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