un viatge de 25 anys en el tractament adaptat al risc de ... · risc de la lma: experiència del...

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

LMA: Index pronòsticLMA: Index pronòstic

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 Comissió Assessora de TMO (1987)

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

ElsEls primersprimers resultatsresultats, les , les primeresprimeres reunionsreunions

“El Castell” Seu d’Urgell, Lleida, abril 1993

El grup creix i madura: Del grup Català

de trasplantament al CETLAMde trasplantament al CETLAM

“Mas Torrent”, l’Empordà, Girona, abril 1994

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

AML 94

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

Les reunions a la Torre Mapfre, Port Olímpic


• 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

CBF

Normal

Other

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

Les reunions al 22@


• 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


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


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.

After induction After consolidation

SpanishSpanish CETLAM: CentersCETLAM: CentersSpanish CETLAM

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

Agraiments especials

Un record Un record emocionatemocionat

† Andreu Domingo

† Manel Ribas Mundó

† Pepe Petit

† Joan Berlanga

† Andreu Llorente

Hi ha núvolsHi ha núvols

Hi ha crísiHi ha crísi

¡Pero ens surtirem, perque

estem preparats per el que

pugui caure!

¡Moltes gràcies a tots!¡Moltes gràcies a tots!

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