Transcript Patient characteristics

Ph positive ALL;
Is transplant still
necessary?
Adele K. Fielding MB BS, PhD
Chair UK National Cancer Research Institute
Adult ALL Subgroup
Outline of talk
Why we use alloHSCT in Ph+ ALL – what is the evidence
it is of value?
Why is it so difficult to draw firm conclusions about the
role of alloHSCT?
Where does non-myeloablative alloHSCT fit in?
Now we have TKIs, do we still need transplant
Illustrate various points above with some data from
UKALL12/ECOG2993
Conclusions about current role of TKI and alloHSCT
Ph+ ALL - the scope of the problem
Long been concluded that patients with t(9;22)
have a poor outcome with conventional therapy
Considered “Very high risk” by all clinical studies
Typically ‘assigned’ to alloHSCT
Ph+ ALL - the scope of the problem
Karyotype
t(4;11)
*% Adults
**% Children
5
1
t(9;22)
21
2
t(12;21)
<1
19
Poor risk
Good risk
High
hyperdiploidy
9
32
*Moorman et al Blood 2007
**Hann et al BJH 2002
Age in ALL; tolerance of therapy ?
Group
Induction
Death %
Resistance to
induction Rx
“Children”
AIEOP-91
COALL-92
DFCI-01
EORTCCCLG
SJ CRH 13B
1.4
0.4
0.5
0.9
1.2
2.1
0.9
1.3
1.3
0.8
“Adults”
GMALL05/93
GOELAM-02
HyperCVAD
JALSG-93
LALA-94
6
3
5
6
5
11
18
3
16
11
After Pui and Evans, NEJM 2006
Myeloablative allogeneic HSCT
The most active anti-ALL therapy currently available, but
also the most toxic
For whom?
•Age
Convincing data •Status of disease
•At what level of relapse-risk
Useful data
Conflicting data
Scant data
What is the best method ?
•Conditioning regimen
•Stem cell source
•Unrelated vs. sibling donor
•Role of T cell depletion
•GVHD prophylaxis/ KGF e.g. palifermin
•Post-BMT interventions e.g. DLI, TKI
GVL effect
The most active anti-ALL therapy currently available,
but also the most toxic
Relationship between acute graft versus
host disease and outcome.
GVHD
No
Yes
%RFS
35%
68%
% EFS
30%
39%
TRM
14%
42%
Fielding et al Blood 2009 UKALL12/ECOG2993
OS > 600 patients after relapse
At what level of relapse-risk?
Percent surviving
100
75
Fielding et al 2007 UKALL12/ECOG2993
50
7%
25
0
0
1
2
3
Time (years)
Other large relapse studies:
Tavernier et al 2007
LALA94
Oriol et al 2010
PETHEMA
4
DFS 5 yr
OS 5yr
5
12%
10%
Myeloablative alloHSCT
A ‘transplanters’ perspective?
“That which doesn’t kill us makes us
stronger”
Nietzsche
“If it doesn’t feel bad, it can’t be doing
you any good”
Alice Fielding (my mum)
Sibling Myeloablative allo HSCT
Pre-TKI era
N
CR?
Forman 1987
10
Mixed Cy, CyVP/TBI
40%
Median 19 mo.
Chao 1995
38
Mixed mixed
N/s
46% @ 2yr (CR1)
Snyder 1999
23
CR1
40%
65% @ 3 yr
Barrett 1992
67
Mixed Mixed
42%
38% @ 2 yr
*Dombret 2002
74 (154) CR1
N/S
24% (donor
28% @ 3yr (donor
*Fielding 2009
50 (267) CR1
VP/TBI
30%
41% @ 5 yr
*prospective studies
Conditioning TRM
VP/TBI
Survival
UD donor Myeloablative allo
HSCT; preTKI era
•Retrospective studies, not all patients Ph+
•Mixed ages
•Some patients beyond CR1
Equivalent outcome between
unrelated and sibling donor:
Cornillissen, 2001 Blood
Dahlke, 2006 BMT
Kiehl, 2004 J Clin Oncol
PERCENT
UD donor Myeloablative allo HSCT
OS UKALL12/ECOG2993
Pre-TKI
100
75
50
44 Sib
36 MUD
25
19 chemo
0
0
At risk:
Sib
MUD
Chemo
1
2
3
4
TIME IN YEARS
5
45
31
35
23
29
12
25
12
19
11
18
11
82
43
23
19
15
12
Fielding et al Blood 2009
Difficulties in studying the
alloHSCT question
1. Trial Design
Equipoise problems in designing RCTs with
myeloablative alloHSCT as an arm
Impossibility of “donor vs. no donor”analysis
in modern transplant studies where UD
are commonly available
Difficulties in studying the
alloHSCT question
2. Selection bias
“Transplant only” retrospective studies do
not include a denominator. Hence, benefit
can only apply to those selected for
reporting
Those might be only a tiny fraction of the
at-risk population & are unlikely to be
representative
Difficulties in studying the
alloHSCT question
3. Immortal time bias
A patient receiving a transplant within a
prospective study is guaranteed to have entered
CR and survived, disease free to the time of
transplant
A simple analysis by therapy received during trial
doesn’t represent the reality for a future new
patient accurately
Immortal time bias: an example
Sib
MUD
Chemo
alloHSCT alloHSCT
(n=45)
(n=31)
(n=82)
% event-free at 5y (CI)
*OS
*EFS
*RFS
44%
36%
(29-59%) (19-52%)
41%
36%
(27-56%) (19-52%)
57%
66%
(40-73%) (48-85%)
19%
(10-28%)
9%
(3-15%)
10%
(3-18%)
* P=0.001
Fielding et al, Blood 2009 UKALL12/ECOG2993 – pre TKI era
Immortal time bias: an example
Adjust for sex, age and WBC & exclude
those who relapsed or died before the
median time to alloHSCT.
RFS remained significantly superior to
chemotherapy in the HSCT groups
However, there was no longer a
significant difference in OS or EFS
between HSCT and chemotherapy.
Fielding et al Blood 2009
UKALL12/ECOG2993
Myeloablative Allo in Ph ALL
•Weight of evidence has been interpreted
In favour of myeloablative allo HSCT
Those patients who
•Achieve CR
•Have a donor
•Are fit enough to have a transplant
•…Receive the transplant
Will have a better outcome than those who don’t
Non-myeloablative alloHSCT
N N
CR1 % Conditioning
Ph+
Arnold 2002
22 11 50
various
Martino 2003
27 11 15
Flu/Mel
Flu/Mel/Cam
Stein 2009
24
Flu/Mel
Mohty 2008
97 37 29
Various
Bachanova 2009 22 14 55
Flu/Cy/TBI
Ram 2011
51 25 19
Flu/Cy/TBI
Non-myeloablative alloHSCT
Arnold 2002
Martino 2003
Stein 2009
Mohty 2008
Bachanova
2009
Ram 2011
TKI post TRM
%
allo?
(total)
45
No
23
N/S
Various 21
28
N/S
Rel only 27
cGVHD OS %
Ph+
%
46
72
86
37
45
18
31 2yr
61 2 yr
32 2yr
50 2yr
4-600im 28
for 1yr
44
62 3 yr
Likely to be
 much more regimen-dependent,
 more dependent on disease burden at allo
 require more focused post-transplant monitoring (+ intervention
?) than myeloablative
TKI in Ph ALL
1. Is there a higher CR rate with no excess
cost ?
2. Do TKI facilitate alloBMT?
3. Is there a survival advantage for TKIcontaining regimens?
4. Does this advantage occur in the absence
of alloHSCT
For purpose of this talk TKI = largely Imatinib
Data on dasatinib during induction are much
fewer/shorter follow up
TKI in Ph+ ALL
Cautionary note
Hu et al. Nat Genet. 2004
Requirement of Src kinases for BCR-ABL-induced B-ALL
but not CML.
Pfeifer et al Blood 2007
BCR-ABL KD mutation in 40% at presentation
Soverini et al Hematolgica 2011
2-4 clones of 200 for each patient harboured
pre-exisiting KD mutations
Induction therapy Ph pos ALL:Imatinib
Imatinib added to induction/consol’n.
N
CR(%) CR1 SCT (%)
Thomas 2004
20
93
50
Yanda 2006
80
96
49
Wassmann 2006
92
95
77
De Labarthe 2007
45
96
51
Ribera 2009
30
90
78
Bassan 2010
59
92
63
Fielding 2014
175 92
46
Chalandon ongoing
188 95/100
Older
Ottman 2007
55
96
N/A
Vignetti 2007
30
96
N/A
Children
only sibs
Schultz
92
Induction therapy Ph pos ALL:Imatinib
Imatinib added to induction/consol’n.
N
OS
time
Thomas 2004
20
75
20m
Yanda 2006
80
75
12m
Wassmann 2006
92
36/43
24m
De Labarthe 2007
45
65
18m
Ribera 2009
30
30
4yr
Bassan 2010
59
38
5yr
Fielding 2011
175 43
3yr
Chalandon ongoing
188 62
2yr
Older
Ottman 2007
55
74
12m
Vignetti 2007
30
42
24m
Children
Schultz
92
80(EFS)
3yr
Induction therapy Ph pos ALL:Dasatinib
Dasatinib added to induction/consol’n.
Ravandi
Foa
Rousselot
N
CR(%) CR1 SCT (%)
35
48
71
94
100
90
50
N/A
N/A
combo
hyperCVAD
Steroid
EWALL elderly backbone
Induction therapy Ph pos ALL:Dasatinib
Dasatinib added to induction/consol’n.
Ravandi
Foa
Rousselot
N
OS
time
35
48
71
64
80.7
24m
10m
median 21.7m
TKI without transplant in Ph+ ALL
•Older patients
•Patients unfit for alloHSCT
•Those fit, but without any donor
•Children, in whom there is reluctance
to use UDs
TKI without transplant in Ph ALL
NoBMT
BMT
JALSG: Yanada et al, JCO 2006
Children with Ph+ ALL
Risk:benefit ratio of Rx is unfavourable for UD
Arico et al, NEJM 2009
93 Ph+
Children with Ph+ ALL;
COG study
N=25 chemo+ im 87.7%
N=11 UD HSCT 71.6%
N=25 sibHSCT 56.6%
Schultz et al, 2009 J Clin Onc
UKALLXII/ECOG2993 Ph+: up to 65y
INDUCTION
Phase 1
Phase 2
Early Imatinib N=89
response
determination
Late Imatinib (as a consolidation) N=86
Allogeneic
HSCT
(Etoposide/TBI)
up to 55y.
All patients IMATINIB 600mg od
no donor/unfit
for allo
Autologous HSCT
(Etoposide/TBI)
recommend
Patient characteristics
Pre Imatinib*
266
Total
175
Imatinib
Late
86
Early
89
Male
Female
149 (56%)
117 (44%)
110 (63%)
65 (37%)
54 (63%)
32 (37%)
56 (63%)
33 (37%)
unknown
<30
≥30
median
2 (1%)
140 (52%)
124 (47%)
26.8.0
0
96 (55%)
79 (45%)
21.0
0
46 (53%)
40 (47%)
21.0
0
50 (56%)
39 (44%)
21.0
65 (24%) *
155 (58%)
46 (17%)
40 (15-60)
38 (22%)
75 (43%)
62 (35%)
42 (16-64)
17 (20%)
39 (45%)
30 (35%)
43 (16-63)
21 (24%)
36 (40%)
32 (36%)
42 (16-64)
23 (26%)
3 (3%)
60 (70%)
30 (34%)
0
59 (66%)
N
Sex
WBC
Age
<30
30-49
≥50
median
CNS disease
unknown
Yes
No
12 (5%)
14 (5%)
240 (90%)
53 (30%)
3 $ (2%)
119 (68%)
* Pre-imatinib results: Fielding et al, Blood 2009, “imatinib” paper Fielding et al Blood 2014
Response to Induction
Flow Chart of Post-Induction Therapy
N = 175
Total alive/CR
137 (77%)
Induction death/No CR 14 (8%)
Protocol deviation induction 24 (14%)
Chemo/imatinib
39/137 eligible (28%)
39/175 total (22%)
Myeloablative allo HSCT
82/137 eligible (60%)
82/175 total (46%)
43 sibling donor
33 Matched unrelated donor
3 cord blood
2
Mismatched
unrelated
donor
1 Haploidentical donor
“Non-protocol” RIC alloHSCT
11/137 eligible (8%)
11/175 total (6%)
6 sibling donor
5 Matched unrelated donor
Transplant details
Protocol BMT rate
Pre-imatinib
Imatinib
28%
46%
Reach 84 day in CR
78%
Median days diag to BMT135d
% elig pt receiving BMT
71%
66% .009
160d <.0001
55% <.0001
Both imatinib, overall better BMT practice contributed to the
improved alloHSCT rate after imatinib
Overall outcomes
Imatinib vs.Pre-Imatinib
Pre Imatinib
Imatinib
% (95% CI) % (95% CI)
OS 3 years
EFS 3 years
RFS 3 years
22 (20-30)
18 (14-24)
36 (28-43)
Median FU Pre-imatinib
Median FU Imatinib
38 (35-50)
33 (29-44)
50 (44-62)
10 years
3 years
p=0.0001
p<0.0001
p=0.0001
OS
Imatinib vs. pre-Imatinib
Percent surviving
100
Pre-imatinib versus imatinib, p=0.0003
75
50
imatinib
32%
25
19%
Pre-imatinib
0
0
1
2
3
4
5
6
7
Time (years)
Pre-imatinib
266
144
81
67
57
54
49
Imatinib
175
115
81
69
53
31
17
8
9
10
46
41
40
35
9
4
0
0
At risk:
Relapse risk
Imatinib vs. Pre-Imatinib
% relapsing
100
64% Imatinib
75
50
47% Pre-imatinib
25
0
1
2
Time in years
3
2P = 0·0001
OS within imatinib cohort
from diagnosis, by treatment in CR1
Percent surviving
100
Protocol alloHSCT
75
50%
50
Non-protocol RIC alloHSCT 39%
25
19%
No alloHSCT
0
0
1
2
Time (years)
3
4
76
11
57
8
45
6
42
5
31
3
38
20
9
7
6
At risk:
Protocol alloHSCT
Non-protocol RIC alloHSCT
No alloHSCT
% relapsing
Relapse risk within imatinib cohort
by treatment in CR1
100
73% No BMT
75
49% Non Protocol
BMT
50
25
0
25% Prot BMT
0
1
2
Time (years)
3
Outcome by timing of imatinib
start
LATE
EARLY
Imatinib Imatinib
% (95% CI) % (95% CI)
OS 3 years
EFS 3 years
RFS 3 years
34(34-49)
29 (19-38)
45 (33-57)
48(33-60)
45(34-56)
62 (50-75)
p=0.05
p=0.04
p=0.02
Multivariate Cox Regression
OS
Co-Variate HR
95%CI
P
Imatinib
0.56
0.44 - 0.71
<0.0001
Age
1.02
1.02 - 1.03
<0.0001
Pres.WCC
1.32
1.21 - 1.43
<0.0001
OS for patients not receiving alloHSCT
100
ALL CRs but NO BMT
75
50
24% Imatinib
% still alive
25
0
18%Pre-imatinib
3
1
2
Univariate: unadjusted p=0.08
Cox, allowing for age and WBC p=0.02
100
Excl. Rel/died within
median time to BMT
75
50
24% Imatinib
22% Pre-imatinib
25
0
1
2
3
Time in years
Univariate unadjusted: p>0.1
Cox, allowing for age and WBC p=0.05
TKI post alloHSCT
Yes/No?
PETHEMA: post myeloablative alloHSCT poorly tolerated
only 62% started, many discontinued
U of Minn trend towards better outcome on those given imatinib
(v. small study)
Seattle RIC allo – trend towards better outcome when imatinib was
given but no effect on relapse
For everyone or selected patients ?
GMALL up-front at 3 months vs. only upon BCR-ABL re-appearance
Poorly tolerated when started early
No difference so far between the groups
For how long?
No idea….! Most studies select 1-2 years - empirically
Conclusions
•Higher CR rate by 10% with no increase in TRM
when imatinib is added to therapy
•
Imatinib almost doubled the rate of alloHSCT in
UKALL12/ECOG2993
•
Overall, significantly improved outcomes in all
endpoints measured are typical in imatinib containing
regimens
Overall Outcomes for Ph+ ALL Rx are now encouraging:
UKALL
62%
GMALL
72%OS @3y imatinib/allo
JALSG
65%
Conclusions
•improved outcome in TKI era relates mostly to a higher rate
of alloHSCT --- modest (?no) long term benefit to imatinib
where HSCT not achieved
•UKALL12/E2993 and GMALL studies – still poor outcome
where no myeloablative alloHSCT
No role for omitting alloHSCT in adults with Ph+ ALL
Not yet clear how best to use TKI post allo
Strong argument for future, large international co-operative studies
I think I’d rather manage a large
international collaboration
of transplant physicians
UKALL12/ECOG2993
Ph positive arm: imatinib
Funded:
UK National
Cancer Research
Institute
Adult ALL
Subgroup
Adele K. Fielding
Georgina Buck
Letizia Foroni
Hillard Lazarus
Mark Litzow
Selina M. Luger
David I. Marks
Andrew K. McMillan
Anthony Moorman
Elisabeth Paietta USA
Susan M. Richards Eastern Co-operative
Jacob M. Rowe
Oncology Group
Marty S. Tallman
Anthony H.Goldstone