EBV Related Lymphoproliferative Disorders Post Allogeneic Bone Marrow Transplantation for Haematological Malignancies

Background: Post transplant lymphoproliferative disorder (PTLD) is a heterogeneous complication of HSCT. It comprises a spectrum of pathogenetic mechanisms and clinical manifestations. It is mostly associated with EBV infection, either as a consequence of reactivation in the post transplant period or less frequently from primary infection. WHO classification defines four major histopathologic subtypes: 1. early plasmacytic hyperplasia and infectious mononucleosis (IM)-like 2. polymorphic lesions which may be polyclonal or focally monoclonal (P-PTLD) 3. monomorphic lesions that fulfill criteria for aggressive B- or T/NL-cell neoplasm (M-PTLD) 4. classic Hodgkin-type Lymphomas (CHL-PTLD). Indistinguishable categories, such as Hodgkin-like P-or M-PTLD might represent laborious diagnostic dilemmas. In literature, PTLD occurs in less than 1% of non T-cell-depleted grafts from matched siblings compared with as high as 25% in unrelated donor (VUD) recipients. There are several risk factors such as the type of conditioning and the use of ATG, the degree of immunosuppression and complications such as concurrent infections and GvHD.

Objectives: To present our experience regarding the frequency, presentation and outcome of EBV related PTLD in a paediatric population of allo-HSCT recipients with haematological malignancies, to assess the risk factors and inquire into the heterogeneity in clinical presentation and outcome.

Patients-Methods: From January 2004 until December 2014, 177 allo-HSCTs for myeloid and lymphoid malignancies were performed in patients aged 3 months to 19 years. PTLD was recorded in 15 (8 male) with median age of 13.24 yrs (range 5.0-17.9yrs). 11 patients had VUD, 4 patients had an haploidentical related donor and the grafts depleted of T-cells. 12 patients had peripheral blood and 3 had bone marrow as the source of HSCs. 4 were given a fully matched graft, 6 had 1 HLA antigen or allele mismatched donors, 1 patient had a 2 HLA antigen mismatched donor and 4 had 5/10 HLA matched haploidentical donors. All except for 2 patients were EBV IgG positive and the two seronegative patients had an EBV IgG positive donor. The conditioning regimens used were Busulfan or Treosulfan based in 11 patients with the addition of a combination of Cyclophosphamide, Fludarabine, Melphalan, VP16 and ATG. The latter was administered to all patients. GvHD prophylaxis consisted of Cyclosporin A and Methotrexate. Five patients (1 male) are alive and well with a median follow up of 43.1 months (range 8.3-69.2).

Results: Neutrophil and platelet engraftment occurred at a median of 20 (range 14-24) and 21 days (range 14-48) respectively. Acute GvHD (stage II-IV) was recorded in 9 patients. Serial quantitative EBV-DNA/ml was employed routinely and the median day of confirmation of a rising level above 1.0x10³/ml was day +58 post transplant. Median EBV copies at diagnosis were 2.3x10⁴/ml(range 1.3x10³/ml-2.15x10⁵/ml). EBV positivity was immediately recorded post DLI in 3 patients and reactivation occurred post subsequent DLI. Immune reconstitution had not been achieved in any patient at the time of diagnosis. Median WBC count was 4.1x10⁹/lt (1.04X10⁹/lt - 8.78x10⁹/lt) and all patients had absolute lymphopenia. 9 patients had documented other viral and/or bacterial infections. 2 patients developed M-PTLD, consistent unequivocally with DLBCL, 7 patients had P-PTLD and 6 patients had IM-like PTLD with plasmacytic hyperplasia only. All had anti-CD20, two patients had additional chemotherapy. Although responsive to EBV treatment, 3 died of primary disease recurrence while PTLD failed to regress in 7 patients who died of a multitude of complications. With a median follow up of 43,1 months (range 8.3-69.2), 5 patients (1 male) are alive and well.

Conclusions: Nearly all HSCT recipients are EBV infected or will be infected eventually, yet only a fraction develop EBV driven PTLD. In our population the incidence was found to be 8.47%. PTLD exhibits a spectrum of features ranging from non specific and reactive to life threatening, indistinguishable from lymphoma. Administration of ATG, the type and extend of HLA mismatch, multiple sites of disease, immune suppression and concurrent infections heighten the risk of systemic manifestation. Rising EBV loads are strongly associated with impending PTLD, which can occur even with an overall modest viral load, thus requiring prompt recognition and early intervention.