Post Transplant Lymphoproliferative Disorder


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A short presentation of PTLD in solid organ transplants for the Internist and general Nephrologists

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Post Transplant Lymphoproliferative Disorder

  1. 1. Arun Chawla , MD Hofstra North Shore LIJ School of Medicine
  2. 2. <ul><li>Most serious and potentially fatal complication of chronic immunosuppression in organ transplant recipients. </li></ul><ul><li>In adult transplant recipients, it is the second most common malignancy after skin cancer, and in children the most common post-transplant malignancy (Boubenider et al, 1997) </li></ul><ul><li>These tumors are mostly large-cell lymphomas (NHL), the great majority of which are of the B-cell type </li></ul><ul><li>10% in solid organ transplant recipients, Complicates about 1%-3% of renal transplant patients. </li></ul>
  3. 4. <ul><li>B cell proliferation induced by infection with Epstein-Barr virus (EBV) in the setting of chronic immunosuppression . </li></ul><ul><li>An EBV-associated protein (LMP-1) interacts with host proteins from the TNF receptor family that leads to cell growth and transformation </li></ul><ul><li>Yes! These tumors are of host origin but…donor related PTLD is known to occur in a solid organ transplant. (how is it different?) </li></ul>EBV and a cellular signaling pathway in lymphomas from immunosuppressed patients. Liebowitz . NEJM 1998 May 14;338(20):1413-21. Influence of host-recipient origin on clinical aspects of PTLD in kidney transplantation. Petit et al Transplantation 2002 Jan 27;73(2):265-71.
  4. 5. British Journal of Haematology, 149, 675–692
  5. 6. <ul><li>Benign polyclonal – (55%) - IM-type acute illness that develops 2-8 weeks into immunosuppressive therapy. It characterized by polyclonal B cell proliferation with normal cytogenetics and no evidence of immunoglobulin gene rearrangements . </li></ul><ul><li>The second (30%) 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 & Ig gene rearrangements. </li></ul><ul><li>The last disorder (15%), is usually an extranodal condition presenting with localized solid tumors characterized by monoclonal  B cell proliferation with malignant cytogenetic abnormalities and Ig gene rearrangements </li></ul>
  6. 7. <ul><li>Degree of overall immunosuppression - impairing EBV-specific T cell-mediated immunity </li></ul><ul><li>EBV serostatus of the recipient </li></ul><ul><li>time post-transplant </li></ul><ul><li>recipient age & ethnicity </li></ul><ul><li>history of pretransplant malignancy </li></ul>
  7. 8. <ul><li>fewer HLA matches - one mismatch at HLA-B was associated with a hazard ratio of 1.4 and two HLA-B mismatches with a hazard ratio of 5.1 for PTLD </li></ul><ul><li>Mismatches at HLA-A and HLA-DR were not independently associated with an increased hazard ratio </li></ul>HLA antigens and post renal transplant lymphoproliferative disease: HLA-B matching is critical.Bakker et al. Transplantation. 2005 Sep 15;80(5):595-9.
  8. 10. <ul><li>Nonspecific </li></ul><ul><li>Classic lymphadenopathy – ABSENT in majority </li></ul><ul><li>Pyrexia, weight loss, night sweats common </li></ul><ul><li>Really depends on the organ that is involved. </li></ul>
  9. 11. <ul><li>Lymph node Biopsy </li></ul><ul><li>Bone marrow biopsy - in any patient with falling peripheral blood counts for whom obvious causes, such as drugs, infection etc., have been excluded.. </li></ul><ul><li>Inc LDH, pancytopenia etc.. </li></ul><ul><li>BIOPSY WHATEVER YOU CAN!! </li></ul>
  10. 12. <ul><li>Ultrasound is useful at picking up changes in solid organs, such as liver and kidney grafts </li></ul><ul><li>CT scanning in PTLD can be helpful in identifying areas for biopsy, staging and treatment response. </li></ul><ul><li>PET scan shows areas of increased metabolic activity and has advantages over CT in that it can identify areas infiltrated by lymphoma that have not yet increased in size, and is better at detecting bone involvement </li></ul><ul><li>??MRI…. </li></ul>
  11. 13. <ul><li>poor performance status </li></ul><ul><li>EBV- negative tumour </li></ul><ul><li>graft involvement </li></ul><ul><li>monomorphic pathology </li></ul><ul><li>Multiorgan involvement </li></ul>
  12. 14. <ul><li>Limited disease: a 25% reduction in immunosuppression; </li></ul><ul><li>Extensive disease and critically ill: stop all agents except prednisone 7.5–10 mg/d; </li></ul><ul><li>Extensive disease not critically ill: decrease ciclosporin/tacrolimus by 50%, discontinue azathioprine/mycopheno- late and maintain prednisone 7.5–10 mg/d. </li></ul><ul><li>European guidelines: recommending steroid maintenance alone or reducing calcineurin inhibitors e.g, ciclosporin by 50% and stopping all other agents e.g. mycophenolate or azathioprine. </li></ul>
  13. 15. <ul><li>Monoclonal antibody directed against CD20, an antigen expressed on the surface of mature and immature B lymphocytes. </li></ul><ul><li>Case series and phase II studies of rituximab monotherapy following RIS have confirmed its efficacy in inducing remission in 44–65% of PTLD patients (Milpied et al, 2000; Blaes et al, 2005; Jain et al, 2005) </li></ul>
  14. 16. <ul><li>Anthracycline-based chemotherapy in combination with rituximab (R-CHOP) </li></ul><ul><li>Overall response rates are higher & range from 65% to 100%. </li></ul><ul><li>But… </li></ul>
  15. 17. <ul><li>RIS + antiviral treatment has been use with variable success specially in first two forms/stages of the disease. </li></ul><ul><li>Surgery and radiation treatment only if PTLD is localized </li></ul><ul><li>IFN-alpha – of the 14 patients who received at least three weeks of therapy, eight had total regression of their disease; therapy was continued for six to nine months in the responders. </li></ul><ul><li>Ivig in combination </li></ul>
  16. 18. <ul><li>The routine surveillance of adult transplant populations for EBV DNAemia by PCR is not recommended outside the stem cell transplant population </li></ul><ul><li>The use of EBV DNA load measurement after initiation of therapy for PTLD to monitor response to therapy is not recommended </li></ul><ul><li>Can think about retransplant after 2 years of complete remission </li></ul>