Current level of evidence
Alterations associated with an inflamed lymphoma environment
Clinical response to checkpoint inhibitors
DLBCL
Weak to moderate (i) Up to 20-25% of DLBCLs have characteristics of an inflamed lymphoma () [26, 28, 31]. (ii) Newly proposed molecular classifications of DLBCLs contain genetic clusters (C1 cluster by Chapuy et al. [34] and BN2/N1 clusters by Schmitz et al. [33]) that encompass characteristics of inflamed lymphomas. (iii) Development of robust platforms to identify inflamed cases are warranted.
ICIs: weak (i) Disapointing activity of monotherapy with anti-PD1 and anti-PD-L1 ICIs in r/r DLBCL [28, 41–44]. (ii) Significant association of presence of PD-L1 SVs with response to anti-PD1 ICIs [28], although results based on a small number of cases. (iii) Results of an ongoing study of pembrolizumab in patients with r/r disease and PD-L1 SVs (NCT03990961) will determine the future development of anti-PD1 ICIs in subsets of DLBCL. MCIs: moderate (i) Magrolimab demonstrates a favorable toxicity profile and notable activity in r/r DLBCL, supporting its further development and investigation in combination with other agents [49].
PMBCL
Strong (i) Two-thirds of cases have characteristics of an inflamed lymphoma [23, 30, 31].
Strong (i) Currently the only approved lymphoma with indication for treatment with a ICI. (ii) Significant activity and durable remissions with pembrolizumab in r/r PMBCL [69], burden of 9p24.1 SVs associated with PD-L1 expression and improved PFS. (iii) The combination of nivolumab and brentuximab vedotin is highly active in r/r PMBCL [72]. And effective bridging therapy for other consolidative treatments (auto- or allo-SCT) of curative intent. (iv) Clinical trial assessing the addition of anti-PD-1 ICIs to standard regimens in the upfront setting is warranted for patients with high-risk advanced stage disease.
PCNSL and PTL
Strong (i) Two-thirds of cases have characteristics of an inflamed lymphoma [76–78, 82, 83].
Moderate to strong (i) High clinical and radiological response rates to monotherapy with anti-PD1 ICIs but studied in a limited number of patients [84–86]. (ii) Results of ongoing clinical trials will determine further development.
RT-DLBCL
Moderate (i) Strong expression of PD-1 in majority of cases [104].
Weak to moderate (i) Noteworthy activity of anti-PD1 ICIs, higher ORRs when combined with ibrutinib [106, 107]. (ii) Ongoing clinical trials of anti-PD1 ICIs with novel agents will determine further development.
FL
Weak (i) PD-L1/PD-L2 SVs are rare in FL [93]. (ii) In contrast, abundant expression of PD-1 is found in cells of the immune ME (TILs, TFH cells, and macrophages) [74–76].
ICIs: weak (i) Disappointing activity of monotherapy with anti-PD1 or anti-PD-L1 ICIs in r/r FL [41, 44, 121]. (ii) Preliminary results of clinical trials combining ICIs with other agents have not demonstrated any apparent incremental benefit [122, 126, 129, 131]. MCIs: moderate to strong (i) Magrolimab demonstrates a favorable toxicity profile and significant activity in r/r FL, supporting its further development and investigation in combination with other agents [59, 132].
Abbreviations: CNS: central nervous system; CR: complete remission; DLBCL: diffuse large B-cell lymphoma; DOR: duration of response; GCB: germinal center B cell; ICI: immune checkpoint inhibitor; MCI: macrophage checkpoint inhibitor; ME: microenvironment; ORR: overall response rate; PCNSL: primary central nervous system lymphoma; PD-1: programmed cell-death protein 1; PD-L1: programmed cell-death 1 ligand 1; PFS: progression-free survival; PMBCL: primary mediastinal B-cell lymphoma; PTL: primary testicular lymphoma; PTLD: posttransplant lymphoproliferative disorder; RT-CLL: Richter’s transformation of chronic lymphocytic leukemia; SVs: structural variations; TFH: T follicular helper; TILs: tumor-infiltrating lymphocytes.
