Lymphomas after organ transplantation

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1 Produced Revision due Lymphomas after organ transplantation People who have undergone an organ transplant are more at risk of developing lymphoma known as post-transplant lymphoproliferative disorder (PTLD). This generally occurs as a result of the effects of immunosuppressive drugs used in the prevention of the rejection of the new organ. In this article we will: discuss how common PTLD is explore why lymphomas arise in post-transplant patients explain the treatment choices available. For the patient who has spent years waiting for the transplant that he or she hopes will transform their life for the better, the development of a lymphoma soon afterwards can seem a devastating complication. However, now that much more is known about the underlying reasons behind these lymphomas, treatment is more likely to be successful. How common is PTLD? After an organ transplant, patients with weakened immune systems can develop PTLD. This occurs when a group of white blood cells called B cells grows out of control. This disorder is seen in about 1% to10% of transplant recipients overall, but varies considerably according to the type of transplant. It is least common in donor bone marrow and stem cell transplants, where the incidence is only about 0.5%. In kidney and liver transplants the incidence is 1% to 3%, rising in heart and heart-lung transplants to between 1% and 6%. It is most common after small-bowel transplants (20%). Usually lymphoma occurs in the first year after the transplant, although it can occur later sometimes up to 5 years after the transplant has taken place. The lymphomas which develop after a transplant are usually B-cell non-hodgkin lymphomas, which tend to occur in people with impaired immune systems. 1

2 Why do lymphomas occur after transplants? Following a transplant, about 90% of lymphomas occur when the immune system is suppressed. They are related to the Epstein Barr virus (EBV), which can be reactivated (see below) or may be passed on by the donor. EBV is one of the most common viruses. It infects most people at an early age, when their immune system suppresses rather than destroys it. As a result, it may remain dormant in some of the B cells (memory B cells) of the immune system. In most people, the initial infection with EBV appears in early childhood and does not display any symptoms. When the virus occurs later in adolescence or early adulthood, it may cause the symptoms of glandular fever. Once the symptoms clear up, the virus remains in the body, but is inactive. The existence of EBV in the body is not usually a problem when a person has a normally functioning immune system. However following a transplant, the immune system does not always function properly. This is so when the person is on immunosuppressive drugs to prevent the body rejecting the transplanted donor organ or bone marrow. Immunosuppressive drugs inhibit the ability of the body s immune system to respond effectively to infections. As a result, a patient is very vulnerable to viral illnesses such as viral pneumonias, or to developing lymphoproliferative disorders or lymphoma. While immunosuppressive drugs (such as ciclosporin, azathioprine and steroids) help with the prevention of rejection, they also influence the immune system by suppressing T-cell (or cellular) immunity. T cells are important in fighting viral infections and in keeping latent viral infections such as EBV under control. Because the normal T-cell response is lacking or has been weakened, the body is unable to control the virus or viral infections. In addition, these infections can cause some of the B cells to multiply in an uncontrolled way. The multiplication of B cells on its own may not always result in lymphoma. However, when the degree of multiplication is significant, changes in the B-cell genes can occur, resulting in some cases in a malignant lymphoma. This involves normal cells being converted into cancer cells, or the failure of the immune system to destroy abnormal cells. Usually several factors are at play in the development of lymphoma. The greatest risk occurs during the first few months after a transplant, when the usage of immunosuppressive drugs is at its greatest. 2

3 Understanding the mechanisms involved in causing lymphomas is important in identifying successful treatments. The small proportion of post-transplant lymphomas which are not related to EBV infection tend to occur some months after the transplant. What are the symptoms of lymphoma developing? The symptoms of a lymphoma are general, such as fever, night sweats and feeling generally unwell. These symptoms can be confused with those relating to rejection of the transplant, which can make early identification difficult. Great care is needed in order to make an early diagnosis. Enlarged tonsils or glands, particularly in the neck, are a common symptom, but also problems in other organs such as kidneys, liver, spleen and the central nervous system (and possibly also in the transplanted organ) are quite common. As with other lymphomas, a biopsy is important for diagnosis. Investigations called staging are required, such as CT scans, bone marrow biopsy and sometimes MRI or PET scans. Please call the helpline if you would like more information on these investigations. Treatments The first important step is to reduce the immunosuppressant (anti-rejection) drugs. This has to be done carefully to try to avoid rejection of the transplant, but sometimes this is necessary in order to cure the lymphoma. In patients with early or polymorphic post-transplant lymphoproliferative disorder this may be sufficient. The use of the monoclonal antibody drug rituximab, which is now part of standard treatment of B-cell non-hodgkin lymphoma, is successful in treating PTLD. It may be effective as a single agent, especially when combined with reduced immunosuppressive drugs, and can be less toxic for patients for whom chemotherapy may be hazardous. Chemotherapy with a combination of drugs may be needed if reduction in immunosuppression and rituximab are not sufficient, or if the lymphoma is more aggressive or more widespread initially. A standard regimen might be CHOP which is short for cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine) and prednisolone. There are other similar regimens. The risks of infection with these drugs are slightly higher than in patients who have not been previously immunosuppressed. 3

4 Radiotherapy can be very useful, particularly if the disease is localised. It may play an important role in treating central nervous system disease. Surgery may also be an option for localised masses. Cellular therapy this is an option in PTLD arising after donor bone marrow or stem cell transplants. Cytotoxic T cells (a type of white blood cell that kill cells that are infected with viruses, or are otherwise damaged or dysfunctional) from the original donor can be given by infusion and can kill the EBV-infected cells, causing the lymphoma to regress. Antiviral drugs such as aciclovir or ganciclovir might prevent the progress of early PTLD, but would not offer an adequate treatment for more advanced disease. Interferon is a drug that interferes with the immune response. However, it is rarely used because of its unpleasant side effects and its tendency to increase the risk of graft rejection. How successful is treatment? The success of the treatment varies very much from person to person. Treatment is more likely to be successful in people who have early post-transplant lymphoproliferative disorder, which: is EBV-positive develops soon after the transplant is localised does not involve the transplanted organ occurs in someone who is in quite good health, generally, at the time of the diagnosis. Can chemotherapy and other immunosuppressive drugs be given together? Chemotherapy for lymphoma may be needed for someone on immunosuppressive drugs for a separate condition, such as rheumatoid arthritis. In fact, immunosuppressive drugs work in a similar way to some anti-cancer drugs, and some of them are used in cancer treatment Cyclophosphamide, for example, is commonly used in lymphoma treatment. Many patients with immune inflammatory disorders comment that their signs and 4

5 symptoms are much improved when they are given cytotoxic chemotherapy for a malignant condition. There is not much written on this subject, but it does seem sensible to reduce or stop other immunosuppressive therapies during anti-cancer chemotherapy, unless the results of this will be a major threat to health. However, any changes must be made in consultation with the clinician with expertise in the disorder for which the immunosuppressive drugs are being given. Conclusion Lymphomas are an uncommon but recognised and potentially serious complication of organ and donor bone marrow or stem cell transplantation. They are closely linked with the presence of the Epstein Barr virus, and the use of strong immunosuppressant drugs. Reduction in immunosuppression is an important part of the treatment, but often monoclonal antibodies, chemotherapy or radiotherapy will also be needed. Treatment has the best chance of success if the lymphoma is detected early. Acknowledgements We are grateful to Professor B Hancock OBE, Emeritus Professor of Oncology, Sheffield and Dr MB Birtwhistle, Sheffield, for their expert help in writing this article. We would also like to thank our buddies whose feedback continually helps in the development of our resources. References Evens AM, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol, : Khedmat, H, Taheri S. Early-onset post-transplantation lymphoproliferative disorders: analysis of international data from 5 studies. Ann Transplant, : Khedmat, H, Taheri S. Late-onset post-transplantation lymphoproliferative disorders: analysis of international data from 5 studies. Ann Transplant, :

6 About our publications: The Lymphoma Association is committed to the provision of high quality information for people with lymphoma, their families and friends. We produce our information in accordance with nationally recognised guidelines. These include the DISCERN tool for information about treatments, the NHS Toolkit for producing patient information, and the Campaign for Plain English guidelines. Our publications are written by experienced medical writers, in close collaboration with medical advisers with expertise in the appropriate field. Textbooks and professional journals are consulted to ensure that information is as up to date as possible. References are provided where they have been used. Some publications are written by professionals themselves, acting on guidance provided by the Lymphoma Association. Our publications are reviewed every two years and updated as necessary. Our publications are reviewed by a panel of volunteers with experience of lymphoma. Publications are also reviewed by members of the Lymphoma Association helpline team, who have many years collective experience of supporting those with lymphoma. In some instances, our publications are funded by educational grants from pharmaceutical companies. These sponsors do not have any involvement in the content of a publication. They are not invited to see the content and have no editorial input. Lymphoma Association Views expressed in this publication are those of the contributors. The Lymphoma Association does not necessarily agree with or endorse the comments included here. 6

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