PTLD (2): BMTU
PTLD tumours post BMT:
- skin
- oral cavity
- uterus or cervix
- thyroid
- breast
- glial tissue
Major risk factors include:
- Older patients.
- Chronic GVHD is the major risk factor for late onset PTLD.
- Pre-Tx chemoRx for autologous BMT.
- CyA to prevent GVHD.
- chronic GVHD.
- risk not increased in BMTs for non-mitotic diagnoses (e.g. aplastic anaemias).
- Soild tumours occur more frequently in those patients post BMT for HD.
Pathogenesis:
EBV is a common pathogen in most parts of the world as approximately 90 to 95 percent of adults show serologic evidence of infection. A small fraction of B lymphocytes in infected patients harbor the EBV genome throughout life.
If a bone marrow donor has been infected with EBV, he or she will have a small number of transformed B-cells carrying the virus (about one per million B-cells). These B-cells are "held in check" by cytotoxic T-cells, resulting in an equilibrium between cell division and death of EBV-infected B-cells. Methods of treating bone marrow that remove both mature B- and T-cells (such as soybean lectin depletion) have a lower rate of EBV lymphoproliferative disease after transplantation.
If, however, mature T-cells are depleted from a marrow graft (to reduce the risk of GVHD) but B-cells are left, then the transformed B-cells may "escape" from surveillance by these cytotoxic cells and proliferate at a high rate. Reactivation has been observed more frequently in recipients of a T-cell depleted allograft (TCD-SCT), and EBV-associated PTLD occurred only in those receiving a TCD-SCT. In addition, plasma EBV DNA levels have been shown quantitatively predicted EBV-PTLD.
In addition to the risk imposed by the donor, the transplant recipient is also likely to have been infected with EBV. Ablation of the recipient's immune system prior to transplantation may remove enough cytotoxic cells to tip the balance in favor of transformed B cells. Profound deficiencies of EBV-specific T cell-mediated immunity have been documented in the early posttransplant period, the period of greatest risk for PTLD.
Clinical manifestations:
Three types of EBV-related lymphoproliferative disease occur in transplant recipients.
- Benign polyclonal lymphoproliferation is an infectious mononucleosis-type acute illness which develops two to eight weeks after induction or antirejection therapy. This disorder is characterized by polyclonal B cell proliferation with normal cytogenetics and no evidence of immunoglobulin gene rearrangements to suggest malignant transformation.
- The second disorder is similar to the first in its clinical presentation, but is characterized by polyclonal B cell proliferation with evidence of early malignant transformation, such as clonal cytogenetic abnormalities and immunoglobulin gene rearrangements.
- The last disorder, accounting for about 15 percent of cases, is usually an extranodal condition presenting with localized solid tumors characterized by monoclonal B cell proliferation with malignant cytogenetic abnormalities and immunoglobulin gene rearrangements.
Treatment:
The first two polyclonal EBV-induced diseases mentioned above are generally treated with reduction of immunosuppressive medications and antiviral therapy. Patients with the third condition, which is a monoclonal lymphoma, and those with polyclonal disease that does not respond to reduced immunosuppression, require therapy. Chemotherapy and radiation therapy have been used in this situation, but mortality is common.
Immunotherapeutic approaches appear to improve the outcome. Among HCT recipients, two forms of immunotherapy have had some success in the treatment and prevention of PTLD: anti-B-cell monoclonal antibodies, and adoptive immunotherapy.
Anti-B cell antibodies: Single dose of the anti-CD20 monoclonal antibody rituximab has been shown to be effective.
Adoptive immunotherapy: With adoptive immunotherapy, EBV-specific cytotoxic T-cells can be obtained "crude" from donor blood or expanded in vitro by culturing with EBV-transformed donor cells. These cytotoxic cells are transfused into the transplant recipient in an attempt kill the dividing B cells. Remission of EBV-induced PTLD has been achieved in this manner in as many as 90 percent of patients. Histologic responses occur in 8 to 21 days and clinical remission in 14 to 30 days.
The major complication of adoptive immunotherapy is acute and chronic graft-versus-host disease (GVHD), although no GVHD was seen in one small study which used partly HLA-matched T cells from a bank containing 70 EBV-specific cells lines covering common HLA haplotypes. A similar approach has been used to treat cytomegalovirus infection following bone marrow transplantation.
Measurement of Epstein-Barr viral load: It may be possible to diagnose PTLD and monitor response to treatment by use of a polymerase chain reaction assay to detect and quantify serial changes in EBV-DNA levels in plasma or peripheral blood mononuclear cells.
- A value >1,000 EBV genomes/100 µL of plasma had a sensitivity and specificity of 1.00 for the diagnosis of PTLD in a study of randomly selected renal transplant patients. The specificity was lower when peripheral blood mononuclear cells were assayed.
- In a study of 13 patients with EBV-lymphoproliferative disease following allogeneic stem cell transplantation, all of the clinical responders showed decreased levels of EBV-DNA within 72 hours of initiation of treatment. In contrast, all of the six non-responders showed an increase in EBV-DNA at 72 hours.
Prevention:
- Cytotoxic T-cells have been used as prophylaxis in allogeneic HCT recipients considered to be at high risk for EBV-induced lymphoma.
- A second prevention approach includes periodic monitoring of plasma levels of EBV-DNA, followed by preemptive treatment for subjects showing viral reactivation:
- Rituximab therapy seems most appropriate for patients at high risk of EBV lymphoproliferative disorder and has been utilized at a number of centers with success.
A simpler approach may be to remove donor B-cells, which appear to be the source of the posttransplant EBV-associated lymphoma.
AMH.
