Un viatge de 25 anys en el tractament adaptat al
risc de la LMA: experiència del grup CETLAM
Jordi Sierra27 de setembre de 2013
El El pronòsticpronòstic de la LMA de de la LMA de l’adultl’adult finsfins 19871987
(Hospital (Hospital ClínicClínic))
J. Sierra, tesi doctoral 1987
L’inici del treball cooperatiu en L’inici del treball cooperatiu en
LMA: El Grup Català de LMA: El Grup Català de
Trasplantament de Moll d’OsTrasplantament de Moll d’OsTrasplantament de Moll d’OsTrasplantament de Moll d’Os
La La ComissióComissió AssessoraAssessora de TMO de TMO encarregaencarrega la la
redaccióredacció un un protocolprotocol cooperatiucooperatiu
AMLAML--88: 88: BackgroundBackground and and ObjectivesObjectives
• AML in young adults was cuarble in less than 15-20% of
patients. APL treated with CT. Early experiences on
autologous HCT
• Treatment (up to 50 years): DA+T (OP) followed by
consolidaton (DA) and: a) intensive maintenance rotating
agents (VAPA and similars); b) repeated induction courses agents (VAPA and similars); b) repeated induction courses
(Bart’s); c) early experiences HDAC (Preisler, Capizzi,
Arlin); d) HLA-id sibling transplants (up to the age of 40-45
yrs (in selected centers, not more than 5 in Spain)
• AML-88: Combine DA+etoposide, HDAC as intensification
rotating MTN and Amsacrine, followed by HLA-id sib or
autologous transplantation
AMLAML--94: 94: BackgroundBackground and Planand Plan
• Upper age for intensive protocols increased up to 60 years (allos
up to 50)
• Idarubicin could be superior to daunorubicin
• Second intensification in AML-88 was too toxic and precluded
transplantation in a significant number of patientstransplantation in a significant number of patients
• Mortality of allogeneic HCT was remarkable, particularly in APL
• APL should be approached independently (Degos, Fenaux,
Inclusion in Pethema trials)
• Plan: Induction with ICE, a single intensification with IDAC, allo or
auto depending on age (50 yrs) and HLA identical sibling
OSOS1,0
,8
p<.0001
Favorable, n=29, 61 + 9%
AMLAML--9494
Months
100806040200
,6
,4
,2
0,0
Adverse, n= 13, 0%
Intermediate n=123, 35 + 5%
AML 88 (n=50)AML 88 (n=50) AML 94 (n=140)AML 94 (n=140) P-value
Induction DCE (3x7x3) ICE (3x7x3)
Patients 50 140
CR: No (%) 38 (76%) 103 (73%) 0.736
CETLAM AML 88 vs 94 protocols for primary AML
Patients up to the age of 50 yrs
CR: No (%) 38 (76%) 103 (73%) 0.736
CR with one course: N (%) 26 (68%) 86 (83%) 0.049
Refractory (%) / Toxic death (%) 7 (14%)/ 5 (10%) 29 (21%) / 8 (6%) 0.171
Cum incidence of relapse (4 yrs) 37±8% 41±5% 0.390
LFS at 4 years 53±8% 50±5% 0.570
OS at 4 years 42±7% 44±4% 0.999
¿La quimioteràpia amb ICE es pot aplicar als ¿La quimioteràpia amb ICE es pot aplicar als
adults d’edat avançada?: El protocol LMAadults d’edat avançada?: El protocol LMA--99 99
dels “vells”dels “vells”dels “vells”dels “vells”
LMA-99 per adults fins 60 anys:
La terapia adaptada al risc citogenèticLa terapia adaptada al risc citogenètic
AMLAML--99: 99: BackgroundBackground and Planand Plan
• Intermediate dose cytarabine investigated during induction
• Try to avoid allo in first CR in patients potentially curable
with CT only (CBF AML and normal karyotype and one course
to CR)
• Upper age for HLA-id sibling transplants up to 60 years
• PBSC introduced in auto and allogeneneic transplants
• Investigate the impact of biological markers (FLT3, MRD by
flow): Translational research
• Plan: Induction with IDICE, a single intensification with IDAC,
CBF: HDAC; others allo or auto depending on and HLA
identical sibling availability
CETLAM AMLCETLAM AML--9999
INDUCTION (1 or 2 courses)INDUCTION (1 or 2 courses)
Idarubicin 12 mg/m2 iv 1,3,5
Cytarabine 500 mg/m2 /12h iv 1,3,5,7
VP-16 100 mg/m2 iv 1,2,3
CONSOLIDATIONCONSOLIDATION
Cytarabine 500 mg/m2/12h iv 1-6Cytarabine 500 mg/m2/12h iv 1-6
Mitoxantrone 12 mg/m2 iv 4-6
Favorable:t(8;21) or inv(16):
High dose High dose AraAra--C x 2C x 2
Intermediate:
(1 course to CR and normal
karyotype): AutoAuto--PBTPBT
Adverse:
NK & 2 courses to
CR / Other
chromosomal abn:
Auto or Auto or AlloAllo--PBTPBT
AMLAML--99: Favorable risk 99: Favorable risk (HDAC)(HDAC)
Impact of WBC counts at Impact of WBC counts at DxDx
< 20x109/l (n=23), 68+10
> 20x109/l (n=21)
> 20x109/l (n=21), 40+11
P= 0.03 P= 0.03
< 20x109/l (n=23)
AMLAML--99: 99: IntermediateIntermediate riskrisk ((AutologousAutologous))
Intention to treat Autografted
N Events Censored
74 45 29 39,2%N Events Censored
56 30 26 46,4%
Better discrimination of this
group is mandatory!
AMLAML--99 99 HighHigh RiskRiskIntentionIntention ToTo TreatTreat: : AutologousAutologous vs HLAvs HLA--id id sibingsibing HCTHCT
P=0.06 P=0.005
Autologous
N Events Censored
Auto 58 40 18 31,0%
HLA-id Sib 55 31 24 43,6%
Overall 113 71 42 37,2%
HLA-id Sib HCT
AutologousHLA-id Sib HCT
Autologous
FLT3FLT3--ITD: ITD: ImpactImpact onon OutcomeOutcome in AMLin AML--99 trial99 trial
Autologous Allogeneic
FLT3-wt (n=57), 41+7
FLT3-ITD (n=22), 21+10
P: 0.01
FLT3-ITD (n=16), 44+12
FLT3-wt (n=24), 40+10
P: 0.1
Refinant els grups pronòstics: Refinant els grups pronòstics:
Citogenètica, molecular i malaltia Citogenètica, molecular i malaltia
residual per la pressa de decissions residual per la pressa de decissions
terapèutiquesterapèutiquesterapèutiquesterapèutiques
LMA-03
AMLAML--03: 03: BackgroundBackground and Planand Plan
• Patients may be included in the same protocol up to the
age of 70 (RIC transplants)
• Priming with G-CSF led to encouraging results (HOVON)
• CBF AML with high leukocytes frequently relapse after
HDACHDAC
• Mylotarg may be beneficial for treating MRD and in vivo
purging of autografts
• Normal karyotype AML is heterogeneous regarding
biology (FLT3, MLL, MRD) and prognosis
• URD transplantation shoud be included in the algorythm
INTERMEDIATEINTERMEDIATE RISKRISK (IR(IR)):: CR with 1 induction cycle, ≤50x109/L WBC at diagnosis,
normal karyotype, FLT3-ITD, absence of MLL rearrangement and/or MRD (> 0.1% after
consolidation, Munoz L et al*).
FAVORABLE RISK (FR):FAVORABLE RISK (FR): favorable cytogenetics according to MRC
�WBC ≤ 20x109/L HDAC 3g/m2/12h days 1-3-5
�WBC > 20x109/L Autologous transplant (ASCT))
CETLAM 03: POST-REMISSION RISK ALLOCATION
ADVERSEADVERSE RISKRISK (AR)(AR):: patients not included in FR or IR
�HLA compatible donor Allogeneic SCT*
�No donor and ≤ 60 yo AntiCD33 + ASCT
�No donor and > 60 yo ASCT
consolidation, Munoz L et al*).
�ASCT (regardless of having an HLA-compatible donor)
**Alternative donor/source up to 55-65 yrs
CLINICAL CHARACTERISTICS (n=860)CLINICAL CHARACTERISTICS (n=860)
PERIOD : December 2003 - June 2012
SEX n (%)
Male 473 (55%)
Female 387 (45%)
AGE 51
Median (range) 53 (16-71)
WHITE BLOOD CELLS 39x10e9/L
Median (range) 12x10e9/L (0,23-408)
CYTOGENETICS (MRC) 792/860 (92%)CYTOGENETICS (MRC) 792/860 (92%)
Favorable prognosis 97 (12%)
Intermediate prognosis 577 (73%)
Normal karyotype (NK) 389 (67% of IP)
Adverse prognosis 118 (15%)
FLT3 in NK 350/389 (90%)
Wild-type 225 (64%)
DIT-FLT3 125 (35%)
NPM in NK 307/389 (79%)
Wild-type 156 (51%)
Mutated 151 (49%)
CR RATE ACCORDING TO GENETICSCR RATE ACCORDING TO GENETICS
70%
80%
90%
100%
1% 14%
10% 14% 28%
6% 10% 0% 10% 6% 16% 13% 17%
CR Induction failure Induction death
Overall CR rate: 78% (88% with 1 cycle)
0%
10%
20%
30%
40%
50%
60%
70%
AML1-ETO CBF-MYH11
CEBPAmut NPM1-mut/FLT3wt
no-mut FLT3-ITD Adv P-no-MK
Adv P MK o MK
94% 90% 100% 89% 80% 74% 73% 55%
MK
Intermediate-II; n=104
Favorable: n=187Favorable: n=94; 73±5%
Intermediate: n=553; 39±2%
MRC Cytogenetics ELN Classification
AMLAML--03: 03: OverallOverall SurvivalSurvival
Intermediate-I: n=180
Intermediate-II; n=104
p<0.001
Adverse: n=202Adverse: n=117; 17±4%
p<0,001
Months Months
FAVORABLE RISK CATEGORY (n= 87)FAVORABLE RISK CATEGORY (n= 87)
INTENTION TO TREAT OS DFS CIR
HDAC (n=64) 87±5% 77±6% 17±5%
ASCT (n=22) 69±11% 61±11% 34±11%
DFS CIR
HDAC: 77±6%
ASCT: 34±11%
HDAC: 17±5%
ASCT: 61±11%
HDAC: 77±6%
AMLAML--03: 03: OverallOverall SurvivalSurvivalPatientsPatients withwith Normal Normal KaryotypeKaryotype
NPM1 mut / FLT3 wt: n=78; 61±6%
CEBPA mut: n=16; 86±9%S
urv
iva
l
NPM1 mut / FLT3 wt: n=78; 61±6%
Other genotypes: n=204; 29±4%
p<0.0001
Su
rviv
al
Months
ADVERSE RISK CATEGORY (n= 399)ADVERSE RISK CATEGORY (n= 399)
INTENTION TO TREAT OS DFS CIR
ASCT (n=89) 36±6% 34±6% 56±6%
ALLO-SCT (n=217) 49±4% 47±4% 34±6%
ASCT+antiCD33 (n=79) 48±6% 36±6% 63±6%
p=0.384 p=0.103 P<0.001
DFS CIR
ASCT+antiCD33
Allo-SCT
ASCT Allo-SCT
ASCT+antiCD33
ASCT
AML 94 AML 94
(n=200)(n=200)
AML 99 AML 99
(n=352 )(n=352 )
AMLAML--0303
(n=609 )(n=609 )
P-value
Induction ICE
(3x7x3)
IDICE
(3x8x3)
IDICE-G
(G+3x8x3)
Patients 200 352 609
CR: No (%) 144 (72%) 249 (72%) 484 (80%) 0.004
CR with 1 course: N (%) 117 (81%) 198 (79%) 419 (87%) 0.034
CETLAM AML 94 vs 99 vs 03 protocols for primary AML
Patients up to the age of 60 yrs
CR with 1 course: N (%) 117 (81%) 198 (79%) 419 (87%) 0.034
Refractory (%) /
TDeath (%)
40 (20%)/
16 (8%)
59 (17%)/
36 (11%)
56 (10%)/
61 (10%)
0.008
Cum inc of relapse (4 yrs) 45±4% 47±3% 34±2% 0.001
LFS at 4 years 44±4% 40±3% 53±2% 0.009
OS at 4 years 40±3% 34±3% 49±2% <.001
Main differences between AML-99 and AML-03: a) G-CSF priming during CT,
b) Molecular and MRD factors in postremission allocation, c) increased access
to allogeneic sources for HCT
CETLAM AML 94 vs 99 vs 03 protocols for primary AML
Patients up to the age of 60 yrs
Overall Survival
AML 03: 49±2%, n=609
AML 94: 40±3%, n=200
AML 99: 34±3%, n=352
P<.001
AMLAML--13: 13: BackgroundBackground
• AML is a large group of different diseases
• Biology is essential in thetapeutic decissions
• Intensifying anthracycline induction deserves • Intensifying anthracycline induction deserves
investigation
• Donor group now includes HLA-id sib, URD, UCB
and haplo
¡Hi ha raons per sentir¡Hi ha raons per sentir--se se
orgullosos!orgullosos!
20131987
>= 55 años
< 55 años
El Grup CETLAM: un eixempla de El Grup CETLAM: un eixempla de
col.laboració obertacol.laboració oberta
Relapse Disease-free survival
CT60 AA (n=38): 56.4% CT60 AG/GG
(n=96): 53.9%
P=0.003P=0.003
CT60 AA (n=38): 56.4%
CT60 AA (n=38): 32.3%CT60 AG/GG (n=96): 35.6%
(n=96): 53.9%
Months Months
Study cohort (n=570) Study cohort (n=570)
Validation cohort (n=209) Validation cohort (n=209)
Low-risk: 0 factors
Intermediate-risk: 1 factor
High-risk: 2-3 factors
Valcarcel D, Cancer 2012;118:410-7.
SpanishSpanish CETLAM: CentersCETLAM: Centers
Clínic
Sant Pau
Germans Trias, Badalona
Joan XXIII, Tarragona
Son Espases
Mar
Mutua Terrassa
Virgen de la ArrixacaJoan XXIII, Tarragona
Trueta, Girona
Vall d´Hebrón
ICO Bellvitge
Clínico Valencia
General Málaga
Son Llatzer
Virgen de la Arrixaca
Arnau de Vilanova, Lleida
Juan Canalejo, Coruña
Verge de la Cinta, Tortosa
Virgen del Rocío, Sevilla
La Paz, Madrid
Teknon, Barcelona
Un record Un record emocionatemocionat
† Andreu Domingo
† Manel Ribas Mundó
† Pepe Petit
† Joan Berlanga
† Andreu Llorente
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