Posttransplant Lymphoproliferative Disease (PTLD) Guidelines

Updated: Dec 23, 2020
  • Author: Phillip M Garfin, MD, PhD; Chief Editor: Ron Shapiro, MD  more...
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Guidelines

Guidelines Summary

Guidelines for the management of PTLD have been published by the following groups:

  • National Comprehensive Cancer Network (NCCN)
  • American Society of Transplantation (AST)
  • Sixth European Conference on Infections in Leukemia (ECIL-6), a joint venture of the Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation (EBMT-IDWP), the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer (EORTC-IDG), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN)

Diagnosis

The NCCN guideline for PTLD, which is integrated into the larger B-cell lymphoma guideline, provides the following algorithm to diagnose the disorder with steps categorized as either "essential" or "useful under certain circumstances." [51]

Essential steps include the following:

  • Adequate immunophenotyping by immunohistochemistry (IHC) panel, with or without cell surface marker analysis by flow cytometry
  • Epstein-Barr virus (EBV) evaluation by EBV latent membrane protein 1 (LMP1) or Epstein–Barr encoding region in situ hybridization (EBER-ISH); EBER-ISH recommended if EBV-LMP1 is negative

Tests useful under certain circumstances include the following:

  • Additional immunophenotyping
  • Molecular analysis to detect IgH gene rearrangements
  • BCL6 gene mutation analysis— BCL6 positivity is associated with poor response to immunosuppression reduction
  • EBV evaluation by Southern blot

AST guidelines recommend the following for the diagnosis of PTLD [79]

  • Cytomegalovirus (CMV) status testing
  • Viral-load testing for EBV
  • Total body CT scan (head to pelvis) 
  • Immunophenotyping to determine lineage and therapy dependent markers (ie, CD20) 
  • Molecular genetic markers of antigen-receptor genes to assess clonality
  • Donor versus recipient origin

ECIL-6 guidelines recommend quantitative PCR of whole blood, plasma, or serum to screen for EBV DNA in allogeneic hematopoietic stem cell transplant (HSCT) recipients and to monitor EBV DNA-emia. [71] Screening should begin no later than 4 weeks after HSCT, with consideration of earlier screening in patients with several risk factors. Testing should be once weekly in high-risk EBV PCR-negative patients and perhaps more frequently in patients with rising EBV DNA levels. Screening should end at least 4 months after HSCT; longer monitoring is recommended in patients with poor T-cell reconstitution, as follows:

  • On treatment for severe acute or chronic graft versus host disease
  • After haploidentical HSCT
  • In T-cell–depleted HSCT
  • After conditioning with anti-thymocyte globulin (ATG)/alemtuzumab
  • With early EBV reactivation

ECIL-6 recommendations for PTLD diagnosis are as follows [71] :

  • Diagnosis of EBV-PTLD must be based on clinical presentation plus detection of EBV by an appropriate method in a specimen from involved tissue.
  • Noninvasive diagnostic methods include quantitative EBV DNA measurement in blood, plasma, or serum and PET-CT or CT; PET-CT is preferred over CT in extranodal disease
  • Invasive methods include biopsy of lymph nodes and/or other suspected sites
  • Definitive diagnosis requires biopsy and histological examination with EBV detection.
  • In situ hybridization for EBER transcripts or detection of viral antigens is necessary.

Treatment

According to the NCCN guidelines, treatment depends on the PTLD subtype and has varying rates of response. Reduction in immunosuppression (RI) is the initial treatment in nearly all cases. However, response is variable and patients should be closely monitored. Additional treatment options vary according to the World Health Organization (WHO) classification. [51]

Non-destructive lesions

  • For patients with a complete response (CR), re-escalation of immunosuppression should be individualized, with monitoring of EBV viral load by PCR assays and of graft organ function
  • For patients with persistent or progression, second-line treatment with rituximab

AST guidelines concur with the recommendations above, but also suggest complete or partial surgical resection, as well as local radiotherapy as adjunctive therapy along with reduced immunosuppression. [79]

Monomorphic PTLD (B-cell type)

 RI if possible, with or without one of the following:

  • Rituximab
  • Rituximab as part of a concurrent or sequential chemoimmunotherapy regimen

Polymorphic PTLD

For patients with localized disease, RI if possible plus one of the following:

  • Rituximab
  • Radiation therapy (RT) with or without rituximab
  • Surgery with or without rituximab

For patients with systemic disease, RI if possible plus one of the following:

  • Rituximab
  • Rituximab as part of a concurrent or sequential chemoimmunotherapy regimen

ECIL-6 guidelines

ECIL-6 recommendations for first-line therapy of EBV PTLD are as follows [71] :

  • Rituximab, 375 mg/m 2 once weekly
  • Always consider RI combined with rituximab
  • Adoptive immunotherapy with in vitro–generated donor or third-party EBV-specific T lymphocytes (CTLs), if available

ECIL-6 recommendations for second-line therapy of EBV PTLD are as follows [71] :

  • Cellular therapy with EBV-specific CTLs or donor lymphocyte infusion
  • Consider chemotherapy with or without rituximab, if other methods fail
  • Surgery, intravenous immunoglobulin, and antiviral agents are not recommended

For preemptive therapy, the ECIL-6 guidelines recommend significant EBV DNA-emia without clinical related clinical manifestations as an indication, although no specific EBV DNA level can be recommended as a treatment threshold. Rituximab once weekly, 1-4 doses until EBV DNA levels are negative, is recommended; if possible, rituximab should be combined with RI. Donor or third-party EBV specific cytotoxic CTLs, if available, should be considered. Antiviral drugs are not recommended. [71]