Arun Chawla , MDArun Chawla , MDHofstra North Hofstra North

Shore LIJ School of Shore LIJ School of MedicineMedicine

Most serious and potentially fatal complication of Most serious and potentially fatal complication of chronic immunosuppression in organ transplant chronic immunosuppression in organ transplant recipients. recipients.

In adult transplant recipients, it is the second most In adult transplant recipients, it is the second most common malignancy after skin cancer, and in common malignancy after skin cancer, and in children the most common post-transplant children the most common post-transplant malignancy (Boubenider et al, 1997)malignancy (Boubenider et al, 1997)

These tumors are mostly large-cell lymphomas These tumors are mostly large-cell lymphomas (NHL), the great majority of which are of the B-cell (NHL), the great majority of which are of the B-cell typetype

10% in solid organ transplant recipients, Complicates 10% in solid organ transplant recipients, Complicates about 1%-3% of renal transplant patients.about 1%-3% of renal transplant patients.

B cell proliferation induced by infection with B cell proliferation induced by infection with Epstein-Barr virus (EBV) in the setting of chronic Epstein-Barr virus (EBV) in the setting of chronic immunosuppression .immunosuppression .

An EBV-associated protein (LMP-1) interacts with An EBV-associated protein (LMP-1) interacts with host proteins from the TNF receptor family that host proteins from the TNF receptor family that leads to cell growth and transformation leads to cell growth and transformation

Yes! These tumors are of host origin but…donor Yes! These tumors are of host origin but…donor related PTLD is known to occur in a solid organ related PTLD is known to occur in a solid organ transplant. (how is it different?)transplant. (how is it different?)

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.

British Journal of Haematology, 149, 675–692

Benign polyclonal – (55%) - IM-type acute illness that Benign polyclonal – (55%) - IM-type acute illness that develops 2-8 weeks into immunosuppressive therapy. It develops 2-8 weeks into immunosuppressive therapy. It characterized by polyclonal B cell proliferation with characterized by polyclonal B cell proliferation with normal cytogenetics and no evidence of immunoglobulin normal cytogenetics and no evidence of immunoglobulin gene rearrangements .gene rearrangements .

The second (30%) is similar to the first in its clinical The second (30%) is similar to the first in its clinical presentation, but is characterized by polyclonal B cell presentation, but is characterized by polyclonal B cell proliferation with evidence of early malignant proliferation with evidence of early malignant transformation, such as clonal cytogenetic abnormalities transformation, such as clonal cytogenetic abnormalities & Ig gene rearrangements.& Ig gene rearrangements.

The last disorder (15%), is usually an extranodal condition The last disorder (15%), is usually an extranodal condition presenting with localized solid tumors characterized by presenting with localized solid tumors characterized by monoclonalmonoclonal B cell proliferation with malignant cytogenetic  B cell proliferation with malignant cytogenetic abnormalities and Ig gene rearrangementsabnormalities and Ig gene rearrangements

Degree of overall immunosuppression - Degree of overall immunosuppression - impairing EBV-specific T cell-mediated impairing EBV-specific T cell-mediated immunityimmunity

EBV serostatus of the recipientEBV serostatus of the recipient time post-transplanttime post-transplant recipient age & ethnicityrecipient age & ethnicity history of pretransplant malignancy history of pretransplant malignancy

fewer HLA matches - one mismatch at HLA-B fewer HLA matches - one mismatch at HLA-B was associated with a hazard ratio of 1.4 and was associated with a hazard ratio of 1.4 and two HLA-B mismatches with a hazard ratio of 5.1 two HLA-B mismatches with a hazard ratio of 5.1 for PTLD for PTLD

Mismatches at HLA-A and HLA-DR were not Mismatches at HLA-A and HLA-DR were not independently associated with an increased independently associated with an increased hazard ratiohazard ratio

HLA antigens and post renal transplant lymphoproliferative disease: HLA-B matching is critical.Bakker et al. Transplantation. 2005 Sep 15;80(5):595-9.

NonspecificNonspecific Classic lymphadenopathy – ABSENT in Classic lymphadenopathy – ABSENT in

majoritymajority Pyrexia, weight loss, night sweats Pyrexia, weight loss, night sweats

commoncommon Really depends on the organ that is Really depends on the organ that is

involved.involved.

Lymph node Biopsy Lymph node Biopsy Bone marrow biopsy - in any patient with Bone marrow biopsy - in any patient with

falling peripheral blood counts for whom falling peripheral blood counts for whom obvious causes, such as drugs, infection obvious causes, such as drugs, infection etc., have been excluded.. etc., have been excluded..

Inc LDH, pancytopenia etc.. Inc LDH, pancytopenia etc.. BIOPSY WHATEVER YOU CAN!!BIOPSY WHATEVER YOU CAN!!

Ultrasound is useful at picking up changes in solid Ultrasound is useful at picking up changes in solid organs, such as liver and kidney graftsorgans, such as liver and kidney grafts

CT scanning in PTLD can be helpful in identifying CT scanning in PTLD can be helpful in identifying areas for biopsy, staging and treatment response.areas for biopsy, staging and treatment response.

PET scan shows areas of increased metabolic activity PET scan shows areas of increased metabolic activity and has advantages over CT in that it can identify and has advantages over CT in that it can identify areas infiltrated by lymphoma that have not yet areas infiltrated by lymphoma that have not yet increased in size, and is better at detecting bone increased in size, and is better at detecting bone involvementinvolvement

??MRI….??MRI….

poor performance statuspoor performance status EBV- negative tumourEBV- negative tumour graft involvementgraft involvement monomorphic pathologymonomorphic pathology Multiorgan involvement Multiorgan involvement

Limited disease: a 25% reduction in Limited disease: a 25% reduction in immunosuppression; immunosuppression;

Extensive disease and critically ill: stop all agents Extensive disease and critically ill: stop all agents except prednisone 7.5–10 mg/d; except prednisone 7.5–10 mg/d;

Extensive disease not critically ill: decrease Extensive disease not critically ill: decrease ciclosporin/tacrolimus by 50%, discontinue ciclosporin/tacrolimus by 50%, discontinue azathioprine/mycopheno- late and maintain azathioprine/mycopheno- late and maintain prednisone 7.5–10 mg/d.prednisone 7.5–10 mg/d.

European guidelines: recommending steroid European guidelines: recommending steroid maintenance alone or reducing calcineurin inhibitors maintenance alone or reducing calcineurin inhibitors e.g, ciclosporin by 50% and stopping all other agents e.g, ciclosporin by 50% and stopping all other agents e.g. mycophenolate or azathioprine.e.g. mycophenolate or azathioprine.

Monoclonal antibody directed against Monoclonal antibody directed against CD20, an antigen expressed on the CD20, an antigen expressed on the surface of mature and immature B surface of mature and immature B lymphocytes.lymphocytes.

Case series and phase II studies of Case series and phase II studies of rituximab monotherapy following RIS rituximab monotherapy following RIS have confirmed its efficacy in inducing have confirmed its efficacy in inducing remission in 44–65% of PTLD patients remission in 44–65% of PTLD patients (Milpied et al, 2000; Blaes et al, 2005; (Milpied et al, 2000; Blaes et al, 2005; Jain et al, 2005)Jain et al, 2005)

Anthracycline-based chemotherapy in Anthracycline-based chemotherapy in combination with rituximab (R-CHOP)combination with rituximab (R-CHOP)

Overall response rates are higher & Overall response rates are higher & range from 65% to 100%.range from 65% to 100%.

But…But…

RIS + antiviral treatment has been RIS + antiviral treatment has been use with variable success specially in use with variable success specially in first two forms/stages of the disease.first two forms/stages of the disease.

Surgery and radiation treatment only Surgery and radiation treatment only if PTLD is localizedif PTLD is localized

IFN-alpha – of the 14 patients who IFN-alpha – of the 14 patients who received at least three weeks of received at least three weeks of therapy, eight had total regression of therapy, eight had total regression of their disease; therapy was continued their disease; therapy was continued for six to nine months in the for six to nine months in the responders.responders.

Ivig in combinationIvig in combination

The routine surveillance of adult The routine surveillance of adult transplant populations for EBV DNAemia transplant populations for EBV DNAemia by PCR is not recommended outside the by PCR is not recommended outside the stem cell transplant populationstem cell transplant population

The use of EBV DNA load measurement The use of EBV DNA load measurement after initiation of therapy for PTLD to after initiation of therapy for PTLD to monitor response to therapy is not monitor response to therapy is not recommended recommended

Can think about retransplant after 2 Can think about retransplant after 2 years of complete remissionyears of complete remission