Epstein-Barr Virus (EBV) complications following HSCT: from viremia to post transplant lymphoproliferative disease (PTLD) and lymphoma Laurie A. Milner, MD Laurie A. Milner, MD Associate Professor, Pediatric Hematology / Oncology / HSCT Pediatric Hematology / Oncology / HSCT Pathology and Laboratory Medicine Medical Oncology and the Wilmot Cancer Center Medical Director, Stem Cell Processing Laboratory University of Rochester Medical Center February 12, 2009 No conflicts of interest or financial disclosures
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Epstein-Barr Virus (EBV) complications following HSCT:from viremia to post transplant lymphoproliferativep p y p p
2. Once you’ve had it…..you have it “forever”(virus becomes latent in memory B cells)( y )
B B
3. Expansion of infected B cells is controlled by CD 8+ cytotoxic T cells (CTL)by CD 8 cytotoxic T cells (CTL)
and NK/LAK cells
B TT
B TT
EBV Infection Post-HSCT
1 Viral Reactivation B B1. Viral Reactivation B B
2. T cell immunosuppressionT
TT
BT
3. Expansion of infected B cells
B B BB
BB B
BB
B
Clinical Manifestations of EBV Infection
1. Asymptomaticy p2. Fever3. Tonsillar enlargement4. Lymphadenopathy5. Hepatosplenomegaly6 Bowel obstruction6. Bowel obstruction7. Respiratory symptoms due to pulmonary
infiltration or airway compressioninfiltration or airway compression8. “B” symptoms: sweats, weight loss9. CNS symptoms10. Cytopenias due to BM involvement
Spectrum of EBV infections in the immunocompetent hostimmunocompetent host
Spectrum of EBV infections in the immunocompromised hostimmunocompromised host
Ct ti“R ti ti ” Common
Nonspecific
asymptomatic“Reactivation”
Nonspecific (fever, rash, fatigue)
Viremia
focal ordisseminatedPTLD
HLH
disseminated
l h
PTLD
Malignancies lymphomaleukemia Uncommon
Natural history of EBV infections in the immunocompromised hostimmunocompromised host
low copy number spontaneous“Reactivation” low copy number(viral genome)
spontaneousresolution
Reactivation
rapid
Viremiahigh copy number rapid
progression
PTLDHLH
high cop n mberPTLD high copy number& cellular proliferation
FatalMalignancy
Fatal (~90% MR)
Development of EBV-associated PTLD requires:
1. EBV reactivation
2. T cell suppression T
3 Presence of B cells3. Presence of B cells
B BBB B B
BB
B B B B
Factors that influence the development of PTLD
1. EBV reactivationSerologic status of donor and recipient
2 T cell suppression
g pAge: children > adults
2. T cell suppressionT cell depletion of the stem cell productT ll di t d i i f th ti tT cell directed immunosuppression of the patient- especially antibody therapy: ATG, OKT3, α-CD3
3. Presence of B cellsStem cell product - “early” PTLD (< 1 year) almostalways involves proliferation of donor B cellsCell dose
EBV infections post HSCT: therapeutic options
1 Virus
Target Agents Response
Antiviral drugs Mixed1. VirusGanciclovir
Antiviral drugs Mixed (not usually sufficient)
2. B cells Very good (if used early)
Rituximab(α-CD20 MoAb)
3. T cells
chemotherapy anecdotal responses
Discontinue3. T cells
Donor Lymphocyte Infusions (DLI)
immunosuppression Mixed(limited by GVHD)
EBV specific cytotoxic T cells (CTL)
Infusions (DLI)Very good (if available)
Monitoring HSCT patients for EBV infection/PTLD
Pre-transplant Post-transplantp p
Clinical symptoms
generally not helpful(non-specific too late)
helpful (postpone transplant)
Serologieshelpful to NOT h l f l
symptoms (non-specific, too late)(postpone transplant)
Serologies(recipient and donor)
helpful to assess risk of “reactivation”
NOT helpful
Quantitativemay be helpful in Helpful(if done correctlyPCR for viral DNAspecific cases (if done correctly& standardized)
Studies using Q-PCR to evaluate EBV viremia &PTLD have been limited by numerous factorsy
Relatively low incidence of PTLDunrecognized and unreported casesunrecognized and unreported cases
Single institution and retrospective analyses
few cases in any given study
Ch i t h l i t d t t i i
Single institution and retrospective analysesvariable treatment regimens & patient populations
Changing technologies to detect viremialack of standardization and variable sensitivityuse of different patient samples & unit basis
Evolving transplant regimens and the use of new immunosuppressive agents
use of different patient samples & unit basis
new immunosuppressive agentsespecially the increasing use of reduced intensity (RIC) and nonmyeloablative (NMA) regimens
Despite the complicating factors, Q-PCR studies have led to important insights into the incidence and risk
factors for EBV viremia & PTLD following HSCT
Th f ll i lid t bi d d t fThe following slides represent combined data from multiple studies; they are intended to illustrate
trends and consensus observationstrends and consensus observations.
Variable patient populations transplantVariable patient populations, transplant regimens, and other factors unique to each
study preclude direct comparisons in most cases.y p p
4 patients developed PTLD resistant to Rituximab and were salvaged with CTL
Preemptive therapy: unresolved issues
Untreated PTLD has a very high MR: >90%
Rituximab is highly effective if used early:
But many patients get treated unnecessarily to
Rituximab is highly effective if used early: 70-100% RR
But…many patients get treated unnecessarily to prevent PTLD in a single patient
EBV infected B cells may become CD20− and
EBV CTLs are highly effective
EBV infected B cells may become CD20 andthus resistant to rituximab
EBV-CTLs are highly effective
But…are also time consuming, expensive, & req ire a GMP facilit& require a GMP facilityCannot be derived for all patients
Bottom Line?
1. Monitor at risk patients by weekly Q-PCR
2. Pre-emptive treatment when viremia reaches threshold
Rituximab (+/- ganciclovir, IVIG)
3 Di ti i i (if ibl )3. Discontinue immunosuppression (if possible)
4 Consider DLI (Donor Lymphocyte Infusion)- or EBV specific CTL, if available
4. Consider DLI (Donor Lymphocyte Infusion)
5. Chemotherapy for evidence of clonal malignancy
Risk Factors for developing PTLD: Summary
T ll d l i f h ll dT cell depletion of the stem cell productHaploidentical HSCTHLA mismatched donors
T cell immunosuppressionATG OKT3 α-CD3
HLA mismatched donors
NMA / RIC regimens
ATG, OKT3, α CD3
EBV serologic status of donor and recipient
Grade III-IV GVHD
Primary immunodeficiency disorders
EBV serologic status of donor and recipientseropositive donor and naïve recipient
Primary immunodeficiency disorders
Age: children at higher risk than adults
References
1. Brunstein, et.al. Blood. 2006;108:2874.2. Cohen, et.al. Leukemia & Lymphoma. 2007;48:256.y p3. Comoli, et.al. Amer.J.Transplantation. 2007;7:1648.4. Juvonen, et.al. Bone Marrow Transplantation. 2003;32:97.5. Kinch, et.al. Scandinavian J.Infectious Disease. 2007;39:235. 6. Ocheni, et.al. Bone Marrow Transplantation. 2008;42:189.7 M b h t l J M d Vi l 2008 80 4417. Meerbach, et.al. J.Med.Virology. 2008;80:441.8. Van Esser, et.al. Blood. 2001; 98:972.9 Van Esser et al Blood 2002; 99:43649. Van Esser, et.al. Blood. 2002; 99:4364.10.Wagner, et.al. Blood. 2004;103:3979.11.Weinstock, et.al. Bone Marrow Transplantation. 2006;37:539., p ;