The role of transplant for CML in the
imatinib era
Dr Wendy Ingram
Consultant Haematologist
University Hospital of Wales
What is Haematopoietic Stem Cell
Transplantation?
• Deliver high dose chemotherapy +/- radiotherapy
– Eradicate tumour cells
– Destroys haematopoietic stem cells in bone marrow
• Autologous transplant
– Infuse stored stem cells from the patient
• Allogeneic transplant
– Replace with alternative donor stem cells
• New blood cells
• New immune system – survey the body and aim to prevent
tumour cells from returning
Allogeneic Stem Cell Transplantation
Shlomchik WD, Nature Reviews Immunology 7, 340-352 (May 2007)
Allogeneic Transplantation
Benefits
• Potential Cure
– Graft versus Leukaemia
effect
Risks
• Toxicity of conditioning
– Immediate
– Late
• Avoid long term therapy
– Side effects of TKIs
– Lack of efficacy
• Infection
• Graft versus host disease
• Relapse
Absolute numbers of allogeneic and
autologous SCT performed for CML in Europe
from 1990–2004
•
Reduction in alloSCT for CML in 1st CP preceded demonstration of
survival benefit for imatinib
•
AlloSCT now ‘second-line’ or ‘third-line’ strategy for patients failing
imatinib
Number of allogeneic transplants,
by disease, registered with CIBMTR
1998-2008
3,000
Transplants
2,500
AML
ALL
CML
AA
LYM / MM / CLL
2,000
1,500
1,000
500
0
1999
2000
2001
2002
2003
2004
2005
2006
2007 *
2008 *
* Data incomplete
Changing trends in the characteristics of
patients transplanted since 1980
Median age (years)
Donor type
HLA ident. sib.
Unrelated donor
Stem cell source
Bone marrow
PBSC
Conditioning
Standard
RIC
1980–1990
(N=2628)
33
1991–1999
(N=7770)
37
2000–2003
(N=3018)
37
85%
7%
62%
29%
56%
36%
100%
–
79%
21%
47%
53%
99%
1%
94%
6%
83%
17%
2007-2008
(N=627)
45%
55%
74%
26%
•
Proportion of patients age >40 years increased from 22% to 41%
between first and last cohort
•
Increased transplant of patients with EBMT risk score 5 (from 5% up
to 12%)
EBMT Registry data
Overall Survival of CML by disease stage
and type of donor (1997-2008)
CP1
CP2/AP
HLA-id sib (N=3931)
MUD (N=1806)
HLA-id sib (N=936)
MUD (N=719)
p<0.001
p<0.001
BC
MUD (N=150)
p=0.55
EBMT Registry data
HLA-id sib (N=236)
Probability of survival after HLA-matched
sibling donor transplant for CML, by disease
status and transplant year, 1998-2008
Probability of Survival, %
100
100
90
90
80
80
CP, 2001-2008 (N=2,412)
70
70
CP, 1998-2000 (N=2,302)
60
50
60
50
AP, 2001-2008 (N=314)
40
40
AP, 1998-2000 (N=301)
30
30
20
20
10
10
P < 0.0001
0
0
0
1
2
3
Years
4
5
6
Reduced Intensity SCT in CML
• Percentage of patients undergoing RIC SCT for CML
has risen from 1% in 1990 to 31% in 2004
• Highly immunosuppressive
• Relies more on graft-versus-leukaemia (GvL) effect than
myeloablation for anti-tumour activity
OS
PFS
Time (months)
•
•
•
Effect of disease phase on
overall survival with RIC
SCT for CML
Survival probability
Survival probability
Overall survival and
progression free survival
for RIC SCT in CML
CP (n=144)
AP/BC (n=42)
Time (months)
Analysis of outcomes stratified to risk group suggest that PFS and OS
at 3 years equivalent to those of standard alloSCT
BUT – short follow-up
Standard alloSCT survival continues to improve
Crawley et al, Blood 2005; 106: 2969–2976
UHW experience since 2000
• 9 Chronic Phase 1
• Median age 44 yrs
(17-63 yrs)
• Median time from
diagnosis to
transplant 589 days
• 3 sibling, 6 unrelated
• 2 standard, 7 RIC
• 10 Chronic Phase 2
• 4 AP, 2 Blast crisis
• Median age 50 yrs
(26-65 yrs)
• Median time from
diagnosis to
transplant 589 days
• 7 sibling, 9 unrelated
• 4 standard, 12 RIC
12
UHW experience since 2000
CP1
• 10 patients
• 2 deaths due to TRM
• 2 relapse – 1 rescued
with donor lymphocytes
CP2, AP, BC
• 16 patients
• 6 deaths due to TRM
• 5 relapse – 1 rescued
with donor lymphocytes
13
Relapse post Allogeneic SCT
• Occurs in 16–33% of patients post SCT
• Decision on how to treat based on risk of GvHD and how
fast BCR-ABL levels are rising
–
–
–
–
Unrelated donor versus sibling donor
Previous GvHD
Mismatched donor
Age
• Choice lies between either Donor Lymphocyte Infusion
(DLI) or imatinib or both
– Rarely will consider second alloSCT from different donor
Donor lymphocyte infusions can be used
to manage relapse
• Patients relapsing after SCT for CML are very sensitive
to DLI
• 60–90% response rate/remission
– >90% response in patients transplanted in early CP
– Further benefit in subsequent relapse
• Incremental dosing reduces risk of GvHD
Guglielmi et al, Blood 2002; 100: 397–405.
Imatinib for relapse post SCT: What is
the evidence for efficacy?
• Imatinib also effective post SCT with benefits in all stages of
disease
• Hammersmith study (n=128)1
–
–
–
–
–
CP = 51; AP = 31; BC = 46
50 patients failed DLI prior to imatinib
Overall haematologic response 84%; 98% for patients relapsing in CP
CCyR: CP, 58%; AP, 48%; BC, 22%
25 patients achieved complete molecular remission
• However, response may be less durable than DLI
– Higher incidence of relapse and inferior leukaemia-free survival (6/10
patients relapsed on Imatinib)2
• DLI and imatinib may be synergistic3
• However majority of patients now being transplanted are imatinibresistant or intolerant
1Olavarria
et al, Leukaemia 2003; 17(9): 1707–1712; 2Weisser et al, Haematologica 2006; 91: 663–666;
3Savani et al, Lancet Oncology 2005;6:809-812
The impact of newer TKIs on SCT
• Limited data
• Likely to have a role in patients relapsing post SCT who
were resistant to / intolerant of imatinib
• Often patients have already failed second generation
TKI prior to transplant
• For patients who are resistant to or intolerant of imatinib
as first-line therapy, choice lies between alloSCT (if
available donor) and second generation TKI
Summary
Who is a candidate for SCT?
• High Sokal score and low EBMT score at presentation
– Discuss choice of alloSCT versus imatinib
– Consider trial of Imatinib in these high-risk patients
– Decision to transplant may be based on response
• Intolerance to imatinib and second generation TKI
– Consider alloSCT, IFN or experimental therapy
• Choices after failure of or suboptimal response to imatinib 400 mg:
– Dose escalation
– Second generation TKI
– For T315I BCR-ABL kinase domain mutation consider SCT or clinical
trial
• For patients with blast crisis, consider imatinib or other TKI followed
by alloSCT and restart TKI when counts recover post transplant
Acknowledgments
• Dr Mhairi Copland, University of Glasgow
• Dr Keith Wilson BMT Programme Director, University
Hospital of Wales
• Dr Andy Goringe
• Dr Jonathan Kell
• Dr Steve Knapper
• Referring clinicians