Post-Transplant Lymphoproliferative Disorder

EBV-driven B-cell proliferation after solid organ or hematopoietic stem cell transplantation — immunosuppression reduction, rituximab, and sequential chemotherapy

Key Points

• PTLD is a spectrum of lymphoid proliferations arising in the setting of post-transplant immunosuppression, occurring in 1–3% of solid organ transplant (SOT) recipients and 2–3% of allogeneic HSCT recipients; incidence is highest in recipients of intestinal transplants (>10%).
• EBV drives the majority of early PTLD — normally cytotoxic T-cell surveillance holds EBV-infected B cells in check; immunosuppression removes this restraint, allowing uncontrolled B-cell proliferation that may evolve from polyclonal hyperplasia to monoclonal lymphoma.
• WHO 2022 classifies PTLD into four categories: non-destructive PTLD, polymorphic PTLD, monomorphic PTLD (most commonly DLBCL-like), and classic Hodgkin lymphoma PTLD; only monomorphic PTLD meets criteria for a specific lymphoma diagnosis.
• First-line management for EBV+ PTLD is reduction of immunosuppression (RIS), which achieves responses in ~25–50% of early/polymorphic disease; rituximab is added for EBV+ B-cell PTLD not responding to RIS, with an ORR of ~44–50%.
• The sequential approach — RIS → rituximab → rituximab + CHOP (R-CHOP) for non-responders — was validated in the PTLD-1 trial, achieving an overall response rate of ~90% and 3-year OS ~70%.
• EBV-negative PTLD, which presents later post-transplant and resembles de novo DLBCL, responds less predictably to RIS and typically requires upfront rituximab-based chemoimmunotherapy.

Epidemiology, Risk Factors, and Pathogenesis

PTLD encompasses a broad spectrum of lymphoid proliferations that arise as a consequence of impaired immune surveillance in transplant recipients. The overall incidence among solid organ transplant (SOT) recipients ranges from 1–3% but varies dramatically by organ transplanted — reflecting both the degree of immunosuppression required and the exposure to EBV via the donor organ: - Kidney: ~1–2% - Liver: ~1–2% - Heart: ~2–6% - Lung: ~5–9% - Intestine/multivisceral: >10% Among allogeneic HSCT recipients, PTLD occurs in ~2–3% overall but rises sharply with T-cell–depleted grafts, HLA mismatch,…

Classification and Clinical Presentation

**WHO 2022 Classification of PTLD:** 1. **Non-destructive PTLD (~10%):** Preserves underlying lymph node architecture; three subtypes — plasmacytic hyperplasia, infectious mononucleosis-like PTLD (often EBV-driven primary infection), and florid follicular hyperplasia. Typically polyclonal. Responds well to RIS. Histologically resembles reactive processes. 2. **Polymorphic PTLD (~15–20%):** Effacement of normal architecture by a polymorphous infiltrate of immunoblasts, plasma cells, and small lymphocytes; may be EBV+. Clonal IG or TCR rearrangements present but does not meet criteria for a…

Staging and Risk Stratification

Monomorphic PTLD is staged using the Lugano classification (Ann Arbor modified). PET/CT is the preferred staging modality and provides baseline for response assessment. The PTLD-1 prognostic score incorporates clinical factors: age >60, ECOG PS ≥2, LDH >ULN, and advanced Ann Arbor stage — stratifying patients into low- and high-risk groups with markedly different outcomes after sequential therapy. The IPI (International Prognostic Index), originally developed for DLBCL, also provides prognostic information in monomorphic DLBCL-like PTLD. **Key prognostic factors:** - EBV status: EBV+ PTLD…

Treatment

Treatment of PTLD is guided by PTLD type, EBV status, extent of disease, and transplant type (SOT vs. HSCT). The central challenge is balancing lymphoma control against the risk of allograft rejection (SOT) or GVHD (HSCT) from immune reconstitution. **Step 1 — Reduction of Immunosuppression (RIS):** The cornerstone of early/polymorphic and many monomorphic EBV+ PTLD. Calcineurin inhibitor and antimetabolite doses are reduced by ~50%; steroids may be maintained to protect the allograft. RIS achieves complete or partial remission in ~25–50% of early/polymorphic PTLD and ~30–40% of monomorphic…

Prevention, Monitoring, and Prognosis

**Prevention:** Pre-emptive strategies are used routinely in HSCT and increasingly in SOT: - Serial plasma EBV DNA monitoring (every 1–4 weeks in the early post-transplant period for high-risk patients) - Pre-emptive RIS or rituximab when EBV DNA rises above threshold without clinical PTLD — shown to reduce PTLD incidence in HSCT - Minimizing overall immunosuppressive burden; avoiding prolonged ATG courses - EBV serologic matching (preferring EBV+ donors for EBV+ recipients when possible) **Prognosis:** PTLD prognosis is highly variable: - Non-destructive/polymorphic PTLD: 5-year OS >85%…