RESEARCH

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Blood Res (2024) 59:36

Published online October 30, 2024

https://doi.org/10.1007/s44313-024-00042-6

© The Korean Society of Hematology

PD-1 inhibitors plus chemotherapy for refractory EBV-positive DLBCL: a retrospective analysis

Youli Li1,3† , Yonghe Wu4†, Sufen Cao1,6†, Baohua Yu5, Qunling Zhang1,2, Zuguang Xia1,2, Junning Cao1,2*, Fangfang Lv1,2* and Guang‑Liang Chen1,2*

1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China. 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. 3 Department of Medical Oncology, Fudan University Shanghai Cancer Center Xiamen Hospital, Xiamen 361026, P.R. China. 4 Department of Pathology, Fujian Province, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou 363000, P.R. China. 5 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China. 6 Present Address: Department of Nursing, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.

Correspondence to : *Correspondence:
Junning Cao
cao_junning@126.com
Fangfang Lv
lvff80@163.com
Guang‑Liang Chen
guangliang_chen@fudan.edu.cn
Full list of author information is available at the end of the article

Youli Li, Yonghe Wu and Sufen Cao are equal contributors to this work and designated as co-first authors.

Received: August 16, 2024; Accepted: October 15, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Abstract

Background Immunochemotherapy has demonstrated a promising efficacy for a variety of B-cell lymphoma but has limited efficacy for Epstein–Barr virus-positive (EBV +) diffuse large B-cell lymphoma (DLBCL) that is refractory or relapsed to conventional chemotherapy regimens. Considering higher programmed death-ligand 1 (PD-L1) expression in the subset of patients with DLBCL with positive EBV, we speculated that PD-1 inhibitors plus chemotherapy may be an alternative regimen in patients with refractory/relapsed EBV + DLBCL.
Methods This retrospective study included six adult patients diagnosed with refractory EBV + DLBCL resistant to first-line immunochemotherapy regimens (R-CHOP). These patients received PD-1 inhibitors plus chemotherapy as second-line treatment.
Results The final analysis included six patients (four men and two women (median age, 50 years; range, 39–83 years)). Four patients were diagnosed with Epstein–Barr virus (EBV) + DLBCL, and two had DLBCL associated with chronic inflammation. Over a median follow-up of 20 months (range, 2–31 months), the objective response rate was 83% (5/6) and the complete remission rate was 67% (4/6). No severe immune-related adverse reactions occurred, and only a mild rash was reported, which did not necessitate the discontinuation of therapy.
Conclusion The combination of PD-1 inhibitors and chemotherapy offers promising results as a second-line treatment for patients with refractory EBV + DLBCL that is resistant to first-line immunochemotherapy regimens. These preliminary findings warrant further investigation in larger clinical trials to validate the efficacy and safety of this therapeutic approach.

Keywords Epstein–Barr virus, Diffuse large B-cell lymphoma, Chemotherapy, PD-1 inhibitors, Treatment resistance, Immunotherapy

Article

RESEARCH

Blood Res 2024; 59():

Published online October 30, 2024 https://doi.org/10.1007/s44313-024-00042-6

Copyright © The Korean Society of Hematology.

PD-1 inhibitors plus chemotherapy for refractory EBV-positive DLBCL: a retrospective analysis

Youli Li1,3† , Yonghe Wu4†, Sufen Cao1,6†, Baohua Yu5, Qunling Zhang1,2, Zuguang Xia1,2, Junning Cao1,2*, Fangfang Lv1,2* and Guang‑Liang Chen1,2*

1 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China. 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. 3 Department of Medical Oncology, Fudan University Shanghai Cancer Center Xiamen Hospital, Xiamen 361026, P.R. China. 4 Department of Pathology, Fujian Province, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou 363000, P.R. China. 5 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China. 6 Present Address: Department of Nursing, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.

Correspondence to:*Correspondence:
Junning Cao
cao_junning@126.com
Fangfang Lv
lvff80@163.com
Guang‑Liang Chen
guangliang_chen@fudan.edu.cn
Full list of author information is available at the end of the article

Youli Li, Yonghe Wu and Sufen Cao are equal contributors to this work and designated as co-first authors.

Received: August 16, 2024; Accepted: October 15, 2024

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Abstract

Background Immunochemotherapy has demonstrated a promising efficacy for a variety of B-cell lymphoma but has limited efficacy for Epstein–Barr virus-positive (EBV +) diffuse large B-cell lymphoma (DLBCL) that is refractory or relapsed to conventional chemotherapy regimens. Considering higher programmed death-ligand 1 (PD-L1) expression in the subset of patients with DLBCL with positive EBV, we speculated that PD-1 inhibitors plus chemotherapy may be an alternative regimen in patients with refractory/relapsed EBV + DLBCL.
Methods This retrospective study included six adult patients diagnosed with refractory EBV + DLBCL resistant to first-line immunochemotherapy regimens (R-CHOP). These patients received PD-1 inhibitors plus chemotherapy as second-line treatment.
Results The final analysis included six patients (four men and two women (median age, 50 years; range, 39–83 years)). Four patients were diagnosed with Epstein–Barr virus (EBV) + DLBCL, and two had DLBCL associated with chronic inflammation. Over a median follow-up of 20 months (range, 2–31 months), the objective response rate was 83% (5/6) and the complete remission rate was 67% (4/6). No severe immune-related adverse reactions occurred, and only a mild rash was reported, which did not necessitate the discontinuation of therapy.
Conclusion The combination of PD-1 inhibitors and chemotherapy offers promising results as a second-line treatment for patients with refractory EBV + DLBCL that is resistant to first-line immunochemotherapy regimens. These preliminary findings warrant further investigation in larger clinical trials to validate the efficacy and safety of this therapeutic approach.

Keywords: Epstein&ndash,Barr virus, Diffuse large B-cell lymphoma, Chemotherapy, PD-1 inhibitors, Treatment resistance, Immunotherapy

Fig 1.

Figure 1.Programmed death-ligand 1 (PD-1) inhibitors plus chemotherapy treatment response and outcomes
Five of the six patients achieved objective responses including four complete remissions and one partial remission following PD-1 blockade therapy. Patient 5 achieved partial response with a progression-free survival (PFS) of 10 months but subsequently experienced disease progression twice and ultimately died with an overall survival of 20 months. Patient 6 progressed after three cycles of immunotherapy with a PFS of 2 months and was subsequently lost to follow-up. CR: complete response; PR: partial response; PD: progressive disease; SD: stable disease

Fig 2.

Figure 2.Pre- and post- programmed death-ligand 1 (PD-1) inhibitors plus chemotherapy treatment response on positron emission tomography (PET)/computed tomography (CT) or CT scans
(a) Patient 1: Significant reduction in right lung lesion (white arrow) and complete response on PET/CT after two cycles (b) Patient 4: Most lesions (white arrows) undetectable after five cycles

Fig 3.

Figure 3.Changes in circulating Epstein–Barr virus (EBV) DNA levels with programmed death-ligand 1 (PD-1) inhibitors plus chemotherapy treatment
(a) Patient 2: Ongoing remission with undetectable EBV DNA during treatment (b) Patient 3: Received sintilimab combined with gemcitabine and achieved partial response and then complete response (CR) with radiotherapy. EBV DNA decreased to undetectable levels (initial: 3.08x104 copies/mL). c Patient 4: Achieved CR after five cycles, and the EBV DNA was monitored after 11 cycles of PD-1 inhibitor treatment and remained undetectable subsequently (initial: 3.56x104 copies/mL)

Table 1 . Baseline characteristics, first-line immunochemotherapy regimens and response of patients with refractory Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma.

Patient no123456
Age, years466083485139
SexMaleFemaleMaleMaleMaleFemale
StageIIIIIIVIVIVII
ECOG PS111321
Elevated LDHNoYesYesYesYesYes
IPI score034431
Bulky diseaseYesNoNoNoNoYes
Cell of originNANon-GCBNon-GCBNon-GCBNon-GCBNon-GCB
Immunochemotherapy(cycles)R-CHOP (6)R-CHOP (8)R-miniCDOP (3)R-miniCHOP (3)R-CHOP (6)R-CHOP(3), CHOP(2)
ResponsePRPDPDPDPDPR

ECOG PS Eastern Cooperative Oncology Group Performance Status, LDH lactate dehydrogenase, IPI International Prognostic Index, GCB germinal center B cell, NA not applicable, R-CHOP rituximab, cyclophosphamide, vindesine, doxorubicin, prednisone, PR partial response, PD progressive disease.


Table 2 . The outcomes of PD-1 inhibitors plus chemotherapy in patients with refractory EBV-positive diffuse large B-cell lymphoma.

Patient no123456
PD-1 inhibitors (cycles)Tislelizumab (32)Tislelizumab (5)Sintilimab (8)Sintilimab (16)Sintilimab (18)Camrelizumab (3)
Combined chemotherapy regimensR-CHOP × 2R-GP × 5G × 6R-ICE × 6P × 8; G × 6R-CHOP × 3
ResponseCRCRCRCRPRPD
Final responseCRCRCRCRPDPD
PFS (months)19 +20 +22 +31 +102
OS (months)19 +20 +22 +31 +202 +
irADRs (grade)NoneNoneNoneNoneSkin rash (1)None

R-CHOP rituximab, cyclophosphamide, vindesine, doxorubicin, prednisone, R-GP rituximab, gemcitabine, cisplatinum, R-ICE rituximab, ifosfamide, carboplatin, and etoposide, G gemcitabine, P cisplatinum, CR complete response, PR partial response, PD progressive disease, OS Overall Survival, PFS progression-free survival, irADRs immune-related adverse drug reactions.


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