Post-Transplant Lymphoproliferative Disorders Arising after Allogeneic Hematopoietic Cell Transplantation: A Comprehensive Review

Review Article

Ann Hematol Oncol. 2020; 7(1): 1279.

Post-Transplant Lymphoproliferative Disorders Arising after Allogeneic Hematopoietic Cell Transplantation: A Comprehensive Review

Kamble RT1*, Brown VI2, Prockop S3, Holter Chakrabarty J4, Chhabra S5, Olsson RF6,7, Ghobadi A8, Dahi PB9, Lazaryan A10, Beitinjaneh A11, Kalra A12, Klein A13, Ustun C14, Bachier C15, Daly A16, Auletta JJ17, Cerny J18, Storek J12, Yared J19, Naik S2, Freytes CO20, Savani BN21, Williams K22, Komanduri K11, Page K23, Aljurf M24, Angel Diaz M25, Perales MA9, Hale G26, Riches M27, Hari P5 and Lazarus HM28

1Division of Hematology and Oncology, Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, USA

2Division of Pediatric Oncology/Hematology, Department of Pediatrics, Penn State Hershey Children’s Hospital and College of Medicine, USA

3Memorial Sloan Kettering Cancer Center, USA

4Department of Hematology/Oncology, University of Oklahoma, USA

5CIBMTR (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, USA

6Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolina Institute, Stockholm, USA

7Centre for Clinical Research Sormland, Uppsala University, USA

8Barnes Jewish Hospital, St. Louis, USA

9Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, USA

10H. Lee Moffitt Cancer Center and Research Institute, USA

11University of Miami, USA

12Department of Medicine, University of Calgary, Canada

13Division of Hematology/Oncology, Department of Medicine, Tufts Medical Center, USA

14Division of Hematology-Oncology and Transplantation, University of Minnesota, USA

15Sarah Cannon BMT Program, USA

16Tom Baker Cancer Center, Calgary, Canada

17Blood and Marrow Transplant Program and Host Defense Program, Divisions of Hematology/Oncology/ Bone Marrow Transplant and Infectious Diseases, Nationwide Children’s Hospital, USA

18Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical Center, Worcester, USA

19Blood & Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Greenebaum Cancer Center, University of Maryland, USA

20Texas Transplant Institute, USA

21Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, USA

22Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, USA

23Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, USA

24Department of Oncology, King Faisal Specialist Hospital Center & Research, Saudi Arabia

25Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Spain

26Department of Hematology/Oncology, Johns Hopkins All Children’s Hospital, USA

27Division of Hematology/Oncology, The University of North Carolina at Chapel Hill, USA

28Seidman Cancer Center, University Hospitals Cleveland Medical Center, Case Western Reserve University, USA

*Corresponding author: Rammurti T. Kamble, Professor of Medicine, Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, 6565 Fannin St. Suite #964, Houston, TX 77030, USA

Received: November 26, 2019; Accepted: January 02, 2020; Published: January 09, 2020


Post-Transplant Lymphoproliferative Disorder (PTLD) is a heterogeneous disorder that complicates both Solid Organ Transplantation (SOT) and Allogeneic Hematopoietic Cell Transplantation (allo-HCT). While the characterisitcs of SOT and HCT- PTLD are similar, important differences include lower incidence, early onset, rare graft involvement and donor origin for HCT-PTLD. Up to 10-20% of PTLD cases can lack tissue expression of EBV (EBV- PTLD); the response of EBV- PTLD to reduction in immunosuppression and treatment with rituximab is similar to that of EBV+ PTLD. In the allo-HCT, advanced age, T cell depletion (invivo or ex-vivo), use of unrelated and cord blood donors as the graft source, and transplant from HLA mismatched donors, are each associated with an increased incidence of PTLD. However, these risk factors cannot be easily extrapolated, as for example use of post-transplant cyclophosphamide for GvHD prophylaxis in the haploidentical allo-HCT is not associated with an increased risk of PTLD. While most PTLD arise from B cells, T or NK-cell PTLD constitute approximately 10-15% of all PTLD and are associated with extranodal involvement, aggressive course and poor survival. The revised World Health Organization (WHO) classification from 2016 categorizes PTLD into 6 subgroups, ranging from plasmacytic hyperplasia to classical Hodgkin lymphoma. Serial EBV DNAemia monitoring by PCR is effective in facilitating diagnosis but early recognition due to elevated EBV DNAemia alone has failed to significantly improve outcomes. It is essential to confirm the diagnosis and determine PTLD subtype by biopsy in order to deliver the most appropriate therapy as anti-CD20 monoclonal antibody therapy is generally effective but not for the PTLD subtypes of classical Hodgkin lymphoma PTLD. New approaches include cellular therapy with EBV-specific cytotoxic T lymphocytes.

Keywords: Epstein-Barr virus; PTLD; Allogeneic hematopoietic transplant; Solid organ transplant


Post-Transplant Lymphoproliferative Disorder (PTLD) is a heterogeneous condition with widely variable manifestations ranging from an infectious mononucleosis-like condition or a polyclonal B cell hyperplasia, to the development of a malignant lymphoma. While it is recognized that Epstein-Barr Virus (EBV) de novo infection or reactivation and chronic immunosuppression are predisposing factors, study of this disorder is complicated due to significant diversity of underlying disorders, clinical heterogeneity, and lack of prospective trials [1,2].

There is considerable overlap as reported in the literature regarding PTLD arising after SOT and that arising after allo-HCT [3-12]. In this review we focus on post HCT-PTLD to discuss pathogenesis, classification, diagnosis, risk factors, therapeutic strategies, prognosis, outcomes and future initiatives. The emphasis will be on unique aspects of PTLD as it relates to HCT, including EBV-negative PTLD, T or NK-cell PTLD, and risk factors in the contemporary era [13-40]. In absence of a clear information related to HCT-PTLD we clarify shared data from a SOT-PTLD.


PTLD represents a spectrum of lymphoproliferative states ranging from benign, reactive polyclonal hyperplasia to a fulminant malignant lymphoma. Most often, the inciting factor is reactivation of Epstein-Barr Virus (EBV) or human herpesvirus-4, a ubiquitous herpesvirus in human hosts. The pathogenesis of EBV+ PTLD is complex and is dependent on the life cycle of EBV, the EBV serostatus of the donor and recipient, and the capacity of the allo-HCT recipient to mount a protective immune response that limits viral replication. The pathogenesis of EBV- PTLD is less well understood but similarly reflects an impaired capacity of the allo-HCT recipient to appropriately recognize transformed populations of B lymphoblasts. In absence of data from allo-SCT, we herein discuss data from SOT.

EBV oncogenicity and transcription

Expression patterns of EBV latent genes are classified into 3 categories (Latency I, II, or III), and can be associated with different stages of EBV infection as well as different PTLD disorders (Table 1). For example, PTLD arising early after allo-HCT often is associated with a latency expression pattern III (EBNA-1, LMP-1,-2, and EBNA- 2, -3A, -3B, -3C, and –LP) which closely resembles that seen in acute infectious mononucleosis. In contrast, oligoclonal or monoclonal EBV-positive PTLD is associated with a more restricted EBV latency gene expression pattern (Latency I: EBNA-1, as seen in PT- Burkitt Lymphoma; Latency II: EBNA-1 and LMP-1, -2, as seen in PTDLBCL) and typically occurs later in the post-HCT course [15-17]. EBNA2 is considered a master transcriptional regulator of both EBVand cellular-derived genes. LMP-1 is the major oncogenic protein of EBV. LMP-1 mimics CD40, a costimulatory transmembrane molecule that provides a survival and proliferation signal of B cells. LMP-1 leads to B cell proliferation and differentiation via activation of NFKB, AKT, and MAPK signaling pathways as well as activating anti-apoptotic genes (e.g. BCL-2 and c-FLIP) and increasing cytokine production (e.g. IL-10 and CD40L) [18,19]. LMP-2A ensures the survival of infected B cells by activating the B Cell Receptor (BCR) via Spleen Tyrosine Kinase (SYK)-mediated survival signals [20]. Once infection of a memory B cell is complete, viral protein production is shut down in order to minimize the immunogenicity of the infected cell.