Post-transplant lymphoproliferative disease (PTLD)


Post-transplant lymphoproliferative disorder, post-transplant lymphoma

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1. Description of the problem

PTLD is the most common secondary malignancy within the first year after hematopoietic cell transplantation (HCT). PTLD occurs as a result of the proliferation of Epstein-Barr virus (EBV)-transformed B cells in the absence of EBV-specific T-cell immunity.

Clinical features of the condition

1. Systemic symptoms (fever)

2. Lymphadenopathy

3. Extranodal tumor formation

4. PTLD is usually preceded by a rapid rise in blood EBV copies, and may be detected by serial plasma PCR before becoming symptomatic.

Key management points
  • Weekly peripheral blood EBV viral load by PCR in high-risk patients until day 180 post-transplant

  • If a sustained rise in EBV copies is detected (above a threshold of 1000 genome equivalents per ml plasma) in high-risk patients, a single infusion of rituximab (anti-CD20 monoclonal antibody) is given to delete B cells (these are the EBV-infected and -transformed cells).

  • Immunosuppression may be tapered (especially in the presence of early disease appearing late after HCT and where there is no GVHD).

  • Rituximab infusion may be repeated if necessary.

  • In cases resistant to rituximab, chemotherapy or radiotherapy may be attempted (but this may be associated with a high mortality due to previous recent exposure to the HCT conditioning regimen).

  • Reconstitution of EBV-specific immunity may be achieved with a donor lymphocyte infusion (DLI) or the infusion of donor-derived or banked partially HLA-matched, EBV-specific T cells.

2. Emergency Management

  • PTLD is usually detected with serial measurement of EBV copies in time for pre-emptive therapy; however in the case of late presentation with symptomatic disease, localized disease causing organ impairment may require specific and prompt treatment such as surgery or radiation therapy (such presentations are very rare after HCT).

  • If the diagnosis of PTLD is suspected but EBV viremia has not been evaluated, plasma should be sent for viral load.

  • Biopsy of affected nodal or extra-nodal sites should be performed to obtain a histopathologic diagnosis and confirm EBV positivity in the malignant cells.

  • Reduction of immunosuppression (if possible) and/or rituximab administration are the first practical therapeutic options.

3. Diagnosis

1. The presence of peripheral blood EBV genome equivalents > 1000 / μL plasma has high sensitivity and specificity for EBV proliferation; specificity for PTLD is lower as many immunocompromised patients with EBV viremia do not go on to develop PTLD.

2. Clinical examination and appropriate radiological studies (CT neck-pelvis, PET scan as indicated) indicates the sites of disease affected.

3. Biopsy of the affected sites for histopathology, immunohistochemistry, flow cytometry and PCR will provide a definitive diagnosis with the important differentiation between these three entities:

i) Early lesions: an acute infectious mononucleosis-like illness occurring 2-8 weeks after transplant, with no evidence of clonality on special tests; polymorphic PTLD

ii) Monomorphic PTLD: B-cell lymphomas (diffuse large cell lymphoma, Burkitt lymphoma, plasma cell myeloma, plasmacytomas) – clonal cytogenetic abnormalities and immunoglobulin gene rearrangements may be seen.

iii) Classic Hodgkin lymphoma-like PTLD

LMP1 and EBER positivity should be documented to make the diagnosis of EBV-associated PTLD.

How do I know this is what the patient has?

A lymphoproliferative disorder (usually with a B-cell immunophenotype) in a high-risk patient within the first 6 months after allogeneic HCT and accompanied by a rise in EBV viral load, is highly suggestive of PTLD. High-risk patients include those whose donors are unrelated or mismatched, or who have received T-cell-depleted grafts or intensive immunosuppression including antibodies to deplete T cells.

Differential diagnosis
  • Relapse of the patient’s underlying malignancy (especially where the patient was transplanted for the treatment of a lymphoproliferative disorder)

  • CMV reactivation post HCT (this is not accompanied by nodal or extranodal tumor formation)

  • T-cell PTLD is very uncommon and usually occurs later post HCT. This would not be expected to respond to specific anti B-cell therapy (rituximab) or anti-EBV therapy (adoptive cellular therapy).

Confirmatory tests
  • EBV viral load on peripheral blood

  • Biopsy (fresh and formalin-fixed) for histology, flow cytometry, and PCR

4. Specific Treatment

  • Standard first-line therapy for EBV reactivation with serially increasing viral load in an at-risk patient in the absence of PTLD is a single infusion of rituximab; response can usually be seen within 72 hours.

  • Standard first-line therapy for symptomatic PTLD is withdrawal of immunosuppression (if possible, limited by the presence of GVHD) and administration of rituximab. Rituximab infusions may be repeated weekly as required. Rituximab may be more efficacious in early disease.

  • In the presence of inadequate response to rituximab, and in the absence of GVHD, the patient may receive donor lymphocyte infusions (DLI) with the aim of supplying sufficient donor-derived EBV-specific cytotoxic T-cell (CTL) precursors to mediate lysis of EBV-transformed B cells. This approach may be associated with up to 70% response rate, but may be complicated by the induction of GVHD.

  • Donor (or third-party) CTLs can be grown in vitro in the presence of EBV-transformed cells; these EBV-specific CTLs can be infused into the patient and achieve a high response rate, persist for at least 9 years, and are not associated with the development of GVHD. However, this treatment is currently available only on clinical trials.

Refractory cases

In the absence of response to immune modulatory therapy (see above), chemotherapy may be trialed and may be associated with up to 70% response rates. However, this approach is usually accompanied by a high complication and mortality rate due to the patient’s prior therapy. Radiation may be used for localized difficult-to-treat disease including CNS disease.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

1. EBV viral load in those patients who respond to rituximab can usually be seen to fall by 72 hours; in contrast, in non-responders the EBV viral load continues to rise. This is a useful indictor of the requirement for additional therapy in an individual patient.

2. In patients receiving pre-emptive rituximab based on an EBV viral load >1000 genome equivalents per mL, the incidence of PTLD is reduced from 49% to 18%, and 6-month mortality is reduced from 26% to 0%.

3. After the infusion of EBV-specific CTLs for the treatment of established PTLD, up to 85% of patients achieve sustained complete responses.


1. Continued weekly EBV viral load measurements

2. If the patient was treated for symptomatic PTLD, regular clinical evaluations are performed to detect the presence of recurrent disease.

3. Imaging to exclude recurrent disease may be performed (this practical approach is not supported by evidence).


The requirements for the development of PTLD after HCT are:

  • EBV infection of B cells (95% of adults demonstrate serologic evidence of EBV infection); PTLD usually occurs in donor-derived B cells transferred with the HCT product but may rarely develop in residual patient-derived B cells.

  • Immunosuppression – loss of EBV-specific CTL precursors due to chemotherapy, therapeutic immunosuppression or T-cell depletion.


  • ome degree of EBV reactivation is common after HCT, occurring in 30% of patients post unmanipulated HCT, and up to 65% of patients receiving T-cell-depleted HCT.

  • The cumulative incidence of PTLD is 1-2% over 10 years.

  • PTLD occurs with the highest incidence in the first 3-6 months post HCT (a period of time with the lowest frequency of EBV-specific CTLs).

  • Risk factors for the development of PTLD include: in vitro T-cell depletion of donor bone marrow, unrelated donor or HLA-mismatched related donor, use of in vivo T-cell depletion (such as anti-thymocyte globulin or CD3-depleting antibodies), HCT for primary immunodeficiency; these risk factors are additive such that the risk of PTLD is 8% in patients with 2 risk factors, and up to 22% in the presence of 3 or more risk factors.

  • Chronic GVHD is a risk factor for late-onset PTLD.


PTLD not responding to immune modulation, donor lymphocyte infusion or adoptive cellular therapy is associated with a poor prognosis. While response can be achieved to chemotherapy, this treatment in itself is associated with a high mortality.

Absolute level of EBV viral load at diagnosis does NOT predict for response to therapy.

Special considerations for nursing and allied health professionals.


What's the evidence?

Heslop, HE. “How I treat EBV lymphoproliferation”. Blood. vol. 114. 2009. pp. 4002-4008.

Heslop, HE, Ng, CY, Li, C. “Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes”. Nat Med. vol. 2. 1996. pp. 551-555.

Haque, T, Wilkie, GM, Jones, MM. “Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial”. Blood. vol. 110. 2007. pp. 1123

Heslop, HE, Slobod, KS, Pule, MA. “Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients”. Blood. vol. 115. 2010. pp. 925-935. Follow-up up to 9 years after infusion of EBV-specific CTLs.

van Esser, JW, Niesters, HG, Thijsen, SF. “Molecular quantification of viral load in plasma allows for fast and accurate prediction of response to therapy of Epstein-Barr virus-associated lymphoproliferative disease after allogeneic stem cell transplantation”. Br J Haematol. vol. 113. 2001. pp. 814-821.

van Esser, JW, Niesters, HG, van der Holt. “Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation”. Blood. vol. 99. 2002. pp. 4364-4349. This group demonstrated that serial montoring and preemptive B-cell depletion can reduce PTLD and PTLD mortality.

Curtis, RE, Travis, LB, Rowlings, PA. “Risk of lymphoproliferative disorders after bone marrow transplantation: am multi-institutional study”. Blood. vol. 94. 1999. pp. 2208-2216. A retrospective survey of 18,014 patients to determine the risk of PTLD after HCT.

van Esser, JW, van der Holt, B, Meijer, E. “Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell depleted SCT”. Blood. vol. 98. 2001. pp. 972This study showed a higher incidence of EBV reactivation after T-cell-depleted HCT compared with unmanipulated HCT (reactivation was defined as >50 genome equivalents/mL).