Abstract
Background
Patients with relapsed/refractory post‐transplant lymphoproliferative disorder (R/R PTLD) following solid‐organ transplants (SOT) or hematopoietic stem cell transplants (HSCT) after frontline chemoimmunotherapy have dismal outcomes. There is no standard of care for this group of patients, and they are generally excluded or ineligible for clinical trials. Several effective novel agents have been licensed in recent years for the treatment of diffuse large b‐cell lymphoma (DLBCL), including CD19 CAR‐T cell therapy and CD3xCD20 bispecific antibody.
Case Report
Acknowledging the limited data and extrapolating the evidence from trials in DLBCL, we report a case of R/R PTLD successfully treated with CD3xCD20 bispecific antibody, Epcoritamab, with good tolerability and long‐term response.
Trial Registration
The authors have confirmed clinical trial registration is not needed for this submission.
Keywords: bispecific antibodies, diffuse large b‐cell lymphoma, EBV, post‐transplant lymphoproliferative disorders
1. Background
PTLD is a heterogeneous group of abnormal lymphoid proliferations associated with SOT or HSCT. The overall incidence is low (1%–2%), with the highest incidence seen after multiorgan and small intestinal transplants [1]. Management requires a multidisciplinary team input and involves a reduction in immunosuppression with response‐adapted sequential treatment [2]. The pivotal phase II PTLD‐1 and PTLD‐2 trials provided evidence for this response‐adapted approach in PTLD of DLBCL‐type [3, 4]. Outcomes are generally favorable with a median overall survival (OS) of over 5 years [1]. However, those with high‐risk disease, i.e., international prognostic index (IPI) >3, refractoriness to Rituximab monotherapy, thoracic SOT, and R/R disease have dismal outcomes [5]. There is no standard of care for this group of patients, and they are generally excluded or ineligible for clinical trials [5]. In recent years, both CAR‐T cell therapy and bispecific antibodies have been licensed for the treatment of R/R DLBCL, but neither has been formally evaluated in prospective trials of DLBCL‐type PTLD owing to its rarity [6, 7, 8]. Real‐world evidence of safety and efficacy using CD19 CAR‐T cell therapy has been reported in a small number (n = 22) of R/R PTLD cases [6]. The activity of CD3xCD20 bispecific antibodies has not been reported in this disease. We report a case of primary refractory PTLD treated successfully with CD3xCD20 bispecific antibody, Epcoritamab.
2. Case Presentation
A 68‐year‐old lady received a simultaneous liver–kidney transplant from a CMV‐matched (positive/positive) donor for autosomal dominant polycystic kidney disease with end‐stage renal failure requiring peritoneal dialysis. Her past medical history was significant for subarachnoid hemorrhage and hypertension. Post‐transplant immunosuppression included low‐dose prednisolone and tacrolimus. Mycophenolate mofetil (MMF) was introduced later to permit a lower tacrolimus target level, as an early biopsy of the transplanted kidney showed possible tacrolimus‐induced acute tubular necrosis with borderline features of T‐cell‐mediated rejection. At routine follow‐up 4 months post‐transplant, she reported a several weeks’ history of worsening back pain, accompanied by reduced appetite, weight loss, and intermittent fevers. She was admitted to the hospital for further investigations.
3. Investigations
Full blood count showed anemia (hemoglobin 88 g/L) and lymphopenia (lymphocytes 0.14 x 109/L). Renal profile showed sodium 126 mmol/L, potassium 5.5 mmol/L, and creatinine 131 umol/L. Liver function tests were within acceptable limits. Lactate dehydrogenase and C‐reactive protein were elevated at 381 U/L (100–240 U/L) and 61.8 mg/L. Ebstein–Barr virus (EBV) viral load was detected at 13,093 IU/mL. Biopsy and imaging were consistent with Stage IVB, EBV+ monomorphic PTLD of DLBCL‐type with an IPI score of 4 (Figures 1 and 2).
FIGURE 1.
All images are captured at 600 × magnification – core biopsy of the diaphragmatic soft tissue lesion. H&E demonstrates a population of predominantly large lymphoid cells, positive for CD20, CD79a, and PAX5. EBER shows many of the large cells to be EBV positive. Ki67 is positive in many large cells indicating a high proliferative rate.
FIGURE 2.
Serial PET maximum intensity projection (MIP) images. Baseline FDG‐PET pre‐Epcoritamab on the left showing multiple avid large soft tissue lesions involving lungs bilaterally, abdomen at the diaphragmatic hiatus, serosa of liver and bilateral pelvis. The largest lesion measured approximately 99 × 14 mm with SUVmax 12.6. FDG‐PET post 2 cycles of Epcoritamab showing a partial metabolic response and FDG‐PET post cycle 7 and 12 showing a complete metabolic response. Black arrows represent main sites of disease and dotted arrow represents the transplanted kidney.
4. Outcome
MMF was discontinued, and she commenced Rituximab 375 mg/m2 once weekly for 4 weeks. Repeat staging CT after completing Rituximab showed progressive disease. She was escalated to 2nd line treatment with Pola‐R‐CHP (Polatuzumab Vedotin 1.8 mg/kg, Rituximab 375 mg/m2, Cyclophosphamide 750 mg/m2, Doxorubicin 50 mg/m2, and Prednisolone 100 mg. Interim CT after 2 cycles of Pola‐R‐CHP showed refractory disease.
Her performance status had declined (ECOG Status 2) due to progressive weight loss requiring naso‐gastric (NG) feeding, respiratory infections, increased transfusion requirements, and prolonged hospital stay. She was deemed unsuitable for CAR‐T cell therapy and commenced 3rd line treatment with subcutaneous Epcoritamab. Pre‐Epcoritamab EBV viral load was 61,189 IU/mL. She tolerated Epcoritamab well with no cytokine release syndrome (CRS) or immune effector cell‐associated neurological syndrome (ICANS). Her functional status steadily improved over the course of treatment. Early interim PET‐CT performed after Cycle 2 showed a very good partial metabolic response. Follow‐up PET‐CT after Cycle 7 and 12 showed a complete metabolic response (Figure 2). EBV titres were undetectable after Cycle 3 and maintained at Cycle 12 (Figure 3).
FIGURE 3.
Serial measurements of EBV viral load during Epcoritamab treatment, starting with a pre‐treatment level of 61,189 IU/mL. EBV viral load started to drop after the first priming dose of Epcoritamab, was below limit of detection after Cycle 3 and remained undetectable at Cycle 12.
5. Discussion
Patients with R/R PTLD have poor outcomes and are challenging to manage. The reduction in immunosuppression and treatment with organ‐toxic chemotherapy increases the risk of organ rejection or failure. There is a higher incidence of life‐threatening treatment toxicity with grade 3/4 infections, including opportunistic infections. In the PTLD‐2 very‐high‐risk cohort treated with intensified chemotherapy, treatment‐related mortality was high at 25% with estimated OS < 1 year [4]. 42% of patients within the overall cohort experienced grade 3/4 infections [4].
Following ≥2 lines of treatment, patients with PTLD of DLBCL‐type are eligible for CD19 CAR‐T cell therapy. Although uncommon, there is real‐world evidence of using CAR‐T cell therapy in PTLD, demonstrating an impressive complete response (CR) rate of 55% with 2‐year OS of 58% [6]. These outcomes appear similar to those of patients in the CAR‐T clinical trials [6]. Our patient became progressively unfit with refractory disease. Her disease was also chemo‐refractory with high disease burden, raising concerns about the effectiveness of bridging to CAR‐T cell therapy. This was therefore felt to be an unsuitable option.
HLA‐matched EBV‐specific cytotoxic T‐lymphocytes (CTLs) from a third‐party donor were also considered. Although unavailable in the United Kingdom, Tabelecleucel, an off‐the‐shelf, allogeneic EBV‐specific CTL, has been licensed for R/R PTLD with a CR rate of 28% and median duration of response (mDOR) of 23 months in the ALLELE study [9]. A recent literature review examining Phase I and II trials using EBV‐specific CTLs also described durable response rates of about 50% [10]. The treatment is generally well tolerated with no instances of organ rejection, and significant adverse effects such as graft versus host disease, CRS, or ICANS have rarely been observed [10]. Although we identified suitable cell lines for this patient from the Scottish National Blood Transfusion Service anti‐EBV cytotoxic T‐cell bank, the HLA‐matches were low at 2/10 HLA alleles. This was therefore reserved for the next line of therapy.
CD3xCD20 bispecific antibody has recently been licensed for R/R DLBCL after ≥2 lines of treatment, following outcomes from the pivotal phase II studies NCT03625037 and NCT03075696, with CR rates of about 40% in both studies [7, 8]. mDOR in patients achieving CR were 36.1 and 29.8 months, respectively [7, 8]. Although the trials have not evaluated any patients with PTLD, the bispecific antibody targets the CD20 antigen and has a comparatively lower risk of Grade 3/4 CRS and ICANS. Rates of Grade 3/4 infections were reported between 3% and 17% [7]. We therefore opted for Epcoritamab in this case.
This patient achieved an excellent and maintained response on Epcoritamab. We performed an early interim PET‐CT response assessment, given that it would be difficult to assess this clinically, and the novelty of using a bispecific antibody in this setting. This demonstrated a very good partial metabolic response and correlated with a significant drop in EBV viral load. Response assessment by monitoring of EBV viral load can be considered alongside standard approaches using FDG‐PET‐CT [2]. This should, however, be interpreted contextually as an adjunct to FDG‐PET‐CT, given the interlaboratory variability with testing and awareness of differences between whole blood and plasma EBV viral load [11]. Studies evaluating this were also small and few in number [2].
Use of Epcoritamab was well tolerated with no severe adverse events. The patient experienced no CRS / ICANS. Apart from an episode of CMV‐reactivation managed with oral Valganciclovir, she suffered no other infective episodes thus far. However, it is vital to highlight that real‐world studies evaluating the use of bispecific antibody agents demonstrate much higher rates of Grade 3/4 infections [12]. We would strongly advocate for the use of standard antimicrobial prophylaxis with a low threshold to consider intravenous immunoglobulins if this is accessible.
Treatment with Epcoritamab demonstrated safety and efficacy in this case of primary refractory PTLD and could represent a useful therapy in this disease. To our knowledge, this is the first case report of successful treatment of R/R PTLD using a CD3xCD20 bispecific antibody.
Author Contributions
L.C. collected the data and wrote the manuscript. L.C. S.I. and D.E. provided clinical care to the patient. S.O. provided expert histopathological input on diagnosis. All authors critically reviewed and approved the final version of the manuscript.
Conflicts of Interest
S.O.: No conflicts of interest. S.I.: Advisory board, speaker fees and conference support from AstraZeneca, Beigene, Gilead and Takeda; received Honoria from Incyte. D.E.: Advisory board for AbbVie, Astex Therapeutics, AstraZeneca, BeiGene, Janssen, and Kyowa Kirin, Lilly, Roche and Sobi; received honoraria from AbbVie, Adaptive, AstraZeneca,Beigene, Gilead, Janssen, Nurix, Roche and Takeda; conference and travel support from AbbVie, Novartis and Roche. L.C. conference and travel support from AbbVie and Jazz.
Ethics Statement
The authors have nothing to report.
Consent
Written informed consent was obtained from the individual for the publication.
Chan L. Y., O'Connor S., El‐Sharkawi D., and Iyengar S., “Epcoritamab for Relapsed/Refractory EBV+ Post‐Transplant Lymphoproliferative Disorder of DLBCL‐Type.” eJHaem 6, no. 6 (2025): e70156. 10.1002/jha2.70156
Funding: The authors received no specific funding for this work.
Data Availability Statement
The data that supports the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that supports the findings of this study are available from the corresponding author upon reasonable request.