
==== Front
Int J Surg Case Rep
Int J Surg Case Rep
International Journal of Surgery Case Reports
2210-2612
Elsevier

S2210-2612(24)01048-4
10.1016/j.ijscr.2024.110267
110267
Case Report
Fatal graft-versus-host disease in recipient with pretransplant exposure to immune checkpoint inhibitors and donor-dominant one-way HLA matching after liver transplantation: A case report
Pang Li
Wu Wen-Rui
Xu Lei-Bo
Liu Chao liuchao3@mail.sysu.edu.cn
⁎
Liver Transplantation Center, Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120 Guangzhou, China
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
⁎ Corresponding author at: Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China. liuchao3@mail.sysu.edu.cn
10 9 2024
10 2024
10 9 2024
123 1102673 8 2024
3 9 2024
6 9 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction and importance

Graft-versus-host disease (GvHD) is a rare but severe complication following liver transplantation (LT), occurring in 1‐2 % of cases with a mortality rate exceeding 80 %. Immune checkpoint inhibitors (ICIs) used pretransplant are associated with increased allograft rejection risk, but their impact on GvHD in LT remains unclear. Dominant one-way donor-recipient human leukocyte antigen (HLA) matching is a known risk factor for GvHD. This report presents a rare case of fatal GvHD in a hepatocellular carcinoma (HCC) patient treated with PD-1 inhibitors before LT and transplanted with a liver graft from a deceased donor with donor-dominant one-way HLA matching.

Case presentation

A 59-year-old male with a 30-year history of hepatitis B and unresectable HCC underwent LT after receiving the last dose of PD-1 inhibitors 7 days prior to the transplant. On post-operative day (POD) 12, the patient developed a skin rash, fever, and vomiting, and was diagnosed with GvHD. Despite aggressive treatment, including high-dose corticosteroids and extracorporeal membrane oxygenation (ECMO), the patient succumbed to gastrointestinal bleeding and multi-organ failure on POD 30. HLA genotyping revealed typical donor-dominant one-way HLA matching.

Clinical discussion

This case highlights a potential link between pretransplant exposure to ICIs and GvHD, particularly with donor-dominant one-way HLA matching. Residual anti-PD-1 antibodies may activate graft-resident immune cells, precipitating GvHD. Further research with larger cohorts and animal models is required to clarify this relationship and understand the underlying mechanisms.

Conclusion

Besides allograft rejection, caution should also be exercised regarding GvHD in patients with prior exposure to ICIs before LT.

Highlights

• We reported a rare case of fatal GvHD in a recipient with HCC who received PD-1 inhibitors before LT and transplanted with a liver graft from a deceased donor with donor-dominant one-way HLA matching.

• This report suggests a potential association between pretransplant exposure to ICIs and the development of GvHD in liver transplant recipients.

• Given the significant disruption of immune homeostasis caused by ICIs, their application in liver transplantation necessitates careful consideration.

Keywords

Graft-versus-host disease
Liver transplantation
Immune checkpoint inhibitor
Donor-dominant one-way HLA matching
Hepatocellular carcinoma
Abbreviations

ICIs immune checkpoint inhibitors

GvHD graft-vs.-host disease

LT liver transplantation

LDLT living donor liver transplantation

HSCT hematopoietic stem cell transplantation

HLA human leukocyte antigen
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pmc1 Introduction

The incidence of graft versus host disease (GvHD) after liver transplantation (LT) is estimated to be 1–2 %, but the mortality rate is over 80 % [1,2]. The onset time of GvHD ranges from weeks to months after LT, and the common clinical manifestations include fever, skin rash, gastrointestinal symptoms, as well as pancytopenia [[1], [2], [3], [4]]. Accumulating evidence suggests that the use of ICI before LT could increase the risk of allograft rejection by enhancing the immune response of recipients [[5], [6], [7], [8], [9]]; however, it is still unknown whether ICI exposure correlates with the development of GvHD after LT. It has been reported that the use of an HLA-homozygous donor leading to donor-dominant one-way HLA matching is significantly associated with the occurrence of GvHD in living donor liver transplantation (LDLT) [[10], [11], [12]]. Here, we reported a rare case of fatal GvHD in an HCC recipient with recent exposure to PD-1 inhibitors, who received an HLA-haploidentical liver graft from an HLA-homozygous donor.

2 Case presentation

A 59-year-old male with a history of untreated hepatitis B viral infection for >30 years. In May 2022, the patient presented to the local hospital with fatigue and decreased appetite and was found liver cirrhosis with an unresectable tumor in the S4 segment (8 cm × 7 cm × 7 cm) without the macrovascular and lymph node involvement, and the AFP level was <5.05 ng/ml. Further tumor biopsy showed that the tumor was highly to moderately differentiated (Edmondson Steiner grade I-II). In consideration of the patient's liver cirrhosis, which precluded curative resection of the tumor, and the fact that the patient's tumor met Hangzhou criteria (a total diameter of ≤8 cm or tumors with a diameter of >8 cm if they are grade I or II and have an alpha-fetoprotein (AFP) level ≤ 400 ng/ml simultaneously [13]), the local hospital referred the patient to our center to await a liver transplant.

During the waiting period, the patient received a total of 3 cycles of hepatic artery infusion chemotherapy with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX-HAIC), 4 cycles of PD-1 inhibitors (Karelizumab 200 mg × 1 and Tirelizumab 200 mg × 3) and oral lenvatinib (8 mg, daily). At the end of July, the tumor was evaluated to be a partial response (PR) with a stable AFP level, and no evidence of distant metastasis. In the meantime, the total bilirubin and liver enzymes of the patient were gradually increased. On August 25, 2022, the patient underwent deceased donor LT with a liver graft from a donation after brain death. The patient received the last dose of PD-1 inhibitor 7 days before LT. The donor was a 39-year-old male with normal liver enzymes, bilirubin, and INR. ABO compatibility was also confirmed (AB, Rh+). Back-table biopsy of the donor liver showed no evidence of hepatitis, fibrosis, necrosis, or other abnormality (data not shown). The warm ischemia time of the donor was 2 min and cold ischemia time 352 min, respectively, the inhepatic time was 66 min, and blood loss was around 500 ml without erythrocyte transfusion during operation.

He received our standard immunosuppression with basiliximab on post-operative day (POD) 0 and 4, corticosteroid taper, tacrolimus, and mycophenolate mofetil (MMF) as shown in Fig. 1. His liver function recovered to normal on POD 4 without hepatic artery stenosis and anastomotic biliary stricture (Fig. 2A). On POD 12, the patient developed a skin rash on both upper limbs, accompanied by fatigue and fever. The skin rash rapidly worsened and expanded to the abdomen and back with severe vomiting. The allograft rejection was excluded due to normal levels of liver enzymes and total bilirubin (Fig. 2A), and then GvHD was highly suspected based on the typical clinical manifestations. The patient was urgently transferred to the ICU on POD 15 due to difficulties in maintaining blood oxygen levels and blood pressure. Given the aggressive and highly lethal nature of GvHD, the standard treatment of high-dose corticosteroid pulse therapy was initiated immediately after the transfer.Fig. 1 Postoperative course of immunosuppression regimen and GvHD management.

Fig. 1

Fig. 2 Dynamic tests of liver function (A) and blood cells (B) after LT, and skin presentation (C) and biopsy (D).

Fig. 2

Following the transfer to the ICU, the patient's condition rapidly deteriorated, progressing to oliguria, as well as respiratory and circulatory failure. On POD 16, extracorporeal membrane oxygenation (ECMO) was initiated to sustain vital functions, thereby allowing additional time to address the underlying GvHD. Concurrently, the patient underwent continuous renal replacement therapy (CCRT) and therapeutic plasma exchange (TPE), alongside the administration of prophylactic anti-bacterial, antiviral, and antifungal therapies, given the patient's immunosuppressed state. On POD 23, the patient presented severe pancytopenia (Fig. 2B) with uncontrolled mucosal and skin hemorrhage. At the same time, the skill rash spread throughout the body with extensive detachment and sloughing of the epidermis (Fig. 2C). Skin biopsy revealed exfoliative dermatitis with partial thickness epidermal necrosis, intraepidermal vesiculation, subepidermal blisters, and lymphocyte infiltration (Fig. 2D). Direct Immunofluorescence further revealed negative deposition of IgG, IgM, IgA, and C3c in the affected skin. The patient eventually died of gastrointestinal bleeding and multi-organ failure on POD 30.

During treatment, the HLA genotyping results indicate that the donor is homozygous at HLA-A, B, C, and DPA1 loci, while the recipient is HLA-haploidentical with the donor at HLA-A, B, C, DQB1, DPB1, and DPA1 loci (Table 1). This represents a typical donor-dominant one-way HLA matching. However, on POD 20, we conducted STR analysis, demonstrating no chimerism in the peripheral CD8+ T cells of the patient.Table 1 Genotyping of HLA loci in donor and recipient.

Table 1HLA haplotype	Donor (male, 38 yrs)	Recipient (male, 59 yrs)	
HLA-A	02:07; 02:07	02:06; 02:07	
HLA-B	46:01; 46:01	40:06; 46:01	
HLA-C	01:02; 01:02	01:02; 08:01	
DRB1	12:02; 14:54	09:01; 16:02	
HLA-DQB1	03:01; 05:02	03:03; 05:02	
HLA-DPB1	02:02; 05:01	02:01; 05:01	
HLA-DQA1	01:01; 06:01	01:02; 01:02	
HLA-DPA1	02:02; 02:02	01:03; 02:02	

3 Discussion

Despite increased evidence suggesting that pretransplant ICI exposure could increase the risk of allograft rejection after liver LT, there is currently no reported correlation between ICI exposure and the occurrence of GvHD [14]. In this report, we presented a rare case of fatal GvHD in an HCC recipient who received PD-1 inhibitors before LT and transplanted with a liver graft from a deceased donor with homogenous HLA loci and donor-dominant one-way HLA matching, which is extremely rare in DDLT. It has been reported that the use of an HLA-homozygous donor could significantly increase the risk of developing GvHD after LDLT due to potential donor-dominant one-way HLA matching [10,11,15].

The precise causes of GvHD after organ transplantation are not fully understood, but certain risk factors have been recognized. These include high HLA compatibility between the donor and recipient, pre-transplant blood transfusions, prior immunosuppressive therapy, glucose intolerance, a large age gap between a younger donor and an older recipient, recipient age over 65 years, and undergoing multiorgan transplantation [16]. Moreover, several studies have indicated a potential association between PD-1 inhibitors and the development of GvHD. For instance, clinical studies have documented the occurrence of GvHD following the use of PD-1 inhibitors in patients with allo-HSCT, suggesting an increased risk of GvHD [[17], [18], [19]]. Additionally, experimental studies in animal models have demonstrated that PD-1 blockade can exacerbate GvHD [20]. The mechanism by which ICIs contribute to GvHD primarily involves the disruption of immune tolerance. Normally, the PD-1 pathway plays a crucial role in maintaining immune homeostasis by inhibiting T-cell activation and promoting peripheral tolerance. In the context of organ transplantation or allo-HSCT, this ICI-heightened T-cell activation can trigger or exacerbate GvHD by promoting the donor-derived T-cells' recognition and attack on recipient tissues as foreign. This response can increase the production of inflammatory cytokines, further amplifying immune responses and tissue damage [21]. Additionally, the blockade of the PD-1 pathway may also impair the function of regulatory T cells (Tregs), which are critical for suppressing GvHD, thereby further aggravating GvHD [21,22].

In conclusion, considering the profound disruption of immune homeostasis induced by ICIs, cautious consideration is essential when employing ICIs in LT. If unavoidable, it is advisable to prolong the drug washout period for ICIs to prioritize patient safety.

4 Conclusions

This case underscores the potential risk of GvHD in LT recipients previously treated with ICIs. While pretransplant ICI exposure is recognized for increasing the risk of allograft rejection, our findings indicate that GvHD should also be a significant concern, particularly with donor-dominant one-way HLA matching. Further research is needed to elucidate the mechanisms underlying this association and to develop strategies for mitigating these risks. Clinicians should exercise heightened vigilance and consider extended washout periods for ICIs to optimize patient safety and transplant outcomes.

5 Methods

The work has been reported in line with the SCARE criteria [23].

Patient permission/consent declarations

Written informed consent was obtained from the patient for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethical approval

The case report is part of our registered retrospective study (ClinicalTrials.gov under the identifier NCT05913583). The study protocol was approved by the Ethics Committee, and was conducted in accordance with Good Clinical Practice and the principles of the Declaration of Helsinki.

Fundings

Supported by the 10.13039/501100001809 National Natural Science Foundation of China , No. 82203747 , 82173229 , 81972255 , and 82173195 ; 10.13039/501100002858 China Postdoctoral Science Foundation , No. 2022TQ0388 and 2023M734036 ; Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tract Cancer, No. 202201020375 ; Sun Yat-Sen Memorial Hospital Clinical Research 5010 Program, No. SYSKY-2022-145-02 and No. SYS-5010-202305 . Sun Yat-Sen University Clinical Research 5010 Program, No. 2018008 .

Author contribution

Li Pang wrote the paper; Li Pang, Wen-Rui Wu, and Lei-Bo Xu performed the data collection; Li Pang and Chao Liu conceived the study.

Guarantor

Chao Liu, MD, Ph.D., Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yan Jiang Xi Road, Guangzhou 510120, China. Email: liuchao3@mail.sysu.edu.cn.

Research registration number

1. Name of the registry: ClinicalTrials.gov.

2. Unique identifying number or registration ID: NCT05913583.

3. Hyperlink to your specific registration (must be publicly accessible and will be checked): https://clinicaltrials.gov/study/NCT05913583?tab=results.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the author(s) used ChatGPT in order to improve language and readability. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Conflict of interest statement

The authors declare no conflicts of interest.
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