Post-transplant lymphoproliferative disorder (PTLD)

Etiology

• Two drivers: immunosuppression and EBV infection. In the setting of impaired T-cell immune surveillance, EBV-driven B-cell proliferation goes unchecked.
• Often EBV+ and CD30+. EBV+ PTLD tends to occur early (<1 yr post-transplant) and responds well to reduction in immunosuppression. EBV-negative PTLD tends to occur late (>1 yr, often several years after transplant), is usually monomorphic (mostly DLBCL; T-cell PTLD is overrepresented), and responds poorly to reduction in immunosuppression.

Epidemiology & Risk Factors

• Incidence: solid organ transplant (SOT) ~1 to 2%; varies by organ, highest in intestinal/multivisceral (~10%) and lung (~3 to 10%), lower in renal (~1%) and liver (~2%). Allo-HSCT ~1 to 3%.
• Timing (bimodal):
  • Early (<1 yr post-transplant): acute EBV infection or reactivation in the setting of reduced anti-EBV cytotoxic T-cell precursors; mostly EBV-driven, often polymorphic, B-cell.
  • Late (>1 yr post-transplant): manifestation of lymphocyte deregulation from chronic immunosuppression; more EBV-negative, monomorphic DLBCL, T-cell, or classical-HL-like; worse prognosis.
• Risk factors: EBV mismatch (recipient-negative/donor-positive, R-/D+) is the strongest risk; high cumulative immunosuppression (especially T-cell depletion, anti-thymocyte globulin, OKT3, alemtuzumab, mycophenolate mofetil); CMV mismatch; pediatric recipient; HCV.

EBV Biology

• ~60 to 80% of PTLD are EBV-driven, especially early-onset disease.
• EBV viral load monitoring in EBV-mismatched recipients (peripheral blood EBV PCR); rising titers may prompt preemptive reduction in immunosuppression.
• Late-onset PTLD is increasingly EBV-negative and biologically resembles de novo lymphomas.

PTLD Classification (WHO revised 4th ed / ICC 2022, 4 categories; WHO-HAEM5 uses an integrated framework). 4th category: classic Hodgkin lymphoma PTLD.

Workup

• Tissue biopsy is mandatory: IHC (CD20, CD3, CD30, EBER in situ hybridization for EBV), flow cytometry, clonality (IgH PCR), cytogenetics.
• Imaging: PET-CT (most PTLD is FDG-avid).
• CNS imaging plus LP: Obtain brain MRI (and LP when safe) for neurologic symptoms/signs or high-risk histology rather than routinely in all patients; CNS involvement occurs in a minority (roughly 5 to 15%, cohort-dependent).
• EBV viral load: baseline and serial.
• Allograft function: monitor closely during RIS.

Treatment Ladder

• Step 1: Reduction in immunosuppression (RIS), the first step whenever possible. Standard post-transplant immunosuppression is triple therapy: a calcineurin inhibitor (tacrolimus or cyclosporine) plus an antiproliferative/antimetabolite (mycophenolate mofetil, azathioprine, sirolimus, everolimus) plus corticosteroids.
  • RIS specifically means reducing the calcineurin inhibitor (typically by 50%) and discontinuing the antimetabolite (azathioprine, mycophenolate mofetil).
  • For critically ill patients, discontinue all non-glucocorticoid immunosuppression.
  • Re-escalation after complete remission should be individualized.
  • ~25 to 50% of PTLD overall responds to RIS alone (most non-destructive lesions regress; lower rates in polymorphic and monomorphic disease); EBV status alone does not reliably predict RIS response; treatment selection depends on histology, disease burden, and clinical aggressiveness.
• Step 2: Rituximab monotherapy for CD20+ B-cell PTLD when RIS fails or is not possible; ORR ~45%, CR ~25% (often 4 weekly doses).
• Step 3: Sequential rituximab then R-CHOP (PTLD-1, Trappe JCO 2017; PMID 27992268): risk-stratified. After 4 weekly rituximab induction, reassess: CR receives 4 further rituximab doses every 3 weeks (consolidation); non-CR receives 4 cycles of R-CHOP. No routine rituximab maintenance afterward; 5-yr OS ~65%. R-EPOCH or DA-EPOCH are alternatives.
• Brentuximab vedotin: consider given most PTLD is CD30+.
• Burkitt-type PTLD: DA-EPOCH-R or modified intensive chemotherapy.
• T-cell PTLD: treat as PTCL (CHOP/CHOEP); poor prognosis; consider allo-HSCT.
• EBV-specific cytotoxic T lymphocytes (EBV-CTLs) / Tabelecleucel (Ebvallo): allogeneic off-the-shelf EBV-specific CTLs. EU approved Dec 2022; not FDA approved (FDA complete response letters Jan 2025 and Jan 2026) for EBV+ relapsed/refractory PTLD after SOT or allo-HSCT after at least one prior therapy; for solid organ transplant recipients, prior therapy must include chemotherapy unless chemotherapy is inappropriate; ORR ~50%, durable in responders.
• CAR-T (CD19): case-series experience for R/R B-cell PTLD; balance against allograft rejection risk.
• Antivirals (ganciclovir, acyclovir): not effective for established PTLD (EBV is in the latent phase, not lytic).

Allo-HSCT PTLD

• A distinct setting, usually within the first 6 months; often donor-derived, B-cell, EBV+. Treat with rituximab with or without donor-derived EBV-CTLs or tabelecleucel; reduce immunosuppression cautiously given GVHD risk.

Prognosis

• Overall: variable; non-destructive disease usually responds to RIS; monomorphic disease with PTLD-1 5-yr OS ~65%; CNS involvement and T-cell PTLD carry the worst outcomes.
• Allograft loss: ~20% after aggressive RIS.

High-Yield Pearls

• EBV mismatch (R-/D+) is the highest-risk scenario.
• RIS first, rituximab second, R-CHOP escalation = PTLD-1 paradigm.
• Tabelecleucel / EBV-CTLs for EBV+ R/R PTLD; EU-approved allogeneic CTL therapy (not FDA approved; 2 CRLs, most recent Jan 2026).
• Antivirals do NOT treat established PTLD (latent EBV).
• Late-onset PTLD is often EBV-negative and more like de novo lymphoma, and is less RIS-responsive.
• CNS involvement occurs in a minority (about 5 to 15%): brain MRI (and LP when safe) for neurologic symptoms or high-risk features.
• Most PTLD is CD30+, supporting a role for brentuximab in selected cases.