Post-transplant lymphoproliferative disorder (PTLD)

PTLD spans a spectrum from EBV-driven polyclonal hyperplasia to monomorphic lymphoma (usually diffuse large B-cell, sometimes Burkitt, plasmablastic, T-cell or Hodgkin-like), classified under WHO 2022 as lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation. EBV is detectable in most early and paediatric cases and about half of late adult cases; EBV-negative PTLD arises later and behaves like de novo lymphoma. Risk is driven by the degree of T-cell suppression (T-cell-depleting induction, tacrolimus-based regimens), EBV-seronegative recipients of seropositive organs (the paediatric scenario), and organ type. In allogeneic stem cell transplant the risk factors are T-cell depletion, mismatched or cord blood donors and anti-thymocyte globulin.

Management is stepwise. Reduction of immunosuppression is the first intervention and alone induces remission in a minority, at the cost of rejection risk. Rituximab monotherapy follows for CD20-positive disease; the PTLD-1 trial (Trappe and colleagues, Lancet Oncology 2012) established sequential therapy with four doses of rituximab followed by CHOP, and its risk-stratified successor (JCO 2017) showed that patients in complete remission after rituximab can continue rituximab alone, reserving CHOP for the rest. Surgery or radiotherapy handles localised disease, and EBV DNA monitoring with pre-emptive rituximab is standard after high-risk stem cell transplants. The newest treatment restores what was lost: EBV-specific cytotoxic T cells. Tabelecleucel (Ebvallo), an allogeneic, HLA-matched, off-the-shelf EBV-specific T-cell product, received European approval in December 2022 for relapsed or refractory EBV-positive PTLD after at least one prior therapy, on the basis of the ALLELE study; in the United States it received a complete response letter in January 2025 tied to manufacturing inspection findings and, as of September 2026, it does not appear on the FDA list of approved cellular and gene therapy products, so US patients access EBV-specific T cells through trials and academic programmes. CD19 CAR-T and bispecific antibodies have been used in small numbers of refractory patients.

Open problems are the outcome of rituximab-refractory disease, balancing rejection against lymphoma control, EBV vaccination for seronegative transplant candidates, and paediatric access to virus-specific T cells.