Survival in the United Kingdom Medical Research Council AML trials 1970–1999 for patients aged...

Survival in the United Kingdom Medical Research Council AML Survival in the United Kingdom Medical Research Council AML

trials 1970–1999 for patients aged 15–59 yearstrials 1970–1999 for patients aged 15–59 years

FACTEURS PRONOSTIQUES

- liés au maladeperformance statusâge +++

- liés à histoire de la maladie (de novo/secondaire)- liés à la présentation clinique / biologique

tumeurstaux GBLDH

- liés au type LAMcytologie M3, M2-M4 / M6-M7phénotype (CD34, Pgp)cytogénétiquebiologie moléculaire

- liés à la réponse au traitementRC en 2 cures (MRC)blastose a J15 (German AMLCG)

GOELAM2 TRIAL PROGNOSTIC FACTORS

CR achievement (multivariate analysis)- karyotype (0.0004)- WBC count (0.002)- PS (0.002)

DFS (multivariate analysis)- karyotype (0.0004)- allo BMT (0.005)

t(15;17)

t(8;21)

inv(16)/t(16;16)

CR (%)

ID (%)

RD (%)

11**88 2**

98** 2** 0**

92* 8 0*

671** 23**

82 4 14

t(9;22)

t(6;9)

t(11q23)

inv(3)/t(3;3)

t(3;5)

788 5

35** 19 47**

95 5 0

1648** 36**

91 5 5

t(12p13)

abn(11p13~5)

092 8t(8p11)

Outcome according to hierarchical cytogenetic classificationOutcome according to hierarchical cytogenetic classification

n

569

332

193

31

28

212

44

21

25

22

13

*p<0.01, **p<0.001, Chi-squared test or Fisher exact test (CR/ID/RD), log rank test (RR & OS)

RR (%,5yrs)

OS (5yrs)

23** 69**

22** 70**

35* 61*

92** 5**

84** 30

50 46

80** 6**

47 43

63 25**

33 49

21 66

788 5normal 1066 48 45

abn(16q22~24)

-5/5q/-7/7q

7q, no adverse

CR (%)

ID (%)

RD (%)

1183 6

64** 9 27**

91 2 7

1090 0

70** 4 26**

+4

+11

+8

del(9q)

+21

682* 12

91 9 0

81 5 14

987 4

67* 14 19

del(11)(q23)

abn(3q)

12*78** 11Other

Outcome according to hierarchical cytogenetic classificationOutcome according to hierarchical cytogenetic classification

n

35

276

45

30

28

210

36

47

24

25

373

RR (%,5yrs)

OS (5yrs)

40 46

70** 16**

57 30

73 18*

70 20*

53 37**

37 47

73 38

79** 26

89** 8**

48 37*

788 5normal 1066 48 45

*p<0.01, **p<0.001, Chi-squared test or Fisher exact test (CR/ID/RD), log rank test (RR & OS)

Outcome in AML patients with 11q23 abnormalitiesOutcome in AML patients with 11q23 abnormalities

ID (%)

CR (%)

RD (%)

Median age

RR (%,5yrs)

OS (5yrs)

t(11q23) total (n=212)

7 88 512.5 50 46

t(6;11)(q27;q23) (n=21)

5 95 019.0 76 31

t(9;11)(p21~2;q23) (n=73)

11 86 3 4.0 28 61

t(10;11)(p11~4;q13~23) (n=46)

2 91 712.0 63 35

t(11;19)(q23;p13) (n=18)

0100 019.0 55 60

Other t(11q23) (n=54)

7 81 1124.0 54 38

p value for heterogeneity <0.01 NS

Impact of additional cytogenetic abnormalities:Survival of patients entered into AML 10 & 12 (n=3453)

100

50

75

25

00 1 2 3 4 5

Years from entry

% s

till

aliv

e

Favourable only (n=478)Favourable + intermediate (n=331)Favourable + adverse (n=22)Intermediate only (n=2235)Adverse + intermediate (n=297)Adverse only (n=478)

71%65%59%

42%

17%14%

PROGNOSTIC IMPACT OF KARYOTYPE

PtsPts FavorableFavorable IntermediateIntermediate unfavorableunfavorable

MRCMRC

EBMTEBMT

SWOG/ECOGSWOG/ECOG

16121612

999999

609609

t(8;21)t(8;21)

t(15;17)t(15;17)

inv(16)inv(16)

t(8;21)t(8;21)

AbnormalitiAbnormalities of 16es of 16


t(8;21)t(8;21)

All othersAll others

Including Including 11q2311q23

AbnormalitiesAbnormalities

t(15;17)t(15;17)

Pseudidiploid Pseudidiploid hyperdiploid hyperdiploid or diploidor diploid

NormalNormal

+8, -y, +6, del +8, -y, +6, del (12p)(12p)

ComplexComplex

-5, (del 5q)-5, (del 5q)

-7 abnormalities of 3q-7 abnormalities of 3q

Abnormalities of 5 and/or 7Abnormalities of 5 and/or 7

Abnormalities of 11q hypodiploidAbnormalities of 11q hypodiploid

-5, del (5q)-5, del (5q)

-7, del (7a)-7, del (7a)

Inv 3Inv 3

Complex abnormalities of 11q, Complex abnormalities of 11q, 20q, 21q20q, 21q

Del (9q)Del (9q)

t(6;9), t(9;22)t(6;9), t(9;22)

Abn 17pAbn 17p

TRAITEMENT D’INDUCTION

« Gold standard » : DNR +ARA-C 3 (45-50 mg/m2) + 7 (200 mg/m2)

Variantes - 3 +10 (100mg/m2) -Doses plus élevées de DNR (60-90 mg/m2) -IDR (12-13 mg/m2 x 3 ou 8mg/m2 x 5 ) -3eme drogue (6TG Etoposide)


- Facteurs de croissance hématopoiétique

- Modulateurs mdr

-Hautes doses d’ARA-C (1 à 3 g/m2, seule ou associée à anthracyclines ou Fludarabine )

- Date d’administration de la deuxième cure

G-CSF DANS LES LAM G-CSF DANS LES LAM G-CSFR EXPRIME A LA SURFACE DES G-CSFR EXPRIME A LA SURFACE DES

BLASTES DE LAMBLASTES DE LAMAprès traitement d’induction

- nombreuses études randomisées avec G ou GM-CSF (surtout chez le sujet âgé)- diminution de la durée neutropénie de 2 à 6 J- augmentation du taux de RC seulement dans 2/9- pas d’impact sur la survie ou EFS- généralement diminution de la durée d’hospitalisation et de l’utilisation d’ATB- réduction du cout d’hospitalisation dans 2 études- pas d’augmentation du risque de progression ou de rechute

Après consolidation

- 2 études (Heil Blood 1997, Harousseau JCO 2000) Réduction de la durée neutropénie et d’hospitalisation

PRIMING DANS LES LAMPRIMING DANS LES LAM

Neuf études randomisées avec G ou GM-CSF

Nombre de patients et modalités d’administration du FCH variables

pas d’augmentation significative du taux de RC quelques arguments en faveur du priming

- Witz (Blood 1998) : augmentation de la DFS à 2 A surtout entre 55 et 65 A (57% vs 20%) p=0.002)

- Lowenberg (NEJM 2003) : augmentation de la DFS à 4 A (42% vs 33%) et de la SV dans les LAM à risque standard (45% vs 35%)

MODULATEURS MDR

- Gène code pour protéine pgp (réduit concentration intracellulaire des anthracyclines et de VP16 )- Expression de pgp - corrélée à pronostic défavorable (Marie 91,Pirker 91,Campos 92) -associée à d’autres facteurs de mauvais pc (CD34,Cytogénétique,LAM réfractaires ou en rechute) -rare au Dg chez sujets jeunes mais fréquente chez sujets agés (Leith 97)

*

MODULATEURS MDR

- Cyclosporine - 1 essai >0 ds LAM à haut risque (List,Blood 2001 ) - 1 essai <0 (Liu,BJH 2001) - PSC- 833 - 3 essais interrompus précocément ou négatifs (Baer Blood 2002, Greenberg JCO 2004, Chauncey) -Cyclo et PSC modifient la pharmacocinétique des drogues dont il faut réduire les doses (Kolitz JCO 2004)

Modulateurs MDR (GOELAM 2 )

- 425 pts 15-60 A Quinine 30 mg/kq pdt ind et 2 conso 81% RC,à 3A DFS 43%,SV 42% Globalement pas de différence entre les deux bras

- Pas de valeur pronostique de mdr et pgp

- Mais sous-groupe de 54 pts avec efflux de rhodamine +) : 83% RC vs 48% avec quinine

HAUTES DOSES ARA-C

BDBD100mg/m²/PCx7100mg/m²/PCx7

HDHD

3g/m² (J1,3,5,73g/m² (J1,3,5,7))

SDSD200mg/m²/PCx7200mg/m²/PCx7

HPHP2g/m²x2 J1-62g/m²x2 J1-6

% RC% RC

Durée med RCDurée med RC

DFS (%)DFS (%)

SV (%)SV (%)

7474

12 m12 m

24*24*

25*25*

7171

45 m45 m

49*49*

31*31*

5858

< 50A 21< 50A 21

50-64 950-64 9

< 50A 22< 50A 22

50-64 1150-64 11

5555

3333

2121

3232

1313

* À 5 ans* À 5 ans

BISHOP Blood 96

301 pts15-60 Adenovo

Weick Blood 96

493 pts< 65 A

De novo ou secondaire

DATE ADMINISTRATION2ème CURE

- A sortie d’aplasie après 1ère (ou à J30)

- En fonction des résultats du myélogramme intermédiaire (J15)

- Systématiquement (quel que soit le résultat d’un éventuel myélogramme intermédiaire)

- timed-sequential- double induction

TRAITEMENT INDUCTION2ème CURE

- Timed sequential« Intensive timing » vs standard timing (Woods Blood 1996) pas de différence en taux de RC mais EFS à 3A 42% vs 27%

- Double induction (Buchner Blood 1999) soit reprise traitement induction standard (TAD/TAD)soit 2ème cure + intense (TAD/HAM) : TAD/HAM supérieur dans formes de mauvais pronostic

- Comparaison 3 modalités (Castaigne Blood 2004)* pas de différence en taux RC (76%) ou en taux de décès toxique * timed-sequential retarde la rechute < 50A

TRAITEMENT INDUCTION

- Avec les progrès de la réanimation hématolo-gique : taux de décès toxique < 5% et taux de RC élevés dans les LAM de novo < 60A

- Difficile de démontrer la supériorité d’un régime par rapport à un autre pour le taux de RC

- « qualité » de RC peut expliquer certaines différences en DFS

- Taux de RC dépend des facteurs pronostiquesinitiaux (cytogénétique +++)

POST-REMISSION THERAPY IN AML

Allogeneic BMT

- Most effective antileukemic treatmentMyeloablative preparative regimenGVL effect

- High incidence of severe procedure-related toxicity

High transplant-related mortalityIndicated only in patients < 55 yo

- Only patients with an HLA-identical sibling

POST-REMISSION THERAPY IN AMLAUTOLOGOUS SCT

- Toxic death rate much lower than after allo BMT

- High relapse rateContamination by malignant cellsAbsence of GVL

- Age limit 60 y

- Uncontrolled studies have shown DFS rates of 30% to 60%In AML CR1

Selection bias ?

POST-REMISSION THERAPY ICC

- Non myeloablative

- Age limit : 60y

- High relapse rate

- DFS 30-50% in pilot uncontrolled studies

RANDOMIZED TRIALS COMPARING ASCT AND ICCDFS

PtsPts AutoAuto ChemoChemo pp

Adult studiesAdult studies

Zittoun 95Zittoun 95

Harousseau 97Harousseau 97

Burnett* 98Burnett* 98

Cassileth 98Cassileth 98

Pediatric studiesPediatric studies

Ravindranath 96Ravindranath 96

Woods** 01Woods** 01

990990

535535

196196

808808

666666

887887

48 (128)48 (128)

44 (86)44 (86)

53 (190)53 (190)

35 (116)35 (116)

38 (89)38 (89)

42 (177)42 (177)

30 (126)30 (126)

40 (78)40 (78)

40 (191)40 (191)

35 (117)35 (117)

36 (115)36 (115)

47 (179)47 (179)

0.050.05

0.410.41

0.040.04

0.770.77

0.200.20

0.310.31*Autologous BMT was compared to no further treatment after 4 courses of intensive chemo** Bone marrow was purged with 4 HC in the autologous transplantation arm.Number of patients is shown in parenthses

RANDOMIZED TRIALS COMPARING ASCT AND ICCOS

PtsPts AutoAuto ChemoChemo pp









990990

535535

196196

808808

666666

887887

5656

5050

5757

4343

4040

4848

4646

5454

4545

5252

4444

5353

0.430.43

0.720.72

0.20.2

0.050.05

0.100.10

0.210.21*Autologous BMT was compared to no further treatment after 4 courses of intensive chemo** Bone marrow was purged with 4 HC in the autologous transplantation arm.Number of patients is shown in parenthses

COMPARISON AMBT / ICCRELAPSE RATE AND TOXIC-DEATH

ABMTABMT ICCICC ABMTABMT ICCICC









4141

4545

3737

4848

3131

4545

5757

5959

5858

6161

5858

4545

1010

1313

1212

1414

1515

55

66

33

44

33

33

44*Autologous BMT was compared to no further treatment after 4 courses of intensive chemo** Bone marrow was purged with 4 HC in the autologous transplantation arm.

Relapse (%) Toxic death (%)

ABMT / ICC

No convincing evidence that unpurged ABMT is superior to the best available CT

Lower relapse rate but higher toxic death rate with ABMT

Strategies to reduce TRM are needed

ALLO versus AUTO AML in CR1RETROSPECTIVE COMPARISON

ALLOALLO

N=516N=516

AUTOAUTO

N=598N=598

p valuep value

TRMTRM

RelapseRelapse

LFSLFS

2727

2222

5555

1313

5252

4242

p<10p<10-4-4

p<10p<10-4-4

0.0060.006

EBMT (Gorin 1996)

Comparison of allogeneic BMT autologousBMT and ICC

Number of patients in shown in parentheses

DFS intention DFS intention to treatto treat

Age limit Age limit (years)(years)

AUTOAUTO ALLOALLO CHEMOCHEMO

ZittounZittoun

CassilethCassileth

WoodsWoods

4545

5555

2121

48 (n=128)48 (n=128)

35 (n=116)35 (n=116)

42 (n=179)42 (n=179)

55 (n=168)55 (n=168)

43 (n=113)43 (n=113)

55 (n=177)55 (n=177)

30 (n=126)30 (n=126)

35 (n=117)35 (n=117)

47 (n=179)47 (n=179)

THE ROLE OF ALLOGENEIC BMTDONOR / NO DONOR ANALYSIS

Age Age limitlimit

Pts with Pts with HLA id siblHLA id sibl

DonorDonor No donorNo donor DonorDonor No donnorNo donnor

EORTCEORTC

BGMTBGMT

GOELAMGOELAM

MRCMRC

4545

4545

4040

5555

295295

3636

8888

318318

46%46%

66%66%

44%44%

54%54%

33% (p=0.01)33% (p=0.01)

42% (p=0.05)42% (p=0.05)

38% (p=0.6)38% (p=0.6)

42% (p=0.006)42% (p=0.006)

48%48%

65%65%

53%53%

57%57%

40% p=NS40% p=NS

51% p=NS51% p=NS

53% p=NS53% p=NS

50% p=NS50% p=NS

DFS Overall survival

DFS ALLOCOMPARISON GOELAM1 / GOELAM2

0 1000 2000 3000 4000 50000

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

GOELAM 2 56%

GOELAM 1 42%

p = 0.05

GOELAM 2 COMPARISON CHEMO / ALLO

DFS (Intent to treat)

0 1000 2000 3000 4000 50000

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Allo 56%

Chemo 41%

p = 0.017

PROGNOSTIC VALUE OF KARYOTYPE(ALLO BMT)

FerrantFerrant GrimwadeGrimwade FerrantFerrant FerrantFerrant GrimwadeGrimwade

GoodGood

StandardStandard

PoorPoor

99

2525

6161

88

1818

7777

6767

5757

2929

5858

5959

3232

6262

6565

1313

Relapse LFS SV

DONOR VS NO DONOR ROLE OF CYTOGENETICS

DonorDonor No donorNo donor DonorDonor No donorNo donor DonorDonor No donorNo donor

No No

RelapseRelapse

DFSDFS

SVSV

117117

2626

6161

7171

127127

3636

6060

7373

194194

3434

5353

5757

428428

5656

3939

4545

5151

7171

2222

2323

110110

7878

2121

2525

Good risk Standard risk Poor risk

MRC 10 (A. Burnett) donor vs no donor

AML10 and AML12 Recruits <45 yearsAML10 and AML12 Recruits <45 years

n = 2356

1960 CR

729 Donor 1231 No Donor

427 Transplant (60%)

AML 10 & 12: Overall SurvivalDonor vs No Donor

AML 10 & 12AML 10 & 12Donor vs no donor comparisons Donor vs no donor comparisons

Overall survival stratified by risk groupOverall survival stratified by risk group

AML 10 & 12AML 10 & 12Donor vs no donor comparisons Donor vs no donor comparisons Overall survival stratified by ageOverall survival stratified by age

EORTC AML 10EORTC AML 10Comparison ALLO / AUTOComparison ALLO / AUTO

1198 Pts < 464

822 CR

734 IC

293 DONOR 441 NO DONOR

ALLO 69% AUTO 56%

4 year DFS 52% 42%

ALLO vs AUTO

EORTC-GIMEMA (AML10) Suciu Blood 2003

734 pst in CR1 < 46 yo

293* sibling 441** no donor donor p value

4yr DFS4yr DFS

4 yr SV*4 yr SV*

RRRR

Death in CRDeath in CR

52%52%

58%58%

30%30%

17%17%

42%42%

51%51%

52%52%

5%5%

0.0440.044

0.180.18

<0.0001<0.0001

<0.0001<0.0001

Intent to treat analysis* Allo performed in 69% cases ** auto performed in 56% cases

EORTC AML 10 COMPARISONEORTC AML 10 COMPARISONALLO / AUTO ACCORDING TO ALLO / AUTO ACCORDING TO

CYTOGENETICS (4 yr DFS)CYTOGENETICS (4 yr DFS)

Definition

t(8;21) inv 16

NN, -y

all others

Donor

68%

53%

50%

No Donor

74%

54%

29.5%

GOOD

INTERMEDIATE

BAD / VERY BAD

ALLO VS AUTOINFLUENCE OF AGE

DonorDonor No donorNo donor p-valuep-value

15-26 (67) 55%15-26 (67) 55%

26-35 (88) 55%26-35 (88) 55%

36-45 (138) 49%36-45 (138) 49%

(114) 41%(114) 41%

(88) 38%(88) 38%

(185) 46%(185) 46%

0.070.07

0.060.06

0.850.85

EORTC-GIMEMA (AML 10) Suciu Blood 20034 – yr DFS Intent to treat Analyis

ROLE OF ALLO BMT IN AMLROLE OF ALLO BMT IN AML

- Good risk cytogenetics- Good risk cytogenetics not indicated in CR1not indicated in CR1

- Intermediate risk- Intermediate risk indicated in CR1 (MRC)indicated in CR1 (MRC) different definitions (MRC / different definitions (MRC /

EORTC)EORTC) novel prognostic parametersnovel prognostic parameters

- Poor risk- Poor risk poor prognosis even with allopoor prognosis even with allo

RISK ADAPTED TREATMENTIN YOUNGER PATIENTS WITH DE NOVO AML

Risk classification based upon cytogenetic profiles

Define Tx strategy according to risk

Specific molecularly defined entitiesNew strategies (targeted to molecular abnormalities Flt-3)

LAM CBF

Anomalie cytog

Gène fusion

FAB

Fréquence

t(8;21)

AML1/ETO

M2

7-8 %

Rares après 60 ans

Inv(16) t(16;16)

CFB/MYH11

M4eo

4 %

PRONOSTIC t(8;21)

MRC*

Bloomfield

N’Guyen

N

332

84

161

CR (%)

92**

89

96

SV 5 ans (%)

70

50

59

* protocoles AML10 et AML12 (3453 pts)** 2% décès en induction

PRONOSTIC inv(16)/t(16;16)

MRC*

Delaunay

N

193

110

CR (%)

92**

93

PR (%)

35

42

* protocoles AML10 et AML12 (3453 pts)** 8% décès en induction

SV (%)

61

58

TRANSLOCATION t(8;21)ROLE DE L’ALLOGREFFE

Burnett (BJH 2002)

Essai MRC AML10 : 1063 patients

Etude donor / no donor

Bénéfice de l’allogreffe en DFS et en SV seulement dansle groupe de pronostic intermédiaire

Réduction du risque rechute dans tous les groupes sauf CBF

Pas d’allogreffe en 1ère ligne pour ces malades dans AML12

TRANSLOCATION t(8;21)COMPARISON ALLO / AUTO

At 3 yAt 3 y NN RelapseRelapse EFSEFS SV SV

AlloAllo

AutoAuto

4747

4949

1111 0.0010.001 4848

6464 NSNS4646

6565 NSNS5858

Ferrant (EBMT)

TRANSLOCATION t(8;21)COMPARISON ALLO / CHEMO

At 3 yAt 3 y NN DFSDFS SV SV

AlloAllo

ChemoChemo

3737

114114

5656 NSNS5252

5656 NSNS5252

N’Guyen (Blood 2002)

CHIMIOTHERAPIE DE CONSOLIDATION

C. Bloomfield (Cancer Research 1998)

Impact de ARA-C HD dans le groupe des LAM CBF[ t(8;21) inv(16) del(16) t(16;16) ]

3g3gN=18N=18

400mg/m²400mg/m²N=20N=20

100mg/m²100mg/m²N = 19N = 19

DFS à 5 ADFS à 5 A 78%78% 57%57% 16%16%

CHIMIOTHERAPIE CONSOLIDATION

Byrd (JCO 1999)

Les études CALGB successives Rôle du nombre de cycles ARAC-HD

à 5 ans

1 cycle

> 3 cycles

N

29

21

Rechute

620,004

19

DFS

380,03

71

SV

440,04

76

CONCLUSION

Pronostic global favorable- taux très élevé RC- survie à 5 A 60%

Allogreffe en 1ère ligne actuellement non recommandée

Allogreffe pour certains malades ?- index GB élevé- maladie résiduelle après intensification

TRANSLOCATION t(8;21)DETECTION MALADIE RESIDUELLE

Tobal Blood 2000 RRT-PCR quantitative 221 malades Iinduction réduction 2-3 logs Cconsolidation réduction 2-3 logs suppl. TTaux < 1.103/g RNA dans moelle

< 1.102/g RNA dans sangcompatible avec RC prolongée

Définition de malades à haut risque de rechute

Constitutivelyactivated receptor

Internal tandem duplication of the FLT3 gene

Agarose gel electrophoresis

Ladder WT AML patients DDW

PCRTransmembrane

Ig-like domain

Kinase insert

Kinase 1

Kinase 2

C-terminus

Juxtamembrane Internal tandem duplication

WT Mutant

FLT-3 TANDEM DUPLICATIONS

N of N of casescases

% with % with FLT-3 TDFLT-3 TD

CR%*CR%* Inferior OS*Inferior OS* Inferior Inferior EFS*EFS*

Kiyoi 99Kiyoi 99

Kottaridis 01Kottaridis 01

Schnittger 02Schnittger 02

Thiede 02Thiede 02

Frohling 02Frohling 02

201201

854854

10031003

979979

224**224**

2323

2727

2020

2020

3232

--

78 vs 8478 vs 84

70 vs 7070 vs 70

71 vs 6771 vs 67

65 vs 7665 vs 76

0.0080.008

0.0010.001

NSNS

NSNS

0.00010.0001

0.0060.006

0.0010.001

0.0070.007

NSNS

0.0070.007

* Compared to AML without FLT-3 TD** with normal cytogenetics

NEW GENETIC PROGNOSTIC NEW GENETIC PROGNOSTIC FACTORSFACTORS

Frequency

4.5%

8% (normal karyotype)

36%

10%

11% (NK)

Prognosis

UNF

UNF

UNF

UNF

UNF

FAV

Author

Nakano 2000

Döhner 2002

Karakas 2002

Van Waalwijk 2003

Baldus 2003

Preudhomme 2002

P53 mutation

MLL PTD

Bcl2 and WT1

EVI 1

BAALC

CEBP mutation

HOW TO IMPROVE THE RESULTS OF ABMT

1) Purged marrow

2) PBSC

3) Double transplantations

4) Maintenance therapy

IN VITRO PURGING

Retrospective analysis of the EBMT database suggested that purged marrow is superior in selected cases (Gorin)

- After TBI- Slow responding to induction CT- Transplanted early

Kinetics of engraftment slower

No randomised study

Retrospective comparison of bone marrow and peripheral blood as the source of stem cells for autolgous

transplantation in AML

AuthorsAuthors Source of Source of stem cellstem cell

Granulocyte recovery Granulocyte recovery (D) <0.5x10(D) <0.5x1099/l/l

Platelet Platelet recovery (D)recovery (D)

OutcomeOutcome

VisaniVisani

VellengaVellenga

ReiffersReiffers

Marrow n=21Marrow n=21

PB n=23PB n=23

Marro n=41Marro n=41

PB n=28PB n=28

Unpurged Unpurged marrowmarrow

Purged Purged

MarrowMarrow

PBPB

3636

p<0.01p<0.01

1717

3737

p<0.001p<0.001

1717

2929

29 p<0.000129 p<0.0001

1313

150150

p<0.3p<0.3

2020

9696

p<0.001p<0.001

2020

6464

60 p<0.000160 p<0.0001

4242

Identical Identical relapse rate relapse rate and DFSand DFS

--

Purged Purged marrow marrow betterbetter

PBSC vs BMAUTOLOGOUS TRANSPLANTATION

NbNb RelapseRelapse LFSLFS

Non purged BMNon purged BM

Purged BMPurged BM

PBSCPBSC

10411041

252252

100100

4545

3737

5050

4949

5757

4444

EBMT retrospective analysis 1393 pts (Reiffers 2000)Hematopoietic recovery significantly quicker after PBSC

Selection bias ?

CAN WE IMPROVE THE RESULTSOF ALLOGENEIC BMT

1)Reduce toxicityBetter control of GVH and infectious complicationsCord bloodPBSCReduced intensity conditioning

2)Reduce relapse Use matched unrelated donors

RANDOMIZED TRIALS COMPARING ALLOGENEIC PERIPHERALBLOOD TO BONE MARROW

Study

Vigorito-1998

Blaise-2000

Powles-2000

Heldal-2000

Schmitz-1998

Couban-2002

Bensinger-2001

n

37

101

39

61

350

228

172

PB

16

15

17.5

17

12

19

16

BM

18

21

23

23

15

22

21

ANCa PLTb TRM Agvhd Cgvhd OSPB

12

13

11

13

15

16

13

BM

17

21

18

21

20

22

19

PB,%

78

23

31

17

ND

7.5

21

BM,%

63

21

35

10

ND

16

30

PB,%

27

44

68

21

52

40

64

BM,%

19

42

58

10

39

40

57

PB,%

100

50

44

56

74

71

46

BM,%

50

28

40

27

53

55

35

PB,%

47

61

70

80

ND

68

66

BM,%

51

61

68

73

ND

55

54

RIC for AML in 1st CR

- 36 pts (26-60 y, med 52)- with comorbidity (12) or adverse prognosticfactors (23)- Flu,Bu,ATG (2.5 to 10 mg/kg)- 20 conso with HDARA-C- 11 with double conso (2nd with ASCT)

- 2 toxic deaths,11 relapses- Med F-up 16 m :65% DFS at 18 m- Prognostic factor :GVHD


LAM 2001LAM 2001INDUCTIONINDUCTION

R

IDA8mg/m2x5

DNR60mg/m2x3

+ ARA-C 200mg/m2

D15

< 5% blasts

> 5% blastsIDA or DNR x 2+ ARA-C 1g/m2

LAM 2001LAM 2001POST REMISSION THERAPYPOST REMISSION THERAPY

No HLA id siblingNo HLA id sibling

R2 Mini conso

SCcollection

1 ASCT Bu-Mel

2 ASCT Mel 200 Bu-Mel

ICCARA-C 3j x 8IDA or DNR x 2

LAM 2001LAM 2001POST REMISSION THERAPYPOST REMISSION THERAPY

HLA id siblingHLA id sibling

Good risk < 30.109 WBC/Lfavorable cytogenetics No AlloCR in one course

All others standard Allo < 50 yoICC and Miniallo > 50 yo

ALLO versus AUTORELAPSE RATE

ALLOALLO AUTOAUTO

Lowenberg (90)Lowenberg (90)

Ferrant (91)Ferrant (91)

Mitus (95)Mitus (95)

Reiffers (96)Reiffers (96)

Sierra (96)Sierra (96)

34 (23)34 (23)

25 (20)25 (20)

20 (31)20 (31)

24 (36)24 (36)

23 (47)23 (47)

60 (32)60 (32)

48 (33)48 (33)

50 (52)50 (52)

56 (60)*56 (60)*

37 (68)37 (68)

* Auto transplantation or intensive chemotherapy

ALLO versus AUTOLEUKEMIA FREE SURVIVAL

ALLOALLO AUTOAUTO

Lowenberg (90)Lowenberg (90)

Ferrant (91)Ferrant (91)

Mitus (95)Mitus (95)

Reiffers (96)Reiffers (96)

Sierra (96)Sierra (96)

51 (23)51 (23)

71 (20)71 (20)

56 (31)56 (31)

66 (36)66 (36)

31 (47)31 (47)

35 (32)35 (32)

31 (33)31 (33)

45 (52)45 (52)

42 (60)*42 (60)*

50 (68)50 (68)

* Auto transplantation or intensive chemotherapy

SURVIVAL ACCORDING TO CYTOGENETICSTATUS AND POST REMISSION THERAPY

CytogeneticCytogenetic

SubgroupSubgroup

AlloAllo AutoAuto ChemoChemo DonorDonor NoNo

donordonor

AlloAllo AutoAuto ChemoChemo

FavorableFavorable

IntermediateIntermediate

UnfavorableUnfavorable

62 (50)62 (50)

65 (148)65 (148)

13 (13)13 (13)

78 (50)78 (50)

56 (131)56 (131)

46 (18)46 (18)

76 (242)76 (242)

48 (626)48 (626)

25 (69)25 (69)

61 (129)61 (129)

66 (100)66 (100)

28 (46)28 (46)

56 (155)56 (155)

38 (130)38 (130)

22 (69)22 (69)

63 (19)63 (19)

52 (37)52 (37)

44 (18)44 (18)

71 (26)71 (26)

36 (37)36 (37)

13 (20)13 (20)

35 (22)35 (22)

55 (44)55 (44)

15 (20)15 (20)

MRC* EORTC** SWOG/ECOG***

Number of patients is shown in parentheses* at 3 years** at 6 years*** at 5 years

PROGNOSTIC IMPACT OF KARYOTYPE

PtsPts FavorableFavorable IntermediateIntermediate unfavorableunfavorable

MRCMRC

EBMTEBMT

SWOG/ECOGSWOG/ECOG

16121612

999999

609609

t(8;21)t(8;21)

t(15;17)t(15;17)

inv(16)inv(16)

t(8;21)t(8;21)



t(8;21)t(8;21)

All othersAll others

Including Including 11q2311q23

AbnormalitiesAbnormalities

t(15;17)t(15;17)

Pseudidiploid Pseudidiploid hyperdiploid hyperdiploid or diploidor diploid

NormalNormal

+8, -y, +6, del +8, -y, +6, del (12p)(12p)

ComplexComplex

-5, (del 5q)-5, (del 5q)

-7 abnormalities of 3q-7 abnormalities of 3q

Abnormalities of 5 and/or 7Abnormalities of 5 and/or 7

Abnormalities of 11q hypodiploidAbnormalities of 11q hypodiploid

-5, del (5q)-5, del (5q)

-7, del (7a)-7, del (7a)

Inv 39Inv 39

Complex abnormalities of 11q, Complex abnormalities of 11q, 20q, 21q20q, 21q

Del (9q)Del (9q)

t(6;9), t(9;22)t(6;9), t(9;22)

Abn 17pAbn 17p

GOELAM 2INDUCTION TREATMENT

R1

Quinine30mg/kg CI

Control

IND

UC

TIO

N IDR8x5

ARA-C200x7

D2

O E

VA

LU

AT

ION

>20%blasts

MTZ12x2

ARA-C6gx4

Impact of additional cytogenetic abnormalities:Survival of patients entered into AML 10 & 12 (n=3453)

100

50

75

25

00 1 2 3 4 5

Years from entry

% s

till

aliv

e

Favourable only (n=478)Favourable + intermediate (n=331)Favourable + adverse (n=22)Intermediate only (n=2235)Adverse + intermediate (n=297)Adverse only (n=478)

71%65%59%

42%

17%14%

Outcome of those with done Outcome of those with done and no transplantand no transplant

Donor – Allo (195)Donor – No allo (110)

DONOR vs NO DONOR ROLE OF CYTOGENETICS

DonorDonor No donorNo donor DonorDonor No donorNo donor DonorDonor No donorNo donor

No No

RelapseRelapse

DFSDFS

SVSV

117117

2626

6161

7171

127127

3636

6060

7373

194194

3434

5353

5757

428428

5656

3939

4545

5151

7171

2222

2323

110110

7878

2121

2525

Good risk Standard risk Poor risk

MRC 10 (A. Burnett) donor vs no donor

ALLO vs AUTOINFLUENCE OF CYTOGENETICS

EORTC-GIMEMA (AML10) Suciu Blood 2003

4-yr DFS Intent to treat analysis

DonorDonor No donorNo donor P valueP value

Good riskGood risk

IntermInterm

Bad riskBad risk

UnknownUnknown

(50) 62%(50) 62%

(61) 45%(61) 45%

(64) 43%(64) 43%

(118) 58%(118) 58%

(73) 66%(73) 66%

(104) 48.5%(104) 48.5%

(94) 18%(94) 18%

(170) 41%(170) 41%

0.540.54

0.510.51

0.0070.007

0.0270.027

GOELAM 2CONSOLIDATION

< 45 yo HLA identical sibling

Allo BMT

45-60 yo or no identical sibling

ICC1 ICC2

ARA-C 6gx4 Amsa 150x5 MTZ 12x2 VP16 100x5

+ QUININE + QUININE

Peripheral blood vs bone marrow allogeneic transplantationResults of randomized studies

AuthorAuthor N° N° ptspts

BloodBlood MarrowMarrow BloodBlood MarrowMarrow BloodBlood MarrowMarrow BloodBlood MarrowMarrow

SchmitzSchmitz

VigoritoVigorito

PowlesPowles

BlaiseBlaise

HeldalHeldal

BensingerBensinger

6666

3737

3939

101101

6161

172172

1414

1616

17.517.5

1515

1717

1616

1515

1818

2323

2121

2323

2121

1515

1212

1111

1313

1313

1313

1919

1717

1818

1919

2121

2121

54%54%

27%27%

NSNS

44%44%

6%6%

64%64%

48%48%

19%19%

NSNS

42%42%

3%3%

57%57%

NANA

71%71%

NSNS

50%50%

15%15%

46%46%

NANA

53%53%

NSNS

28%28%

8%8%

35%35%

NSNS

NSNS

2y sv2y sv

70% vs 63%70% vs 63%

NSNS

NSNS

*2y DFS*2y DFS

65% vs 45%65% vs 45%

P=0.03P=0.03

Duration of Duration of a GVHD c GVHD Outcomeneutropenia thrombocytopen grade 2-4(days) (days)

•No significant difference for early stage malignancies•NS = not significant NA = not available

Survival in the United Kingdom Medical Research Council AML Survival in the United Kingdom Medical Research Council AML

trials 1970–1999 for patients aged 15–59 yearstrials 1970–1999 for patients aged 15–59 years

THE ROLE OF TRANSPLANTATIONIN AML

Jean-Luc HAROUSSEAU

Nantes - FRANCE


NSNS

GOELAM2 TRIAL PROGNOSTIC FACTORS

CR achievement (multivariate analysis)- karyotype (0.0004)- WBC count (0.002)- PS (0.002)


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