le leucemie - chped.itchped.it/gico/ferrara_2013/la malattia neoplastica...

LE LEUCEMIE DELL’ADOLOSCENTE/GIOVANE ADULTO:

DALLA PARTE DEL BAMBINO Andrea Pession

Le leucemie dell’adolescente: dalla parte del bambino

A remarkable triumph of modern medicine is the cure of most forms of

childhood cancer. By the turn of the century, it is estimated that 1 in 900

persons between 21 and 45 years of age will be a survivor of childhood

cancer. The defining event that initiated this awesome achievement

was the cure of acute lymphocytic leukemia.

The Cure of Childhood Leukemia: Into the age of miracles

N Engl J Med 1996; 334:275 January 25, 1996

Acute Lymphoblastic Leukemia

La LAL dell’adolescente: dalla parte del bambino

Kaplan–Meier Analyses of Event-free Survival (Panel A) and Overall Survival (Panel B) in

2628 Children with Newly Diagnosed ALL. The patients participated in 15 consecutive

studies conducted at St. Jude Children’s Research Hospital from 1962 to 2005. The five-

year event-free and overall survival estimates (±SE) are shown, except for Study 15, for

which preliminary results at four years are provided.


L’esperienza AIEOP

377 deaths 89.8% (0.6)5 yrs Prob.

SURVIVAL669 ev ents 80.7% (0.8)

5 yrs Prob.

EFS

AIEOP-BFM 2000

4826 patients

CORS/Hannover - Apr 2007

Pro

bab

ilit

y

0.0

0.2

0.4

0.6

0.8

1.0

YEARS FROM DIAGNOSIS

0 1 2 3 4 5


1) Optimal use of the antileukemic agents

2) Improvement in supportive care and HSCT procedure

3) Stringent application of prognostic factors for risk directed therapy

(eg MRD)

• Four drug remission induction therapy (4-5 week)

• Consolidation treatment (HD-MTX)

• Late intensification/reinduction + following continuation

therapy.

• CNS-directed therapy.

PEDIATRIC ALL: keys of success


Le leucemie dell’adolescente: dalla parte del bambino

L’esperienza AIEOP

377 deaths 89.8% (0.6)5 yrs Prob.

SURVIVAL669 ev ents 80.7% (0.8)

5 yrs Prob.

EFS

AIEOP-BFM 2000

4826 patients

CORS/Hannover - Apr 2007

Pro

bab

ilit

y

0.0

0.2

0.4

0.6

0.8

1.0


0 1 2 3 4 5


2713N. pts

273N. ev ents

86.8% (0.8)4 yrs EFS

1-5 YRS924

N. pts

131

N. ev ents

81.4% (1.6)

4 yrs EFS

6-9 YRS809

N. pts

148

N. ev ents

78.5% (1.7)

4 yrs EFS

10-14 YRS284

N. pts

71

N. ev ents

70.9% (3.2)

4 yrs EFS

15-17 YRS

AIEOP-BFM 2000

by age

4730 patients

no Ph+CORS/Hannover - Apr 2007

EF

S

0.0

0.2

0.4

0.6

0.8

1.0


0 1 2 3 4

ALL – ADOLESCENTS vs. YOUNGER CHILDREN

Higher incidence of T cell immunophenotype:

25% vs 10%

Higher incidence of PH+ ALL: 1.3-3.3% vs >3.5

Lower incidence of hyperdiploidy and TEL-

AML1 translocations

AVN a significant complication


Children

Adults/Adolescent


• n=1522 (only randomized pts)

• ALL-BFM 2000 07/00 - 03/04

• w/o infants

ALL-BFM 2000:

Life-threatening SAE in Protocol I

Impact of Age

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

life-threatening SAE, cured

death from SAE

Age (years)

Trial Steering Committee (TSC) Each group repr. by nat. coordinator

Trial Data Analysis Com. M.-G. Valsecchi, Monza, Italy

M. Zimmermann, Hannover,

Germany

International

structure of

trial AIEOP-

BFM ALL

2009

DSMC

Trial Diagnostics Committee (TDC) (Coordinators below)

Collaborative groups: National Coordinators /

represented by • AIEOP: AIEOP Bologna / V. Conter, Monza, Italy

• BFM-A: St. Anna Children‘s Hospital, Vienna / G. Mann,

Vienna, Austria

• BFM-G: UK S-H Kiel / M. Schrappe, Kiel, Germany

• BFM-CH: Univ. Children‘s Hosp. Zürich / F. Niggli, Zürich,

Switzerland

• CPH: Univ. Hosp. Prague / J. Stary, Prague, Czech Republic

• INS: Tel Aviv / B. Stark, Tel Aviv, Israel

• AUS: Sydney / L. D‘Pozza, Sydney, Australia

PCR-MRD

(QC in ESG-MRD)

through ESG network

Cyto- and

molecular genetics

J. Harbott

Immunphenotyping

and FCM-MRD

M. Dworzak

Pharmacology of

ASP‘ase

C. Rizzari, J. Boos

Trial Research Committee (TRC) J.P. Bourquin, G. Cazzaniga, S. Izraeli,

R. Panzer, M. Stanulla, R. Sutton, J. Trka


AIEOP-BFM LLA 2009

PEG-ASP data per 20 settimane

Prot. IB-ASP+ (con 4 x 2500

E PEG-L-ASP

Prot. IA‘ (con Pred e 2 dosi DNR

nei giorni 8 and 15)

Prot. IA (con Pred e 4 dosi DNR

nei giorni 8, 15, 22 e 29)

IBASP+

IAD IA

IA’

Prot. IAD (con Dexa e 4 dosi

DNR nei giorni 8, 15, 22 e 29)

IACPM

Prot. IACPM (con Pred, 4 dosi DNR

e 1 dose CPM al giorno 10)

T/non-HR

pB#/ non-HR

53 104 sett. 12 1 22 31 43 20 10

Pazienti selezionati $

M

M

HR 1‘

HR 2‘

HR 3‘

MR

II

II

R2

II SR

II

SCT

DNX-FLA + SCT

III

± pCRT *

III III HR

LLA-T

pB-LLA#

± pCRT *

# o immunofenotipo non noto

* pCRT 12 Gy se età 2 aa / in sottogruppi selezionati non

pCRT + 6x IT MTX / in pazienti con malattia SNC (SNC 3)

tCRT con 12 Gy o 18 Gy (dose età-dipendente)

§ per eleggibilità alla randomizzazione vedi

protocollo

$ vedi protocollo

IBASP+

IB

IB IAD

IA

IB

IA’

IA

R1§

IA

IACPM

RHR

STRATIFICAZIONE GRUPPO AD ALTO RISCHIO (HR):

• Positività per MLL/AF4 o t(4;11)

• Prednisone Poor Response (PPR)

• Non remissione completa al giorno +33

• IPODIPLOIDIA (<45 cromosomi e/o DNA index < 0.8)

• PCR-MRD HR (MRD ≥ 10-3 al TP2)

• pB-LAL con PCR-MRD MR SER (Slow Early Responders: MRD ≥10-3 al TP1 e MRD positiva ma <10-3 al TP2)

• FCM-MRD al giorno +15 ≥ 10%


Adolescenti - giovani adulti? Eleggibilità ai protocolli pediatrici

• 10-14 anni AIEOP 91

• 15-17 anni AIEOP + BFM 95; UK

• 15-18 anni DCOG

• 15-20 anni FRALLE, NOPHO

• 16-21 anni CCG

• < 30 anni COG

• < 55 anni DFCI


Acute Myeloid Leukemia

La LAM dell’adolescente: dalla parte del bambino

VARIABLE Aged 0-14 N (%) Adolescents Aged 14-18 N (%)

Patients evaluable 404 (100) 78 (100)

CR rate after Induction 359 (88.8) 62 (79.4)

Death in Induction 10 (2.4) 3 (3.8)

Primary Induction Failure 35 (8.6) 13 (16.6)

Death in CCR 23 (6.4) 14 (22.5)

Relapsed 84 (23.3) 19 (30.6)

OS At 10 Years 69.1 (SE 2.6) 60.4 (SE 5.9)

EFS At 10 Years 55.7 (SE 2.8) 50.8 (SE 5.8)

AML 2002/01 Protocol


AML 2002/01 Protocol

A d o le s c e n ts O v e r a l l S u rv iv a l

T im e

Pe

rc

en

t s

urv

iva

l

0 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0 5 0 0 0

0

5 0

1 0 0 A g e d 0 -1 4

A g e d 1 4 -1 8

Log-rank (Mantel-Cox) test

Chi square

df

P value

P value summary

Are the survival curves sig different?

1.856

1

0.1731

ns

No

A g ed 0 -1 4 : N 40 4 E 1 11

A g ed 1 4 -1 8 : N 7 8 E 28

6 9 .1 (2 .6 )

6 0 .4 (5 .9 )


New patient stratification in the forthcoming AIEOP trial

STANDARD RISK (SR)

20-22%

CBFb anomalies after 1° induction course and MRD < 1% at TP1

t(8;21)(q22;q22)/[inv(16)(p13q22)/t(16;16)(p13;q22)

Patients with normal karyotype and mutated NPM-1 and MRD < 1% at TP1

INTERMEDIATE RISK

(IR)

50-55%

Normal karyotype

t(9;11)(p22;q23) without other cytogenetic aberrations

t(1;11)(p32;q23) without other cytogenetic aberrations

t(11;19) (p13;q23)

t(16;21)(p11;q22)FUS-ERG, t(3;5)(q25;q34)

Other cytogenetic aberrations.

M7 with t(1;22)

Other patients not eligible to SR and HR treatment

HIGH RISK (HR)

25-30%

Cytogenetic aberrations associated with dismal outcome

Complex karyotype (> 3 either numeric or structural aberrations).

Monosomal Karyotype (-7, -5)

t(9;11)(p22;q23) associated with other cytogenetic aberrations

Cytogenetic aberrations involving’ 11q23 other than those included in the IR: t(11;17)(q23;q21),

t(10;11)(p12;q23), t(4;11)(q21;q23), t(6;11)(q27;q23), t(x;11)

Rare cytogenetic aberrations: t(6;9)(p23;q34), t(8-16)(p11;p13), t(9;22)(q34;q11) t(5;11)NUP98/NSD1,

t(4;11)MLL/ArgBP2

FLT3-ITD

Patients with CN AML and ETO2-GISL2 fusion transcript

FAB M6, M7 without t(1;22), AML with minimal differentiation (FAB M0)

Infants

Patients not in CR at the end of the 1° induction course

MRD > 1% at TP1 o > 0.1% at TP2

Patients with non-SR criteria and WBC >100.000/mL

AML WP- Protocol LAM 2012

Legend: APL, Acute Promyelocytic Leukemia; CBF, t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) collectively referred to as core-binding factor

(CBF) AML; SR, Standard Risk; HR, High Risk; VHR, Very High Risk; CR, Complete Remission; PR, Partial Remission; NR, Non Responder; PIF,

Primary Induction Failure; ICE, 3+5+7 Idarubicin+Cyclophosphamide+Citarabine; GO, Gentuzumab Orgozamicin (Mylotarg®); sICE, Short 2+3+7 ICE;

FLA, Fludarabin+Citarabine; My, Liposomial Doxorubicin (Myocet®); CLO, Clofarabine; DNX, liposomial daunomycin (Daunoxome®); ARAC, Citarabine;

AVE, Citarabine+Etoposide; HAM, Citarabine+Mitoxantrone; Auto, Autologous; HSCT, Hematopoietic Stem Cell Transplantation; MFD, Match Family

Donor; UD, Unrelated Donor; PMFD, Partially Match Family Donor.

MFD HSCT

UD HSCT

PMFD HSCT

MFD yes

sMEC AVE HAM SR

AVE HAM HR

AML-IBFM 2010 REL

Or

ANY OTHER EXP

CLINICAL TRIAL

PIF

CR

E

VA

LU

AT

ION

OF

F

ST

UD

Y

NR

HAM FLAMSA

MFD HSCT AVE IR CR

C R

E V

A L

U A

T I

O N

ICE

FLA-DX

R

AML no APL

no DS

ICE

MFD no

Cycle sMEC

GIORNO 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

BM

TIT

Ara-C (ev)

Etoposide (ev)

Mitoxantrone (ev)

Ara-C 500mg/mq in SG 5% ev in 3 ore (gg 1,2,3,4,5)

Etoposide 100 mg/mq/die in SF ev in 1 ora (gg 1,2,3,4,5)

Mitoxantrone 8 mg/mq/die in SF ev in 4 ore (gg 1,2,3,4)

La dose di Mitoxantrone va infusa prima dell’Ara-C.

e

TIT

Età in

anni

Dose in mg

MTX ARA-C PDN

< 1 6 16 4

> 1 e <2 8 20 6

> 2 e <3 10 26 8

> 3 12 30 10

AIEOP AML Protocol

Cycle FLA-Dnx

GIORNO 1 2 3 4 5 6 7 8 9 10 11 12 13 14 21 28

BM

TIT (*) (*) (*) (*)

Fludarabine (ev)

Ara-C (ev)

Myocet®

Citarabina 2000 mg/mq/die in SF ev per 3 ore (gg 1,2,3,4,5,6,7)

Fludarabine 30 mg/mq/die in SF ev in 30 minuti (gg 1,2,3,4,5)

Dnx®

50 mg/mq/die in SG 5% ev in 2 ore (gg 1,3,5) e

TIT

Età in

anni

Dose in mg

MTX ARA-C PDN

< 1 6 16 4

> 1 e <2 8 20 6

> 2 e <3 10 26 8

> 3 12 30 10

AIEOP AML Protocol

Cycle FLAMSA

GIORNO 1 2 3 4 5 6 7 8 9 10 11 12 13 14 21 28

BM

TIT

Fludarabine (ev)

Ara-C (ev)

Amsacrina

Citarabina 2000 mg/mq/die in SF ev per 4 ore (gg 1,2,3,4,5)

Fludarabine 30 mg/mq/die in SF ev in 30 minuti (gg 1,2,3,4,5)

Amsacrina 100 mg/mq/die in SF ev in 1 ora (gg 1,2,3)

La Citarabina va infusa 4 ore dopo l’inizio della Fludarabina e

TIT

Età in

anni

Dose in mg

MTX ARA-C PDN

< 1 6 16 4

> 1 e <2 8 20 6

> 2 e <3 10 26 8

> 3 12 30 10

AIEOP AML Protocol

Prof. Andrea Pession

Cattedra di Pediatria

[email protected]

www.unibo.it

Grazie

le leucemie - chped.itchped.it/gico/ferrara_2013/la malattia neoplastica...

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