Akute Myeloische Leukämien Studien der OSHO · PDF fileOstdeutsche Studiengruppe Hämatologie und Onkologie. Hämatologie im Wandel 2015. Akute Myeloische Leukämien. Studien der

Ostdeutsche Studiengruppe Hämatologie und Onkologie

Hämatologie im Wandel 2015

Akute Myeloische Leukämien

Studien der OSHO


Frühjahrsberatung 2015AML Studien <60 Jahre

IntergroupAML 2002

AML

PKC StudieFLT3+

High risk cytogenetics

normal risk cytogenetics

good risk cytogenetics

Standard arm

AML – M3Napoleon – RNeue Studie

Refraktäre oder rezidivierte AML

AC220-FLT3 mut

MEK111759-K- / N-ras mut / wtMEK Inhibitor

RAS-AZIC <60aJAKVIDA

ETAL Studie


AML studies <60 yearsHigh Risk Cytogenetics

Basara N, et al. Leukemia, 2009; 23:635-40.




Outcome according to intention to treat




Transplant Related Mortality


JAKVIDA

AML 2002: Aktueller StandArm Registratur

bis 31.01.2008n

Ausschluss

n

Registraturbis 06.11.2014

n

studienintern 423 45 + 407Standardarm 50 7 entfällt

gesamt 473 52 8802. Random.3. Random.

121: 61 / 60177: 88 / 89


AML 2002: 2. RandomisierungIMD Ara-C/Mito vs. Mito-FLAG als Induktion 2

0

10

20

30

40

50

60

70

IMD Ara-C/ Mito

55%47%

Mito-FLAG

0

10

20

30

40

50

60

70

AML ´96Wdh. derInd 1

CR

nac

h In

dukt

ion

2

36%

60%

Mito-FLAG

2002 2014


AML 2002: 3. Randomisierung

Jahre nach Aktivierung

1 Konsol vor Tx 2 Konsol vor Tx

randomisiert

Tx erfolgt:

autolog

verwandt

unverwandt

88

52

18

15

19

87

45

10

15

200

20

40

60

80

100

120

140

160

180

0 2 4 6 8 10 12

n = 175


AML 2002: 3. RandomisierungIntervall CR1 - HCT : 1 vs. 2 Konsol.

1,0

0,8

0,6

0,4

0,2

0

Inte

rval

l CR

1 -H

CT

100 200 3000Tage nach CR1

n Median

1 Konsol. vor HCT 45 78 d2 Konsol. vor HCT 52 117 d

p = 0,002

05/14



1,0

0,8

0,6

0,4

0,2

0

O S

0Jahre nach CR1

1 Konsol. vor HCT n = 45


p = 0,41

2 4 6 8

0,54 ± 0,10

10 12

0,69 ± 0,07

05/14



1,0

0,8

0,6

0,4

0,2

0

E F

S

0Jahre nach CR1



p = 0,93

2 4 6 8

0,39 ± 0,14

10 12

0,57 ± 0,07

05/14


Frühjahrstagung 2015AML Studien >60 Jahre

IntergroupAML 2004

kurativ(75,5%)

palliativ(19,0%)

supportiv(5,5%)

OSHO/EBMT

vidaza

clofarabine

AML 2004

RAS-AZIC OSHO #83Vidaza+ AZA-AML 001

Akute LeukämienPatient characteristics and Response

Patient Age (years)

Type ofAML

WBC d0

(x109/L)

Marrowblasts d0

(%)

Cytogenetics WBC > 1 x109/L after

IC (days)

CR/CRid56

Alive

Dose level 1Cohort 1

#1#2#3

656876

de novosecondaryde novo

3.57.8

16.6

445450

unfavorableunfavorablenormal (NC)

35267

NoNoYes

NoYesNo


#4#5#6

757173

de novode novo

secondary

6.74.10.9

264536

NCNCNC

191420

YesYesYes

YesYesYes


#7#8#9

637263

secondaryt-AML

secondary

1.43.453

442122

NCunfavorable

NC

242624

YesYesYes

YesNoYes

Higher LFS after Post-Induction Hematopoietic CellTransplantation Compared to Consolidation Therapy in

Patients >60 Years: Report from the OSHO-AML 2004 study

D. Niederwieser, H. Al-Ali, V. Hoffmann, R. Krahl, Ch. Kahl, H-H. Wolf, U. Kreibich, V. Vucinic, D. Hähling, U. Hegenbart, A.

Krämer, C. Hirt, N. Peter, B. Opitz, A. Florschütz, K. Reifenrath, A. Schulze, N. Zojer, S. Scholl, Ch. Jakob, Ch. Junghanss, W.

Pönisch, S. Heyn, H. Sayer, A. Hochhaus, T. Heinicke, T. Fischer, P. Dreger and G. Maschmeyer

Higher LFS after HCT vs. CT in AML >60 aGerman AML intergroup design

Group B

Group AR

R

Common Arm

R R

9:1

9:1

Higher LFS after HCT vs. CT in AML >60 aRandomized/included patients in OSHO AML 04 (April 2014)

Group A Group B Total

CommonArm 100/ 88 25 113

(10.2%)

Study specific 859/776 221 997

(89.8%)

Total 959/864(77.8%)

246(22.2%) 1110

12.5%9.9%excluded 8.0%

Higher LFS after after HCT vs. CT in AML >60 aincluded patients (April 2014)

AML 2004randomized n = 959

excluded n = 95 n = 864

Evaluable patients n = 81762% (n= 505) CR1

no further therapy

n = 73 (16.1%)CT

n = 206 (45.6%)

relapse 31 (6.9%)TRM 10 (2.2%)

HCT

n = 132 (29.2%)

Higher LFS after HCT vs. CT in AML >60 aPatient characteristics

CTn = 183

HCT n = 132

p

age (median, range) years 67 (60-74) 65 (60-74) < .0005

AML type % (de novo / after MDS / t-AML) 68 / 24 / 5 61 / 28 / 10 n.s.

cytogenetic risk % (low- / nKT / others / high) 4 / 69 / 13 / 13 3 / 45 / 27 / 26 < .0005

cytogenetic risk % (monosomaler KT /. „all others“ ) 4 / 96 12 / 88 .02

FLT3 - ITD % (mut / wt) 22 / 78 22 / 78 n.s.

NPM1 % (mut / wt) 39 / 61 28 / 72 .07

CEBPA % (wt / single mut / double mut) n=97 87 / 1 / 2 86 / 12 / 2 n.s.

CR after 1 oder 2 induction cycles % 89 / 11 81 / 19 .05

Related / unrelated donor 27 / 105

Higher LFS after HCT vs. CT in AML >60 acytogenetic distribution among HCT vs CT

CT n = 183

HCTn = 132

n

100

0

b - low-risk[inv(16); t(8;21)]

c - normal karyotyped - otherse - high-risk

[abn(3q26), t(6;9), -5/5q-, -7/7q-, abn(11q23), komplex]

a - unknown

a b c d e

14%

4%

60%

9%11%

2%

41%

24%23%

11%

p < ,0005

a b c d e

80

60

40

20

120

Higher LFS after HCT vs. CT in AML >60 adonor characteristics

study center n related unrelated identical mismatch

A 73 12 61 50 23

B 23 7 16 19 4

C 9 2 7 9

D 8 2 6 7 1

E 6 6 5 1

F 6 2 4 6

G 4 1 3 4

H 3 1 2 3

132 27 105 103 29

Higher LFS after HCT vs. CT in AML >60 aconditioning regimens

study center n Flu / TBI(2 Gy)

Flu Treo

FluBu FLAMSA TLI

10x8 Gy

A 73 73

B 23 18 3 2

C 9 6 3

D 8 1 6 1

E 6 3 1 2

F 6 6

G 4 1 3

H 3 2 1

132 110 16 4 1 1

Flu, fludarabine; TBI, total body iradiation; Treo, treosulfan; Bu, busulfan; TLI, total lymphoid irradiation

Higher LFS after HCT vs. CT in AML >60 aoverall survival according to treatment and matched donor

04/2014

0

1

,8

,6

,4

,2

02 4 8 10

years after CR

over

alls

urvi

val

6

n median 5-year OS

CT 183 1.7 .27 ± .04

MRD + MUD 103 2.9 .41 ± .06

.41 ± .06

.24 ± .04

p = .09

Higher LFS after HCT vs. CT in AML >60 aLFS according to treatment and matched donor

04/2014

0

1

,8

,6

,4

,2

02 4 8 10

years after CR

L F

S

6

n median 5-year LFS

CT 183 1.0 .20 ± .03

MRD + MUD 103 2.1 .38 ± .05

.36 ± .06

.13 ± .04p < .0005

Higher LFS after HCT vs. CT in AML >60 aRelapse incidence according to treatment

04/2014

0

1

,8

,6

,4

,2

02 4 8 10

years after CR

rela

pse

inci

denc

e

6

.79 ± .05

.40 ± .06

n Median 5-year RICT 183 1.2 .74 ± .04MRD + MUD 103 .37 ± .06

p < .0005

Higher LFS after HCT vs. CT in AML >60 aNon-relapse mortality according to treatment

04/2014

0

1

,8

,6

,4

,2

02 4 8 10

years after CR

NR

M in

cide

nce

6

.24 ± .06

.09 ± .11

n Median 5-year NRMCT 183 .07 ± .05MRD+MUD 103 .24 ± .06

p = .0006

Higher LFS after HCT vs. CT in AML >60 aunivariate analysis on risk factors

04/2014

variables OS LFS RI NRM

age (≤ 66 vs. > 66 years) .01 .02 .07 -

AML type % de novo, aus MDS, nach RT/CT

- - - -

cytogenetic risklow- , nKT, others, high-risk .01 .02 .006 -

cytogenetic riskmonosomal vs. non-monosomal < .0005 < .0005 < .0005 -

FLT3 ( mut / wt ) - .09 < .05 -NPM1 ( mut / wt ) - - - -CR after 1 or 2 induction cycles - - - -Interval CR -> CT / HCT - - .01 .006HCT vs. CT .14 .01 < .0005 .002

Higher LFS after HCT vs. CT in AML >60 amultivariate analysis on risk factors

04/2014

Prognostic factors p – value

OSagecytogenetic risk* CT / HCT

.07

.01.14

LFSage cytogenetic risk* FLT3 wt/mutCT / HCT

.02

.04

.03

.01

RIage cytogenetic risk*FLT3 wt/mutCT / HCT

.07< .0006

< .03< .0005

NRM HCT / CT .002

*low risk, normal karyotype, others, high risk; Cox Regression,„Wald vorwärts“, time dependent; for RI and NRM competing risk regression

Higher LFS after HCT vs. CT in AML >60 aconclusions

Increase in LFS of AML patients >60 a using HCT in comparison to CT as consolidation (32% vs 13% at 8 years; 36% vs 13% at 8 years).

Improvement in normal risk and high risk Independent risk factors for

LFS: age, cytogenetics, FLT3-ITD and HCTOS : cytogenetics, age, (HCT)RI: cytogenetics, age, FLT3-ITD; HCTTRM: HCT

MUD and MRD better results than MMUD TRM at 24% for matched HCT at 8 years.

<60 a >60 a

Standards for induction, consolidation and HSCTCR – rates after chemotherapy <60 vs. >60a


New study

Akute Leukämien

Response-Adapted Sequential Azacitidine and Induction Chemotherapy in

Patients > 60 Years Old with Newly Diagnosed AML Eligible for Chemotherapy (RAS-AZIC)

Results of the Phase I of the DRKS00004519 Study

Haifa Kathrin Al-Ali, MD1*, Rainer Krahl, PhD1*, Michael Cross, PhD2*, Hubert Karolin, Mrs2*, Nadja Jaekel, MD1* and Dietger Niederwieser, MD1

Akute LeukämienRAS-AZICPhase I schedule

Day 56

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

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

H. Al-Ali et al ASH 2014

HCT vs. CT in elderly AML

Current statusas of 14-March-2014


Rolle der SCT bei AML >60 Jahre


Rolle der SCT bei AML >60 JahreHCT – CT

Registered: 176

InductionI / II

Consol-idation

Observation arm: 37

Non-SCT:

28

SCT:

53R*

Donor search:12

Randomised: 81

Observation: 37

CR1:Registration

Diagnosed

End of study prior to randomisation: 46


Future of AML

Fallbeispiel I: Patient M.K, 69 Jahre

• 12/2005 ED tAML nach Mamma CanKT, NPM1 pos, FLT3-ITD neg, CEBPA wt

• 12/2005 OSHO Induktion 1. CR• 03/2006 OSHO Konsolidierung• 04/2006 RIC-MUD • 07/2006 1. Rezidiv• 08/2006 Verstorben

NPM1 Mutation im Verlauf M.K.

NPM1 Mutation im Verlauf R.H.

High Pri-miR-181a-1 and Pri-miR-181a-2 Expression Associates with Improved Outcomes in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem

Cell Transplantation After Non-MyeloablativeConditioning

University of Leipzig; Dept. Hematology and Clinical Oncology

ASH Abstract #732 ASH Abstract Achievement Award

13. Hämatologisches Wintersymposium

High pri-miR 181a-1 and/ orpri-miR 181a-2 expression is

associated with longer overall survival and event-free survival

Even

t Fre

e Su

rviv

al

Years after Transplantation

P=0.002

high pri-miR-181a-1 and/or high pri-miR-181a-2

low pri-miR-181a-1 and low pri-miR-181a-2

Years after Transplantation

Ove

rall

Surv

ival high pri-miR-181a-1 and/or high pri-miR-181a-2

low pri-miR-181a-1 and low pri-miR-181a-2

P=0.004

0 2 4 6 8 10

0.0

0 .2

0 .4

0 .6

0 .8

1 .0

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

25%Low miR-181a

50%High miR-181a

OS at 5 yrs

20%Low miR-181a

42%High miR-181a

EFS at 5 yrs

Overall Survival Event-Free Survival

41

Conclusion I

pri-miR-181a-1 and pri-miR-181a-2 expression correlated well, but was not fully concordant

pri-miR-181a-1 and pri-miR-181a-2 expression associated with different clinical characteristics

high expression status of pri-miR-181a-1 and/or pri-miR-181a-2 at diagnosis associated with improved outcome in AML pts undergoing NMA-HCT

the prognostic impact was strongest in the ELN favorableand intermediate-II groups

42

Therapy

Research

Diagnostics

43

Thank you for your Attention

Acknowledgements:

Dietger Niederwieser

Guido Marcucci

Clara D. Bloomfield

M. JentzschM. BillK. SchubertL. SchmalbrockH. Weidner

L. KlossT. GaberL. BonifacioK. WildenbergerW. Pönisch

V. VucinicG-N. FrankeT. LangeM. CrossG. Behre

44


Rostock

Hamburg

Bremen

Hannover

Dortmund

Bonn

Mainz

Heidelberg

Stuttgart

Munchen

Nurnberg

Chemnitz

Dresden

Leipzig

Magdeburg

Berlin

Frankfurt

Potsdam

Erfrurt

Greifswald

Osterfeld

Danke allen OSHO Zentren


WP- AMLEvaluationen / Aktueller Stand der Studien

AML 2002( bis 60 Jahre )

AML 2004( über 60 Jahre )

registriert 880 985

Ind. dokumentiertØ Ausschluss

700 845

Tx in CR1 207 137

Tx1 ≠ CR1 129 86

Tx2 39 7


AML ´02 & ´04: Allo in CR1MRD+MUD; PBSC; keine günstige ZytogenetikO

S

Jahre nach SCT

1,0

0,8

0,6

0,4

0,2

00 2 4 6 8 10 12

11/14

0,46 ± 0,04

0,20 ± 0,03

0,36 ± 0,03

OS

LFS

NRM

RI

0,43 ± 0,04

n = 260


AML ´02 & ´04: Allo in CR1Rolle des Alters

,82 ± ,07

0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

Übe

rlebe

n

6 10 0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

L F

S

6 10

,49 ± ,06

,37 ± ,06

p = ,001

18 - 39 J., 40 - 59 J., 60 - 70 J., > 70 Jahre

11/14

,69 ± ,08

,48 ± ,06

,33 ± ,06

p = ,01

n = 33 n = 116 n = 100 n = 11


AML ´02 & ´04: Allo in CR1Rolle des Alters; competing risk

0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

Rez

idiv

inzi

denz

6 10 0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

N R

M

6 10

,43 ± ,06

,31 ± ,05

p = ,50

11/14

,03 ± ,03,20 ± ,05

,23 ± ,04

p = ,01

18 - 39 J., 40 - 59 J., 60 - 70 J., > 70 Jahre


AML ´02 & ´04: Allo in CR1Alter 40 – 59 Jahre

11/14

,65 ± ,08

0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

Übe

rlebe

n

6 10 0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

L F

S

6 10

p = ,45

,58 ± ,08

p = ,58

,53 ± ,08

,38 ± ,10

,53 ± ,08

,38 ± ,10

MAC, RIC, NMAC = Flud200cGyn = 48 n = 39 n = 29


AML ´02 & ´04: Allo in CR1Alter 40 – 59 Jahre

11/14

0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

Rez

idiv

inzi

denz

6 10 0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

N R

M

6 10

,23 ± ,07

p = ,19

,24 ± ,06

p = ,24

,32 ± ,08,42 ± ,10

,20 ± ,08

,11 ± ,05

MAC, RIC, NMAC = Flud200cGyn = 48 n = 39 n = 29


AML ´02 & ´04: Allo in CR1Zytogenetisches Risiko

11/14

0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

Übe

rlebe

n

6 10 0

1

,8

,6

,4

,2

02 4 8 12

Jahre nach SCT

R I

6 10

p = ,05

,48 ± ,07

,26 ± ,07

,43 ± ,07

p = ,34

,51 ± ,05

normaler/unauffälliger KT sonstiger KT progn. ungünstiger KT

,54 ± ,08

,32 ± ,05

n = 124 n = 50 n = 73

Documents

Akute Myeloische Leukämien Studien der OSHO · PDF fileOstdeutsche Studiengruppe Hämatologie und Onkologie. Hämatologie im Wandel 2015. Akute Myeloische Leukämien. Studien der