Walking the tightrope: acute liver rejection after chimeric antigen receptor-T cell therapy for post-transplant lymphoproliferative disorder (PTLD)—a case report

Introduction

Ever since the first kidney transplant was performed in 1954, the number of patients receiving solid organ transplants (SOTs) has been increasing every year. Over 46,000 organ transplants were performed in the USA in 2023 (1). For patients with organ transplantation, the introduction of novel immunosuppression (IS) drugs, improved surgical techniques, and proactive infection control measures have resulted in a significant improvement in both short- and long-term survival (2-4). As the life expectancy and average age at transplant are improving, lymphoma associated with immune deficiency has emerged as one of the leading causes of death in transplant patients (5). There are variations in lymphoma classification terminology, with increasing utilization of international consensus classification (ICC) nomenclature to classify immune deficiency-related lymphoma as post-transplant lymphoproliferative disorder (PTLD), as the management approach differs based on this classification (6). The risk for development of PTLD varies based on various factors such as the degree of IS, type of transplant, Epstein-Barr virus (EBV) infection status, age, and race of the recipient and genetic factors (7). PTLD is usually treated by withdrawing IS agents, immunotherapy like rituximab alone, as well as with combination chemoimmunotherapy. Treating relapsed/refractory (R/R) PTLD is challenging, and chimeric antigen receptor (CAR)-T cell immunotherapy is increasingly being considered as a treatment option, showing similar response and toxicity rates compared with previously reported CAR-T data (8) in the non-organ transplant setting. The optimal approach to managing IS during CAR-T cell therapy remains uncertain due to a lack of any prospective data collection; rather, CAR-T cell therapy for SOT subjects remains as a “real world” treatment. Major concerns include the risk of allograft failure, determining the optimal timing for resuming IS drugs, and the duration of the treatment response.

In this case report, we present a patient who developed PTLD after liver transplantation and was treated with lisocabtagene maraleucel (liso-cel) after relapsing on rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). His post-CAR-T course was complicated by acute hepatic allograft rejection requiring resumption of IS. At present, the patient remains in remission two years after CAR-T infusion, now with normal hepatic function. We present this case in accordance with the CARE reporting checklist (available at https://aol.amegroups.com/article/view/10.21037/aol-24-14/rc).

Case presentation

The patient is a 45-year-old male with a history of ulcerative colitis, primary sclerosing cholangitis and liver cirrhosis who underwent orthotopic liver transplantation in July 2016. His IS drug included tacrolimus 3 mg two times a day, azathioprine 150 mg daily and prednisone 20 mg daily. His post-liver transplant course was complicated by mild cellular rejection, managed by increasing the tacrolimus dose to 5 mg two times daily. In January 2022, he presented to the emergency department with abdominal pain, poor appetite, and ten pounds of weight loss over two weeks. He was on azathioprine 150 mg daily, prednisone 5 mg daily, and tacrolimus 7 mg daily. A computed tomography (CT) scan revealed a lobular mass in the mesentery measuring about 7 cm with extension into the superior mesenteric vein along with multiple small satellite lesions. There was a thrombus within a small segment of the superior mesenteric vein immediately contiguous with the mass and direct tumor extension into the vein was suspected. There was also splenomegaly but no other lymphadenopathy.

A CT-guided biopsy of the mass revealed diffuse large B-cell lymphoma (DLBCL), double expressor, non-germinal center B-cell (non-GCB) subtype (Figure 1). Immunohistochemistry was positive for cluster of differentiation (CD) 20 and multiple myeloma oncogene 1 (MUM1) but negative for CD10 (Figure 2). Tumor cells were positive for MYC and BCL2 by paraffin immunoperoxidase; however, fluorescence in situ hybridization (FISH) was negative for BCL6 and MYC gene rearrangements. Tumor cells were negative for IgH/BCL2 translocation. Ki-67 proliferation index was 90% (Figure 3). Plasma EBV polymerase chain reaction (PCR) was negative. Epstein-Barr encoding region (EBER) in situ hybridization was not done. After diagnosis azathioprine, was discontinued while tacrolimus and prednisone were continued. A positron emission tomography-computed tomography (PET-CT) was obtained, which revealed a large soft tissue mass involving the third and fourth portions of duodenum and proximal jejunum with an adjacent fluorodeoxyglucose (FDG)-avid mesenteric mass approximately 13.7 cm × 7.5 cm with a standard uptake value maximum (SUV_max) of 31.0. There were additional foci of increased radiotracer uptake in duodenum with SUV_max of 21.9. There were no pathologically enlarged or hypermetabolic pelvic or inguinal lymph nodes (Figure 4A). He was then started on pre-phase steroid, followed by R-CHOP and not risk-stratified sequential rituximab-chemoimmunotherapy due to International Prognostic Index (IPI) score of 3 and diagnosis of double expressor DLBCL. An interval PET-CT after 4 cycles of R-CHOP showed significant improvement in the size of the mesenteric mass to about 2 cm with an SUV_max of 3.0. However, end of treatment PET-CT showed increased FDG activity in soft tissue mass involving small bowel and adjacent mesenteric mass, measuring 5.5 cm × 3 cm with SUV_max of 28.8 (Figure 4B). A biopsy was obtained from the bowel lesion which showed DLBCL non-GCB subtype, positive for CD20, MUM1, consistent with primary chemotherapy refractory disease.

Figure 1 Hpeny&E staining shows a diffuse sheet of large, atypical lymphocytes with irregular nuclei, prominent nucleoli, and scant cytoplasm (magnification ×20). H&E, hematoxylin and eosin.

Figure 2 MUM1 and CD20 positive on immunohistochemistry staining (magnification ×20). CD20, cluster of differentiation 20; MUM1, multiple myeloma oncogene 1.

Figure 3 Ki-67 proliferation index (magnification ×20).

Figure 4 PET scan of abdominal mass. (A) Initial PET-CT shows a large soft tissue mass involving third and fourth portions of duodenum and proximal jejunum with an adjacent FDG avid mesenteric mass approximately 13.7 cm × 7.5 cm with SUV_max of 31.0. (B) PET scan after 6 cycles of R-CHOP shows increased FDG activity in soft tissue mass involving small bowel and adjacent mesenteric mass, measuring 5.5 cm × 3 cm with SUV_max of 28.8. (C) Complete metabolic response in the dominant mesenteric mass after CAR-T on day 30. CAR-T, chimeric antigen receptor-T cell; FDG, fluorodeoxyglucose; PET-CT, positron emission tomography-computed tomography; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; SUV, standard uptake value.

Given the poor response to R-CHOP a decision was made to treat him with CAR-T immunotherapy in second line. He received one cycle of polatuzumab, bendamustine and rituximab as a bridge therapy following leukapheresis and prior to his CAR-T. He continued on tacrolimus and reduced-dose prednisone (5 mg/day). A CT scan after bridging chemotherapy showed stable residual mesenteric lymphadenopathy with no new lesions.

He received bendamustine as lymphodepleting chemotherapy followed by liso-cel containing 100 million CAR-positive viable T-cells, with a 1:1 ratio of CD8 to CD4 cells. Tacrolimus was held one day prior to initiation of bendamustine on day 5. He was continued on prednisone 5 mg daily. He had an unremarkable post-CAR-T treatment course and did not develop any cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). He did not develop any cytopenia, and his liver function tests (LFTs) remained stable. Day 30 PET scan was notable for complete metabolic response in the dominant mesenteric mass (Figure 4C). The day 30 lymphocyte reconstitution panel showed B-cell aplasia and an increased number of activated T-cells, with CD3⁺HLA-DR⁺ T cells at 179 cells/µL (50% of all lymphocytes).

He remained off tacrolimus with plans to resume on day 60. However, on day 39, his LFTs began to rise, with peak alanine aminotransferase (ALT) of 1,822 U/L, aspartate aminotransferase (AST) of 745 U/L, and total bilirubin of 1.5 mg/dL (National Cancer Institute Common Toxicity Criteria Grade III) raising concern for graft rejection (Figure 5A,5B). He was started on prednisone 40 mg daily and tacrolimus 1 mg twice daily on day 54, which was later increased to 3 mg twice daily. His LFTs showed gradual improvement after initiation of IS and normalized by day 116. He continued tacrolimus 3 mg twice daily and prednisone was tapered down to 20 mg/day on day 87 and gradually down to 5 mg/day.

Figure 5 Liver function test trend. (A) AST and ALT trend post-CAR-T infusion. Prednisone 40 mg/day and tacrolimus 1 mg two times daily were started on day 54. (B) Total bilirubin trend post CAT-T. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CAR-T, chimeric antigen receptor-T cell.

On day 256, LFTs indicated a slow uptrend with AST of 96 U/L, ALT of 151 U/L and total bilirubin of 1.1 mg/dL. Repeat liver biopsy had no evidence of acute cellular rejection but showed some mild centrilobular fibrosis changes. He was on tacrolimus 2 mg in the morning and 3 mg in the evening, along with prednisone 5 mg at the time. Prednisone dose was increased to 10 mg/day and LFTs gradually returned to baseline. A 1-year PET scan showed Deauville score of 2 and no new FDG uptake consistent with continued remission.

The patient continues on tacrolimus 3 mg two times daily and prednisone 10 mg daily, with stable LFTs and no evidence of recurrent transaminitis. He remains in remission from PTLD, now over 2 years since treatment with liso-cel CAR-T.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee (s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

We present a patient who had undergone liver transplant with refractory PTLD treated with CAR-T therapy, who unfortunately developed acute graft rejection requiring resumption of his IS but achieved complete remission while remaining on IS treatment. We recognize that differentiating between true PTLD and de novo DLBCL in this patient is challenging. The EBV PCR was negative, and unfortunately, Epstein-Barr encoding region in situ hybridization (EBER-ISH) was not performed. Various studies have shown that the incidence of lymphomas, particularly non-Hodgkin lymphoma, including DLBCL, is high in patients with inflammatory bowel disease, particularly those who receive thiopurines (9,10). However, since he developed DLBCL while on chronic IS following liver transplant, we presume it was related to the IS therapy. In the majority of patients with PTLD, latent EBV reactivation during the immunosuppressed post-transplant period can evade immune surveillance and destruction, allowing it to persist in the germinal center. Here, it becomes susceptible to somatic hypermutation of proto-oncogenes, ultimately driving lymphoproliferation and progressing from early lesions to polymorphic PTLD and eventually to monomorphic PTLD. One third of patients with PTLD can be EBV negative which typically occurs late and has high-risk features (11). With recognition of the aggressive disease, the patient was referred for second-line CAR-T cell therapy. At the same time, there was a severe national shortage of fludarabine (12), so his situation was further unusual, where for bridging therapy, bendamustine was administered along with polatuzumab and rituximab and subsequently used again as a lymphodepleting agent. The extensive bendamustine exposure was anticipated to add significantly to his immune-suppressed state, but was pursued based on our internal observations in an outcome study, shared with the University of Pennsylvania, which suggested that bendamustine is equally safe and effective (13). Of note, CD19 expression was not assessed on biopsy specimens as the reported CD19 expression correlated well with CD20. In a phase II registrational study for tisagenlecleucel, authors found that low or absent CD19 expression prior to CAR-T cell therapy did not negatively impact outcomes (14). It is now known that relapse following CAR-T cell therapy is often linked to CD19 loss mutations, a scenario distinct from cases such as ours, where a patient has never received anti-CD19 treatment.

Although CAR-T has been suggested as a treatment option for R/R PTLD, none of the original registrational trials included this subset of patients (14-16). The primary challenge is ensuring adequate and robust T-cell collection in patients who have undergone long-term IS for organ transplantation. Recent findings by Iacoboni et al. highlight that recent bendamustine treatment before leukapheresis negatively affects outcomes in patients with DLBCL treated with CAR-T, leading to lower response rates, shorter progression-free survival and overall survival (17). Similarly, patients with PTLD have been exposed to long-term IS that could impact outcomes, with recognition that the potential adverse effects on CAR-T cell viability and production remain largely unknown. Given the challenges of CAR-T cell manufacture in this patient population, allogeneic “off-the-shelf” CAR-T cells have been proposed as an alternative. However, they face two major hurdles: potential graft versus host disease (GVHD) and rapid rejection by the host immune system. Recent murine studies by Ghosh et al. showed that allogeneic CD19-specific CAR-T cells can exhibit anti-lymphoma activity with minimal GVHD, offering future promise (18). Another significant challenge is determining the optimal timing for the cessation of IS prior to CAR-T therapy. Current data are anecdotal and available from limited case reports and series, and show high variability regarding the timeline for stopping IS. In some instances, IS was withheld several weeks before T-cell collection (15), whereas in others, patients continued IS throughout T-cell collection and CAR-T infusion (19,20). Concerns about ongoing IS affecting CAR-T cell efficacy have led to varying recommendations: some suggest withholding IS 3 weeks before leukapheresis (15), while others report that ongoing IS does not impact CAR-T efficacy (20). We elected to maintain prednisone and tacrolimus during leukapheresis and still generated an acceptable product. Except in limited cases, calcineurin inhibitors were withheld during CAR-T administration. CAR-T cells could provoke a strong immune response, potentially leading to graft rejection, especially when patients are no longer on IS. Despite these concerns, CAR-T cells are designed to specifically activate T-cells against CD19-positive cancer cells, so T cell-mediated rejection is not expected to occur immediately. Furthermore, targeting CD19 with CAR-T cells temporarily induces B-cell aplasia and hypogammaglobulinemia, which, according to some murine models, may significantly lower the risk of allograft rejection (21). There is currently no consensus regarding the optimal timing for resuming IS post-CAR-T infusion, with reported cases ranging from one month to some not needing IS at all. In our situation, we planned a two-month hiatus, partly based on institutional immune reconstitution data, demonstrating significant T-cell cytopenia still at day 90. The highlight of this case is that our experience would indicate that the two-month IS interruption is too long.

McKenna et al. conducted a multicenter, retrospective analysis of adult patients with PTLD treated with CAR-T. Their analysis revealed that 3 out of 22 patients experienced graft rejection, all of whom had received kidney transplants (8). Three liver transplant recipients with PTLD were included in this study, where tacrolimus was reintroduced at day 120 and day 36 in two of the patients, while the third patient did not resume tacrolimus. Importantly, none of these three patients experienced graft rejection. Similarly, in a case series by Mamlouk et al., three kidney transplant recipients with PTLD discontinued IS therapy before receiving CAR-T infusion. One patient experienced graft rejection at 5 months, while the remaining two patients maintained stable kidney function for four and nine months off IS (22). Luttwak et al. described a case of a liver transplant recipient treated with CAR-T cell therapy. Notably, tacrolimus was continued throughout both the pre-infusion and post-infusion periods. This patient importantly did not experience graft rejection and had a partial response lasting 3 months (20). Wang et al. report a pediatric liver transplant recipient with Burkitt lymphoma who was treated with an investigational anti-CD19 CAR-T cell therapy (ChiCTR2000032211). Tacrolimus was held at diagnosis, and interestingly, the patient remained in remission and maintained graft function for 12 months following CAR-T therapy without requiring any further IS (23). There are no established guidelines for monitoring patients with PTLD following CAR-T therapy for graft rejection. Among the limited number of PTLD patients who experienced organ rejection after CAR-T, the timing for graft rejection varied widely from 1 to 15 months while they were off immunosuppressive therapy (8,22). Since the earliest reported rejection occurred around one month, it now seems reasonable to maintain off IS for at least that duration to strike a balance between minimizing the risk of rejection and maximizing CAR-T cell efficiency. However, this decision can vary greatly depending on individual factors such as the time elapsed since the transplant, the type of original transplant, and the aggressiveness of the disease.

While there is no established consensus on post-treatment monitoring of PTLD, our patient received PET-CT scans at 30, 90, 180, and 360 days, similar to patients with de novo DLBCL. He is also monitored with monthly LFTs. Circulating tumour deoxyribonucleic acid (ctDNA) is increasingly utilized as a tool for tracking disease progression and treatment response across various cancers. In a study by Frank et al., ctDNA-based minimal residual disease (MRD) monitoring in R/R DLBCL post-CAR-T therapy correlated well with clinical outcomes (24). Patients with ctDNA-MRD positivity faced significantly higher progression risks, with marked differences in median progression-free and overall survival between MRD-positive and negative groups, indicating ctDNA’s potential for early risk assessment in CAR-T patients. Similarly, Soo et al. demonstrated ctDNA’s promise for early PTLD detection in transplant recipients (25). Using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) for ctDNA detection, PTLD could be identified on average 114 days before clinical diagnosis. ctDNA levels paralleled clinical responses and EBV titers, suggesting ctDNA as a complementary tool to EBV monitoring, enhancing early detection in post-transplant care. Additionally, no significant difference was observed in mutational burden between PTLD, DLBCL, and de novo DLBCL, supporting ctDNA’s potential role in monitoring disease progression in patients with PTLD after CAR-T. Early loss of B-cell aplasia is linked to a high relapse risk in B-cell ALL, but data on PTLD remains unknown.

To the best of our knowledge, this case represents the first case of liver graft rejection following CAR-T therapy for PTLD. Notably, previous reports of allograft rejection have been limited to kidney transplants. This is likely due to kidney transplants being a lot more common than liver transplants. De Nattes et al. report on a case of a kidney transplant recipient with Burkitt lymphoma who was treated with tisagenlecleucel but had T-cell mediated rejection. Biopsy revealed kidney infiltrates with T-cells expressing anti-CD19 CAR (26). Like this patient, graft function improved promptly after steroids and IS. Although this patient did not undergo a liver biopsy when he was experiencing his grade III transaminitis, a similar underlying mechanism of rejection is plausible.

Conclusions

The optimal timing for withholding and resuming IS in patients with PTLD undergoing CAR-T therapy remains a critical challenge. This case highlights the delicate balance between maintaining CAR-T efficacy and preventing graft rejection. Despite experiencing allograft rejection, this patient’s successful outcome underscores the potential of CAR-T therapy in this population. However, further research is urgently needed to establish evidence-based guidelines for IS management in these complex cases, aiming to maximize treatment efficacy while minimizing the risk of graft rejection.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://aol.amegroups.com/article/view/10.21037/aol-24-14/rc

Peer Review File: Available at https://aol.amegroups.com/article/view/10.21037/aol-24-14/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aol.amegroups.com/article/view/10.21037/aol-24-14/coif). A.I.C. reports consultant fees received from: ADCT Therapeutics, Pierre-Fabre, Elsevier, and FDA, and payments for Clinical Trials from Novartis, Bristol Meyers Squibb, Kite, Fate Therapeutics, and Atara. R.T.M. served as a consultant for Artiva, CRISPR Therapeutics, Incyte, and Novartis, received honoraria from Bristol Myers Squibb/Celgene, Incyte, and Kite, and received research support from Allovir and Novartis. R.T.M. participated in a data and safety monitoring board for Athersys, Century Therapeutics, and VorPharma. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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