the evolving role of transplantation in lymphoma stephen mackinnon royal free hospital / university...
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The Evolving Role of
Transplantation in Lymphoma
Stephen Mackinnon
Royal Free Hospital / University College London
Theoretical Advantages for Allogeneic Transplantation
• Tumour free graft
• Undamaged Stem Cells
• Avoidance of MDS/secondary AML
• Graft versus lymphoma effect
Disadvantages of Allogeneic Transplantation in Lymphoma
• Lack of suitable donors
• High Treatment Related Mortality
– Regimen related toxicity
– Infection
– GVHD
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
Allogeneic Transplantation
Myeloablative or Reduced Intensity?
Peneket el al, Bone Marrow Transplant 31:667, 2003
Auto vs Ablative Allo Transplant
TRM
Graft Versus Lymphoma effect or effect of tumour free graft?
Low Grade Histology
Bierman et al. J Clin Oncol 21:3711, 2003
RelapseProgression Free Survival
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-intensitytransplantation with an alemtuzumab-containing regimen:
Aggressive NHL
J Clin Oncol. 2009;27:426-32
10
High-grade NHL: Patients (I)
• n=48• Median age 46 years (range 23–64)• Median lines therapy 5 (range 2–7)• Prior autograft 34 (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
Conditioning regimen
Alemtuzumab 20 mg/d
Fludarabine 30 mg/m2/d
Melphalan 140 mg/m2
Unmanipulated PBSC / Marrow
–8 –7 –6 –5 –4 –3 –2 –1 0Day:
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
Cu
mu
lati
ve I
nci
den
ce
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
Cu
mu
lati
ve I
nci
den
ce
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
Su
rviv
al
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 infusionaGVHD/cGVHD, acute/chronic graft-versus-host disease
17
Current PFS (n=48)
PFS, progression-free survival
0.25
0.50
0.75
1.00
Su
rviv
al
48%
Time (years)
2 4 6 8
18
Current PFS by donor type
0.25
0.50
0.75
1.00
Su
rviv
al
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
Su
rviv
al
55%
12%
0 2 4 6 8
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?
Follicular Lymphoma
Seattle Regimen 2 Gy TBI ± Flu
Transformed follicular
Follicular
J Clin Oncol 26:211,2008
Chronic extensive GVHD in 45%
Related TransplantsIndolent Disease
Overall Survival
Progression Free Survival
Flu / Cy / Rituximab
• Patients– 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
Flu / Cy / Rituximab
Khouri et al. Blood 2008, 111: 5530
Survival
Progression Free Survival
Flu / Cy / Rituximab
Khouri et al. Blood 2008, 111: 5530
Acute GVHD Chronic GVHD
Chronic
Chronic Extensive
II - IV
III - IV
26
Follicular NHL: Patients (I)
• n=78• 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– 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 mortalityby donor type
9% Sibling
22% Unrelated0.25
0.5
0.75
1.0
1000 2000 3000
Cum
ulat
ive
Inci
denc
e
Days
Thomson et al. ASH 2007; abstr 1661
31
Follicular NHL: Overall survival (n=78) GVHD and donor type
0.25
0.5
0.75
1.0
1.8 3.6 5.4 7.2 9
0.25
0.5
0.75
1.0
1.8 3.6 5.4 7.2 9
76%
Impact of GVHD
Sibling 90%
Unrelated 61%
Years
p<0.005
Years
Thomson et al. ASH 2007; abstr 1661
32
Follicular NHL: Overall survival by prior autograft and chemosensitivity
0.25
0.5
0.75
1.0
0.25
0.5
0.75
1.0
1.8 3.6 5.4 7.2 9 1.8 3.6 5.4 7.2 9
Prior Autologous Transplant
No 85%
Yes 52%
p<0.002
Chemosensitive
Yes 79%
No 50%
p<0.04
Thomson et al. ASH 2007; abstr 1661
Years Years
33
- Donor
- Recipient
- Post-Transplant +60 Days
- Post-transplant +90 Days
- Post DLI + 73 Days
(Post Transplant + 6 Months)
34
0 1 2 3 4 5 6 7 8 9 10 11
0.25
0.50
0.75
1.00
Time (years)
Relapse and Chimerism
Full Donor
Mixed Chimerism
p < 0.01
13%
40%
35
Follicular NHL: Relapse (n=78)
0.25
0.5
0.75
1.0
1000 2000 3000
0.25
0.5
0.75
1.0
1000 2000 3000
All patientsImpact of GVHD
acute II–IV or chronic
No GVHD 35%
GVHD 14%
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
1 2 3 4 5 6 7 8 9 10
0.25
0.5
0.75
1.0
1 2 3 4 5 6 7 8 9 10
74%
All patients
Siblings 87%
Unrelated 62%
p<0.02
Thomson et al. ASH 2007; abstr 1661
Years Years
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 ?
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?
Prognostic Role of PET
before and after Allogeneic
Stem Cell Transplantation
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
Prognostic value of PET status pre-auto-transplant for aggressive lymphoma: PFS
40
60
80
100
Time (days)
Cum
ulat
ive
perc
ent
surv
ivin
g
0
20
0
Spaepen et al. Blood 2003;102:53–59
PET –PET +
Copyright ©2003 American Society of Hematology.
500 1000 1500 2000 2500
Trial Aims
1. Is pre-transplant PET predictive of outcome ?
2. Is post-transplant PET clinically useful ?
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
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
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 4 4 11 3
Mantle cell lymphoma 1 4 6 0
Diffuse large B-cell lymphoma 2 4 1 0
Transformed follicular 1 2 2 1
Peripheral T-cell lymphoma 1 1 2 0
47
Relapse
0 20 40 60 80 1000
20
40
60
80
100
Time (months)
p=0.52
Per
cen
t
Overall survival
0 20 40 60 80 1000
20
40
60
80
100p=0.91
Time (months)
Per
cen
t
Disease-free survival
0 20 40 60 80 1000
20
40
60
80
100p=0.78
Time (months)
Per
cen
t
Current DFS
0 20 40 60 80 1000
20
40
60
80
100p=0.87
Time (months)
Pe
rce
nt
48
Follicular Lymphoma cPFS by PET Status
Pretransplant
Months
PET negative
PET positive
49
subsequent coursefirst 6 monthspre-RIT subsequent coursefirst 6 monthspre-RITPre Tx 1st 6 months Subsequent follow up
PET +ve(n = 38)
PET +ve(n = 13)
PET +ve(n = 21)
NRM(n = 5)
50
subsequent coursefirst 6 monthspre-RIT subsequent coursefirst 6 monthspre-RITPre Tx 1st 6 months Subsequent follow up
PET +ve(n = 38)
PET +ve(n = 13)
PET +ve(n = 21)
PET -ve(n = 15)
NRM(n = 4)
51
subsequent coursefirst 6 monthspre-RIT subsequent coursefirst 6 monthspre-RITPre Tx 1st 6 months Subsequent follow up
PET +ve(n = 38)
PET +ve(n = 13)
No DLI(n = 5)
Rel(n = 4)
No DLI(n = 1)
PET +ve(n = 21)
PET -ve(n = 15)
NRM(n = 4)
NRM(n = 2)
DLI(n = 3)
DLI(n = 8)
52
subsequent coursefirst 6 monthspre-RIT subsequent coursefirst 6 monthspre-RITPre Tx 1st 6 months Subsequent follow up
PET +ve(n = 38)
PET +ve(n = 13)
No DLI(n = 5)
PR(n = 2)
Rel(n = 4)
No DLI(n = 1)
PET +ve(n = 1)
PET +ve(n = 21)
PET -ve(n = 6)
PET -ve(n = 3)
PET -ve(n = 15)
PET -ve(n = 2)
NRM(n = 4)
NRM(n = 2)
DLI(n = 3)
DLI(n = 8)
53
subsequent coursefirst 6 monthspre-RIT subsequent coursefirst 6 monthspre-RITPre Tx 1st 6 months Subsequent follow up
PET +ve(n = 38)
PET +ve(n = 13)
No DLI(n = 5)
PR(n = 2)
2nd Rel(n = 3)
No DLI(n = 1)
Rel(n = 4)
No DLI(n = 1)
PET +ve(n = 1)
PET +ve(n = 21)
PET -ve(n = 6)
PET -ve(n = 3)
PET -ve(n = 2)
PET -ve(n = 15)
PET -ve(n = 2)
NRM(n = 4)
NRM(n = 2)
DLI(n = 3)
DLI(n = 8)
DLI(n = 2)
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
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
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
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
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
61
Principles of Radioimmunotherapy
External-beam radiation Radioimmunotherapy
62
Principles of radioimmunotherapy
63
Principles of Radioimmunotherapy
Naked antibody Radio-labelled antibody
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)
65
Objectives
• Primary endpoints
– Toxicity
– Pharmacokinetics and dosimetry
• Secondary endpoints
– Preliminary evidence of response
– ImmunogenicityRoyal Free Hospital
66
Study Information
• 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
Eligibility
67
Study details
• Therapy 10 mg CHT25 escalating 131Iodine activity 14 patients had 26 treatments (range 1-3)
131I activity
MBq/m2 370 740 1200 1480 2220 2960
No
patients
3 6 3 6 3 1
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
70
Toxicity - haematological
• 1 death – Reported as PCP when neutropenic • 6 patients had platelet support – at doses ≥ 1200 MBq/m2
Administered
Activity
MBq/m2
370 740 1200 1480 ≥ 2220
Platelets:
Grade 3 (%)/
duration (days)
nil nil 60%
3-42
83%
27-78
100%
32-176
Neutrophils:
Grade 4 (%)/
duration (days)
nil nil nil 50%
2-30+
25%
36
71
Response Data -modified Cheson criteria
2007
• 1 of 3 responses in T cell patients• 2 went on to transplant with successful engraftment
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%
72
73
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