Managing post-transplant lymphoproliferative disorder

ABSTRACT

Introduction: Post-transplant lymphoproliferative disorders (PTLD) constitute a heterogeneous group of lymphoproliferative diseases that occur in the setting of transplantation of either hematopoietic stem cells (HSCT) or solid organs (SOT), and results from the uncontrolled neoplastic proliferation of plasmacytic or lymphoid cells in the context of extrinsic immunosuppression after transplantation. PTLD in HSCT setting are largely caused by latent Epstein-Barr Virus (EBV).

Areas covered: In patients after HSCT, EBV infections can cause life-threatening multiorgan disease. This review summarizes the incidence and risk factors of EBV-PTLD in transplant patients as well as the recently developed standards for diagnostic methods and strategies with respect to the predominant risk factors in adults and children. Recommendations for preemptive and targeted treatment strategies and outcomes in different risk groups are presented. Novel therapeutic approaches in the context of allogeneic HSCT, including rituximab and EBV-specific cytotoxic T lymphocytes (EBV-CTL), are discussed.

Expert opinion: With the current diagnostic and therapeutic strategy, a positive outcome is reached in 70% of patients. Further research in the area should focus on resistant cases of PTLD, that is EBV-low expression PTLD, EBV-negative PTLD, T-PTLD, or composite B/T-PTLD. Research should also concentrate on molecular, proteomic, metabolic, or genomewide studies aiming to find new markers constituting possible new targets for personalized therapy.

KEYWORDS:

• PTLD
• EBV
• HSCT
• rituximab
• preemptive therapy

Article highlights

• Post-transplant lymphoproliferative disorders (PTLD) result from the uncontrolled neoplastic proliferation of lymphoid or plasmacytic cells in the context of extrinsic immunosuppression after transplantation. PTLD in HSCT setting are largely caused by latent Epstein-Barr virus (EBV). Risk factors for EBV-PTLD are proportional to the degree of T-cell impairment.

• The new 2016 WHO classification of lymphoid malignancies recognizes six types of morphological lesions: plasmacytic hyperplasia PTLD, infectious mononucleosis PTLD, florid follicular hyperplasia PTLD, polymorphic PTLD, monomorphic PTLD (B-cell and T-/NK-cell types), and classical Hodgkin lymphoma PTLD.

• Diagnosis of EBV-PTLD is based on invasive techniques including biopsy of the lymph node and/or other sites suspected for EBV disease. Non-invasive diagnostic methods have accessory value and include the quantitative determination of EBV-DNA-emia in blood, plasma or serum and PET-CT/CT/MRI imaging.

• The use of the four-stage classification of PTLD, adapted and modified based on the Ann Arbor and Lugano classifications for malignant lymphoma by PET-CT imaging, is proposed.

• There are three major approaches to EBV infection after HSCT: prophylaxis, preemptive treatment (also known as preemptive prophylaxis) and therapy of established EBV-PTLD. Therapeutic approaches applied in the prevention and treatment of EBV-PTLD include: administration of rituximab, reduction of immunosuppression (RIS), use of EBV-CTL (EBV-specific cytotoxic T-lymphocytes), or donor lymphocyte infusion and chemotherapy, while other methods have only a historical value nowadays.

• Pooling results from published studies in HSCT recipients reveals that administration of rituximab results in a positive outcome for over 90% of patients treated preemptively, and over 65% when it is used as targeted therapy for EBV-PTLD. RIS when applied in combination with rituximab improved the outcome over 80%. The use of EBV-CTLs gave a positive outcome for >90% of patients treated preemptively, and approximately 75% in therapy of EBV-PTLD.

• Currently available data does not allow for the determination of an unambiguous EBV-DNA-emia threshold value for the diagnosis of EBV-PTLD or other end-organ EBV disease in HSCT patients. This is due to the lack of universal standards for nucleic acid tests. Nevertheless, in order to initiate preemptive therapy, transplant centers use own threshold values of EBV-DNA-emia varying between 10³-10⁵ EBV copies/mL.

• EBV-negative B-PTLD and T-PTLD cases occurring late (>5 years off immunosuppression) in patients after HSCT should be regarded as malignant lymphomas, not PTLD. These disorders should therefore be treated using protocols for malignant lymphoma.

• Post-HSCT PTLD varies from post-SOT PTLD in terms of biological and epidemiological aspects, treatment priorities and response to therapy.

This box summarizes key points contained in the article.

Acknowledgments

I would like to thank the participants of ECIL-6 EBV-PTLD working group (Walter van der Velden, The Netherlands; Christopher P. Fox, United Kingdom; Dan Engelhard, Israel; Rafael de la Camara, Spain; Catherine Cordonnier, France; Per Ljungman, Sweden) for cooperation and fruitful discussion during preparation of ECIL-6 guidelines, published in 2016. I also thank dr Lidia Gil from Department of Hematology and Transplantation, Poznan, Poland, for critical review of this paper.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.