Survival in the United Kingdom Medical Research Council AML trials 1970

1
Survival in the United Kingdom Medical Research
Council AML trials 19701999 for patients aged
1559 years
2
FACTEURS PRONOSTIQUES

• liés au malade
• performance status
• âge
• liés à histoire de la maladie (de
  novo/secondaire)
• liés à la présentation clinique / biologique
• tumeurs
• taux GB
• LDH
• liés au type LAM
• cytologie M3, M2-M4 / M6-M7
• phénotype (CD34, Pgp)
• cytogénétique
• biologie moléculaire
• liés à la réponse au traitement
• RC en 2 cures (MRC)
• blastose a J15 (German AMLCG)

3
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)
4
Outcome according to hierarchical cytogenetic
classification
OS (5yrs)
CR ()
ID ()
RD ()
n
RR (,5yrs)
t(1517)
88
569
23
69
11
2
70
t(821)
98
2
0
332
22
8
92
0
193
35
61
inv(16)/t(1616)
31
92
6
71
23
t(922)
5
4
28
84
82
14
t(69)
30
7
88
t(11q23)
5
212
50
46
19
47
6
inv(3)/t(33)
35
44
80
5
0
t(35)
95
21
47
43
16
48
25
63
25
36
t(12p13)
5
22
49
91
5
33
abn(11p135)
0
92
8
t(8p11)
13
21
66
88
5
48
45
7
normal
1066
plt0.01, plt0.001, Chi-squared test or Fisher
exact test (CR/ID/RD), log rank test (RR OS)
5
Outcome according to hierarchical cytogenetic
classification
OS (5yrs)
CR ()
ID ()
RD ()
n
RR (,5yrs)
abn(16q2224)
11
83
6
35
40
46
9
-5/5q/-7/7q
64
27
276
70
16
91
2
7
45
57
30
7q, no adverse
10
90
0
30
73
18
4
70
4
26
11
28
70
20
8
6
82
12
210
53
37
del(9q)
91
9
0
36
37
47
5
21
81
14
47
73
38
9
87
24
79
26
4
del(11)(q23)
67
14
19
abn(3q)
25
89
8
37
12
78
11
Other
373
48
7
88
5
normal
1066
48
45
plt0.01, plt0.001, Chi-squared test or Fisher
exact test (CR/ID/RD), log rank test (RR OS)
6
Outcome in AML patients with 11q23 abnormalities
ID ()
CR ()
RD ()
Median age
RR (,5yrs)
OS (5yrs)
t(11q23) total (n212)
7
88
5
12.5
50
46
31
t(611)(q27q23) (n21)
5
95
0
19.0
76
11
61
t(911)(p212q23) (n73)
86
3
4.0
28
2
t(1011)(p114q1323) (n46)
91
7
12.0
63
35
t(1119)(q23p13) (n18)
0
100
0
19.0
55
60
Other t(11q23) (n54)
7
81
24.0
38
11
54
p value for heterogeneity
lt0.01
NS
7
Impact of additional cytogenetic
abnormalities Survival of patients entered into
AML 10 12 (n3453)
Favourable only (n478)
Favourable intermediate (n331)
Favourable adverse (n22)
Intermediate only (n2235)
100
Adverse intermediate (n297)
Adverse only (n478)
75
71
65
59
still alive
50
42
25
17
14
0
0
1
2
3
4
5
Years from entry
8
PROGNOSTIC IMPACT OF KARYOTYPE
Pts Favorable Intermediate unfavorable
MRC EBMT SWOG/ECOG 1612 999 609 t(821) t(1517) inv(16) t(821) Abnormalities of 16 Abnormalities of 16 t(821) All others Including 11q23 Abnormalities t(1517) Pseudidiploid hyperdiploid or diploid Normal 8, -y, 6, del (12p) Complex -5, (del 5q) -7 abnormalities of 3q Abnormalities of 5 and/or 7 Abnormalities of 11q hypodiploid -5, del (5q) -7, del (7a) Inv 3 Complex abnormalities of 11q, 20q, 21q Del (9q) t(69), t(922) Abn 17p
9
TRAITEMENT DINDUCTION
 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)
10
TRAITEMENT DINDUCTION

• - Facteurs de croissance hématopoiétique
• - Modulateurs mdr
• Hautes doses dARA-C (1 à 3 g/m2, seule ou
  associée
• à anthracyclines ou Fludarabine )
• - Date dadministration de la deuxième cure

11
G-CSF DANS LES LAM G-CSFR EXPRIME A LA SURFACE
DES BLASTES DE LAM

• Après traitement dinduction
• 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 dimpact sur la survie ou EFS
• généralement diminution de la durée
  dhospitalisation et de lutilisation
• dATB
• réduction du cout dhospitalisation dans 2
  études
• pas daugmentation du risque de progression ou
  de rechute
• Après consolidation
• 2 études (Heil Blood 1997, Harousseau JCO 2000)
• ? Réduction de la durée neutropénie et
  dhospitalisation

12
PRIMING DANS LES LAM

• Neuf études randomisées avec G ou GM-CSF
• Nombre de patients et modalités dadministration
  du FCH
• variables
• ? pas daugmentation 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) p0.002)
• - 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)

13

• 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 dautres facteurs de mauvais
  pc (CD34,Cytogénétique,LAM réfractaires ou en
  rechute)
• -rare au Dg chez sujets jeunes mais
  fréquente chez sujets agés (Leith 97)

14
MODULATEURS MDR
- Cyclosporine - 1 essai gt0 ds
LAM à haut risque (List,Blood 2001 )
- 1 essai lt0 (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)
15
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

16
HAUTES DOSES ARA-C
Weick Blood 96 493 pts lt 65 A De novo ou
secondaire
BISHOP Blood 96 301 pts 15-60 A denovo
BD 100mg/m²/PCx7 HD 3g/m² (J1,3,5,7) SD 200mg/m²/PCx7 HP 2g/m²x2 J1-6
RC Durée med RC DFS () SV () 74 12 m 24 25 71 45 m 49 31 58 lt 50A 21 50-64 9 lt 50A 22 50-64 11 55 33 21 32 13
À 5 ans
17
DATE ADMINISTRATION 2ème CURE
- A sortie daplasie après 1ère (ou à J30) - En
fonction des résultats du myélogramme
intermédiaire (J15) - Systématiquement (quel que
soit le résultat dun éventuel myélogramme
intermédiaire) - timed-sequential - double
induction
18
TRAITEMENT INDUCTION 2ème 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 lt 50A
19
TRAITEMENT INDUCTION
- Avec les progrès de la réanimation
hématolo- gique taux de décès toxique lt 5 et
taux de RC élevés dans les LAM de novo lt 60A -
Difficile de démontrer la supériorité dun
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 pronostiques initiaux (cytogénétique )
20
POST-REMISSION THERAPY IN AML

• Allogeneic BMT
• - Most effective antileukemic treatment
• Myeloablative preparative regimen
• GVL effect
• - High incidence of severe procedure-related
• toxicity
• High transplant-related mortality
• Indicated only in patients lt 55 yo
• - Only patients with an HLA-identical sibling

21
POST-REMISSION THERAPY IN AML AUTOLOGOUS SCT
- Toxic death rate much lower than after allo
BMT - High relapse rate Contamination by
malignant cells Absence of GVL - Age limit 60
y - Uncontrolled studies have shown DFS rates of
30 to 60 In AML CR1 Selection bias ?
22
POST-REMISSION THERAPY ICC
- Non myeloablative - Age limit 60y - High
relapse rate - DFS 30-50 in pilot uncontrolled
studies
23
RANDOMIZED TRIALS COMPARING ASCT AND ICC DFS
Pts Auto Chemo p
Adult studies Zittoun 95 Harousseau 97 Burnett 98 Cassileth 98 Pediatric studies Ravindranath 96 Woods 01 990 535 196 808 666 887 48 (128) 44 (86) 53 (190) 35 (116) 38 (89) 42 (177) 30 (126) 40 (78) 40 (191) 35 (117) 36 (115) 47 (179) 0.05 0.41 0.04 0.77 0.20 0.31
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
24
RANDOMIZED TRIALS COMPARING ASCT AND ICC OS
Pts Auto Chemo p
Adult studies Zittoun 95 Harousseau 97 Burnett 98 Cassileth 98 Pediatric studies Ravindranath 96 Woods 01 990 535 196 808 666 887 56 50 57 43 40 48 46 54 45 52 44 53 0.43 0.72 0.2 0.05 0.10 0.21
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
25
COMPARISON AMBT / ICC RELAPSE RATE AND TOXIC-DEATH
Relapse () Toxic death ()
ABMT ICC ABMT ICC
Adult studies Zittoun 95 Harousseau 97 Burnett 98 Cassileth 98 Pediatric studies Ravindranath 96 Woods 01 41 45 37 48 31 45 57 59 58 61 58 45 10 13 12 14 15 5 6 3 4 3 3 4
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.
26
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
27
ALLO versus AUTO AML in CR1 RETROSPECTIVE
COMPARISON
EBMT (Gorin 1996)
ALLO N516 AUTO N598 p value
TRM Relapse LFS 27 22 55 13 52 42 plt10-4 plt10-4 0.006
28
Comparison of allogeneic BMT autologous BMT and
ICC
DFS intention to treat Age limit (years) AUTO ALLO CHEMO
Zittoun Cassileth Woods 45 55 21 48 (n128) 35 (n116) 42 (n179) 55 (n168) 43 (n113) 55 (n177) 30 (n126) 35 (n117) 47 (n179)
Number of patients in shown in parentheses
29
THE ROLE OF ALLOGENEIC BMT DONOR / NO DONOR
ANALYSIS
DFS Overall survival
Age limit Pts with HLA id sibl Donor No donor Donor No donnor
EORTC BGMT GOELAM MRC 45 45 40 55 295 36 88 318 46 66 44 54 33 (p0.01) 42 (p0.05) 38 (p0.6) 42 (p0.006) 48 65 53 57 40 pNS 51 pNS 53 pNS 50 pNS
30
DFS ALLO COMPARISON GOELAM1 / GOELAM2
1.0
0.9
0.8
0.7
0.6
GOELAM 2 56
0.5
GOELAM 1 42
0.4
0.3
0.2
p 0.05
0.1
0
0
1000
2000
3000
4000
5000
31
GOELAM 2 COMPARISON CHEMO / ALLO DFS (Intent to
treat)
1.0
0.9
0.8
0.7
0.6
Allo 56
0.5
Chemo 41
0.4
0.3
0.2
0.1
p 0.017
0
0
1000
2000
3000
4000
5000
32
PROGNOSTIC VALUE OF KARYOTYPE (ALLO BMT)
Relapse LFS SV
Ferrant Grimwade Ferrant Ferrant Grimwade
Good Standard Poor 9 25 61 8 18 77 67 57 29 58 59 32 62 65 13
33
DONOR VS NO DONOR ROLE OF CYTOGENETICS
MRC 10 (A. Burnett) donor vs no donor
Good risk Standard risk
Poor risk
Donor No donor Donor No donor Donor No donor
No Relapse DFS SV 117 26 61 71 127 36 60 73 194 34 53 57 428 56 39 45 51 71 22 23 110 78 21 25
34
AML10 and AML12 Recruits lt45 years
n 2356 1960 CR 729 Donor 1231 No Donor
427 Transplant (60)
35
AML 10 12 Overall Survival Donor vs No Donor
36
AML 10 12Donor vs no donor comparisons
Overall survival stratified by risk group
37
AML 10 12Donor vs no donor comparisons
Overall survival stratified by risk group
38
AML 10 12Donor vs no donor comparisons
Overall survival stratified by age
39
AML 10 12Donor vs no donor comparisons
Overall survival stratified by age
40
AML 10 12Donor vs no donor comparisons
Overall survival stratified by age
41
EORTC AML 10Comparison ALLO / AUTO
1198 Pts lt 464 822 CR 734 IC
293 DONOR 441 NO DONOR ALLO
69 AUTO 56
4 year DFS 52
42
42
ALLO vs AUTO
EORTC-GIMEMA (AML10) Suciu Blood 2003 734
pst in CR1 lt 46 yo 293 sibling
441 no donor donor
p value

4yr DFS 4 yr SV RR Death in CR 52 58 30 17 42 51 52 5 0.044 0.18 lt0.0001 lt0.0001
Intent to treat analysis Allo performed in 69
cases auto performed in 56 cases
43
EORTC AML 10 COMPARISONALLO / AUTO ACCORDING TO
CYTOGENETICS (4 yr DFS)
Definition t(821) inv 16 NN, -y all others
Donor 68 53 50
No Donor 74 54 29.5
GOOD INTERMEDIATE BAD / VERY BAD
44
ALLO VS AUTO INFLUENCE OF AGE
EORTC-GIMEMA (AML 10) Suciu Blood 2003 4 yr DFS
Intent to treat Analyis
Donor No donor p-value
15-26 (67) 55 26-35 (88) 55 36-45 (138) 49 (114) 41 (88) 38 (185) 46 0.07 0.06 0.85
45
ROLE OF ALLO BMT IN AML

• - Good risk cytogenetics
• ? not indicated in CR1
• - Intermediate risk
• ? indicated in CR1 (MRC)
• ? different definitions (MRC / EORTC)
• ? novel prognostic parameters
• - Poor risk
• ? poor prognosis even with allo

46
RISK ADAPTED TREATMENT IN YOUNGER PATIENTS WITH
DE NOVO AML
Risk classification based upon cytogenetic
profiles Define Tx strategy according to
risk Specific molecularly defined entities New
strategies (targeted to molecular abnormalities
Flt-3)
47
LAM CBF
Anomalie cytog Gène fusion FAB Fréquence
t(821) AML1/ETO M2 7-8 Rares après 60
ans
Inv(16) t(1616) CFBb/MYH11 M4eo 4
48
PRONOSTIC t(821)
MRC Bloomfield NGuyen
N 332 84 161
CR () 92 89 96
SV 5 ans () 70 50 59
protocoles AML10 et AML12 (3453 pts) 2
décès en induction
49
PRONOSTIC inv(16)/t(1616)
SV () 61 58
MRC Delaunay
N 193 110
CR () 92 93
PR () 35 42
protocoles AML10 et AML12 (3453 pts) 8
décès en induction
50
TRANSLOCATION t(821) ROLE DE LALLOGREFFE

• Burnett (BJH 2002)
• Essai MRC AML10 1063 patients
• Etude donor / no donor
• Bénéfice de lallogreffe en DFS et en SV
  seulement dans
• le groupe de pronostic intermédiaire
• Réduction du risque rechute dans tous les groupes
  
• sauf CBF
• Pas dallogreffe en 1ère ligne pour ces
  malades
• dans AML12

51
TRANSLOCATION t(821) COMPARISON ALLO / AUTO
Ferrant (EBMT)
At 3 y N Relapse EFS SV
Allo Auto 47 49 11 0.001 48 64 NS 46 65 NS 58
52
TRANSLOCATION t(821) COMPARISON ALLO / CHEMO
NGuyen (Blood 2002)
At 3 y N DFS SV
Allo Chemo 37 114 56 NS 52 56 NS 52
53
CHIMIOTHERAPIE DE CONSOLIDATION
C. Bloomfield (Cancer Research 1998) Impact de
ARA-C HD dans le groupe des LAM CBF t(821)
inv(16) del(16) t(1616)
3g N18 400mg/m² N20 100mg/m² N 19
DFS à 5 A 78 57 16
54
CHIMIOTHERAPIE CONSOLIDATION
Byrd (JCO 1999) Les études CALGB successives
Rôle du nombre de cycles ARAC-HD
à 5 ans 1 cycle gt 3 cycles
N 29 21
Rechute 62 0,004 19
DFS 38 0,03 71
SV 44 0,04 76
55
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
56
TRANSLOCATION t(821) DETECTION MALADIE RESIDUELLE

• Tobal Blood 2000
• RRT-PCR quantitative
• 221 malades
• Iinduction réduction 2-3 logs
• Cconsolidation réduction 2-3 logs suppl.
• TTaux lt 1.103/mg RNA dans moelle
• lt 1.102/mg RNA dans sang
• compatible avec RC prolongée
• Définition de malades à haut risque de rechute

57
Internal tandem duplication of the FLT3 gene
Ig-like domain
Agarose gel electrophoresis
PCR
Transmembrane
Ladder WT AML patients
DDW
WT Mutant
58
FLT-3 TANDEM DUPLICATIONS
N of cases with FLT-3 TD CR Inferior OS Inferior EFS
Kiyoi 99 Kottaridis 01 Schnittger 02 Thiede 02 Frohling 02 201 854 1003 979 224 23 27 20 20 32 - 78 vs 84 70 vs 70 71 vs 67 65 vs 76 0.008 0.001 NS NS 0.0001 0.006 0.001 0.007 NS 0.007
Compared to AML without FLT-3 TD with normal
cytogenetics
59
NEW GENETIC PROGNOSTIC FACTORS
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 a mutation
60
HOW TO IMPROVE THE RESULTS OF ABMT
1) Purged marrow 2) PBSC 3) Double
transplantations 4) Maintenance therapy
61
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
62
Retrospective comparison of bone marrow and
peripheral blood as the source of stem cells for
autolgous transplantation in AML
Authors Source of stem cell Granulocyte recovery (D) lt0.5x109/l Platelet recovery (D) Outcome
Visani Vellenga Reiffers Marrow n21 PB n23 Marro n41 PB n28 Unpurged marrow Purged Marrow PB 36 plt0.01 17 37 plt0.001 17 29 29 plt0.0001 13 150 plt0.3 20 96 plt0.001 20 64 60 plt0.0001 42 Identical relapse rate and DFS - Purged marrow better
63
PBSC vs BM AUTOLOGOUS TRANSPLANTATION
EBMT retrospective analysis 1393 pts (Reiffers
2000) Hematopoietic recovery significantly
quicker after PBSC
Nb Relapse LFS
Non purged BM Purged BM PBSC 1041 252 100 45 37 50 49 57 44
Selection bias ?
64
CAN WE IMPROVE THE RESULTS OF ALLOGENEIC BMT
1)Reduce toxicity Better control of GVH and
infectious complications Cord blood PBSC Reduced
intensity conditioning 2)Reduce relapse Use
matched unrelated donors
65
RANDOMIZED TRIALS COMPARING ALLOGENEIC
PERIPHERAL BLOOD TO BONE MARROW
ANCa PLTb TRM
Agvhd Cgvhd OS
Study Vigorito-1998 Blaise-2000 Powles-2000 He
ldal-2000 Schmitz-1998 Couban-2002 Bensinger-20
01
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
PB 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
66
RIC for AML in 1st CR

• 36 pts (26-60 y, med 52)
• - with comorbidity (12) or adverse prognostic
• factors (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)

67
LAM 2001 INDUCTION
IDA 8mg/m2x5 DNR 60mg/m2x3

• lt 5 blasts
• gt 5 blasts
• IDA or DNR x 2
• ARA-C 1g/m2

ARA-C 200mg/m2
D15
R
68
LAM 2001 POST REMISSION THERAPY No HLA id sibling
SC collection
1 ASCT Bu-Mel 2 ASCT Mel 200 Bu-Mel
Mini conso
ICC ARA-C 3j x 8 IDA or DNR x 2
R2
69
LAM 2001 POST REMISSION THERAPY HLA id sibling
Good risk lt 30.109 WBC/L favorable
cytogenetics No Allo CR in one course All
others standard Allo lt 50 yo ICC and
Miniallo gt 50 yo
70
ALLO versus AUTO RELAPSE RATE
ALLO AUTO
Lowenberg (90) Ferrant (91) Mitus (95) Reiffers (96) Sierra (96) 34 (23) 25 (20) 20 (31) 24 (36) 23 (47) 60 (32) 48 (33) 50 (52) 56 (60) 37 (68)
Auto transplantation or intensive chemotherapy
71
ALLO versus AUTO LEUKEMIA FREE SURVIVAL
ALLO AUTO
Lowenberg (90) Ferrant (91) Mitus (95) Reiffers (96) Sierra (96) 51 (23) 71 (20) 56 (31) 66 (36) 31 (47) 35 (32) 31 (33) 45 (52) 42 (60) 50 (68)
Auto transplantation or intensive chemotherapy
72
SURVIVAL ACCORDING TO CYTOGENETIC STATUS AND POST
REMISSION THERAPY
MRC EORTC
SWOG/ECOG
Cytogenetic Subgroup Allo Auto Chemo Donor No donor Allo Auto Chemo
Favorable Intermediate Unfavorable 62 (50) 65 (148) 13 (13) 78 (50) 56 (131) 46 (18) 76 (242) 48 (626) 25 (69) 61 (129) 66 (100) 28 (46) 56 (155) 38 (130) 22 (69) 63 (19) 52 (37) 44 (18) 71 (26) 36 (37) 13 (20) 35 (22) 55 (44) 15 (20)
Number of patients is shown in parentheses at
3 years at 6 years at 5 years
73
PROGNOSTIC IMPACT OF KARYOTYPE
Pts Favorable Intermediate unfavorable
MRC EBMT SWOG/ECOG 1612 999 609 t(821) t(1517) inv(16) t(821) Abnormalities of 16 Abnormalities of 16 t(821) All others Including 11q23 Abnormalities t(1517) Pseudidiploid hyperdiploid or diploid Normal 8, -y, 6, del (12p) Complex -5, (del 5q) -7 abnormalities of 3q Abnormalities of 5 and/or 7 Abnormalities of 11q hypodiploid -5, del (5q) -7, del (7a) Inv 39 Complex abnormalities of 11q, 20q, 21q Del (9q) t(69), t(922) Abn 17p
74
GOELAM 2 INDUCTION TREATMENT
Quinine 30mg/kg CI Control
MTZ 12x2 ARA-C 6gx4
IDR 8x5 ARA-C 200x7
D2O EVALUATION
gt20 blasts
INDUCTION
R1
75
Impact of additional cytogenetic
abnormalities Survival of patients entered into
AML 10 12 (n3453)
Favourable only (n478)
Favourable intermediate (n331)
Favourable adverse (n22)
Intermediate only (n2235)
100
Adverse intermediate (n297)
Adverse only (n478)
75
71
65
59
still alive
50
42
25
17
14
0
0
1
2
3
4
5
Years from entry
76
Outcome of those with done and no transplant
Donor Allo (195) Donor No allo (110)
77
DONOR vs NO DONOR ROLE OF CYTOGENETICS
MRC 10 (A. Burnett) donor vs no donor
Good risk Standard risk
Poor risk
Donor No donor Donor No donor Donor No donor
No Relapse DFS SV 117 26 61 71 127 36 60 73 194 34 53 57 428 56 39 45 51 71 22 23 110 78 21 25
78
ALLO vs AUTO INFLUENCE OF CYTOGENETICS
EORTC-GIMEMA (AML10) Suciu Blood 2003 4-yr
DFS Intent to treat analysis
Donor No donor P value
Good risk Interm Bad risk Unknown (50) 62 (61) 45 (64) 43 (118) 58 (73) 66 (104) 48.5 (94) 18 (170) 41 0.54 0.51 0.007 0.027
79
GOELAM 2 CONSOLIDATION
lt 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
80
Peripheral blood vs bone marrow allogeneic
transplantation Results of randomized studies
Duration of Duration of a GVHD
c GVHD
Outcome neutropenia thrombocytopen grade
2-4 (days) (days)
Author N pts Blood Marrow Blood Marrow Blood Marrow Blood Marrow
Schmitz Vigorito Powles Blaise Heldal Bensinger 66 37 39 101 61 172 14 16 17.5 15 17 16 15 18 23 21 23 21 15 12 11 13 13 13 19 17 18 19 21 21 54 27 NS 44 6 64 48 19 NS 42 3 57 NA 71 NS 50 15 46 NA 53 NS 28 8 35 NS NS 2y sv 70 vs 63 NS NS 2y DFS 65 vs 45 P0.03

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

81
Survival in the United Kingdom Medical Research
Council AML trials 19701999 for patients aged
1559 years
82
THE ROLE OF TRANSPLANTATION IN AML

Jean-Luc HAROUSSEAU Nantes - FRANCE
83
TRAITEMENT DINDUCTION

NS
84
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)