Ocular Involvement in Post-Transplantation Lymphoproliferative Disorder: A Rare Case with Rituximab Hypersensitivity

Introduction

Post-transplantation lymphoproliferative disorders (PTLD) are lymphomas that develop in the post-transplant setting because of the immunosuppressed state. Pediatric-onset LT-PTLD is more common and occurs earlier in the post-LT period compared to adult-onset LT-PTLD [1]. In the pediatric population, PTLD is seen in 4.6–20%, with a death rate of 6.7–60% [2]. Risk factors of PTLD include the reactivation of latent Epstein-Barr virus (EBV) and higher intensity of immunosuppression [3].

According to the WHO Classification of Hematolymphoid Tumors, 4th edition revised (WHO-HAEM4R), PTLD is categorized into 4 types: non-destructive PTLD, polymorphic PTLD, monomorphic PTLD, and classical Hodgkin lymphoma-type PTLD (CHL-PTLD). In the 5th edition (WHO-HAEM5), the classification was updated to reflect the pathological and biological similarities among proliferative disorders arising in various immunodeficient settings. The new framework emphasizes histological features, viral associations, and the underlying type of immunodeficiency or dysregulation to guide nomenclature and classification. In current clinical practice, many cases are still classified according to the WHO-HAEM4R pathological classification system [4].

The management of PTLD consists of reduction in immunosuppression (RIS) and rituximab±chemotherapy [5]. However, a few cases of hypersensitivity reactions to rituximab (RTX) have been reported in children, including skin rash, fever, and other symptoms [6].

Herein, we report a pediatric case of LT-PTLD who experienced recurrent allergic reactions and rapid rebounds in the proportion of B lymphocytes following multiple courses of rituximab (RTX) treatment. The patient developed intraocular PTLD and was successfully treated with obinutuzumab.

Case Report

A 1-year-old boy underwent liver transplantation for biliary atresia with the liver of his mother. Post-LTx (post-liver transplantation), immunosuppression comprised tapering doses of prednisolone and tacrolimus. The patient was admitted to our hospital with recurrent abnormal liver function 6 years after LTx due to mild rejection. His liver function recovered after immunosuppression therapy. He had enlarged cervical lymph nodes with peripheral EBV DNA (PBMC) of 5.3×105 copies/ml, while EBV DNA in plasma was negative. PET/CT revealed multiple enlarged bilateral cervical lymph nodes with increased FDG uptake (measuring 1.0×1.6 cm, SUVmax 3.7). The biopsy of cervical lymph nodes showed lymphoid hyperplasia with EBER+. After the reduction in tacrolimus, the peripheral blood EBV DNA decreased and fluctuated at 104 copies/ml. The tacrolimus (FK506) trough level was 2.9 ng/mL.

Two years later, the patient presented with blurring of right-eye vision. His visual acuity (VA) was 20/125 on the right and 20/30 on the left. The fundoscopy showed that there was an abnormal mass in the iris and ciliary body of the right eye. The iris and ciliary body of the left eye were mildly uplifted. The aqueous humor was positive for EBV. He was considered for a diagnosis of PTLD involving the eyes. He received intravitreal methotrexate injections at a dose of 0.4 g once weekly for 2 treatment cycles; however, the treatment was ineffective.

Then, he underwent iridectomy of the iris mass and vitreous chamber 1-mg rituximab injection. The patient also underwent cataract phacoemulsification with aspiration and pupiloplasty. The histological examination of the iris and the ciliary body confirmed polymorphic PTLD, with about 100 EBER-positive cells/HPF. The immunohistochemical analysis revealed that the eye biopsy was negative for CD21 and EBNA2, with scattered positivity for CD4, CD8, Kappa, and Lambda light chains. PAX5 and CD38 showed weak positivity, while CD30 was positive in only a few cells.

He received 4 doses of rituximab (375 mg/m2 BSA) over 3 weeks, but had recurrent rash with itching and swelling of the upper lip during the treatment. The symptoms were relieved by intravenous dexamethasone and loratadine. Moreover, during rituximab treatment, there was a rapid rebound in the proportion of B lymphocytes, along with a slow decline in EBV DNA levels and subsequent recrudescence. Although the PET/CT showed that the lymph node volume has decreased compared to before, the ultrasound bio-microscopy (UBM) showed that the iris and ciliary body were again irregularly enlarged (Figure 1). All laboratory and diagnostic findings were indicative of PTLD recurrence. Due to the allergy and poor effect, the 4th cycle of rituximab was not completed.

After adjusting the treatment plan, he was given third-generation glycosylated human anti-CD20 monoclonal antibody (obinutuzumab 300 mg). The B lymphocytes were 0.03% and the peripheral blood EBV DNA became negative (Figure 2). Fundoscopy showed that the inflammation had subsided. Four months later, he was given obinutuzumab for a second time as a consolidation therapy without allergic symptoms. The follow-up tests showed that the B lymphocytes were 0.13% and the peripheral blood EBV DNA remained negative. The patient is currently receiving no immunosuppressive agents. Liver biopsy showed no signs of graft rejection or liver fibrosis.

Discussion

PTLD is a rare but severe complication after solid organ transplantations, particularly in children. There are many risk factors for PTLD, including EBV load, young age, and intensity of immunosuppression [7]. For pediatric recipients, PTLD is associated with older age, higher tacrolimus blood levels before EBV DNA viremia, at 1 month of EBV DNA viremia, and higher peak EBV viral load [8]. Chen et al [9] suggested that a peak EBV viral load greater than 4100 copies/μg PBMC DNA and a peak tacrolimus level above 14.8 ng/mL, both within 3 months after LTx, contributed to a high risk of PTLD in pediatric liver transplant recipients. Our patient had EBV DNA viremia at 11 months after transplantation, when the FK506 trough level was 8.6 ng/ml while the highest FK506 trough lever was 12.2 ng/ml at 3 months after LTx. The highest peak EBV viral load was 6.78×105 copies/ml at 2 years after LTx. Although several studies have reported that the earlier EBV DNA viremia is associated with the earlier PTLD, our patient developed EBV viremia 11 months after LTx and was diagnosed with PTLD 8 years after LTx. This may be attributed to intensive EBV monitoring and proactive adjustments to immunosuppressive therapy.

Pediatric PTLD patients often have better survival rates since they have less comorbidity, but survival rates are lower for patients diagnosed at OLT with late-onset PTLD [8]. Therefore, for this patient, we should continue vigilant monitoring to prevent over-immunosuppression in the long term after LTx.

A study of 20 years of experience shows that lymph nodes were the most common site involved in PTLD pediatric patients (41%). The gastrointestinal tract was affected in 25%, with liver and spleen involvement in 16% [10]. According to our literature search, only 21 children with PTLD have been reported with ocular involvement (Table 1), and most were female (16/21, 66.7%). All patients had late-onset PTLD, with a median time from transplantation to PTLD onset of 53 months (IQR: 41–60 months). The PTLD types included 62.5% polymorphic B-cell (10/16), with 70.6% EBER-positive (12/17), but the affected eye was not fixed. Most patients responded well to standard treatment, although some experienced death or graft loss.

In addition to PTLD, transplant recipients may develop a range of ocular diseases [11]. Since patients can present with various symptoms, such as blurry vision, floaters, or eye pain, timely differential diagnosis is crucial and includes infections such as cytomegalovirus (CMV) retinitis and herpetic keratitis, as well as non-infectious conditions like posterior subcapsular cataracts (PSCs) and cyclosporine retinopathy. In the present case, CMV DNA testing remained negative throughout the post-transplant period.

An initial step is to immediately reduce immunosuppression (RIS) to partially restore T cell activity. There are no universal guidelines or protocols on tapering immunosuppression, and it is mostly individualized to each patient [1]. Rituximab is a monoclonal anti-CD20 antibody that has become a standard of care in patients with polymorphic PTLD unresponsive to initial RIS [5]. Our patient was allergic to rituximab, with symptoms including recurrent rashes and itching. Several studies reported that hypersensitivity to RTX is becoming more common in the pediatric population [6]. Adverse drug reactions to rituximab are classified into infusion-related reactions (IRRs), cytokine-release reactions (CRRs), and type I IgE-mediated, type III, and delayed-type IV reactions.

Obinutuzumab, a third-generation anti-CD20 humanized monoclonal antibody, can overcome primary rituximab failure or loss of effectiveness. Rituximab is a chimeric monoclonal antibody containing murine-derived variable regions, which can trigger allergic responses in some individuals. In contrast, obinutuzumab is a fully humanized monoclonal antibody with a glycoengineered Fc region that enhances antigen-binding affinity and specificity, while reducing immunogenicity due to the minimized presence of non-human components. According to published data, obinutuzumab demonstrates 35- to 100-fold greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab in vitro [12]. Preclinical studies have also shown that obinutuzumab can effectively induce direct cell death (DCD) and complement-dependent cytotoxicity (CDC) [13]. Research has reported the use of obinutuzumab in nephrotic syndrome patients who did not respond well to rituximab, indicating that obinutuzumab can effectively deplete B lymphocytes, leading to therapeutic benefit [14,15]. For lymphoma patients, obinutuzumab can provide a good therapeutic effect, potentially even better than rituximab [16,17]. However, there have been no reports on the use of obinutuzumab for PTLD patients. Our patient was the first to receive obinutuzumab for PTLD. His B lymphocytes and EBV DNA levels significantly decreased with no signs of allergic reactions. He did not experience adverse events associated with obinutuzumab, such as infections, infusion-related events, or neutropenia [18,19]. The treatment has proven effective, adding valuable experience to the management of PTLD.

Conclusions

PTLD is a common complication in pediatric transplant recipients, presenting with variable clinical manifestations and sites of involvement. Ocular involvement is uncommon and must be distinguished from other ocular pathologies. In patients with hypersensitivity to rituximab, third-generation anti-CD20 monoclonal antibodies may provide an effective therapeutic alternative. Obinutuzumab has demonstrated efficacy in the treatment of PTLD.