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

Abstract

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.

Keywords: 9p24.1; CTLA-4; Lymphoma; MHC; MMR; MSI; PD-1; PD-L1; TMB; biomarker; checkpoint blockade; hematological malignancies.

Figure 1.

Proposed algorithm for anti-PD-1 inhibitor use in (A) cHL and PMBCL, and (B) in DLBCL and GZL. cHL indicates classical Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; dMMR, mismatch repair deficient; GZL, gray zone lymphoma; IHC, immunohistochemistry; MHCII, major histocompatibility complex class II; MSI-H, microsatellite instability high; PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1; PMBCL, primary mediastinal B-cell lymphoma; R/R, relapsed/refractory; TMB, tumor mutational burden.