A tale of two lymphomas: A rare case of transformative post-transplant lymphoproliferative disorder

Abstract

Abstract Post-transplant lymphoproliferative disorders (PTLD) are immunodeficiency-related lymphoid proliferations that arise in the setting of chronic immunosuppression after solid organ or hematopoietic stem cell transplantation. We present a patient who developed both Epstein-Barr virus (EBV)-positive monomorphic B-cell PTLD and peripheral T-cell lymphoma (PTCL), follicular helper T-cell subtype not otherwise specified (TFHLNOS), nearly a decade post-renal transplant. Our 61-year-old patient underwent a living-unrelated renal transplant in 2014 for focal segmental glomerulosclerosis and was maintained on mycophenolate mofetil (MMF) and cyclosporine (CsA). In Aug 2023, he presented with biopsy-proven EBV-positive monomorphic B-cell PTLD involving the skin, with no nodal involvement on PET scan. MMF was discontinued, and he received four weekly doses of rituximab (375 mg/m²), achieving complete remission (CR) and was consolidated with four additional Rituximab doses by Jan 2024. In May 2024, surveillance PET revealed widespread hypermetabolic lymphadenopathy, raising concern for disease transformation or recurrence. He was emergently admitted for tumor lysis syndrome (TLS) and hemophagocytic lymphohistiocytosis (HLH), requiring ICU admission, high-dose steroids, and initiation of dialysis. Excisional lymph node biopsy showed a CD4+, CD5+, CD7+, BCL6+, PD-1+, ICOS+ T-cell neoplasm with Ki-67 of 40–50% and rare CD21+ dendritic meshworks. CD30 was weakly positive (10%). Molecular profiling revealed clonal TCR gene rearrangements and pathogenic mutations in RHOA, SAMHD1, TET2, and JAK1, consistent with TFHLNOS, a rare and aggressive subtype of PTCL. Given his fragile clinical state and hepatic and renal dysfunction, he was started on reduced-dose azacitidine and romidepsin. After improvement of liver and kidney function, therapy was escalated to brentuximab vedotin (BV) with cyclophosphamide, doxorubicin, and prednisone (CHP), given his CD30 expression. After six cycles, he achieved CR, dialysis independence, and clinical improvement of his functional status. Autologous stem cell transplantation, BV maintenance, or active surveillance were all considered for his post-remission therapy in a multidisciplinary fashion. Due to patient's tenuous performance status, he was maintained on BV. However, after two cycles, he declined clinically with poor appetite, weight loss, and fatigue. His work up was remarkable for recurrent TLS and HLH, with PET imaging confirming recurrent disease. After detailed goals-of-care discussions, he and the care team elected to proceed with additional therapy with EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), since he already received azacitidine, romidepsin, and BV-CHP. Cycle one was complicated by neutropenic fever secondary to gram-negative bacteremia, managed with broad-spectrum antibiotics. Repeat echocardiography after recovery showed a reduced LVEF of 39%, prompting omission of doxorubicin in cycle two. During cycle two, he developed drug-induced liver injury attributed to CsA, which was subsequently discontinued. Cyclophosphamide provided adequate T-cell suppression to maintain renal graft integrity. Interval imaging showed no new areas of disease and significantly improved lymphadenopathy. His HLH resolved with therapy and a gradual steroid taper. Despite these events, he had marked improvement in quality of life, appetite, and functional status, which had been severely impaired previously due to his disease. At the time of submission, patient had completed 4 cycles of EPOCH and continues to have clinical and radiographic improvement. Doxorubicin was reintroduced in cycle three after recovery of his LVEF to >50% He remains transfusion-independent, dialysis-independent, and free from hospitalization. This case highlights the rare clinical challenge of managing dual-lineage post-transplant lymphomas and the adaptability required in treatment selection. His care underscores the importance of multidisciplinary collaboration, patient-centered decision-making, and longitudinal follow-up. He has been referred to our bone marrow transplant team and is pending evaluation for an autologous stem cell transplantation for potential long-term disease control.