Post-transplant lymphoproliferative disorder (PTLD) is a serious complication following organ or stem cell transplantation. It involves the uncontrolled growth of lymphoid cells, a type of white blood cell. PTLD can range from an overgrowth of non-cancerous cells to lymphoma, a type of cancer. This potentially life-threatening condition affects transplant recipients whose immune systems are weakened by necessary medications.
How PTLD Develops
The development of PTLD is closely tied to the immune system after a transplant. Patients receive immunosuppressive medications to prevent organ or cell rejection. These medications intentionally weaken the immune system, which normally controls abnormal cell growth and fights infections. A suppressed immune system is less effective at keeping certain viruses, such as the Epstein-Barr Virus (EBV), in check.
Many PTLD cases are linked to EBV infection. This common virus infects over 90% of adults, often without noticeable symptoms. After initial exposure, EBV typically remains dormant in B cells, held in check by a healthy immune system. However, in an immunocompromised state, EBV can reactivate or be newly acquired. This leads to the uncontrolled proliferation of EBV-infected B cells, as the weakened immune system, particularly T cells, is unable to stop their replication.
The risk of developing PTLD varies depending on the transplant type and degree of immunosuppression. Lung and heart transplant recipients generally face higher rates of PTLD compared to kidney or bone marrow recipients, due to more intense immunosuppression. Patients who have not been previously exposed to EBV (EBV-negative recipients) and receive an organ from an EBV-positive donor have a particularly elevated risk. While most PTLD cases are associated with EBV, about 20% to 30% are not, and their exact mechanisms are less understood.
Identifying PTLD
The signs and symptoms of PTLD can vary widely, making diagnosis challenging. They often depend on where the disease begins and how far it has spread. Common, non-specific symptoms may include fever, unexplained weight loss, night sweats, and fatigue. Patients may also experience pain or discomfort from enlarged lymph nodes, appearing as painless swelling in areas like the neck, armpit, or groin. If lymph nodes in the chest or abdomen are affected, they might cause coughing, breathing difficulties, abdominal pain, vomiting, diarrhea, or constipation.
To confirm a PTLD diagnosis, a tissue biopsy is usually necessary. This involves examining a small piece of suspicious tissue, such as an enlarged lymph node or a mass, under a microscope. Pathologists classify PTLD into different forms, such as polymorphic PTLD (a mix of cell types) or monomorphic PTLD (a single cell type, often resembling diffuse large B-cell lymphoma). This classification helps guide treatment decisions.
Imaging studies are commonly used to identify disease extent and locate potential biopsy sites. Computed tomography (CT) scans of the neck, chest, abdomen, and pelvis help in initial diagnosis, staging, and monitoring treatment response. Positron emission tomography (PET) scans identify metabolically active disease areas and are better at detecting bone marrow involvement. Blood tests, particularly EBV viral load monitoring, are frequently performed, especially in high-risk patients. While an elevated EBV viral load raises suspicion for EBV-positive PTLD, it is not sufficient for diagnosis alone; a tissue biopsy is still needed for confirmation.
Treatment Approaches for PTLD
Treating PTLD is a complex process requiring a tailored approach for each patient. The initial step is reducing immunosuppression. This aims to allow the patient’s immune system to regain function and fight uncontrolled lymphoid cell growth. While effective, particularly in early or polymorphic PTLD, reducing immunosuppression carries the risk of transplant rejection. Response rates to immunosuppression reduction alone are around 45%, but it can also lead to organ loss in many cases.
Beyond immunosuppression reduction, specific therapies are employed based on the PTLD subtype, EBV status, disease extent, and transplant type. Rituximab, an anti-CD20 monoclonal antibody, is a frequently used treatment, especially for EBV-positive PTLD. It works by targeting and depleting B cells, which often carry the CD20 protein on their surface and are the primary cells involved in many PTLD cases. Rituximab monotherapy has shown significant complete remission rates with manageable toxicity.
Chemotherapy regimens, often including combinations of drugs like cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), are used for patients who do not respond to rituximab or have EBV-negative tumors. Chemotherapy can be effective, with overall response rates around 74%, but it is associated with more toxicity compared to rituximab. In some cases, a sequential approach of rituximab followed by chemotherapy has shown promising results.
Radiation therapy may be considered for localized disease, offering a way to target specific areas of abnormal cell growth. This approach is useful for managing symptoms caused by large masses or for achieving local control. The decision to use radiation therapy is carefully weighed against potential side effects and the overall treatment plan.
More advanced therapies are also becoming available for resistant cases. Adoptive cell therapy, specifically using Epstein-Barr Virus-specific cytotoxic T-lymphocytes (EBV-CTLs), is a targeted approach. These immune cells are trained to recognize and eliminate EBV-infected cells. This therapy aims to restore the patient’s immune response against the virus and has shown low toxicity and high efficacy in EBV-driven PTLD. While promising, EBV-CTL therapy can be labor-intensive and may have limitations in availability and cost. Other emerging therapies are under investigation to improve outcomes for patients with PTLD.