Cancer Res Treat.  2019 Apr;51(2):611-622. 10.4143/crt.2018.191.

Comparison of Efficacy of Pembrolizumab between Epstein-Barr Virus‒Positive and ‒Negative Relapsed or Refractory Non-Hodgkin Lymphomas

• Kim SJ
• Hyeon J
• Cho I
• Ko YH
• Kim WS

• KMID: 2464408
• DOI: http://doi.org/10.4143/crt.2018.191

Abstract

PURPOSE
Pembrolizumab, a programmed cell death protein 1 (PD1) inhibitor inhibits the interplay between PD1 of T-cell and programmed cell death ligand 1 (PDL1) on tumor cells. Although pembrolizumab has been tried to various subtypes of non-Hodgkin lymphoma (NHL), real-world data about the efficacy of pembrolizumab in NHL patients are limited.
MATERIALS AND METHODS
We analyzed the outcome of 30 relapsed or refractory NHL patients treated with pembrolizumab, and compared the outcome between Epstein-Barr virus (EBV)"’positive and negative subtypes because EBV infection of tumor cells can upregulate PDL1 expression.
RESULTS
Seven patients with EBV-positive NHL showed a response including NK/T-cell lymphoma (6/14, 44%) and primary mediastinal B-cell lymphoma (1/4, 25%) whereas EBV-negative subtypes did not respond such as diffuse large B-cell lymphoma and T-lymphoblastic lymphoma. We also evaluated PDL1 expression using tumor tissue of 76 patients. High PDL1 expression (positive staining of > 50% of tumor cells) was more frequent in NK/T-cell lymphoma and primary mediastinal B-cell lymphoma than other subtypes. Thus, PDL1 expression was significantly higher in EBV-positive (18/32, 56%) than EBV-negative NHL (4/38, 11%, p < 0.001). Furthermore, NK/T-cell lymphoma patients with high PDL1 expression showed a higher response (4/6, 67%) than those with low PDL1 expression (1/5, 20%).
CONCLUSION
Pembrolizumab could be useful as a salvage treatment for relapsed or refractory EBV-positive NHL, especially NK/T-cell lymphoma. However, its efficacy in EBV-negative NHL with low or absent PDL1 expression is still not clear although pembrolizumab could be a potential treatment option for relapsed or refractory NHL.

Keyword

Lymphoma; Pembrolizumab; PDL1; Epstein-Barr virus

MeSH Terms

Cell Death
Epstein-Barr Virus Infections
Herpesvirus 4, Human
Humans
Lymphoma
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin*
Salvage Therapy
T-Lymphocytes

Figure

• 

  Fig. 1. Clinical outcome and treatment cycles of NK/T-cell lymphoma (NKTCL), primary mediastinal B-cell lymphoma (PMBCL), diffuse large B-cell lymphoma (DLBCL), and T-lymphoblastic lymphoma (T-LBL). EBV, Epstein-Barr virus; PDL1, programmed cell death ligand 1; H, high; CR, complete response; NA, not available; L, low; PR, partial response; PD, progressive disease.

• 

  Fig. 2. (A) Comparison of programmed cell death ligand 1 (PDL1) expression in 76 patients with non-Hodgkin lymphoma shows different frequencies of high (≥ 50% of PDL1-positive tumor cells), low (1%-49% of PDL1-positive tumor cells), and no expression. High PDL1 expression is more frequent in NK/T-cell lymphoma (NKTCL; 15/28, 54%) and primary mediastinal B-cell lymphoma (PMBCL; 4/6, 67%) than in peripheral T-cell lymphoma (PTCL; 2/7, 28%), diffuse large B-cell lymphoma (DLBCL; 2/18, 11%), and T-lymphoblastic lymphoma (T-LBL; 0/8, 0%). No case of PDL1 high expression is observed in primary central nervous system diffuse large B-cell lymphoma (CNS DLBCL; 0/3), mantle cell lymphoma (MCL, 0/2), or enteropathy-associated T-cell lymphoma (EATL; 0/1). However, subcutaneous panniculitis-like T-cell lymphoma (SPTCL; 2/2) and angioimmunoblastic T-cell lymphoma (AITL; 1/1) show high PDL1 expression. (B) Epstein-Barr virus (EBV)–positive non-Hodgkin lymphoma (NHL) shows a significantly higher proportion of high PDL1 expression (18/32, 56%) than EBV-negative NHL (4/38, 11%, p < 0.001).

• 

  Fig. 3. (A) Immunohistochemistry for programmed cell death ligand 1 (PDL1) shows ≥ 50% of tumor cells positively stained (brown membranous staining) in a case of extranodal NK/T-cell lymphoma (top left); decrease in blood Epstein-Barr virus (EBV) DNA level after pembrolizumab treatment (top right); decrease in fluorodeoxyglucose (FDG) uptake in liver and spleen after pembrolizumab treatment (bottom). (B) Immunohistochemistry for PDL1 shows < 1% of tumor cells positively stained in a case of extranodal NK/T-cell lymphoma (top left); increase in blood EBV DNA level even after pembrolizumab treatment (top right); increase in the extent and intensity of FDG uptake in a soft tissue mass in an extremity after pembrolizumab treatment (bottom).

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