Incidence And Risk Factors

The incidence of PTLD varies depending on the type of transplant, recipient age, and type of immunosuppres-sion used (Tables 62.1 and 62.2). The incidence of PTLD is 4 times higher in pediatric than in adult transplant recipients.16 In SOT recipients, the incidence of PTLD varies with the type of allograft: 19% of intestinal transplants, 2-10% of heart transplants, 5-9% of heart-lung transplants, 2-8% of liver transplants, and 1-10% of renal transplants.16 Additional risk factors for PTLD in SOT patients include high levels of immunosuppression (particularly with antithymocyte globulin), EBV seronegative recipient of a seropositive donor, development of primary EBV infection after transplant, and presence of cytomegalovirus (CMV) disease. For example, PTLDs are the most common tumors in children after organ transplant and represent over 50% of all posttransplant tumors; this is in contrast to adults where such tumors comprise only

Table 62.2 Relative risk of PTLD in HSCT by method of T-cell depletion19

Method of T-cell depletion (TCD) Relative risk

No TCD 1

CAMPATH-1 monoclonal antibody 2

Elutriation/density gradient 2.6 centrifugation

Lectins 4.1

Anti-T-cell monoclonal antibody 12.3

Sheep red blood cell rosetting 15.6

15% of posttransplant malignancies.17 In addition, children undergoing small intestine transplants may have an EBV-PTLD incidence as high as 32%.18

For patients undergoing HSCT, several risk factors have been identified to predict for the risk of PTLD in different settings. Curtis et al. evaluated over 18,000 patients who underwent allogeneic HSCT at 235 centers worldwide. The cumulative incidence of PTLD was 1% at 10 years. The incidence was found to vary markedly with time after transplant, with high rates occurring during the first 5 months, followed by a steep decline in incidence between 6 and 12 months post-transplant.19 The high incidence of PTLD during the first 5 months after transplant is consistent with studies that show the temporal pattern of immune reconstitution in HSCT recipients. For example, Lucas et al. noted that levels of anti-EBV CTL precursors appear to return to normal by 6 months posttransplant in most patients.20 In their multivariate analysis, Curtis et al. found that the risk of early (<1 year posttransplant) PTLD was strongly associated with unrelated or >2 human leukocyte antigen (HLA)-mismatched related donors, T-cell depletion methods that selectively target T cells or T + NK cells or E-rosetting, use of antithymo-cyte globulin for prophylaxis or treatment of acute graft-versus-host disease (GVHD), and use of the anti-CD3 monoclonal antibody 64.1 (given for therapy of acute GVHD). The cumulative incidence of PTLD for patients with 0, 1, 2, or 3-4 major risk factors were 0.5, 1.7, 8, and 22.3%, respectively. They also noted a weaker association with the occurrence of acute GVHD grades II-IV and with conditioning regimens that included total body irradiation (TBI). The risk appeared to vary by dose of fractionated TBI, with a 3.5- to

Table 62.1 Risk factors for PTLD

Solid organ transplant

Hematopoietic SCT

Allograft type (e.g., intestinal)

Type of transplant

High levels of immunosuppression (e.g., Antithymocyte globulin)

High levels of immunosuppression (e.g., Antithymocyte globulin)

EBV seronegative recipient of seropositive donor

Donor type: unrelated of >2 HLA-mismatched related donor

Presence of CMV disease

T-cell depletion

EBV, Epstein-Barr virus; HLA, human leukocyte antigen; CMV,

EBV, Epstein-Barr virus; HLA, human leukocyte antigen; CMV,

4.3-fold increased risk seen for doses >13 Gy. The only risk factors identified for late-onset (>1-year posttransplant) PTLD were extensive chronic GVHD and TBI dose.19 There is a suggestion that conditioning regimens containing fludarabine also may be associated with an increased risk of PTLD.21

Significant differences were detected among T-cell depletion techniques used. As noted above, a high risk of PTLD was observed among recipients of grafts that were T-cell depleted using monoclonal antibodies or sheep red blood cell E-rosetting techniques that selectively targeted T (or T + NK) cells. However, lower rates of PTLD were associated with methods that removed both T and B cells, such as CAMPATH-1 monoclonal antibodies, elu-triation, and lectins.19 This was also confirmed in a study by Hale and Waldmann in which 2401 recipients received grafts that were T-cell-depleted with CAMPATH-1M or 1G; the cumulative risk of PTLD was only 1.1%. They hypothesized that the depletion of B cells may reduce the viral load or virus target tissue in the interval before full recovery of T-cell function.22 Patients receiving CD34 selected allografts do not appear to be at an increase risk of PTLD as the B-lymphocyte contamination of the isolated CD34+ cells is low.23

Rare cases of PTLD have been reported in recipients of autologous HSCTs.15 24 Powell et al.25 reported an unexpectedly high incidence of EBV-PTLD in patients undergoing CD34+ selected autologous peripheral blood stem cell transplant for neuroblastoma: 5 of 156 patients (3.5%). This is in contrast to a report by Gross et al. who reported no cases of EBV-PTLD in their review of 853 autologous stem cell transplants.4

Finally, EBV-negative PTLDs appear to be morphologically and clinically distinct from EBV-positive PTLDs in that they tend to have a later onset, a higher prevalence of monomorphic lymphomas, and a greater proportion derived from T cells.1926-28 Although EBV-negative PTLDs have distinct features and are felt to be associated with a poor prognosis, some do respond to decreased immunosuppression, similar to EBV-positive cases.27'28

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