1. Reduced Intensity Allograft Scopes and Limitations
Stephen Mackinnon
Dept of Haematology, Cancer Institute
University College London

2. Conventional Allogeneic BMT for Hodgkin Lymphoma
100 HLA identical sibling allografts
median age 28 yr
TRM 61%
Relapse 65%
DFS 15%
Gajewski J Clin Oncol 14:572, 1996

3. IBMTR – Hodgkin’s

4. Rationale for Reduced Intensity Conditioning
Less toxic immunosuppressive regimen
limits TRM / expands patient eligibility
allows allogeneic engraftment
Cure mediated by GVL effect of donor T cells

5. The Perfect Regimen Low toxicity and TRM Low incidence of GVHD
High level of tumour control
Good immune reconstitution
Disease responds to DLI

6. Regimen Intensity Cy / TBI Flu / Mel / Campath Immunosuppressive BEAM
Flu / Cy / Ritux
TBI 2Gy
Tumour Control / Myelosuppression

7. Cyclosporin A as GVHD prophylaxis from Day -1
Conditioning Regimen
Day:
- 8
- 7
- 6
- 5
- 4
- 3
- 2
- 1
Alemtuzumab 20mg/d
Fludarabine 30mg/m2/d
Melphalan 140mg/m2
Unmanipulated PBSC / Marrow
Cyclosporin A as GVHD prophylaxis from Day -1

8. Alemtuzumab Advantages engraftment low GVHD unrelated low TRM
Disadvantages
CMV infection
mixed chimerism
lack of GVL

9. Update of Allogeneic Stem Cell Transplant for Hodgkin Lymphoma

10. Patient Characteristics
Patient Number: 76
Age:
Median
Range
Sex:
Male
Female 32
13-59 42 34
Donor:
Matched related
Matched unrelated
Histology:
Nodular sclerosing
Mixed cellularity
Lymphocyte predominant
Nodular LP 69 3 2
Peggs et al. J Clin Oncol 2011, 29:971

11. Patient Characteristics
Patient Number: 76
Status:
Complete response
Partial response
Refractory
Untested relapse 17 32 26 1
Conditioning:
Flu / Mel - Campath
BEAM – Campath 63 13
Previous lines : 2-10 (median 5)
45 previous autograft
Time from diagnosis : years (median 4.8)
Peggs et al. J Clin Oncol 2011, 29:971

12. Engraftment, TRM and GVHD
75 / 76 engrafted
Transplant-related mortality 17%
siblings 12%
unrelated 24%
GVHD (II – III acute)
pre DLI
siblings %
unrelated 29%
GVHD (chronic extensive)
pre DLI %
post DLI %
Peggs et al. J Clin Oncol 2011, 29:971

13. Relapse and GVHD
Peggs et al. J Clin Oncol 2011, 29:971
No GVHD
GVHD

14. Hodgkin’s - DLI for Mixed Chimerism
22 patients given DLI starting at median 9 mos
Median 2 doses given (range, 1 – 5)
starting dose 1 x 106 T cells/kg
19 became full donor chimeras, 13 w/o GVHD
only 1 of these patients relapsed!
22 patients in CR at 9 mos not given DLI
4 mixed chimeras
18 full donor chimeras
Peggs et al. J Clin Oncol 2011, 29:971

15. Relapse and Chimerism Landmark analysis at 9 months
Peggs et al. J Clin Oncol 2011, 29:971
MC – no DLI
FD – no DLI
MC + DLI
Years

16. Management of Relapse 7 / 31 relapses not given DLI 24 received DLI
3 active GVHD, 2 ref to salvage, 1 IF XRT
1 PR to CSA withdrawal pending DLI
24 received DLI
10 also given salvage chemo
14 CRs + 5 PRs with ORR of 79%
10 / 14 CRs only received DLI
12 / 14 CRs durable at median of 26 mos
Peggs et al. J Clin Oncol 2011, 29:971

17. Graft-versus-lymphoma effect
EXCELLENT DEMONSTRATION OF GRAFT VERSUS HODGKIN EFFECT POST DLI

18. Progression Free Survival Impact of DLI
Peggs et al. J Clin Oncol 2011, 29:971
Current PFS
PFS

19. Prognostic Role of PET scanning before and after reduced intensity allogeneic stem cell transplant for lymphoma
S Mackinnon, J Lambert, J Bomanji, K Peggs, K Thomson, R Chakraverty,
A Fielding, M Roughton, E Morris, A Goldstone, D Linch, P Ell
University College London
Lambert et al. Blood 115:2763, 2010

20. PET and AUTO Transplant (PFS)
100 80 60
Cumulative percent surviving
PET –
PET + 40 20
500
1000
1500
2000
2500
Time (days)
Spaepen et al. Blood 2003;102:53–59
Copyright ©2003 American Society of Hematology.

21. PET and Lymphoma Predictive role pre ALLO transplant unknown
Role post ALLO transplant unknown

22. Trial Aims Is pre-transplant PET predictive of outcome ?
Is post-transplant PET clinically useful ?
Lambert et al. Blood 115:2763, 2010

23. Methods Prospective trial 80 consecutive lymphoma patients
43 sibling, 37 unrelated
PET and CT pretransplant
chemosensitivity assessed by CT
Post transplant scans at 3, 6, 9, 15, 24, 36 mo
Lambert et al. Blood 115:2763, 2010

24. Post Transplant Interventions
Patients with evidence of relapse given DLI
clinical, CT or PET
Patients with stable abnormal CT and PET negative were not given DLI
Lambert et al. Blood 115:2763, 2010

25. Disease-free survival
PET NEG pre-RIT (n=26)
PET POS pre-RIT (n=38)
100
100
p=0.52
p=0.91 80 80
Percent
Percent 60 60 40 40
Overall survival
Relapse 20 20 20 40 60 80
100 20 40 60 80
100
Time (months)
Time (months)
100
100
p=0.78 80
p=0.87 80
Percent 60
Percent 60 40 40
Current DFS 20
Disease-free survival 20 20 40 60 80
100 20 40 60 80
100
Time (months)
Time (months)

26. Diagnosis of Relapse 34 episodes of relapse in 28 patients
4 clinically detected
CNS, 3,4, > 36 mos post PET
13 PET + / CT +
17 PET + / CT –
16 / 17 at site positive pretransplant
19 patients were CT + / PET –
13 remained in CR
6 relapsed, 4 at site of prior CT abnormality

27. Indication for DLI Indication CR / Episode Clinical progression alone
1 / 3
PET + and relapse/progression on CT
6 / 9
PET + and normal/unchanged CT
13 / 14
Lambert et al. Blood 115:2763, 2010

28. Conclusions
A positive pre transplant PET does not preclude a successful outcome in ALLO transplant
Post transplant PET picks up relapse earlier and allows optimal efficacy of DLI
Lambert et al. Blood 115:2763, 2010

29. Allo vs autologous transplant
0.0
0.2
0.4
0.6
0.8
1.0 12 24 36 48 60 72 84 96
Months after SCT
Cumulative Incidence
0.0
0.2
0.4
0.6
0.8
1.0 12 24 36 48 60 72 84 96
Months after SCT
Cumulative Incidence
TRM
Relapse risk
0.0
0.2
0.4
0.6
0.8
1.0 12 24 36 48 60 72 84 96
Months after SCT
PFS
PFS OS
Auto
RIST
Robinson et al, ASH, 2008 (updated)

30. RIC-allogeneic transplant
Study
3-yr TRM
3-yr RR
3-yr OS
3-yr EFS/PFS
cGVHD
Robinson, 2002*
31%
20%
65%
54%
16% (ext: 9%)
Vigouroux, 2007
40%
10%
56%
51%
43% (ext: 20%)
Rezvani, 2007
14%
52%
43%
Ext: 47%
Khouri, 2008 NR
85%
83%
60% (ext: 36%)
Hari, 2008
28%
17%
62%
55%
Ingram, 2008
69%
58%
Thomson, 2010** 8%
25%
90%
87%
Ext: 11% (30% post DLI)
Piñana, 2010**
37%
57%
Ext: 53%
* at 2 years, ** at 4 years in siblings
3-yr TRM: 8-40%, 3-yr RR: 8-25%, 3-yr OS: 52-90%, 3-yr PFS: 43-87%

31. Allogeneic transplant
Myeloablative should be avoided
Sibling / unrelated RIC vs Auto
auto failures, marrow involved, failure to mobilise
short response duration
≥ CR3 / PR3
PET +ve post salvage
Centre effect may be important

32. Elderly and High-Risk AML
High risk of relapse with chemo alone
High risk of death with myeloablative transplant
Reduced intensity transplants less toxic, but
GVHD a major problem in the elderly
more relapse with reduced intensity regimens

40. Patient Characteristics
Patients
Median age (17 – 70)
Disease status CR CR
standard risk 33
high risk 37
Poor risk cytogenetics, FLT3-ITD mutated, previous MDS / 2° AML

41. Patient Characteristics Highly selected?
Donors
siblings 29
unrelated 41
Only 10 pts were < 60 yrs + standard risk AML + a sibling donor
Only 2 / 23 patients > 60 yrs + standard risk AML + a sibling donor

45. Chimerism, GVHD and Relapse
Acute II-IV and chronic GVHD prevented relapse
0% vs 27%
28 / 41 were full donor chimeras
11 / 13 mixed chimeras remain in CR
GVL good but not essential in preventing relapse
regimen intensity may be important

48. Conclusions
Many elderly pts with high-risk AML have durable remissions with RIC transplantation
Transplant mortality limited
good control of GVHD
Relapse risk low even for pts with high-risk AML
More pts could and should benefit
FLT3-ITD mutated
MRD positive chemo

49. Can we improve the current results?
Promote GVL
pre-emptive DLI
Molecular risk / MRD monitoring
Increase regimen intensity without toxicity
targeted radiotherapy

50. Whole body data
24 hrs post infusion
Anterior Posterior

51. For autologous transplant (HD melphalan)
D –22 to D –16 In-111 imaging Dosimetry
Y-90 labelled
Anti-CD66
Review, fbc
HD Melphalan
D – D – D – D 0
Autologous stem cells

52. For allogeneic transplantation
D –22 to D –16 In-111 imaging Dosimetry
Y-90 labelled
Anti-CD66
Melphalan 140mg/m2
Fludarabine 30mg/m2
CAMPATH 1H 10mg/m2
D – D – D – D 0
CyA 5mg/kg d –3
3mg/kg d –2
level ng/ml
tailing from d +60
MTX d 3, 6, mg/m2
Allogeneic stem cells