Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplant. Therapies include reduction of immunosuppression (RIS), CD20 antibodies and chemoimmunotherapy. R-CHOP yields responses in upwards of 60% of patients (pts) but has high treatment-related mortality (TRM). Thus, novel approaches are necessary, particularly in Epstein Barr virus (EBV)- disease. Bispecific antibodies (BsAb) including glofitamab (glofit), epcoritamab (epcor) and mosunetuzumab (mosun) are revolutionizing the treatment of B-cell lymphomas. However landmark BsAb trials excluded pts with PTLD due to concerns for organ rejection, graft failure and lack of response due to IS. Thus, data is limited on the safety and efficacy of BsAb in this population.

We conducted a retrospective multicenter review of pts with PTLD treated with at least 1 full dose of BsAb from Jan 2020–Nov 2024. Primary endpoints include rates of organ rejection, graft failure, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Secondary endpoints were response rate (RR), overall survival (OS) and progression-free survival (PFS).

Ten pts met criteria for analysis; 6 were male, 5 had non-thoracic transplants (kidney, pancreas, liver), 1 hematopoietic stem cell transplant (HCT), 3 heart and 1 lung transplant. 9 had late-onset PTLD. 9 had monomorphic disease of whom 7 had diffuse large B-cell lymphoma. 3 were EBER+. Median lines of therapy (LOT) prior to BsAb were 2 (range 1-5). Frontline, 5 received rituximab alone (1 PR, 1 CR), 3 DA-R-EPOCH (1 PR, 1 CR), 2 Pola-R-CHP (1 PR). 4 pts received CAR-T prior to BsAb (2 axi-cel, 2 liso-cel) with 3 responses (1 CR, 2 PR) and median duration of response (DOR) 2.7 months (mo). During prior CAR-T, 3 pts had low grade CRS and 1 had ICANS (grade 2). At the time of BsAb, 40% had prior organ rejection that resolved with a median time from rejection to BsAb of 28mo. Median ECOG was 1. All but 1 had advanced stage and IPI > 2. 7 pts had extranodal (EN) disease and all had > 1 EN site. Two had bulky disease (>10cm). Mean absolute lymphocyte count was 475 cells/uL. 7 pts underwent biopsy confirming CD20+ prior to BsAb. Median follow up after 1st step up dose was 7mo (range 1.8-16.8). Pts were treated with epcor (4), glofit (4) and mosun (2). Median age at BsAb at 51. Median time from PTLD diagnosis to 1st step up dose was 11.6mo (range 6.5-42.9). Median number of full doses of BsAb was 3 (range 1-27). The overall response rate was 60% (5 CR, 1 PR, 2 SD, 2 PD). 3 pts with initial response subsequently progressed. Median DOR was 6.8mo (range, 1.6-11.8), median PFS 3.5mo (95% CI 1.53-NR), and 6mo OS rate 65% (95%CI 0.25-0.87). All but 2 pts have discontinued BsAb: 1 currently with PD and unknown treatment plan, 1 with Gem-Ox added to glofit with ongoing response. Of the remaining 8 pts, 1 completed the course of mosun, 1 had CR to epcor but stopped due to infection, 3 had PD and moved on to other systemic therapy, 1 died of PD, and 2 with BsAb response died of infection. 40% developed CRS (3 grade 1, 1 grade 2). All were treated with dexamethasone +/- tocilizumab. There were no cases of ICANS. 1 pt with a kidney transplant developed organ rejection that was treated with steroids and continues on BsAb (Glofit-Gem-Ox); no other pts developed graft failure. 1 pt required PRBC transfusion after they developed fulminant Clostridium difficile (C. diff.). 7 pts developed infections: 4 respiratory syncytial virus, 1 bacterial pneumonia, 1 cellulitis along with MRI concerning for progressive multifocal leukoencephalopathy (PML), 1 fulminant C. diff., and 1 polymicrobial bacteremia. The pt with suspected PML discontinued BsAb and has remained in CR. Pts with C. diff. and polymicrobial bacteremia died from these complications. 4 pts are deceased at the time of analysis: 2 due to PD, 2 due to infection.

In the largest experience with BsAb in PTLD, report an ORR of 60% and median DOR of 7mo in a heavily pre-treated population. Immunotherapy-related adverse events were uncommon. Rates of organ rejection and graft failure were low. In this limited data set with 10 pts, the majority had responses with a reasonable safety profile, although responses did not seem as durable as in immunocompetent pts. Our results support investigation of BsAb as a therapeutic option for PTLD. We hope to further evaluate the safety and efficacy of BsAb in PTLD in an ongoing prospective trial.

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2025
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