Sections

Posttransplant Lymphoproliferative Disease (PTLD)

Sections Posttransplant Lymphoproliferative Disease (PTLD)
Overview
Presentation
DDx
Workup
Treatment
Guidelines
Medication
Questions & Answers
Media Gallery
References

Medication

Medication Summary

Immunosuppressive agents are often an important part of graft maintenance and posttransplant care. Nevertheless, when faced with posttransplant lymphoproliferative disease (PTLD), it is important to reduce or modify the immunosuppressive regimen if at all possible. Because of the complexity and variety of immunosuppressive regimens, there are no standard approaches to achieve this reduction in immunosuppression. It is left to the combined judgement of the transplanting and PTLD-treating physicians. Any reduction in immunosuppression warrants close monitoring for the possibility of allograft dysfunction or rejection.

In addition to immunosuppression, a variety of additional therapeutic measures have been used, each with varying degrees of success. These include antiviral, immunomodulator, and chemotherapy agents.

Class Summary

These agents inhibit key factors that mediate immune reactions, which, in turn. decrease inflammatory responses.

Cyclosporine (Sandimmune, Neoral)

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Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs.

For children and adults, base dosing on ideal body weight.

Tacrolimus (Prograf)

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Tacrolimus suppresses humoral immunity (T-lymphocyte) activity.

Mycophenolate (CellCept)

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Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. It inhibits antibody production.

Prednisone (Deltasone, Orasone, Meticorten, Sterapred)

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Prednisone is used as an immunosuppressive, anti-inflammatory agent and as a component of both CHOP and ProMACE-CytaBOM chemotherapeutic regimens, which have been used to treat PTLD.

It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. It stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Class Summary

These are nucleoside analogs phosphorylated by viral thymidine kinase to form a nucleoside triphosphate. These nucleoside triphosphates inhibit herpes simplex virus (HSV) polymerase with 30-50 times more than they inhibit human alpha-DNA polymerase.

Acyclovir (Zovirax)

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Acyclovir inhibits activity of both HSV-1 and HSV-2. It has affinity for viral thymidine kinase and, once phosphorylated, causes DNA chain termination when acted on by DNA polymerase.

It is routinely used to treat infections with HSV, mainly HSV-1 and HSV-2. EBV also is a herpes virus, but its use as prophylaxis against and treatment for EBV-related illness posttransplantation is controversial. If used for these purposes, doses and duration of treatment are variable and are determined by the clinician.

Ganciclovir (Cytovene)

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Ganciclovir is a synthetic guanine derivative active against CMV. It is an acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo.

Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly due to preferential phosphorylation of ganciclovir in virus-infected cells.

For patients who experience progression of CMV retinitis while receiving a maintenance treatment with either dosage form of ganciclovir, the re-induction regimen should be administered.

Class Summary

Rituximab (anti-CD20 monoclonal antibody) has successfully treated PTLD. Other monoclonal antibodies, such as anti-CD21, CD24, and immunomodulatory agents such as interferon alfa have also been used in the treatment of PTLD.

Rituximab (Rituxan)

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Rituximab is an antibody genetically engineered. It is a chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences.

Immune globulin intravenous (Gamimune, Gammagard S/D, Sandoglobulin)

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Immune globulin intravenous neutralizes circulating myelin antibodies through anti-idiotypic antibodies. It down-regulates proinflammatory cytokines, including INF-gamma. It blocks Fc receptors on macrophages. It suppresses inducer T and B cells and augments suppressor T cells. It blocks the complement cascade, promotes remyelination, and may increase CSF IgG (10%).

Interferon alfa-2b (Intron A)

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Interferon alfa-2b is a protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not understood clearly; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Doses and duration of treatment are as determined by the involved clinicians.

Class Summary

These agents disrupt DNA replication or cell division, inhibiting cell growth and proliferation. Prednisone (listed above) also can be included in this category.

Cyclophosphamide (Cytoxan, Neosar)

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Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. It is a component of CHOP and ProMACE-CytaBOM chemotherapeutic regimens.

Doxorubicin (Adriamycin, Rubex)

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Doxorubicin inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events can, in turn, inhibit the growth of neoplastic cells. It is a component of the CHOP and ProMACE-CytaBOM chemotherapeutic regimens.

Vincristine (Oncovin, Vincasar PFS)

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Vincristine's mechanism of action is uncertain. It may involve a decrease in reticuloendothelial cell function or an increase in platelet production. However, neither of these mechanisms would fully explain the effect in thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. It is a component of the CHOP and ProMACE-CytaBOM chemotherapeutic regimens.

Etoposide (Toposar, VePesid)

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Etoposide inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of the cell cycle. It is a component of the ProMACE-CytaBOM regimen.

Bleomycin (Blenoxane)

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Bleomycin is a glycopeptide antibiotic that inhibits DNA synthesis. It is used as a palliative measure in the management of several neoplasms. It is a component of the ProMACE-CytaBOM regimen.

Methotrexate (Folex PFS, Rheumatrex)

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Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. Satisfactory response is observed 3-6 weeks following administration. Adjust the dose gradually to attain a satisfactory response. It is a component of the ProMACE-CytaBOM regimen.

Fludarabine (Fludara, Oforta)

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Fludarabine is a purine analog can be given PO or IV. It interferes with ribonucleotide reductase and DNA polymerase. It is active against both resting and dividing cells.

Questions

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Media Gallery

Biopsy of gingival tissue (400 X) with hematoxylin and eosin stain demonstrates polymorphous infiltrate of atypical lymphoid cells, which is consistent with posttransplant lymphoproliferative disease (PTLD).
Biopsy of gingival tissue (400 X). Epstein-Barr virus encoded RNA (EBER) study shows numerous positive cells, which is consistent with posttransplant lymphoproliferative disease (PTLD).

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Author

Phillip M Garfin, MD, PhD Senior Medical Director, Department of Oncology, Zymeworks Biopharmaceuticals, Inc

Phillip M Garfin, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society for Cell Biology, American Society for Transplantation and Cellular Therapy, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Society for Immunotherapy of Cancer

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Zymeworks inc, Seagen inc.

Coauthor(s)

Clare J Twist, MD Associate Professor of Pediatrics, Division of Hematology/Oncology, Medical Center Line, Stanford University School of Medicine; Medical Staff, Lucile Packard Children’s Hospital and Stanford University Medical Center

Clare J Twist, MD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Ron Shapiro, MD Professor of Surgery, Surgical Director, Kidney/Pancreas Transplant Program, The Recanati/Miller Transplantation Institute at Mount Sinai Hospital

Ron Shapiro, MD is a member of the following medical societies: American College of Surgeons, American Society of Transplant Surgeons, American Society of Transplantation, American Surgical Association, Association for Academic Surgery, Central Surgical Association, International Pancreas and Islet Transplant Association, International Pediatric Transplant Association, Society of University Surgeons, Transplantation Society

Disclosure: Nothing to disclose.

Acknowledgements

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Mary Prendergast, MD Department of Internal Medicine, University of Nebraska Medical Center

Mary Prendergast, MD is a member of the following medical societies: Royal College of Physicians

Disclosure: Nothing to disclose.

Vinay Ranga, MD Assistant Professor, Department of Internal Medicine, Division of Nephrology, Hartford Hospital

Disclosure: Nothing to disclose.