OSHO AML Studies - Leukemia Net · OSHO #083 . RAS-AZIC Day 56 Phase I Day 56 Æ Phase II with Aza...
Transcript of OSHO AML Studies - Leukemia Net · OSHO #083 . RAS-AZIC Day 56 Phase I Day 56 Æ Phase II with Aza...
OSHO AML Studies
Haifa Kathrin Al-Ali
Department of Haematology/Oncology
University of Leipzig
Acute Myeloid Leukemia (AML) < 60 years: Different Treatment
Strategies Versus a Common Standard Arm—Combined Prospective
Analysis by the German AML Intergroup
Büchner T et al. JCO; 2012 CR > 70%; OS 41.4%-47.5%“!!
Age < 60 years; de novo and secondary AML
PR , NR : off study
R
induction A
ind. A*
consol A1 consol A2
consol A3
PR , NR
CR
PR , NR : off study
CR
HCT
( < 55 yrs. )
Option :
allo - HCT
MUD ( < 50y )
auto - HCT
( < 60 yrs. ) induction B
ind. A*
consol A1 consol A2
CR
CR
PR , NR
HLA-identical sibling
consol 1 consol 2 consol 3
induction 1 CR
allo HCT
related
auto
HCT consol 1 consol 2
consol 1
R
R
allo HCT
MRD /MUD
unfavourable
cytogenetics
HCT
as soon as possible ind. 2a
ind. 2b
PR, NR
R Standard arm
AML ´2002
AML ´96
Others
CBF
p =0 .9
OS
1,0
,8
,6
,4
,2
0,0 10 5 0
Years
OS
1,0
,8
,6
,4
,2
0,0 10 5 0
High risk
NC
p < 0,0005
OS
1,0
,8
,6
,4
,2
0,0 10 5 0
Years
OS
1,0
,8
,6
,4
,2
0,0 10 5 0
p = 0.8
p = .15
AML ´96, n=249
AML ´02, n=440
Survival in patients with AML < 60 years according to cytogenetics
Allogeneic HCT in intermediate risk AML in CR1
Yanada M et al.
Cancer 2005; 103:1652-58
Metaanalysis
5 prospective Studies: n = 3100
MRD : n = 1151
„donor vs. no donor“ / „intention to treat“
Survival benefit for allo HCT trend
Cornelissen JJ et al.
Blood 2007; 109:3658-66
Metaanalyse
6 prospective Studies: n > 4000
„donor vs. no donor“ ( n=603 vs. 1106 )
Significant survival benefit for allo HCT
Others
CBF
p =0 .9
OS
1,0
,8
,6
,4
,2
0,0 10 5 0
Years
OS
1,0
,8
,6
,4
,2
0,0 10 5 0
High risk
NC
p < 0,0005
OS
1,0
,8
,6
,4
,2
0,0 10 5 0
Years
OS
1,0
,8
,6
,4
,2
0,0 10 5 0
p = 0.8
p = .15
AML ´96, n=249
AML ´02, n=440
Survival in patients with AML < 60 years according to cytogenetics
Allogeneic HCT
R
PR, NR
ID-AraC/IDA
Mito-FLAG
ID-AraC/Mito
CR
CR
Favorable-risk
Intermediate
risk
High risk
Cytogenetics
as early as possible
Consol
R
allo HCT
Konsol 1
Tx
CT Konsol 2 Konsol 3
ETAL-1 (SAL, AMLCG, OSHO)
Upfront
registration
CR1/CR1i &
HLA-identtical
donor
allo HCT
R* Konsol 1 Konsol 2
Konsol 1
Treatment strategies in patients with AML < 60 years
MRD monitoring
allo HCT
auto Tx
*For OSHO centers not taking part in the ETAL study
Intergroup
AML 2004
kurativ
(75,5%)
palliativ
(19,0%)
supportiv
(5,5%)
OSHO/EBMT
AML studies in patients > 60 years
AML > 60
*Azacitidine
OSHO #75
*Clofarabine
OSHO #75
AML 2004 (OSHO #69)
RAS-AZIC OSHO #83 *Closed
Intergroup
AML 2004
kurativ
(75,5%)
palliativ
(19,0%)
supportiv
(5,5%)
OSHO/EBMT
AML studies in patients > 60 years
AML > 60
*Azacitidine
OSHO #75
*Clofarabine
OSHO #75
AML 2004 (OSHO #69)
RAS-AZIC OSHO #83 *Closed
Common Arm
median follow up of patients
alive:
Group B (38 mts)
Group A (23 mts)
Common arm (34 mts)
Factors Influencing CR Rate in elderly AML Report From the German Intergroup Study
Overall survival
Niederwieser D et al. ASH 2012; Abstract 128
High CR rates can be achieved in patients with AML >60 years CR-rate depends on:
Age WBC count AML type cytogenetic risk
OS Cytogenetics, age, diagnosis, WBC count, gender RFS Cytogenetics, age
No difference between common arm vs. Group A and B arms in
OS, RFS, EFS
Factors Influencing CR Rate in elderly AML
Conclusions
Niederwieser D et al. ASH 2012; Abstract 128
0 5 10 2
Years
Study n
AML 93 83
AML 97 411
AML 04 594
AML 04 IG 66
100
80
60
40
20
Su
rviv
al
(%)
04/12
n=1154
CR rate (AML ´04) 61%
median OS 343 days
OS at 2 years 33%
OS at 5 years 18%
Intensive chemotherapy (IC) in patients with AML > 60
years and who are ´fit´ for IC
Consolidation
Consolidation ( 2 Cycles )
Mitoxantron
Ara-C
Pegfilgrastim
10 mg/m²
0,5 g/m²
6 mg
30 min Infusion
12stdl. als 3h-Infusion
1x s.c.
d 1 + 2
d 1 + 3 + 5
d 8
AML 2004 (OSHO #69) IMD-Ara-C / Mito
Consolidation ( 2 Cycles )
Mitoxantron
Ara-C
10 mg/m²
120 mg/m²
30 min Infusion
12stdl. als 1h-Infusion
d 1 + 2
d 1 - 5
AML ´97 : DA 2 + 5
0
0,2
0,4
0,6
0,8
1,0
0 2 4 6 8 10
Years after CR
R F
S
0
0,2
0,4
0,6
0,8
1,0
0 2 4 6 8 10
Years after CR
Su
rviv
al
p = .84 p = .99
,17 ,04 ,10 ,03
11/2012
AML 97 n = 126
DA 2+5 vs. IMD-Ara-C/Mito AML 2004 n = 145
11/2012
0,2
0,4
0,6
0,8
1,0
Years
R F
S
0
0 2 4 6 8
0,2
0,4
0,6
0,8
1,0
Years
Su
rviv
al
0
0 2 4 6 8
HCT n = 108
CT n = 181
,33 ,06
,22 ,04
p = ,006
,34 ,06
,27 ,05
p = ,4
AML 2004: Landmark-Analysis CT vs. HCT
Intergroup
AML 2004
kurativ
(75,5%)
palliativ
(19,0%)
supportiv
(5,5%)
OSHO/EBMT
AML studies in patients > 60 years
AML > 60
*Azacitidine
OSHO #75
*Clofarabine
OSHO #75
AML 2004 (OSHO #69)
RAS-AZIC OSHO #83 *Closed
EBMT study in AML patients older
than 60 years in first CR
Age ≥ 60–75 years,
EMEA EudraCT number 2007-003514-34.
Trial NCT00766779. Available from: www.clinicaltrials.gov.
Randomized, phase 3 study
Max. 6 months
Max. 5 months
EBMT, HOVON,OSHO, ALFA, CETLAM, GOELAMS, SAKK, EORTC
Induction
1 or 2
Induction or
consolidation 1 R
Donor search
(if no matched sibling
unrelated search) Related or
unrelated
SCT
Non-SCT
treatment
Non-SCT
treatment Induction
Related or
unrelated SCT
If relapse
Option 2
option 1
Entry
R = randomization 2(A):1(B).
Conventional chemotherapy vs low-dose total body irradiation-based conditioning and HSCT
(related and unrelated donors) as consolidation therapy
Intergroup
AML 2004
kurativ
(75,5%)
palliativ
(19,0%)
supportiv
(5,5%)
OSHO/EBMT
AML studies in patients > 60 years
AML > 60
*Azacitidine
OSHO #75
*Clofarabine
OSHO #75
AML 2004 (OSHO #69)
RAS-AZIC OSHO #83 *Closed
Intergroup
AML 2004
kurativ
(75,5%)
palliativ
(19,0%)
supportiv
(5,5%)
OSHO/EBMT
AML studies in patients > 60 years
AML > 60
*Azacitidine
OSHO #75
*Clofarabine
OSHO #75
AML 2004 (OSHO #69)
RAS-AZIC OSHO #83 *Closed
100
80
60
40
20
0 0 2 4 6 8 10
2.9 months
OS in patients with newly
diagnosed or relapsed/refractory
AML
Median OS for patients with stable disease (SD) was 4 months, whereas
median OS for patients with CR, PR, or HI was not reached (p = 0.045)
OS according
to haematological
response
7.7 months
Pa
tien
ts s
urv
ivin
g (
%)
Duration (months)
Newly diagnosed (n = 20)
Relapsed or refractory (n = 20)
p = 0.04
CR + PR + HI (n = 12)
SD (n = 15)
PD (n = 2)
NE (n = 11)
Azacitidine in AML patients not eligible for or resistant to
chemotherapy
Duration (months)
18 12 6 0 P
ati
en
ts s
urv
ivin
g (
%)
100
80
60
40
20
0
SD censored
CR/PR/HI censored
SD
PD or NR
CR, PR, or HI
NE
Al-Ali HK, et al .Leuk Lymph. 2012;53:110–7
Bone marrow blasts on day 15 of cycle 1 and not early blast clearance correlated
with subsequent response
(P = 0.006)
Al-Ali HK, et al .Leuk Lymph. 2012;53:110–7
Azacitidine in AML patients not eligible for or resistant to
chemotherapy
100
80
60
20
0
40
Bo
ne m
arr
ow
bla
sts
(%
)
CR/PR
SD
Day 15 p=0.006
Aza-Maintenance Therapy(Start every 4 weeks)
Day 90
Aza 75mg/m25 or 7 days
Aza 75mg/m25 or 7 days
1. InductionChemotherapy
Day 15Blasts < 45%Blasts ≥ 45%
Day 56
2.Induction Chemotherapy
CR, CRiNot CR, CRi
PR, CR, CRi
Not PR, CR, CriEnd of trial treatment
d 1- 5/7
d 28 – 32/34d 17- 45
d 56 – 62, d 84 , …
d 58- 86
HCT Relapse PD
Aza Maintenance, until:
Trial Design – Phase II
: Central laboratory assessment
Follow-up: up to 2 years after start of trial treatment
100
80
60
20
0
40
Bo
ne m
arr
ow
bla
sts
(%
)
CR/PR
SD
Day 15 p=0.006
“RAS-AZIC”
OSHO #083
Aza-Maintenance Therapy(Start every 4 weeks)
Day 90
Aza 75mg/m25 or 7 days
Aza 75mg/m25 or 7 days
1. InductionChemotherapy
Day 15Blasts < 45%Blasts ≥ 45%
Day 56
2.Induction Chemotherapy
CR, CRiNot CR, CRi
PR, CR, CRi
Not PR, CR, CriEnd of trial treatment
d 1- 5/7
d 28 – 32/34d 17- 45
d 56 – 62, d 84 , …
d 58- 86
HCT Relapse PD
Aza Maintenance, until:
Trial Design – Phase II
: Central laboratory assessment
Follow-up: up to 2 years after start of trial treatment
CR + PR + HI (n = 12)
SD (n = 15)
PD (n = 2)
NE (n = 11)
Duration (months)
18 12 6 0
100
80
60
40
20
0
SD censored
CR/PR/HI censored
SD
PD or NR
CR, PR, or HI
NE
“RAS-AZIC”
OSHO #083
RAS-AZIC
Day 56
Phase I
Day 56
Phase II withAza 75mg/m2
5 days
DLT 5 days ≤ 0/3 or 1/6
DLT 5 days >1/6
Phase II withAza 75mg/m2
7 days
: Full Safety Evaluation
DLT 7 days ≤ 0/3 or 1/6
DLT 7 days >1/6
Aza 75mg/m25 days
InductionChemotherapy
d 17- 45
d 1-5
Doselevel 1
Aza 75mg/m27 days
InductionChemotherapy
d 1-7
d 17- 45
Doselevel 2
Vielen Dank