Post Transplant Lymphoproliferative Disorder

Post transplant lymphoproliferative disorder (PTLD) is a rare but serious complication that can develop after organ or stem cell transplant, when white blood cells multiply uncontrollably due to a weakened immune system.

Table of contents

• What is Post Transplant Lymphoproliferative Disorder?
• Types of PTLD
• What Causes PTLD?
• Who Is Affected by PTLD?
• Signs and Symptoms
• How Is PTLD Diagnosed?
• Treatment Approaches
• Outlook and Prognosis

PTLD, Posttransplant lymphoproliferative disorders

What is Post Transplant Lymphoproliferative Disorder?

Post transplant lymphoproliferative disorder is a life-threatening complication that can occur after organ transplantation or hematopoietic stem cell transplantation (also known as bone marrow transplant). PTLD refers to diseases that happen when white blood cells (cells that help your body fight infection) multiply uncontrollably^[1][2].

PTLD is classified as a form of lymphoma. Lymphomas are cancers of your lymphatic system (the network of vessels and tissues that help fight infection) that happen when white blood cells called lymphocytes change into rapidly growing cancer cells that don’t die. The disorders can range from mild, non-cancerous growths to aggressive cancers^[2][3].

The majority of PTLD cases are related to the Epstein-Barr virus (EBV), a very common virus that most people carry without knowing it. PTLD typically occurs within the first year after transplant, though it can develop many years later^[1][8].

Types of PTLD

There are four main types of PTLD based on how the abnormal cells appear when examined under a microscope^[2][3]:

• Early lesion PTLD: People with this type may have symptoms similar to those of Epstein-Barr virus infection. The affected cells are not strictly cancerous, but they divide excessively and can build up in lymph nodes.
• Polymorphic PTLD: This type shows a mixture of lymphoma cells along with normal cells such as lymphocytes, plasma cells, or other types of white blood cells.
• Monomorphic PTLD: This is the most common form. The lymphoma cells look similar to cells found in non-Hodgkin lymphomas such as large diffuse B-cell lymphoma or Burkitt lymphoma.
• Classic Hodgkin lymphoma – PTLD type: This is the least common form of post transplant lymphoproliferative disorder.

What Causes PTLD?

PTLD happens when a very common virus takes advantage of your weakened immune system. The main cause involves the interaction between immunosuppressive medications and the Epstein-Barr virus^[2][8].

After a transplant, you receive immunosuppressant medication (drugs that weaken your immune system) to prevent your body from attacking and rejecting your new organ or stem cells. While these medications protect your transplanted organ or cells, they also make it harder for your body to defend against viruses^[2][3].

Approximately 90% of adults worldwide carry the Epstein-Barr virus from a childhood or teenage infection. In people with normal immune systems, special white blood cells called T cells keep EBV-infected B cells under control. However, immunosuppressive therapy reduces the number and effectiveness of T cells, allowing EBV-infected B cells to multiply uncontrollably^[2][6].

The infection can occur in several ways. It may be a primary infection acquired from the donor organ or from environmental exposure, or it may be a reactivation of virus already present in the patient’s body^[1][7].

About 23% of PTLD cases are EBV-negative, meaning they develop without Epstein-Barr virus involvement. For cases that occur many years after transplant, experts are investigating whether other viruses such as cytomegalovirus (CMV) or adenovirus may play a role^[1][2].

Who Is Affected by PTLD?

PTLD is rare, but certain factors increase the risk. Overall, about 2% of people who receive donor stem cells develop PTLD. People who have organ transplants face different risks depending on the type of transplant^[2].

The incidence varies considerably by organ type. For example, approximately 3% of people who have kidney transplants develop PTLD, while 10% of people who have lung transplants develop the condition. Solid organ transplant recipients are more commonly affected compared to those who receive stem cell transplants^[1][2].

Several factors increase the risk of developing PTLD^[1][3]:

• High-dose immunosuppression, particularly during the first year after transplant
• Use of anti-T cell antibodies (such as ATG, ALG, or OKT3) in preventing or treating transplant rejection
• The type of organ transplanted, with lung, intestine, and heart transplants carrying higher risk
• EBV status of the donor and recipient
• Being EBV-negative before transplant and receiving an organ from an EBV-positive donor

Signs and Symptoms

The symptoms of PTLD are highly variable and can range from no symptoms at all to severe illness. Some people don’t have symptoms right away. When symptoms do appear, they can occur anytime from a few months after a transplant to several years later^[2][6].

Common symptoms may include^[2][6]:

• Fatigue (feeling extremely tired)
• Fever
• Lack of appetite
• Unexpected weight loss
• Night sweats
• Swollen lymph nodes (painless lumps in the neck, armpit, or groin)

PTLD symptoms can imitate those of infectious mononucleosis (caused by EBV). The clinical presentation can range from localized disease affecting one area to disseminated disease spread throughout the body, and it can mimic benign conditions. This makes early diagnosis challenging^[1][6].

Symptoms may also depend on where in the body the disease develops. If lymph nodes in the belly are affected, they may cause pain, vomiting, diarrhea, constipation, or weight loss. If lymph nodes in the neck or chest are affected, they may cause coughing, trouble breathing, and shortness of breath^[5][6].

Pain or discomfort may result from swollen lymph nodes or from the mass effect of growing tumors pressing on nearby organs. When PTLD affects the lungs or heart, it may result in shortness of breath^[6].

How Is PTLD Diagnosed?

Because PTLD can imitate other conditions, a high degree of clinical suspicion is critical for early diagnosis. If your doctor suspects PTLD, the diagnostic process typically includes several steps^[1][5].

The first step usually involves a physical examination and initial testing, which includes^[5][6]:

• Blood tests to check for Epstein-Barr virus infection
• A CT scan (computed tomography scan) to check for PTLD in the neck, chest, or belly
• If you have belly complaints, you may have an endoscopy (a procedure using a tube with a camera) or colonoscopy (examination of the large intestine) performed

Additional tests may be needed to determine the extent of the disease and to see if it has spread through the lymph system to other parts of the body^[5][6]:

• PET scan (positron emission tomography) is useful to see if PTLD has spread to your liver, bones, bone marrow, or spleen
• A bone marrow aspirate (taking out some fluid to test) and biopsy (taking out some tissue to test) if there is concern that PTLD has spread to the bone marrow
• MRI of the brain with contrast and lumbar spinal tap if neurologic symptoms suggest involvement of the nervous system

Definitive diagnosis is achieved by performing a biopsy of the involved tissue. Your doctor removes tissue from a mass or enlarged lymph node and examines it under a microscope. They look at thin slices of the tissue for the presence, type, and arrangement of pre-cancer or cancer cells characteristic of the disease. Most lesions will show malignant B cells, whereas a minority will show T cell abnormalities^[5][6].

Laboratory findings may show abnormally low white blood cell, red blood cell, and platelet counts. In addition, serum uric acid and lactate dehydrogenase levels may be elevated, while serum calcium levels may be decreased^[6].

Treatment Approaches

The management of PTLD remains challenging and generally does not follow a single standardized approach that applies to all patients. Treatment strategies consist of response-adapted, risk-stratified methods using different combinations of therapies^[1][11].

The cornerstone of treatment for EBV-driven B-cell PTLD is reduction of immunosuppression (RIS). This strategy allows the patient’s natural immunity to recover and gain control over proliferating EBV-infected cells. About 40% of patients experience complete regression after reduction or discontinuation of immunosuppressive therapy. Patients with less aggressive or early-stage PTLD tend to respond more favorably to this approach^[8][12].

For patients who have an inadequate response to reduction of immunosuppression, rituximab has become a standard of care. Rituximab is a humanized antibody that targets a protein called CD20 found on B cells. It can be given as a single treatment or in combination with chemotherapy. Reports have demonstrated response rates of approximately 50% with rituximab alone^[8][12].

However, the response to rituximab may be slower than what is observed with chemotherapy, making it less effective for patients with clinically aggressive or rapidly progressing PTLD. Additionally, relapse of PTLD is not uncommon after rituximab alone^[12].

Chemotherapy may be added for patients at higher risk or those who do not respond adequately to initial treatments. Strong medicines are given by mouth or through an IV (intravenously). These drugs target cells that are growing fast, as cancer cells do. The most commonly used chemotherapy regimen is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)^[5][12].

Studies have established that patients who enter complete remission with rituximab treatment alone, or who have fewer risk factors and enter partial remission, are at low risk and can continue with rituximab alone. In contrast, patients with more risk factors or less favorable responses may benefit from the addition of chemotherapy^[12].

With the response-adapted approach, approximately 25% of patients do not need chemotherapy. This is important because chemotherapy has significant side effects and toxicity risks^[11][12].

For refractory cases (PTLD that does not respond to standard treatments), adoptive immunotherapies have become a promising option. These treatments use the patient’s own immune cells or donor immune cells to fight the disease. PTLD is associated with EBV infection in 60% to 80% of cases, making EBV-directed therapy an attractive treatment option^[11].

Outlook and Prognosis

Healthcare providers can treat PTLD, but the condition can come back (relapse). PTLD can often be successfully treated when diagnosed early. However, outcomes for patients with high-risk disease or those who do not respond to frontline therapies remain challenging^[2][3][11].

The disorder can place an additional medical and psychological burden on transplant patients due to its rapid progression. Early diagnosis and prompt treatment are crucial for improving outcomes^[1][7].

The prognosis varies depending on several factors including the type of PTLD, how quickly it is diagnosed, the patient’s response to treatment, and the type of transplant received. The development of new treatment strategies, including novel immunotherapies, offers hope for improved outcomes in the future^[11].