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Patient Management and Treatment Outcomes

Management of EBV+ PTLD and considerations for patient care

A core multidisciplinary team (MDT) should create a management plan for patient care1

mdt2

Consider the patient's

  • General health​
  • Degree of immunosuppression​
  • Histological subtype​
  • Stage of lymphoproliferative disorder​
  • Available therapy modalities​
EBV+ PTLD treatement algorithm following allogenic HCT or SOT1-10

Reduction in immunosuppression

1L therapy

Maintained throughout treatment in some patients​

Often in combination with rituximab​

Rituximab ± chemotherapy​

For patients with no response or disease progression

T-cell immunotherapy

For patients with R/R EBV+ PTLD or those for whom chemotherapy is inappropriate

SOT Key treatment outcomes

RIS

Key treatment outcomes: RIS

In a prospective, multicentre, Phase 2 study of 16 eligible adult SOT recipients with PTLD, RIS resulted in 1 out of 16 PRs (6%) and no CRs, supporting the addition of rituximab to RIS as initial therapy11

Patient characteristics11

Median patient age was 47 years; 75% of patients had late PTLD, and
nearly 70% of patients had advanced stage of disease and/or elevated LDH

 

Management of immunosuppressives

Length of time  

Response,
n (%)

Toxicity
n/N (%)

Group 1:  Clinically urgent disease
(level 1; n=3)

CsA/tacrolimus: reduced to 25% 
AZA/MTX/CTX: stopped
Steroids: reduced to 7.5 mg/day

Immunosuppressives were maintained at this level for a maximum of 10 days
 

CR: 0 (0%)
PR: 1 (6%)

Rejections: 6/16 (38%)

Group 2:  Clinically not urgent 
(level 2; n=13)
 

CsA/tacrolimus: reduced to 50%
AZA/MTX/CTX: stopped
Steroids: reduced by 50% (lower limit 7.5 mg/day)

Immunosuppressives were maintained at this level for a maximum of 14 days
 

Rituximab monotherapy

Key treatment outcomes: Rituximab monotherapy Overview

Prospective, multicentre, Phase 2 trials have investigated the efficacy and safety of rituximab in adults   with PTLD after SOT who did not respond to prior RIS, demonstrating that treatment with rituximab was both effective and well-tolerated12–14

 

N

Response,  
n (%)

Infections  
(WHO grade III/IV)

Rituximab-
related mortality

Median OS
(months)15

Oertel, et al. (2005)12

17

CR: 9 (53%)  
PR: 1 (6%)

None

None

37.0

Choquet, et al. (2006)13

43

CR: 12 (28%)*

PR: 7 (16%)

None

None

14.9

González Barca, et al. (2007)14,†

38

CR: 23 (61%)  
PR: 7 (18%)

None

None

42.0

*Day 80 response: nine patients with CR; three patients with complete unconfirmed response. 
†In case of partial remission, four additional doses of rituximab were administered.

Chemotherapy +/- rituximab

Key treatment outcomes: Chemotherapy overview

Retrospective studies have evaluated the clinical outcomes of CHOP-based chemotherapy in adults with PTLD  after SOT, revealing high rates of toxicity16–20

Group

Chemotherapy regimen (n)

CR, % (n/n)

Treatment-related mortality, 
% (n/n)

Mamzer-Bruneel, et al. (2000)16

CHOP (8), CHOP+RT (2)

60 (6/10)

60 (6/10*)

Norin, et al. (2004)17

CHOP (6), CHOP + MTX (2)  
VACOP-B + R-CHOP (1), 
CHOP + other (3)†

50 (6/12)

17 (2/12)

Elstrom, et al. (2006)18

CHOP (10), R-CHOP (9),  
other(4)‡

57 (13/23)

26 (6/23)

Fohrer, et al. (2006)19

ACVBP (32),
R-ACVBP (1)

67 (22/33)

9 (3/33)

Choquet, et al. (2007)20

CHOP (26)

50 (13/26)

31 (8/26)

*All deaths regardless of causality; †CHOP + dexamethasone, ifosfamide, MTX, cytarabine, etoposide, intrathecal methotrexate, cytarabine, prednisolone; 2 patients received chemotherapy other than CHOP; ‡CEP: CTX, etoposide, prednisone; ESHAP: etoposide, methylprednisolone, cytarabine, cisplatin; ProMACECytaBOM: mechlorethamine, doxorubicin, cyclophosphamide, etoposide, vincristine, prednisone, procarbazine, methotrexate, cytarabine, bleomycin; R/C: rituximab, cyclophosphamide.

Sequential treatment (rituximab followed by chemotherapy)

Key treatment outcomes: PTLD-1 ST study – ST with rituximab then CHOP

In a prospective, open-label, Phase 2 multicentre study of patients with CD20+ PTLD who failed to respond to initial RIS, 90% of patients (53/59) treated with rituximab (once weekly for 4 weeks) followed by CHOP (four 21-day cycles) achieved a CR or PR response with completion of ST15

Treatment-related mortality was lower than previously reported by retrospective studies for 1L CHOP in PTLD15

Key treatment outcomes PTLD-1 ST study – ST with rituximab then CHOP52

CHOP-associated treatment-related mortality:

10.6%
(7/66)

5 out of 7 CHOP-related deaths (71%) occured in non-responders to rituximab

Key treatment outcomes: PTLD-1 ST study

Median OS data supported that 1L ST was efficacious15

Key treatment outcomes pTLD-1 ST study
  • ITT (N=70)
    Median OS: 6.6 years

    OS at 3 years: 61%

    OS at 5 years: 55%
  • Analysis per protocol (N=63)

    Median OS: not reached

    OS at 3 years: 65%

    OS at 5 years: 57%

Used with permission of Elsevier Ltd., from Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Trappe R., Oertel S.,  Leblond V., et al., Lancet Oncol. Vol. 34, 196–206 (2012); permission conveyed through Copyright Clearance Center, Inc.  
 

 

Median TTP was 77.4 months (95% CI: 10.8–148.8): 69% (95% CI: 57–80%) of patients were progression-free at 3 years and 66% of patients (95% CI: 54–78) at 5 years15

Key treatment outcomes PTLD-1 ST study 256
  • The median TTP of patients treated according to the protocol (N=63) was not yet reached (>86.9 months) at the study cutoff dcate
    without PD at 3 years: 70%
    without PD at 5 years: 66%
  • Of the 40 patients who achieved CR, 8 patients (20%) relapsed

Used with permission of Elsevier Ltd., from Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Trappe R., Oertel S.,  Leblond V., et al., Lancet Oncol. Vol. 34, 196–206 (2012); permission conveyed through Copyright Clearance Center, Inc.  


 

Key treatment outcomes: PTLD-1 RSST study  

The subsequent prospective Phase 2 PTLD-1 RSST trial tested a response-adapted treatment strategy based on patient response to rituximab monotherapy induction and established that rituximab consolidation for patients in CR after rituximab induction was safe and effective21

Proportion of patients without progression at 3 years by treatment cohort

RSST (8R)
n=37

89%

95% CI: 76-100%

ST (4R-4CHOP)
n=14

69%

95% CI: 44-95%

 

At 3 years, improved TTP outcomes were observed in the low-risk rituximab consolidation group* compared to the patients in the PTLD-1 ST cohort who had reached CR with rituximab induction and continued ST with CHOP chemotherapy

*patients with CR at interim staging in the low-risk group (RSST cohort)

Key treatment outcomes: PTLD-2 study

A prospective, multicentre, Phase 2 trial tested a modified RSST treatment. In addition to patients who achieved a CR after rituximab induction, rituximab maintenance monotherapy was also given to those in PR and who were considered low risk with <3 IPI risk factors. Similar TTP, OS, and PFS were observed compared to the PTLD-1 ST and RSST trials22

TTP and OS in the ITT population

Key treatment outcomes PTLD-2 study

Used with permission of Springer Nature BV, from Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial. Zimmermann H., Koenecke C.,  Dreyling MH., et al., Leukemia. Vol. 36, 2468–2478 (2022); permission conveyed through Copyright Clearance Center, Inc.  
 

 

Pooled analysis of low-risk groups in the PTLD-1-RSST and PTLD-2 trials (N=58)

Key treatment outcomes PTLD-2 study _3

Adapted in color from Zimmermann H, et al. Leukemia. 2022. https://creativecommons.org/licenses/by/4.0/. 
 

 

EBV-specific CTL immunotherapy

Key treatment outcomes: EBV-specific CTL immunotherapy

Ongoing unmet clinical need

Survival among patients whose disease is refractory to 1L treatment is low  and prognosis remains poor23 

SOT recipients

4.1
MONTHS
n=86

MEDIAN OS

 In a retrospective chart review of patients with EBV+ PTLD following SOT who received rituximab alone or rituximab plus chemotherapy as initial therapy, median OS was 4.1 months from the earliest date when patients developed  R/R disease23 

Effective treatment options are needed to fulfil the unmet medical need for patients who fail available therapies

Experience with third-party EBV-CTLs suggest that EBV-CTLs should be explored as therapy for rituximab-refractory, EBV-positive PTLD emerging after SOT24

Adoptive T-cell therapy in the EBV+ PTLD treatment setting after SOT: third party EBV-CTLs

Study

Method of selection

Prior therapy

n

HLA

Response (CR+PR)
% (n/n)

Mahadeo, et al.25*

EBV-BLCL-stimulated EBV CTLs

Rituximab ± CT

29

≥2

52 (15/29)

Bonifacius, et al.26*

EBV-BLCL-stimulated T-cell line

CT ± rituximab

5

≥3/6

80 (4/5)

Prockop, et al.27*

EBV-BLCL-sensitised T-cell line

Rituximab ± CT/RT

13

≥2/10

54 (7/13)

Chiou, et al.28

EBV-BLCL-stimulated EBV CTLs

RIS ± rituximab/IG/antiviral

10

2-5/6; 5-7/10

80 (8/10)

Gallot, et al.29*

EBV-BLCL-stimulated EBV CTLs

CT ± rituximab/RT

3

≥2

33 (1/3)

Vickers, et al.30*

EBV-LCL-stimulated EBV CTLs

NA

5

3-9/10

100 (5/5)

Gandhi, et al.31

EBV-LCL-sensitised EBV CTLs

RIS, rituximab ± CT

3

≥3/6

66 (2/3)

Haque, et al.32*

EBV-LCL-stimulated EBV CTLs

RIS, rituximab ± other

31

2-5/6

61 (19/31)

Sun, et al.33*

EBV-BLCL-stimulated EBV CTLs

RT; Rituximab + CT

1; 1

4/6; 6/6

100(1/1);100(1/1)

*These studies also investigated third-party EBV-CTLs in patients who received HCT.

Key Takeaways

Key takeaways for the management of EBV+ PTLD after SOT

There are a range of
therapy options for treating EBV+ PTLD
A core multidisciplinary team is important for creating an effective management plan

Patients not responding to 1L therapy face poor outcomes  (4.1m mOS post-SOT in R/R EBV+ PTLD patients23) and limited alternative treatments

Adoptive
T-cell immunotherapy is a novel treatment option for patients with EBV+ PTLD who fail initial therapy

HCT Key treatment outcomes

RIS + rituximab, chemotherapy, DLI

Key treatment outcomes: Retrospective analyses

Variable response and limited 1- and 2-year survival rates with 1L rituximab indicate a need for improved treatment options for patients with EBV+ PTLD after HCT

20-70%

of patients achieve CR to 1L ritixumab, highlighting the 
 variability in response24,34

~40-46%

Reported 1- and 2-year survival rates in patients with EBV+ PTLD, the majority of whom (47/51) received rituximab as 1L treatment34

About 50% of EBV+ PTLD cases relapse or are refractory to initial treatment with rituximab-containing regimens,35 and only a few studies have reported treatment outcomes in patients with rituximab-refractory EBV+ PTLD:

 

n/N*

Type of treatment (n)

Response rate

Relapses

Hou (2009)36

1/12†

RIS + rituximab (1);
DLI (2)

CR: 1/1 (RIS + rituximab)
CR: 0/1, PR: 2/2 (DLI)

-

Fox (2014)34

3/62‡

CHOP (5);
CHOP followed by DLI (2);
DLI (3)

CR: 0/5, PR: 0/5 (CHOP)
CR: 3/5 (DLI)

None

Socié (2024)35

4/81‡

Chemotherapy-containing regimen (32);
Other, not specified (4)

Durable response of >6 months: 4/36
(All therapies)

2/4

*n: the total number of patients who achieved a CR; N: the number of patients constituting the study population.
†One patient achieved CR after 1L therapy.

‡Patients who achieved a CR (or durable response) after next-line therapy.

EBV-specific CTLs

Key treatment outcomes: Ongoing unmet clinical need

Survival among patients whose disease is refractory to 1L treatment is low and prognosis remains poor35

HCT recipients

0.7
MONTHS
n=81

MEDIAN OS

In a retrospective chart review of allogeneic HCT recipients who failed rituximab alone or rituximab plus chemotherapy, the median OS was 0.7 months from the time of initial treatment failure leading to R/R EBV+ PTLD35

Effective treatment options are needed to fulfil the unmet medical need for patients who fail available therapies

 

Treatment with EBV-specific CTLs generated from primary HCT donors was found to be effective in the treatment of EBV+ PTLD; EBV-specific CTLs have been effective in >80% of patients treated for PTLD24

Adoptive T-cell therapy in the EBV+ PTLD treatment setting after HCT: donor-derived EBV-CTLs24

Study

Method of selection

n

Response (CR+PR)
% (n/n)

Acute GvHD

Rooney, et al.
Heslop, et al.

EBV-LCL sensitised

13

85 (11/13)

8%

Lucas, et al.

EBV-LCL sensitised

1

100 (1/1)

100%

Imashuku, et al.

EBV-LCL sensitised

1

0 (0/1)

0%

Gottschalk, et al.

EBV-LCL sensitised

1

0 (0/1)

Not documented

Comoli, et al.

EBV-LCL sensitised

5

100 (5/5)

0%

Moosman, et al.

Peptide stimulation IFN𝛾 capture

6

50 (3/6)

0%

Doubrovina, et al.

EBV-LCL sensitised

19

68 (13/19)

0%

Icheva, et al.

EBNA-1 peptide stimulation IFN𝛾 capture

8

 75 (6/8)

13%

Gerdemann, et al.

DC nucleofection viral plasmids

1

100 (1/1)

100%

Papadopoulou, et al.

Peptide-stimulated

1

100 (1/1)

0%

Adapted from Shahid S, et al. Cancer Drug Resist. 2021. https://creativecommons.org/licenses/by/4.0/.

Adoptive T-cell therapy in the EBV+ PTLD treatment setting after HCT: third-party EBV-CTLs

Study

Method of selection

Prior therapy

n

HLA

Response (CR+PR)% (n/n)

Mahadeo, et al.25*

EBV-BLCL-stimulated EBV CTLs

Rituximab

14

≥2

50 (7/14)

Bonifacius, et al.26*

EBV-BLCL-stimulated T-cell line

Rituximab ± CT

14

≥3/6

60 (6/10)†

Prockop, et al.27*

EBV-BLCL-sensitised T-cell line

Rituximab ± CT/RT

33

≥2/10

67 (22/33)

Tzannou, et al.37

Peptide-stimulated CTLs

Antiviral therapy; None

1; 1

3/8; 5/8

100 (1/1); 
100 (1/1)

Naik, et al.38

EBV-LCL- and multi-virus-sensitised CTLs

None/other or rituximab ± other

12

varies

75 (9/12)

Gallot, et al.29*

EBV-LCL-stimulated EBV CTLs

CT ± rituximab

6

≥2

50 (3/6)

Vickers, et al.30*

EBV-BLCL-stimulated EBV-CTLs

NA

6

3-9/10

67 (4/6)

Leen, et al.39

Transduced multi-virus CTLs

Rituximab

9

1-3/6

67 (6/9)

Barker, et al.40

EBV-BLCL-stimulated T-cell line

Rituximab ± RT

2

5/6, 4/6

100 (2/2)

Haque, et al.32*

EBV-LCL-stimulated EBV CTLs

RIS ± rituximab ± other

2

2–5/6

100 (2/2)

*These studies also investigated third-party EBV-CTLs in patients who received SOT. †Outcome data was available for 10 patients.

Key takeaways

Key takeaways for the management of EBV+ PTLD after HCT

The management of EBV+ PTLD is complex, with limited treatment options for patients who are relapsed/refractory to initial therapy

Patients not responding to 1L therapy face poor outcomes (0.7m mOS post-HCT in R/R EBV+ PTLD patients35)

Adoptive
T-cell immunotherapy serves as an alternative treatment option to help improve outcomes for patients with R/R EBV+ PTLD

References

  1. Shah N, et al. Br J Haematol. 2021;193(4):727–740.
  2. Nijland ML, et al. Transplant Direct. 2015;2(1):e48.
  3. Yamada M, et al. J Pediatric Infect Dis Soc. 2024;13(Suppl 1):S31–S38.
  4. Lindsay J, et al. Curr Opin Infect Dis. 2021;34(6):635–645.
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  7. Dierickx D, Habermann TM. N Engl J Med. 2018;378(6):549–562.
  8. Styczynski J, et al. Anticancer Res. 2022;42:5181-5186.
  9. Clerico M, et al. J Clin Med. 2022;11(24):7542.
  10. Wistinghausen B, et al. Ann Lymphoma. 2022;6:5. 
  11. Swinnen LJ, et al. Transplantation. 2008;86(2):215–222.
  12. Oertel SH, et al. Am J Transplant. 2005;5(12):2901–2906.
  13. Choquet S, et al. Blood. 2006;107(8):3053–3057.
  14. González-Barca E, et al. Haematologica. 2007;92(11):1489–1494.
  15. Trappe R, et al. Lancet Oncol. 2012;13(2):196–206.
  16. Mamzer-Bruneel MF, et al. J Clin Oncol. 2000;18(21):3622.
  17. Norin S, et al. Med Oncol. 2004;21(3):273–284.
  18. Elstrom RL, et al. Am J Transplant. 2006;6(3):569–576.
  19. Fohrer C, et al. Br J Haematol. 2006;134(6):602–612.
  20. Choquet S, et al. Haematologica. 2007;92(2):273–274.
  21. Trappe R, et al. J Clin Oncol. 2017;35:536–543. 
  22. Zimmermann H, et al. Leukemia. 2022;36(10):2468–2478.
  23. Dharnidharka V, et al. Hemasphere. 2022; 6(Suppl): 997–998.
  24. Shahid S, Prockop SE. Cancer Drug Resist. 2021;4(3):646–664.
  25. Mahadeo KM, et al. Lancet Oncol. 2024;25(3):376-387.
  26. Bonifacius A, et al. J Clin Invest. 2023;133(12):e163548.
  27. Prockup S, et al. J Clin Invest. 2020;130(2):733–747.
  28. Chiou FK, et al. Pediatr Transplant. 2018;22(2).
  29. Gallot G, et al. J Immunother. 2014;37(3):170-9.
  30. Vickers MA, et al. Br J Haematol. 2014;167(3):402-10.
  31. Gandhi MK, et al. Am J Transplant. 2007;7(5):1293-9.
  32. Haque T, et al. Blood. 2007;110(4):1123-31.
  33. Sun Q, et al. Br J Haematol. 2002;118(3):799-808.
  34. Fox CP, et al. Bone Marrow Transplant. 2014;49(2):280–286.
  35. Socié  G, et al. Bone Marrow Transplant. 2024;59(1):52–58.
  36. Hou HA, et al. Bone Marrow Transplant. 2009;43(4):315–321.
  37. Tzannou I. J Clin Oncol. 2017;35(31):3547-3557.
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  39. Leen AM, et al. Blood. 2013;121(26):5113-23.
  40. Barker JN, et al. Blood. 2010;116(23):5045-9.

Abbreviations

  • 1L first-line
  • 4CHOP four cycles of CHOP
  • 4R four courses of rituximab
  • 8R eight courses of rituximab
  • ACVBP doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone
  • AZA azathioprine 
  • BLCL EBV-transformed B-lymphoblastoid cell
  • BOR best overall response
  • CD20 cluster of differentiation 20
  • CEP cyclophosphamide, etoposide, prednisone
  • CHOP   cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone
  • CI confidence interval
  • CR complete response
  • CsA cyclosporine 
  • CTLs cytotoxic T lymphocytes
  • CTX  cyclophosphamide
  • DC dendritic cell
  • DLBCL diffuse large B-cell lymphoma
  • DLI donor lymphocyte infusion
  • EBNA-1 Epstein-Barr nuclear antigen 1
  • EBV(+) Epstein–Barr virus (positive)
  • EMA      European Medicines Agency
  • ESHAP etoposide, methylprednisolone, cytarabine, cisplatin
  • GvHD   graft-versus-host disease
  • HCT haematopoietic cell transplantation
  • HLA human leukocyte antigen
  • IFNγ interferon‐gamma
  • IPI International Prognostic Index
  • IS immunosuppression
  • ITT intent-to-treat
  • IV intravenous
  • LCL lymphoblastoid cell lines
  • LDH lactate dehydrogenase
  • MDT multidisciplinary team
  • MTX methotrexate 
  • NA not available
  • ORR overall response rate
  • OS overall survival
  • PD disease progression
  • PFS progression-free survival
  • PR partial response