1. The Evolving Role of Transplantation in Lymphoma
Stephen Mackinnon
Royal Free Hospital / University College London

2. Theoretical Advantages for Allogeneic Transplantation
Tumour free graft
Undamaged Stem Cells
Avoidance of MDS/secondary AML
Graft versus lymphoma effect

3. Disadvantages of Allogeneic Transplantation in Lymphoma
Lack of suitable donors
High Treatment Related Mortality
Regimen related toxicity
Infection
GVHD

4. Allogeneic transplant in NHL
No randomised trials available
Relapse lower than auto transplant
Possibly a graft versus lymphoma effect
Can be used in poor mobilisers
Higher TRM than autologous transplant

5. Allogeneic Transplantation Myeloablative or Reduced Intensity?

6. Auto vs Ablative Allo Transplant
TRM
Peneket el al, Bone Marrow Transplant 31:667, 2003

7. Graft Versus Lymphoma effect or effect of tumour free graft
Graft Versus Lymphoma effect or effect of tumour free graft? Low Grade Histology
Progression Free Survival
Relapse
Bierman et al. J Clin Oncol 21:3711, 2003

8. GVL Effects of DLI / GVHD
Proven to be good
CML
DLI shown to be limited or poor
AML / ALL / MDS / Hodgkin’s
DLI probably good
CLL / Follicular NHL / Myeloma
Unknown
DLBCL

9. Long-term follow-up of reduced-intensity transplantation with an alemtuzumab- containing regimen:
Aggressive NHL
J Clin Oncol. 2009;27:426-32

10. High-grade NHL: Patients (I)
Median age 46 years (range 23–64)
Median lines therapy 5 (range 2–7)
Prior autograft (71%)
No autograft 14 (29%)
8 progression through salvage chemo within 3 months of primary treatment, 3 failed mobilization, 3 MDS/lymphoma/lung fibrosis
Median follow-up 52 months (range 18–89)
Status at transplant
CR 9
PR 31
Refractory 8
J Clin Oncol. 2009;27:426-32

11. High-grade NHL: Patients (II)
High-grade HNL (n=48)
18 HG transformation follicular NHL
30 primary DLBCL
Donor
30 HLA-matched sibling
18 unrelated
12 HLA-matched
8 HLA-mismatched (4 x 1 locus, 3 x 2 loci, 1 x 3 loci)
J Clin Oncol. 2009;27:426-32

12. Cyclosporin A as GVHD prophylaxis from Day –1
Conditioning regimen
Day: –8 –7 –6 –5 –4 –3 –2 –1
Alemtuzumab 20 mg/d
Fludarabine 30 mg/m2/d
Melphalan 140 mg/m2
Unmanipulated PBSC / Marrow
Cyclosporin A as GVHD prophylaxis from Day –1
Thomson et al. J Clin Oncol 2008 (in press)

13. Aggressive NHL: Treatment-related mortality (n=48)
0.25
0.50
0.75
1.00
Cumulative Incidence
32%
Time (years) 2 4 6 8
J Clin Oncol. 2009;27:426-32

14. Aggressive NHL: Relapse (n=48)
0.25
0.50
0.75
1.00
Cumulative Incidence
33%
Time (years) 2 4 6 8
J Clin Oncol. 2009;27:426-32

15. Aggressive NHL: Overall survival (n=48)
0.25
0.50
0.75
1.0
Survival
47%
Time (years) 2 4 6 8
J Clin Oncol. 2009;27:426-32

16. High-grade NHL: DLI for relapse
15 patients relapsed / progressed
Median time to relapse 6 months (2–56)
12 patients given dose-escalated DLI
5 primary high-grade
4 DLI alone, 3 grade 3/4 aGVHD, all had progression
1 surgery + XRT + Ritux then DLI, in CR at 76 months
7 transformed low-grade
3 no GVHD, no response
3 CR ongoing at 7, 27, 37 months – no GVHD in 2/3
1 surgery then DLI in CR at 76 months
Summary 5 / 15 relapses back in remission
DLI, donor lymphocyte infusion
aGVHD/cGVHD, acute/chronic graft-versus-host disease

17. Current PFS (n=48) Survival 48% Time (years) 2 4 6 8 1.00 0.75 0.50
0.25
0.50
0.75
1.00
Survival
48%
Time (years) 2 4 6 8
PFS, progression-free survival

18. Current PFS by donor type
0.25
0.50
0.75
1.00
Survival
50%
43%
Time (years)
p=0.65 2 4 6 8
Sibling
Unrelated

19. Current PFS by chemo-responsiveness
0.25
0.50
0.75
1.00
Survival
55%
12%
Time (years)
p=0.006
Chemorefractory
Chemosensitive
J Clin Oncol. 2009;27:426-32

20. Conclusions – Aggressive NHL
Reduced intensity approaches show:
significant TRM in aggressive lymphoma
surprising low relapse rate
T cell depletion
Non ablative regimen
long-term remissions – cure probable
DLI only benefit a minority
Chemosensitivity is a predictor for outcome
we no longer transplant refractory aggressive NHL
Is there a role for mini allo in preference to auto transplant in patients who remain PET+ following salvage chemo?

21. Follicular Lymphoma

22. Seattle Regimen 2 Gy TBI ± Flu
Chronic extensive GVHD in 45%
Overall Survival
Follicular
Progression Free Survival
Related Transplants
Indolent Disease
Transformed follicular
J Clin Oncol 26:211,2008

23. Flu / Cy / Rituximab Patients Median age 53yrs (33 – 68) Prior therapy
Related 45
Unrelated 2
Median age 53yrs (33 – 68)
Prior therapy
≤ 2 regimens 23
3 – 5 regimens 24
auto transplant 9
Disease status at transplant
CR 18
PR 29
Refractory 0
GVHD prophylaxis Tacro + MTX
Khouri et al. Blood 2008, 111: 5530

24. Flu / Cy / Rituximab Survival Progression Free Survival
Khouri et al. Blood 2008, 111: 5530

25. Flu / Cy / Rituximab Acute GVHD Chronic GVHD Chronic Chronic Extensive
II - IV
III - IV
Khouri et al. Blood 2008, 111: 5530

26. Follicular NHL: Patients (I)
Median age 45 years (range 26–65)
Median lines therapy 3 (range 1–8)
Prior autograft 28%
Median follow-up 40 months (range 4–103)
Thomson et al. ASH 2007; abstr 1661

27. Alemtuzumab Advantages Disadvantages Low GVHD Mixed chimerism
Engraftment
Low GVHD
Unrelated
Low TRM
Disadvantages
CMV infection
Mixed chimerism
Lack of GVL

28. Flu/Mel conditioning & GVHD prophylaxis: CSA/alemtuzumab vs CSA/MTX
Alemtuzumab MTX
Acute GVHD II–IV 9% 43%
Chronic GVHD 5% 67%
CMV infection 85% 24%
TRM 10% 20%
Pérez-Simón et al. Blood 2002;100: 3121–7

29. Follicular NHL: Patients (II)
Donor
39 HLA-matched sibling
39 unrelated
29 HLA-matched
10 HLA-mismatched (7 x 1 locus, 3 x 2 loci)
Chemosensitive
Yes 69
No 8
Untested 1
Thomson et al. ASH 2007; abstr 1661

30. Follicular NHL: Non-relapse mortality by donor type
9% Sibling
22% Unrelated
0.25
0.5
0.75
1.0
1000
2000
3000
Cumulative Incidence
Days
Thomson et al. ASH 2007; abstr 1661

31. Follicular NHL: Overall survival (n=78) GVHD and donor type
Sibling 90%
1.0
1.0
76%
p<0.005
0.75
0.75
0.5
0.5
Unrelated 61%
Impact of GVHD
0.25
0.25
1.8
3.6
5.4
7.2 9
1.8
3.6
5.4
7.2 9
Years
Years
Thomson et al. ASH 2007; abstr 1661

32. Follicular NHL: Overall survival by prior autograft and chemosensitivity
1.0
No 85%
1.0
Yes 79%
0.75
0.75
p<0.002
p<0.04
0.5
0.5
Yes 52%
No 50%
0.25
0.25
Chemosensitive
Prior Autologous Transplant
1.8
3.6
5.4
7.2 9
1.8
3.6
5.4
7.2 9
Years
Years
Thomson et al. ASH 2007; abstr 1661

33. - Donor
- Recipient
- Post-Transplant +60 Days
- Post-transplant +90 Days
- Post DLI + 73 Days
(Post Transplant + 6 Months)

34. Relapse and Chimerism Mixed Chimerism 40% p < 0.01 13% Full Donor
0.25
0.50
0.75
1.00
Time (years)
Mixed Chimerism
40%
p < 0.01
13%
Full Donor 34

35. Follicular NHL: Relapse (n=78)
Impact of GVHD
acute II–IV or chronic
All patients
1.0
1.0
0.75
0.75
0.5
0.5
No GVHD 35%
0.25
0.25
GVHD 14%
1000
2000
3000
1000
2000
3000
Thomson et al. ASH 2007; abstr 1661

36. Follicular NHL: DLI for relapse
16 patients relapsed / progressed
Median time to relapse 8 months (2–43)
10 patients given dose escalated DLI
3 non-responders
no GVHD
7 CRs, 3 with rituximab
3 with GVHD, 4 no GVHD
1 progressed after 6 months
6 CRs ongoing at a median of 41 months (21–60)
Thomson et al. ASH 2007; abstr 1661

37. Follicular NHL: cPFS (n=78) by donor type
0.25
0.5
0.75
1.0
74%
All patients
Siblings 87%
Unrelated 62%
p<0.02
Years
Years
Thomson et al. ASH 2007; abstr 1661

38. RIC Sibling Allo preferred over Auto
Failure to mobilise autologous PBSC
Bone involvement at end of chemotherapy
Relapse post autograft
Younger patients ?
PET+ pretransplant ?
Regimen with TRM < 10% ?
Patient choice ?

39. Conclusions – Follicular Lymphoma
Allogeneic conditioning regimens:
higher TRM with myeloablative conditioning
Some reduced intensity regimens may also have a high TRM
low relapse rate for chemosensitive patients
Lymphoma free stem cells?
GVL?
long-term remissions – cure probable
Chronic GVHD still a problem especially in MUD recipients
DLI are effective in the majority of patients
Chemosensitivity is a predictor for outcome
Role for mini allo in preference to auto transplant?

40. Prognostic Role of PET before and after Allogeneic Stem Cell Transplantation

41. PET and Lymphoma
PET predictive of outcome of chemotherapy or pre AUTO transplant
Predictive role pre ALLO transplant unknown
Role post ALLO transplant unknown

42. Cumulative percent surviving
Prognostic value of PET status pre-auto-transplant for aggressive lymphoma: 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.

43. Trial Aims Is pre-transplant PET predictive of outcome ?
Is post-transplant PET clinically useful ?

44. Methods Prospective trial 80 consecutive lymphoma patients
PET and CT pretransplant
chemosensitivity assessed by CT
Post transplant scans at 3, 6, 9, 15, 24 and 36 months

45. 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

46. Patient Characteristics
Subtype
PET negative (n=38)
PET positive (n=42)
CT positive (n=17)
CT negative (n=21)
CT positive (n=34)
CT negative (n=8)
Follicular lymphoma 8 6 12 4
Hodgkin lymphoma 11 3
Mantle cell lymphoma 1
Diffuse large B-cell lymphoma 2
Transformed follicular
Peripheral T-cell lymphoma

47. 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)

48. Follicular Lymphoma cPFS by PET Status Pretransplant
PET negative
PET positive
Months

49. No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died)
PET +ve
(n = 13)
NRM
(n = 5)
PET +ve
(n = 38)
PET +ve
(n = 21)
Pre Tx
1st 6 months
Subsequent follow up
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15

50. No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died)
PET +ve
(n = 13)
NRM
(n = 4)
PET +ve
(n = 38)
PET +ve
(n = 21)
PET -ve
(n = 15)
Pre Tx
1st 6 months
Subsequent follow up
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15

51. No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died)
PET +ve
(n = 13)
DLI
(n = 8)
No DLI
(n = 5)
NRM
(n = 4)
PET +ve
(n = 38)
PET +ve
(n = 21)
PET -ve
(n = 15)
NRM
(n = 2)
No DLI
(n = 1)
Rel
(n = 4)
DLI
(n = 3)
Pre Tx
1st 6 months
Subsequent follow up
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15

52. No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died)
PET +ve
(n = 13)
DLI
(n = 8)
PET -ve
(n = 6)
PET -ve
(n = 3)
No DLI
(n = 5) PR
(n = 2)
NRM
(n = 4)
PET +ve
(n = 38)
PET +ve
(n = 21)
PET -ve
(n = 15)
NRM
(n = 2)
No DLI
(n = 1)
PET +ve
(n = 1)
Rel
(n = 4)
DLI
(n = 3)
PET -ve
(n = 2)
Pre Tx
1st 6 months
Subsequent follow up
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15

53. No DLI n =1 (alive with disease) DLI n = 3 No response n = 1 (died)
PET +ve
(n = 13)
DLI
(n = 8)
PET -ve
(n = 6)
PET -ve
(n = 3)
No DLI
(n = 5) PR
(n = 2)
2nd Rel
(n = 3)
DLI
(n = 2)
PET -ve
(n = 2)
NRM
(n = 4)
No DLI
(n = 1)
PET +ve
(n = 38)
PET +ve
(n = 21)
PET -ve
(n = 15)
NRM
(n = 2)
No DLI
(n = 1)
PET +ve
(n = 1)
Rel
(n = 4)
DLI
(n = 3)
PET -ve
(n = 2)
Pre Tx
1st 6 months
Subsequent follow up
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15
PET pos n = 38
NRM n = 4
1st relapse n = 13
No DLI n = 5 (died)
DLI n = 8
CR n = 6
2nd relapse n = 3
DLI n = 2
CR n = 2
No DLI n = 1 (alive with disease)
CR n = 3
Minimal response n = 2 (alive with disease)
CR n = 21
NRM n = 2
1st relapse n = 4
No DLI n =1 (alive with disease)
DLI n = 3
No response n = 1 (died)
CR n = 15

54. Diagnosis of Relapse 34 episodes of relapse in 28 patients
4 clinically detected
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

55. 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

56. PET + Infection / Inflammation
11 / 475 scans
5 lesions biopsed
2 infections
1 sarcoidosis
1 non-specific
1 bone remodelling
6 cervical uptake with respiratory infection

57. Potential Problems Relatively small numbers of each lymphoma subtype
e.g. only 7 patients with de novo DLBCL
Few PET + lesions biopsied – false positives ?
majority of abnormalities at site of previous disease
All patients either had resolution with DLI or had overt clinical relapse

58. Conclusions
A positive pre transplant PET does not preclude a successful outcome
Post transplant PET picks up relapse earlier and allows optimal efficacy of DLI

59. The Future
Challenges
Relapse e.g. Hodgkin lymphoma
Increase antitumour activity of conditioning regimen
Without excess regimen-related mortality
Solution?
Targeted radiotherapy
Anti CD25
Anti CD66

60. Why radioimmunotherapy?
Specific, targeted therapy
No grade III/IV non-haematologic toxicity
Outpatient-based
No effect on future therapies
Proven target for lymphoma therapy
Expressed only on B-lineage cells
Does not shed into circulation
Does not modulate upon antibody binding Key Point: CD20 is an ideal target antigen for therapies against B-cell NHL because it is a specific antigen for B-cells that remains bound to the cell and does not modulate upon antibody binding.
The CD20 antigen is a cell surface protein expressed at relatively high levels on NHL cells, but not on haematopoietic or mature plasma cells.1
CD20 is not present in the circulation as a free protein that could block monoclonal antibody therapy and is not shed from the cell surface.2
Monoclonal antibodies directed against CD20 have been demonstrated to effectively target B-cell NHL cells.3
Zevalin®, comprising an anti-CD20 monoclonal antibody conjugated to the radioisotope 90yttrium (90Y), targets radioactive particles to the surface of tumour cells, offering an innovative approach for the treatment of NHL.
1. Zelenetz AD. Radioimmunotherapy for lymphoma. Curr Opin Oncol 1999;11:375–380.
2. Press OW, Appelbaum F, Ledbetter JA et al. Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B-cell lymphomas. Blood 1987;69:584–591.
3. Wood AM. Rituximab: an innovative therapy for non-Hodgkin’s lymphoma. Am J Health Sys Pharm 2001;58:215–229.

61. Principles of Radioimmunotherapy
External-beam radiation
Radioimmunotherapy
“monoclonal antibody mediated cell lysis” Many lymphomas are radio-sensitive but (but delivering
an adequate dose to the tumour can result in
damage to the surrounding healthy tissue. Coupling a
radioisotope to a molecule which would specifically
bind to tumour cells could, in theory, deliver an effective
radiation dose to the tumour without damage to
non-tumour tissues, potentially limiting adverse effects8) that therapy is limited by the fact that it is relatively non-specific in its action- normal tissues, in the path of the radi ation beam are irreversibly injured.
Long history of using radionuclides in medicine-
treatment of leukaemia by 32Phosphorus (32P) was the first therapy modality with radioisotopes in the early thirties of the previous century
1943 first success when metastatic thyroid cancer was cured by administration of rai.
Its unique modality allows to systemically target radiosensitive tumours throughout the body.
3. more sophisticated therapy by radioisotope labelled antibodies i.e. radioimmunotherapy (RIT) for various haematological malignancies, e.g. α- and β emitting radionuclides have been labelled with anti-CD33 antibodyHuM195 for the treatment of myeloid leukaemia.30 High-dose RIT of myeloid leukaemia with β-emitting radionuclides is being investigated for intensifying anti-leukaemia therapy before stem cell transplantation. Another option is the use of targeted α particles with radionuclides such as bismuth-213 or actinium-225, which offers the possibility of selective tumour cell kill with less damage to surrounding normal cells.30 As RIT constitutes the most significant clinical contribution to the treatment options of B-cell lymphomas, the following sections will focus on these haematological malignancies.
Long t1/2 of iodine means that protecting the patient’s environment is impt to prevent exposure to others
Y90 is a pure beta emitter with a much shorter t1/2 meaning that treatment can be given as an outpatient.
MINIMISES EXPOSURE TO NON-MALIGNANT CELLS –IMPORTANT IN
ELDERLY PATIENTS WITH CO-MORBIDITIES
WHO HAVEOFTEN HADSEVERAL LINES OF THERAPY
Key point: Radioimmunotherapy (RIT) targets all sites of lymphoma (known and unknown) with limited exposure of healthy tissue compared with directed external-beam radiation.
External-beam radiation delivers radiation at relatively high-dose rates for short periods of time, separated by intervals of hours or days, to the general area of the known lymphoma from an external source.1 As a result, it does not affect remote sites of lymphoma, and a large area of healthy tissue is exposed to high-energy radiation.
In contrast, low-energy RIT targets both known and unknown sites of lymphoma, with minimal exposure of healthy tissue. Once the radiolabelled monoclonal antibody is bound to the surface of the tumour cell, radiation is delivered continuously at an exponentially declining rate for days or weeks as the bound isotope decays.1
10–20% of patients with indolent NHL are diagnosed with early-stage disease that responds to external-beam radiation therapy.2
2. Vose JM. Classification and clinical course of low-grade non-Hodgkin’s lymphomas with overview of therapy. Ann Oncol 1996;7(suppl 6):S13–S19.
1. Press OW. Physics for practitioners: the use of radiolabeled monoclonal antibodies in B-cell non-Hodgkin’s lymphoma. Semin Hematol 2000;37(4, suppl 7):2–8.

62. Principles of radioimmunotherapy
These agents consist of mAb bound, through a high affinity chelator, to a radioisotope
The mAb specifically targets cell surface antigen, CD20 in the case of licensed RIT for FL, the chelator prevents radio-isotope dissociating and becoming free in the circulation.
Might also mention that other conjugates have been used
Immunotoxins- not abnle to give repaeated courses of therapy, toxin not interanlaised (CLL). Note adticd22 bound to an anti CD22 was used in the 1980’s at the Royal Free in Phase I studies…..vascular leak syndrome, human anti-mouse immunoglobulin antibody
Ibritumomab:
Anti-CD20 murine MAb that targets malignant B-cells
Tiuxetan:
A high-affinity chelator that ensures a stable bond between MAb and 90Yttrium
90Yttrium (90Y):
Emits beta radiation that reaches malignant B-cells, 90% deposited within 5 mm (11 mm maximum path length)
Key Point: Zevalin® combines the tumour targeting power of an anti-CD20 monoclonal antibody (MAb) and the cytotoxicity of 90yttrium radiation.
This slide describes the main components of Zevalin®, i.e. the monoclonal antibody ibritumomab, the chelator tiuxetan and the radioisotope 90Y.
Zevalin® is a radioimmunotherapy in which the, MAb ibritumomab, is covalently bound to a high-affinity chelator (tiuxetan) for the 90Y radioisotope.1–3
The tiuxetan chelator provides a stable linkage between the antibody and the radioisotope, resulting in specific radiation targeting of antigen-positive tumour cells.
As a result of this stable linkage, clearance rates for patients treated with Zevalin® are predictable and dosimetry/imaging is not generally required in the EU.
1. Harrison A, Walker CA, Parker D et al. The in vivo release of 90Y from cyclic and acyclic ligand-antibody conjugates. Nucl Med Biol 1991;18:469–476.
2. Roselli M, Schlom J, Gansow O et al. Comparative biodistribution studies of DTPA-derivative bifunctional chelates for radiometal labeled monoclonal antibodies. Nucl Med Biol 1991;18:389–394.
3. Chinn PC, Leonard JE, Rosenberg et al. Preclinical evaluation of 90Y-labeled anti-CD20 monoclonal antibody for treatment of non-Hodgkin’s lymphoma. Int J Oncol 1999;15:1017–1025.

63. Principles of Radioimmunotherapy
Naked antibody
Radio-labelled antibody
Cross-fire principle.
Another important principle is its so-called ‘cross-fire’ action, whereby, owing to the larger reach of the radiation in relation to the cell diameter, a tumour cell receives lethal hits also from isotopes in the neighbourhood that are not directly associated with this cell. The treatment is therefore less hampered by inhomogeneous distribution and metabolism than for example chemo- or immunotherapy
Also mention
Lou Staudt study and effect of RIT on the background cells.!!!!!!!
RADIO-IMMUNOCONJUGATES CONSISTING OF ANTI BODY LINKED TO RADIONUCLIDES TARGET RADIATION DIRECTLY OT LYMPHOMA CELLS VIA ANTIBODY MEDIATED TRANSPORTAS WELL AS TO NEIGHBOURING CELLS VIA WHAT IS CALLED CROSS FIRE EFFECT- THIS ADDRESSSES A POTENTIAL LIMITATION OF NAKED ANTIBODY TERAPY- DIFFICULTY ACCESSING ALL TUMOUR IN POORLY VASCULARIESD, BULKY TUMOURS
There is targeted delivery of radiation to tumour site as well as the transfer of apoptotoc signals tumour cells from bound anntibody I.E. SYNERGY- IMMUNOLOGIC AND RADIOLYTIC MECHANISMS TO BRING ABOUT CELL DEATH.
The choice of radio-isotope is aimed at maximising delivery of ionising radiation to tumour, whilst attempting to minimise the dose given to normal tissues
Y90 has advantage- no penetrating gamma emisisons/ t1/2 of 2.5 days/64 hours, path length of 5.3 mm cf 0.8 mm
BIG ADVANTAGE IS THAT THESE CHARACTERISTICS ARE IDEAL TREATINGBULKY POORLY VASCULARISED TUMOURS THAT MAY HAVE HETEROGENOUS CD20 ANTIGEN EXPRESSION,FOLLOWING PREVIOUS MABTHERAPY..
Radiation induced cell death is induced in BOTH the targeted cells and adjacent lymphoma cells due to the radiation cross fire effect.
Long t1/2 of iodine means that protecting the patient’s environment is impt to prevent exposure to others
Y90 is a pure beta emitter with a much shorter t1/2 meaning that treatment can be given as an outpatient.
MINIMISES EXPOSURE TO NON-MALIGNANT CELLS –IMPORTANT IN
ELDERLY PATIENTS WITH CO-MORBIDITIES
WHO HAVEOFTEN HADSEVERAL LINES OF THERAPY
Key Point: Radioimmumotherapy (RIT) provides a synergistic therapeutic effect.
Conjugating a monoclonal antibody with a radioactive particle provides a synergistic therapeutic benefit greater than that of each of the separate modalities.1
The continuous targeted delivery of low-dose radiation by RIT to the tumour causes cells to be blocked from progressing past the G2 phase of the cell cycle.2 The accumulation of cells at this stage is thought to increase the cytotoxicity of continuous low doses of radiation by preventing initiation of cellular DNA repair mechanisms.
Radiation can be delivered to neighbouring tumour cells that are antigen negative or to which antibody has not bound through a ‘cross-fire’ effect. This effect is particularly useful in the treatment of tumours with heterogeneous antigen expression, as well as bulky or poorly vascularized tumours where some cells are inaccessible to monoclonal antibodies.3,4
1. Witzig TE, White CA, Wiseman GA et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell non-Hodgkin's lymphoma. J Clin Oncol 1999;17(12):3793–3803.
2. Press OW. Physics for practitioners: the use of radiolabeled monoclonal antibodies in B-cell non-Hodgkin’s lymphoma. Semin Hematol 2000;37(4, suppl 7):2–8.
3. Krasner C, Joyce RM. Zevalin™: 90yttrium labelled anti-CD20 (ibritumomab tiuxetan), a new treatment for non-Hodgkin’s lymphoma. Curr Pharma Biotech 2001;2:341–349.
4. Zelenetz AD. Radioimmunotherapy for lymphoma. Curr Opin Oncol 1999;11:375–380.

64. CHT25 program Challenge of relapsed/refractory lymphomas
CD25 expressed in a range of lymphomas
Hypothesis: RIT may be beneficial
Chimeric antibody CHT25
Labelled with Iodine-131 (Amlot P, et al)
Rationale for cd25?
expressed in diff lymphomas but few normal cells express CD25
Anti tac for human allograft rejection 9dacluzimab licensed 1997) patients with solid organs experiencing rejection have high sirculating IL2-r levels.
Chimeric antibody to alpha chain of ith IL2 receptor- blocks the interaction of this cytokinewith its receptor.
Why iodine?
Priferation franction
Long decay time of Iodine might have theoretical advantage.

65. Objectives Primary endpoints Toxicity Pharmacokinetics and dosimetry
Secondary endpoints
Preliminary evidence of response
Immunogenicity
Royal Free Hospital

66. Eligibility CD25 positive Hodgkin or T-cell lymphomas
Study Information
Eligibility
CD25 positive Hodgkin or T-cell lymphomas
Standard inclusion and exclusion criteria ≥
≤ 25% bone marrow involved
No human anti-CHT25 antibody
50% lymphoma cells to express CD25
Hodgkin in particular:
Apart from the fact that hrs ARE cd25+
THE TUMOUR CONTAINS ONLY FEW MALIGNANT CELLS
Highly vascular tunours
Waldman had produced responses with naked murine anti-Tac

67. Study details
Therapy 10 mg CHT25 escalating 131Iodine activity patients had 26 treatments (range 1-3)
131I activity
MBq/m2
370
740
1200
1480
2220
2960 No
patients 3 6 1
Better know how MTD was defined

68. Patients 14 patients (8 M, 6 F) Median age 38 (28-70)
11 Hodgkin; 3 T-cell lymphoma
Median number of prior treatments 4 (range 2-8)
9 had an ASCT
Stable dose steroids allowed

69. Toxicity: Non-haematological
Infusional reactions
Grade 1 elevation liver enzymes - transient
Tunneled line infections and chest infection
1 patient with renal failure
1 patient hypothyroid
Generally well tolerated

70. Toxicity - haematological
Administered
Activity
MBq/m2
370
740
1200
1480
≥ 2220
Platelets:
Grade 3 (%)/
duration (days)
nil
60%
3-42
83%
27-78
100%
32-176
Neutrophils:
Grade 4 (%)/
50%
2-30+
25% 36
1 death – Reported as PCP when neutropenic
6 patients had platelet support – at doses ≥ 1200 MBq/m2

71. Response Data -modified Cheson criteria 2007
Injected single dose level
PET / CT combined %
< 1200 MBq/m2
1/8 CR
12.5%
≥ 1200 MBq/m2
6/9 ORR
-3/6 PR
-3/6 CR
66.7%
Evidence of the existence of a dose–response relationship can be inferred from several observations. First, the highest CR rate has been reported in the setting of myeloablative RIT
1 of 3 responses in T cell patients
2 went on to transplant with successful engraftment

74. Conclusions CHT25 Demonstrable activity with a chimeric antibody
Well tolerated at a non-myeloablative dose
MTD defined as 1200 MBq/m2
Transplantation possible post-treatment
Future directions
Transplant conditioning regimens in drug resistance
Combination therapy
Earlier treatment in poor prognosis patients