facteurs pronostiques
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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
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)
TRAITEMENT D’INDUCTION
- 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
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
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
Adult studiesAdult studies
Zittoun 95Zittoun 95
Harousseau 97Harousseau 97
Burnett* 98Burnett* 98
Cassileth 98Cassileth 98
Pediatric studiesPediatric studies
Ravindranath 96Ravindranath 96
Woods** 01Woods** 01
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 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
AML 10 & 12AML 10 & 12Donor vs no donor comparisons Donor vs no donor comparisons Overall survival stratified by ageOverall survival stratified by age
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
DFS (multivariate analysis)- karyotype (0.0004)- allo BMT (0.005)
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)
AbnormalitiAbnormalities of 16es of 16
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 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
TRAITEMENT D’INDUCTION
NSNS
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)
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