Living Donor Liver Transplantation as Salvage Therapy for Steroid‐Refractory Chronic Hepatic GVHD Following Allogeneic Hematopoietic Stem Cell Transplantation

ABSTRACT

Background

Hepatic graft‐versus‐host disease (GVHD) is a rare but life‐threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT). Steroid‐refractory hepatic GVHD carries a high risk of mortality with limited salvage options. Liver transplantation after HSCT poses unique challenges due to dual alloimmunity and is rarely pursued, particularly in pediatric patients. We report a pediatric patient with steroid‐refractory chronic hepatic GVHD successfully treated with living donor liver transplantation (LDLT) from a parental donor.

Case Presentation

A 13‐year‐old male underwent allogeneic HSCT for idiopathic severe aplastic anemia and developed progressive chronic hepatic GVHD characterized by ductopenia and severe cholestasis. His disease was refractory to corticosteroids and multiple additional therapies, including ruxolitinib, mesenchymal stromal cells, infliximab, sirolimus, anti‐thymocyte globulin, alpha‐1 antitrypsin, cyclophosphamide, and emapalumab. His course was complicated by Epstein–Barr virus (EBV) associated post‐transplant lymphoproliferative disorder (PTLD), successfully treated with rituximab. Fifteen months after HSCT, and seven months after clearance of EBV viremia, he underwent LDLT from a parental donor. Donor selection preserved the option for future donor‐derived EBV‐specific cytotoxic T lymphocyte therapy if needed. Eleven months following LDLT, the patient remains clinically well, with normal liver function, sustained full donor chimerism, and no evidence of recurrent GVHD or PTLD.

Conclusion

LDLT may represent a viable option in select pediatric patients with irreversible chronic hepatic GVHD. This case underscores the importance of early multidisciplinary planning and highlights the absence of liver‐specific biomarkers or targeted therapies to guide management. Dedicated research into preventive and regenerative strategies is warranted.

Abbreviations

A1AT

alpha‐1 antitrypsin

ATG

anti‐thymocyte globulin

CTL

cytotoxic T lymphocytes

EBV

Epstein‐Barr Virus

GVHD

graft‐versus‐host disease

HSCT

hematopoietic stem cell transplantation

MSCs

mesenchymal stromal cells

PTLD

post‐transplant lymphoproliferative disease

1. Introduction

Graft‐versus‐host disease (GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT), with the liver representing one of the principal target organs alongside the skin and gastrointestinal tract [1, 2]. Although less common, severe chronic hepatic GVHD, particularly when steroid‐refractory, is associated with poor prognosis and increased non‐relapse mortality [3]. Additionally, no liver‐specific diagnostic and prognostic biomarkers exist to guide management in this population. Treatment options beyond corticosteroids remain limited, and effective salvage therapies are rare [4]. Here we report a unique case of successful living donor liver transplantation (LDLT) for isolated, treatment‐refractory chronic hepatic GVHD in a pediatric patient.

2. Case Presentation

A 13‐year‐old boy with severe aplastic anemia underwent matched unrelated donor HSCT after conditioning with fludarabine, cyclophosphamide, and anti‐thymocyte globulin (ATG). GVHD prophylaxis included tacrolimus and mycophenolate mofetil. His pre‐transplant course was complicated by Klebsiella septic shock and acute respiratory distress syndrome (ARDS) requiring intubation two days before transplant. The patient stabilized quickly and transplant proceeded as scheduled. Neutrophil and platelet engraftment occurred on days +12 and +18, respectively. Early post‐transplant complications included BK viruria and EBV viremia by day +15. He received supportive management for the BK viruria and EBV‐specific cytotoxic T lymphocytes (CTLs) on day +22, with some improvement in EBV viral load. However, additional doses were deferred due to hepatotoxicity with elevation in transaminases.

On day +33, he developed a maculopapular rash involving 60% of his body surface area, consistent with stage 2 skin acute GVHD. He received treatment with systemic and topical corticosteroids. Subsequently, he developed steroid‐refractory stage 3 acute hepatic GVHD. Liver biopsy showed bile duct injury, portal inflammation, endothelitis, and dense CD3+ T‐cell infiltration. Bilirubin was elevated at 6 mg/dL, and AST/ALT were 400/697 IU/L. Given the non‐response to steroids, ruxolitinib was added for the management of steroid‐refractory GVHD [5]. While skin GVHD resolved with ruxolitinib, bilirubin increased to 8–9 mg/dL. Sirolimus was initiated for further management while mesenchymal stromal cell (MSC) therapy was being planned [6]. Repeat biopsy showed progression to chronic GVHD with severe ductopenia (2 of 11 portal tracts), fibrosis, and mild lymphocytic infiltrate. At this time despite getting 3 doses of infliximab and subsequent MSCs, bilirubin rose to 13–14 mg/dL. Elevated CXCL9 levels prompted initiation of emapalumab (anti–IFN‐γ) to mitigate IFN‐γ‐mediated cytotoxicity. The patient continued to have elevated bilirubin levels and received alpha‐1 antitrypsin and ATG, which led to temporary stabilization of bilirubin (16–17 mg/dL), followed by a rise to 18–20 mg/dL a few weeks later. A third liver biopsy done at this time showed ongoing ductopenia, cholestasis, fibrosis, and minimal inflammation. Given emerging case reports suggesting potential benefit, pulse cyclophosphamide was administered (2 doses), resulting in partial bilirubin improvement (14–16 mg/dL) and steroid taper [7] (Figure 1).

FIGURE 1.

Trajectory of serum bilirubin levels and graft‐versus‐host disease (GVHD) therapies following hematopoietic stem cell transplantation (HSCT). The red line represents serum bilirubin levels over time. Color‐coded horizontal bars indicate the duration of individual therapies administered for hepatic GVHD. Therapy names and corresponding colors are detailed in the legend. A1AT, Alpha‐1 antitrypsin; ATG, Anti‐thymocyte globulin; GVHD, Graft‐versus‐host disease; HSCT, Hematopoietic stem cell transplantation; MSCs, Mesenchymal stromal cells.

After this temporary stabilization, EBV DNA PCR rose to 74 800 IU/mL and the patient was found to have cervical lymphadenopathy with PET‐CT revealing hypermetabolic activity in the same as well as in the Waldeyer's ring. These findings were presumed to be PTLD, and he empirically received 5 doses of rituximab, resulting in symptom resolution and undetectable EBV PCR.

Two months after cessation of PTLD therapy, bilirubin rose again. Repeat biopsy showed lymphocytic infiltrate, ductopenia, cholestasis, fibrosis, and ceroid‐laden macrophages. Given evidence of progressive liver failure, including rising bilirubin, coagulopathy, hyperammonemia, and biopsy‐confirmed cirrhosis, he was listed for a liver transplantation [8]. LDLT was performed 15 months following HSCT from a parental donor. Living donor transplantation permitted elective transplantation after EBV clearance and during a period of relative immunologic stability. Two parental donors were initially considered; after standard living donor evaluation, only one was eligible to proceed. Donor selection was guided by organ availability and preservation of potential for future donor‐derived EBV‐specific cytotoxic T lymphocyte (CTL) therapy if EBV reactivation recurred.

Post‐transplant complications included a biliary leak requiring bile duct revision and subsequent conversion to Roux‐en‐Y biliary anastomosis. Immunosuppression for this transplant included induction with steroids and basiliximab followed by tacrolimus, mycophenolate, and prednisone. Eleven months post liver transplant, he has normal liver function, full hematopoietic donor chimerism, and no evidence of recurrent GVHD or PTLD.

3. Discussion

Steroid‐refractory chronic hepatic GVHD is rare but a life‐threatening condition. Liver transplantation after recent HSCT requires careful consideration due to concern for dual alloimmunity, risk of infection, and risk of graft rejection, and the possibility of recurrent GVHD within the hepatic allograft. Most reported liver transplants for hepatic GVHD involve deceased donor organs, with a reported survival of 75.7%. In this setting, LDLT may offer practical and immunologic advantages. It allows greater control over transplant timing, which is particularly relevant after viral reactivation or PTLD, and may preserve future cellular therapy options. In our patient, use of a parental living donor preserved the possibility of donor‐derived EBV‐specific CTLs. This approach could theoretically reduce the risk that the liver allograft would become a target of CTL‐associated tissue injury in case cellular therapy was later required.

This case is unique in demonstrating successful LDLT as a salvage therapy in a patient with progressive chronic hepatic GVHD leading to liver failure. A successful outcome in this case may be attributable to sustained donor hematopoiesis, control of viral reactivation pre‐transplant, multidisciplinary planning, and careful perioperative management. Furthermore, this case underscores the need for improved diagnostic markers and therapeutic options specific to hepatic GVHD.

4. Conclusion

Living donor liver transplantation may represent a viable salvage option for select pediatric patients with progressive, treatment‐refractory hepatic GVHD following HSCT. In patients with prior viral reactivations, this approach may also preserve the option to generate donor‐derived CTLs if needed later in the course. Early multidisciplinary evaluation and transplant readiness are critical in patients showing signs of irreversible liver injury. This case highlights both the feasibility of LDLT as a potentially definitive intervention and the significant unmet need for dedicated research into liver‐specific GVHD therapies.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.