Epstein-Barr virus-associated lymphoproliferative disease following allogeneic stem cell transplantation

Transcription

1 Epstein-Barr virus-associated lymphoproliferative disease following allogeneic stem cell transplantation Dr Christopher Fox Consultant Haematologist Nottingham University Hospitals NHS Trust

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3 The Herpesvirus Evolutionary tree

4 Epstein Barr Virus Human 1-herpes virus 95% adult population latently infected Predominantly B lymphotropic Entry via CD21 & HLA class II Potent in-vitro growth transforming properties

5 Epstein Barr Virus Human 1-herpes virus 95% adult population latently infected Predominantly B lymphotropic Entry via CD21 & HLA class II Potent in-vitro growth transforming properties + EBV

6 EBV can adopt different latency states in vivo memory B cells in healthy persistence BL HL ENKTL NPC PTLD

7 EBV can adopt different latency states in vivo memory B cells in healthy persistence BL HL ENKTL NPC PTLD

8 Primary infection Epithelium Latency III Naïve B Lytic cycle 80 proteins EBNA1 EBNA2 EBNA-LP EBNA3A EBNA3B EBNA3C LMP1 LMP2 ncrnas

9 Primary infection Epithelium Latency III Naïve B Lytic cycle 80 proteins EBNA1 EBNA2 EBNA-LP EBNA3A EBNA3B EBNA3C LMP1 LMP2 ncrnas PTLD biopsy

10 EBV-infected cells in infectious mononucleosis tonsil EBER EBNA2 LMP1 From Gerald Niedobitek

11 Primary infection Epithelium Latency III Naïve B Lytic cycle Plasma cell T T T T T T T T T T Lytic Ag specific T Latent Ag specific 1 o CTL response

12 Primary infection Epithelium Latency III Latency I/II Latency 0 Naïve B GC Memory B Lytic cycle Plasma cell Persistent infection T T T T T T T T T Tm Tm T T Tm Tm Lytic Ag specific Latent Ag specific Lytic Ag specific Latent Ag specific 1 o CTL response memory CTL response

13 EBV-specific responses in IM PBMC 46.71% Tonsil 13.13% CD8 Lytic epitope response RAK lytic 2.16% 1.61% CD8 Latent epitope response QAK latent From Prof Martin Rowe

14 EBV-specific responses in healthy carriers PBMC Tonsil 1.31% 3.87% CD8 Lytic epitope response RAK lytic 1.16% 12.18% CD8 Latent epitope response FLR latent From Prof Martin Rowe

15 SCT-PTLD history Donor-derived immunoblastic sarcomas in the early months following allosct reported in the late 1970s and early 1980s 15 patients with a histological spectrum of EBV-associated lymphomas (median D+77) following myeloablative SCT reported 1988 Majority of cases arose from donor B cells Mortality rate was almost 90% Gossett TC et al NEJM 1979, Zutter MM et al Blood 1988

16 SCT-PTLD history Donor-derived immunoblastic sarcomas in the early months following allosct reported in the late 1970s and early 1980s 15 patients with a histological spectrum of EBV-associated lymphomas (median D+77) following myeloablative SCT reported 1988 Majority of cases arose from donor B cells Mortality rate was almost 90% Despite diagnostic and therapeutic advances, SCT-PTLD remains an important cause of mortality PTLD risk increases with the degree of T cell impairment ~ 1-15% Gossett TC et al NEJM 1979, Zutter MM et al Blood 1988

17 Definitions EBV-DNA-emia detection of EBV-DNA in the blood. Probable EBV disease significant lymphadenopathy (or other end-organ disease) with high EBV-DNA load in the blood. Proven EBV disease EBV detected from an organ by biopsy together with symptoms and/or signs from the affected organ Styczynski J et al. Bone Marrow Transplant 2009; 43:

18 Definitions EBV-DNA-emia detection of EBV-DNA in the blood. Probable EBV disease significant lymphadenopathy (or other end-organ disease) with high EBV-DNA load in the blood. Proven EBV disease EBV detected from an organ by biopsy together with symptoms and/or signs from the affected organ Styczynski J et al. Bone Marrow Transplant 2009; 43:

19 Incidence of EBV DNAemia following in vivo T-depleted allosct

20 Cumulative Incidence EBV >10,000 copies/ml Cumulative Incidence EBV >500 copies/ml Cumulative Incidence of EBV DNAemia following in vivo T-depleted allosct Time from Transplant (Mon Time from Transplant (Months) Campath ATG Figure 1. Incidence of EBV Reactivation by TCD Time from Transplant (Months) From David Burns

21 Cumulative In.25.5 Incidence of high-level EBV Reactivation by Risk Factors Time from Transplant (Months) AML/MDS NHL Other Time from Transplant (Months) From David Burns

22 .25 Incidence of high-level EBV Reactivation by Risk Factors Time from Transplant (Months) No Rituximab Rituximab Time from Transplant (Months) From David Burns

23 40 30 EBV qpcr Positivity Alemtuzumab ATG Kinetics of EBV Reactivation Frequency Time post transplant (weeks) >52 20 High Level EBV 15 Frequency Time post transplant (weeks) >52 30 Interval to High Level EBV Frequency Time from EBV qpcr positivity to 10 4 copies/ml (weeks) >12 From David Burns

24 40 30 EBV qpcr Positivity Alemtuzumab ATG Kinetics of EBV Reactivation Frequency Time post transplant (weeks) >52 20 High Level EBV 15 Frequency Time post transplant (weeks) >52 30 Interval to High Level EBV Frequency Time from EBV qpcr positivity to 10 4 copies/ml (weeks) >12 From David Burns

25 Definitions EBV-DNA-emia detection of EBV-DNA in the blood. Probable EBV disease significant lymphadenopathy (or other end-organ disease) with high EBV-DNA load in the blood. Proven EBV disease EBV detected from an organ by biopsy together with symptoms and/or signs from the affected organ Styczynski J et al. Bone Marrow Transplant 2009; 43:

26 PTLD following Alemtuzumab-based allosct Retrospective multicentre UK study Characteristics of disease and outcome Relationship with viral load 69 cases of PTLD 15 BMT centres, Inclusion based on published diagnostic criteria EBV reactivations without evidence of end-organ disease, irrespective of viral load, were not included Most were biopsy proven Fox et al BMT 2014

27 7 cases presented with other end-organ disease or fulminant multi-organ failure

28 The majority of cases (n=62) presented with features characteristic of aggressive lymphoma

29 EBV copy number per ml EBV DNA levels at SCT-PTLD clinical presentation PTLD patients Marked variation in magnitude of EBV DNAemia

30 EBV copy number per ml EBV copy number per ml EBV DNA levels at SCT-PTLD clinical presentation PTLD patients Transplant centre Marked variation in magnitude of EBV DNAemia Not explained simply by inter-laboratory variability

31 PTLD-free Survival (%) Overall Survival (%) 100 SCT-PTLD survival Months from PTLD onset

32 Survival (%) Absence of lymphadenopathy associated with inferior survival Month Survival Rate (95% CI) Lymphadenopathy No Lymphadenopathy 85.9% (76.5%, 96.4%) 40.3% (32.6%, 49.9%) Log-rank p< Months from PTLD onset

33 Survival (%) A modified IPI score is predictive for survival in SCT-PTLD IPI score 0-2 IPI score Month Survival Rate (95% CI) 83.3% (74.3%, 93.3%) 31.3% (25.0%, 39.0%) Log-rank p< Months from PTLD onset

34 Conclusions - PTLD following Alemtuzumab-alloSCT Raw estimate of PTLD risk ~4% Some patients have a fulminant course Markedly variable EBV DNA loads at PTLD onset 23% and 45% of cases, respectively, had < and < copies/ml. Lymphadenopathy may not be clinically apparent Up to a third of patients will fail R-monotherapy Chemotherapy ineffective at salvage Donor lymphocyte infusion can salvage Rituximab-refractory cases Fox et al BMT 2014

35 Case study 42 year old woman Flu-BEAM-Campath MUD for LPL (A mismatch) Early graft failure Reconditioned with Flu/Cy/ATG D+55 High-level EBV reactivation D+44/D+99 Initial fall in EBV qpcr with Rituximab But. severe oropharyngeal ulceration with progressive (absolute) dysphagia

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37 EBV+ Diffuse large B cell lymphoma EBER CD20

38 In vivo kinetics of adoptively transferred T cells HSCT Rituximab DLI 1x10 6 /kg PTLD patient NUHEBV0013

39 Response to Donor Lymphocyte infusion: PET-CT D-1 DLI 6 weeks 6 months

40 Donor Lymphocytes Pre-DLI From Heather Long

41 From Heather Long Donor Lymphocytes Pre-DLI 3 Weeks 1 Month 3 Months 1 Year

42 NUHEBV0013 CD4+ T cell response From Heather Long

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44 NUHEBV0013: EBV antigen expression in tumour cells A B EBER EBNA1 LMP1 BZLF1 CD20 EBNA2 LMP2 gp350

45 Equivalent efficacy of: Unselected DLI GVHD risk Donor-derived ex-vivo expanded EBV-CTLs Time constraints Third-party EBV-CTLs Availability and cost

46 Acknowledgements UHB David Burns Sridhar Chaganti Charlie Craddock Contributing UK BMT centres BSBMT Patients University of Birmingham Heather Long Gordon Ryan Paul Murray Martin Rowe Alan Rickinson Nottingham University Hospitals Nigel Russell Jenny Byrne Emma Das-Gupta Caroline Harvey Lynne Watson Simon Hughes