transplantation in cll · 2013-02-14 · observation pfs . pfs ttrt os fcr auto . the european...
TRANSCRIPT
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Peter Dreger Dept. Internal Medicine V
University of Heidelberg
Gent 25.01.2013
Transplantation
in CLL
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Allogeneic SCT
= initiation of a permanent
immunotherapeutic process!
graft-vs-tumor effect (GVT/GVL)
Autologous SCT
= supportive measure to compensate
hematopoietic toxicity of single-hit
high-dose therapy
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Months from randomisation Months from randomisation
TTRT
ASCT observation
PFS
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PFS TTRT OS
FCR
auto
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The European Group for Blood and Marrow Transplantation
0
50
100
150
200
250
300
350
400
20002001
20022003
20042005
20062007
20082009
2010
allo auto
EBMT: SCT for CLL 2000-2010 Update January 2012
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The European Group for Blood and Marrow Transplantation
0
50
100
150
200
250
300
350
0
50
100
150
200
250
300
350
0
200
400
600
800
1000
1200
1400
1600
1800
Transplant activity for lymphoma
EBMT 2000-2010
auto
allo
Absolute numbers 2010 % increase 2000 -> 2009
CLL HL TCL DLC
L
FL MCL
DLCL HL MCL TCL FL CLL
-100
-50
0
50
100
150
Total lymphoma transplants 2010 (with CLL): allo 1732; auto 5891
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The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation
- Do GVL effects exist?
- Therapeutic benefit?
- Indications?
CLL and alloSCT:
Key questions
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alloSCT for CLL: MRD response patterns
A: MRD- after CSA taper
CSA taper
GVHD
Ritgen et al, Leukemia 22:1377 (2008)
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alloSCT for CLL: MRD response patterns
A: MRD- after CSA taper
CSA taper
GVHD
Dreger et al, Blood 116:2438 (2010)
MRD- immediately
after SCT (16%)
MRD- after CSA
taper (42%)
Other pattern
(42%)
Ritgen et al, Leukemia 22:1377 (2008)
CLL3X (n=52)
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alloSCT for CLL: MRD response patterns
Dreger et al, Blood 116:2438 (2010)
MRD- immediately
after SCT (16%)
MRD- after CSA
taper (42%)
Other pattern
(42%)
Hahn et al, EBMT 2013
CLL3X (n=52)
MRD- immediately
after SCT (34%)
MRD- after CSA
taper (35%)
Heidelberg 2005-2012
(n=62)
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Are MRD responses durable?
Results from landmark analyses
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113
100
90
13 ineligible (no CLL, late
registration, comorbidity etc.)
10 no SCT (Richter‘s, ED,
no donor, refusal)
38 no continuous
MRD sampling
52 13 event <12mo,
CLL3X: Patient flow (MRD)
27 MRD-neg
at +12mo
11 MRD-pos
at +12mo
1 no MRD
at +12mo
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CLL3X 6-year follow-up: Relapse
by MRD negativity at +12mo (of 38 patients with MRD monitoring and event-free at mo +12)
12 36 60 84 1080
50
100 +12 MRD+ (10)
+12 MRD- (28)
HR 26.2 (6-115); p 0.0001
Months from SCT
Perc
en
t re
lap
sed
Clinical Relapse MRD or clinical relapse
36 60 84 1080
50
100
16% (95%CI 1-50)
Months from SCT
Perc
en
t M
RD
or
clin
ical re
lap
se
ASH 2012, abstract #966 Dreger et al
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ASH 2012, abstract #966 Dreger et al
12 36 60 84 108
0
50
100
16% (95%CI 1-51)
17p-
TP53 mut
NOTCH1 mutSF3B1 mut
no marker
Months from SCT
Pe
rce
nt
no
t in
MR
D-n
eg
ati
ve
clin
ical re
mis
sio
n
CLL3X 6-year follow-up: Relapse
by MRD negativity at +12mo (of 38 patients with MRD monitoring and event-free at mo +12)
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53 3 no continuous
MRD sampling
Heidelberg 2005-2012: Patient flow (MRD)
3 MRD-neg
at +12mo
after REL
2 MRD-pos
at +12mo
after REL
9 MRD-pos
and ev.-free
at +12mo
66 13 too early
7 TRM
29 MRD-neg
and ev.-free
at +12mo
58% (29 of 50)
6% 18% 4%
14%
Hahn et al, EBMT 2013
50
43
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Heidelberg CLL 2005-2012:
Relapse by MRD negativity at +12mo (of 38 patients with MRD monitoring and event-free at mo +12)
12 36 60 84
0
25
50
75
100 +12 MRD+ (9)
+12 MRD- (29)
p<0.0001
Months from SCT
Perc
en
t re
lap
sed
Clinical Relapse MRD relapse of patients MRD- at 12months
12 36 60 84
0
50
100
7% (95%CI 0-68)
Months from SCT
Perc
en
t M
RD
rela
pse
Hahn et al, EBMT 2013
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Clinical impact of MRD negativity at the
+6mo landmark (Milan data)
Farina et al, Haematologica 94:654 (2009)
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The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation
- Do GVL effects exist?
yes. Even in poor-risk disease.
- Therapeutic benefit?
- Indications?
CLL and alloSCT:
Key questions
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PFS after RIC alloSCT for CLL
Study GCLLSG Seattle Boston FCGCLL Houston
n 90 82 76 40 86
PFS 38% (6y) 39% (5y) 43% (5y) 46% (3y) 36% (5y)
OS 58% (6y) 50% (5y) 63% (5y) 55% (3y) 51% (5y)
NRM 23% (6y) 23% (5y) 16% (5y) 27% (3y) 17% (1y)
Ext. cGVHD 55% 49-53% 64% 42% 56%
F/U mo 72 (7-129) 11-87 61 28 (3-71) 37(11-131)
0 24 48 72 96 1200
50
100
6-y EFS 38% (27, 48)
Months from SCT
Perc
en
t E
FS
GCLLSG ASH 2012; Sorror JCO 2008; Brown Leukemia 2012;
Michallet Exp Hematol 2012; Khouri Cancer 2011
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What does that mean in
real life?
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I Herth, U Hegenbart, S Dietrich, M Rieger, P Stadtherr, A Bondong, H
Tran, T Zenz, AD Ho, P Dreger
Dept Medicine V, University of Heidelberg, Germany
First evidence that alloSCT can improve the natural
course of poor-risk CLL as defined by the EBMT
consensus criteria:
A retrospective donor vs no donor comparison.
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Department of Internal Medicine V
• Design:
Single center retrospective analysis
• Patient eligibility:
All consecutive patients referred
for alloSCT for CLL between June
2005 and July 2011
to the University of Heidelberg
Study design and patients
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Department of Internal Medicine V
Eligibility for donor search was either
one of the three EBMT consensus criteria
or
Richter‘s transformation.
• symptomatic 17p-
• fludarabine refractoriness (non-response or relapse within 6 months after the last cycle)
• early relapse after intensive pretreatment (relapse after intensive treatment like FR, FCR, BR, R-CHOP or similar later
than 6 months but within 2 years)
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Department of Internal Medicine V
Study population:
patients for whom a 9/10 or 10/10
matched related or unrelated donor could
be found within 3 months
Control population:
patients without 9/10 or 10/10 matched
donor found within 3 months
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Department of Internal Medicine V
Overall survival (OS),
measured from the 3-month
landmark after donor search
initiation
(to eliminate the early relapse-
mortality favoring the donor group).
Primary endpoint
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Department of Internal Medicine V
Donor
search
indication
(=EBMT risk
or Richter’s)
?
B
Observe OS
yes
Observe OS
8 lost w/i
3 months (6 dead PD, 1
refusal, 1 lost
to f/u)
Heidelberg donor vs no-donor CLL study Patient flow
134 113
3
105 SEARCH
8 No
search 5 refusal,
1 comorbidity,
2 lost to f/u R
E
F
E
R
R
A
L
no
21
MCL 2,
MZL 1
donor 9/10
within 3 Mo
83
no donor 9/10
within 3 Mo
14
Herth et al, EBMT 2012
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0 12 24 36 48 60 720
25
50
75
100
p 0.011 ; HR 3.85 (1.36-10.8)
donor yes (83)
donor no (14)
55% (33-85)
78% (65-86)
Months from 3 month after start of search
Perc
en
t alive
Overall survival from 3 months after start of donor
search by donor availability (all patients with donor search completed, n = 97)
Follow-up 25 (0.5-80) months
Medizinische Klinik V
Herth et al, EBMT 2012
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Variable Hazard
ratio Lower CL Upper CL p
Donor yes 0.29 0.15 0.65 0.003
Previous therapies >2 2.88 1.33 6.26 0.008
Age per decade 0.55 0.32 0.94 0.03
Donor availibility and overall survival:
Multivariate analysis Patients with completed search (3-months landmark), n=97
Variables not remaining in the model:
Search indication (EBMT criterion), Binet stage
Herth et al, EBMT 2012
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0 12 24 36 48 60 720
25
50
75
100
p 0.011 ; HR 3.85 (1.36-10.8)
donor yes (83)
donor no (14)
55% (33-85)
78% (65-86)
Months from 3 month after start of search
Perc
en
t alive
Long-term survivors in no-donor group Medizinische Klinik V
m, 55y, early relapse,
5th-line treatment
m, 51y, fludara-refr.,
SCT (late donor),
a&w 55+ months
m, 57y, 17p-,
SCT (2mm donor),
a&w 75+ months
Herth et al, EBMT 2012
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The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation
- Do GVL effects exist?
yes.
- Therapeutic benefit?
Yes! Even in poor-risk disease.
-> …but at what price?
- Indications?
CLL and alloSCT:
Key questions
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Study GCLLSG Seattle Boston FCGCLL Houston
n 90 82 76 40 86
Mucositis 3-4 6% 12% na <5% na
Infection 3-4 55% 60% na 48% na
Early death (< d +100)
<3% <10% <3% 0% 3%
NRM 23% (6y) 23% (5y) 16% (5y) 27% (3y) 17% (1y)
Ext. cGVHD 55% 49-53% 48% 42% 56%
F/U mo 72 (7-129) 11-87 61 28 (3-71) 37(11-131)
Toxicity of RIC alloSCT for CLL
GCLLSG ASH 2012; Sorror JCO 2008; Brown Leukemia 2012;
Michallet Exp Hematol 2012; Khouri Cancer 2011
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The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation
NRM (%) by age groups
0%
10%
20%
30%
40%
50%
60%
100d 6 m 12 m
18-50 yo 51-60 yo 61-70 yo
Lymphoma Registry: Allo-SCT ’06-’10
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25% of allografted patients
will suffer from QOL-relevant
chronic GVHD,
but…
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0 120 240 360 480 600 720
0
20
40
60
80
100
cGVHD cum. incidence:67% at 12months
cGVHD prevalence:52% at 12months
on immunosuppression:39% at 12months
Days from SCT
Perc
en
t w
ith
cG
VH
D
his
tory
Heidelberg CLL 2005-2012:
Chronic GVHD over time (n=66)
Hahn et al, EBMT 2013
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Seattle CLL trial: OS and chronic
GVHD by donor (n=82)
Sorror et al, JCO 26:4912 (2008)
After 5 years, 76% of living patients are off immunosuppression
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The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation
- Do GVL effects exist?
yes.
- Therapeutic benefit?
Cure! Even in poor-risk disease.
But 15-25% 2y-NRM.
- Indications?
CLL and alloSCT:
Key questions
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EBMT CLL transplant consensus
allo-SCT is a reasonable treatmentoption in poor-risk CLL:– .Relapse <24 mo after intensive treatment
(purine analogue combinations or auto-SCT)
– .p53 mutation with treatment indication
– .Non-response or early relapse (<12 mo) afterpurine analogue-based therapy(= fludarabine resistance)
VERY
HI
GH
HI
GH
RISK
Leukemia 21:12-17 (2007)
Still valid in 2013?
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EBMT CLL Transplant Consensus 2013
- Is poor-risk CLL still poor risk?
- Can alloSCT improve the outcome of
poor-risk CLL?
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EBMT CLL Transplant Consensus 2013
- Is poor-risk CLL still poor risk? - 17p-
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1st-line treatment results in 17p- CLL
Overall response Median PFS (mo)
CLL
HL
DLCL
FL
MCL
Hallek 2010, Wierda 2011, Hillmen 2007, Stilgenbauer 2012, Badoux 2011, Fischer 2012
0
20
40
60
80
100
R-
FC
O-
FC
CD52 Lena CD52-
Dexa
0 12 24 36 48
R-FC
O-FC
CD52
Lena
CD52-D
R-B
R-Benda
*
* 27% of patients received alloSCT consolidation
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EBMT CLL Transplant Consensus 2013
- Is poor-risk CLL still poor risk? - 17p-
- PA refractory
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Treatment results in PA-ref CLL
Overall response Median PFS (mo)
CLL
HL
DLCL
FL
MCL
Badoux 2011a, Fischer 2011, Wierda 2010, Stilgenbauer 2012, Badoux 2011b; Lanasa 2010
0
20
40
60
80
100
R-
FC
R-
Ben
da
Ofa Flavo CFAR 0 12 24 36
R-Benda
CD52-D
Ofa
Flavo
CFAR
CD52
R-FC
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EBMT CLL Transplant Consensus 2013
- Is poor-risk CLL still poor risk? - 17p-
- PA refractory
- Relapse within 2 years after intensive therapy
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Overall survival after 1st salvage after
FC/FCR 1st-line failure: CLL8 data
PFS >24 months
Zenz et al, ASH 2010
OS from 2nd-line therapy (months)
PFS <6 months
PFS 12-24 months
PFS 6-12 months
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EBMT CLL Transplant Consensus 2012
- Is poor-risk CLL still poor risk?
yes, but
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BCR kinase inhibitors:
Is the Gleevec of CLL
approaching?
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CLL: B cell receptor signaling downstream
kinase targets and inhibitors
Wiestner et al, Blood Dec 6, 2012
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Risk group n Response rate
All patients 61 67% (CR 2%)
PA-refractory 28 61%
17p- 20 65%
Bruton’s tyrosine kinase inhibitor Ibrutinib:
Phase Ib/II study in rel./ref. CLL (O’Brien et al, ASH 2011)
17p Del No (n=36)
17p Del Yes (n=20)
Median follow-up 9-12mo
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PCYC-1102-CA
Progression-free Survival
Data cut-off of 19OCT2012
R/R + High-Risk R/R (n=85)
Est. PFS at 26 mo is 75%
Months on Study
+ Censored
Logrank p=0.0256
0 5 10 15 20 25
1.0
0.8
0.6
0.4
0.2
0.0
PF
S P
robabili
ty
50
Relapsed/Refractory patients
(n=85; 24 of them relapsed <24mo after immunohemotherapy)
ASH 2012, abstract #188 Byrd et al
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PCYC-1102-CA
Patient Characteristics
TN ≥65 yrs (N=31)
R/R + HR (N=85)
Age, years Median (Range)
71 (65 – 84)
66 (37 – 82)
Fludarabine refractory - 48%
Prognostic Markers, % IgVH unmutated del(17p13.1) del(11q22.3)
55% 7% 3%
85% 35% 39%
51
ASH 2012, abstract #188 Byrd et al
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PCYC-1102-CA
Progression-free Survival
del(17p13.1)/del(11q22.3) Status
Months on Study
Data cut-off of 19OCT2012
del17p (n=28)
Est. PFS at 26 mo is 57%
del11q (n=23)
Est. PFS at 26 mo is 73%
No del17p or del11q (n=29)
Est. PFS at 26 mo is 93%
1.0
0.8
0.6
0.4
0.2
0.0
PF
S P
rob
ab
ility
0 5 10 15 20 25
52
Relapsed/Refractory including High-Risk R/R
+ Censored
Logrank p=0.0437
ASH 2012, abstract #188 Byrd et al
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PCYC-1102-CA
Progression-free Survival
del(17p13.1)/del(11q22.3) Status
Months on Study
Data cut-off of 19OCT2012
del17p (n=28)
Est. PFS at 26 mo is 57%
del11q (n=23)
Est. PFS at 26 mo is 73%
No del17p or del11q (n=29)
Est. PFS at 26 mo is 93%
1.0
0.8
0.6
0.4
0.2
0.0
PF
S P
rob
ab
ility
0 5 10 15 20 25
53
Relapsed/Refractory including High-Risk R/R
+ Censored
Logrank p=0.0437
Months0 6 12 18 24 30 36 42 48 54
0.0
0.2
0.4
0.6
0.8
1.0
CLL2O: Progression free survival
F-refr.: n = 61
17p- relapse: n = 28
17p- 1st-line: n = 42
ASH 2012, abstract #188 Byrd et al
ASH 2012, abstract #716 Stilgenbauer et al
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• Superior disease control in poor-risk
CLL
• Low tox
• Virtually no CRs/mCRs, continuous
progressions in 17p- CLL
• Do they make SCT unnecessary - or
do they help getting patients to
transplant?
BCR kinase inhibitors (Ibrutinib):
The Gleevec of CLL?
↑
↓
↑
?
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EBMT CLL Transplant Consensus 2013
- Is poor-risk CLL still poor risk?
yes - but might be re-shaped once the
therapeutic value of BCR kinase
inhibitors has been defined
- Can alloSCT improve the outcome of
poor-risk CLL?
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EBMT CLL Transplant Consensus 2013
Can alloSCT improve the outcome of
poor-risk CLL? - 17p-
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Allo-SCT in CLL: Effect of del 17p-
EBMT (retrospective; n=44)
Schetelig et al, JCO 26:5094-5100 (2008)
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Allo-SCT in CLL: Effect of del 17p-
EBMT (retrospective; n=44) CLL3X (prospective;
17p- + TP53mut; n=24)
12 MRD-negative at 12mo landmark
MRD-negative at last f/u
Schetelig et al, JCO 26:5094-5100 (2008) Update June 2012
0 24 48 72 96 1200
50
100
TP53 del and/or mut (24)
TP53 normal (49)
1212
*
12
*1212
*12
12
*12
*12
*1212
Months from SCT
Perc
en
t even
t-fr
ee
*
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EBMT CLL Transplant Consensus 2013
Can alloSCT improve the outcome of
poor-risk CLL? - 17p-
- PA refractory
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Study GCLLSG Seattle Boston FCGCLL Houston
n 90 82 76 40 86
Higher age ++ (>55) - ++ (>65) - -
HCT-CI na ++ ++ (>0) na -
Unrelated
donor - - - na -
PA ref - - - na na
Active / bulky
CLL at SCT ++ ++ ++ - -
17p- - - - na na
Prognostic factors for PFS in RIC alloSCT for
CLL: Focus on purine analogue refractoriness
GCLLSG ASH 2012; Sorror JCO 2008; Brown Leukemia 2012;
Michallet Exp Hematol 2012; Khouri Cancer 2011
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EBMT CLL Transplant Consensus 2013
Can alloSCT improve the outcome of
poor-risk CLL? - 17p-
- PA refractory
- Relapse within 2 years after intensive therapy
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Outcome of RIC alloSCT for CLL (by EBMT indication; Heidelberg 2005-2012, n=64)
0 12 24 36 48 60 72 840
20
40
60
80
100
p53 (22)
F-ref (26)
early rel (13)
Richter (3)
Months from Start of Seach
% P
FS
PFS OS
0 12 24 36 48 60 72 840
20
40
60
80
100
Months from Start of Search
% S
urv
ival
Hahn et al, EBMT 2013
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EBMT CLL transplant consensus
allo-SCT is a reasonable treatmentoption in poor-risk CLL:– .Relapse <24 mo after intensive treatment
(purine analogue combinations or auto-SCT)
– .p53 mutation with treatment indication
– .Non-response or early relapse (<12 mo) afterpurine analogue-based therapy(= fludarabine resistance)
VERY
HI
GH
HI
GH
RISK
Leukemia 21:12-17 (2007)
Still valid in 2013 !
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Conclusions:
- AlloSCT seems to have the potential to
improve the natural course of poor-risk
CLL
- The 2007 EBMT/ERIC CLL transplant
consensus is still valid in 2013
- New agents will hopefully improve but
probably not replace alloSCT
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Many Thanks for Invitation and…
Med V
Heidelberg
M Rieger
F McClanahan
U Hegenbart
S Dietrich
M Hahn
I Herth
T Zenz
AD Ho
E Kimby
P Ghia
E Montserrat
C Moreno
EBMT
A van Biezen
H Finel
R Brand
K Cwynarski
D Niederwieser
M Michallet
D Milligan
T de Witte
J Schetelig
DCLLSG
M Ritgen
R Busch
T Zenz
M Hallek
S Böttcher
M Kneba
H Döhner
S Stilgenbauer