terapia dei linfomi non hodgkin pediatrici e risultati dei protocolli … malattia neoplastica...

Angelo Rosolen

Clinica di Oncoematologia Pediatrica

Azienda Ospedaliera-Università di Padova

TERAPIA DEI LINFOMI NON HODGKIN PEDIATRICI

E RISULTATI DEI PROTOCOLLI AIEOP

CATEGORIES OF NHL OF CHILDHOOD

ALCL

non-B cell

B-cell

Others

non-B cell

B-cell

ALCLOthers

30

105

55

G-CSF G-CSF

G-CSF G-CSF

R1 A

P A

P AA BB

B

B

CC

CC

A

AA

AA

B

Z

CC BB

BB

Z

R2

R3

P AA BB

Z

R4 SNC+ Z Z Z

Se massa residua, somministrare G-CSF

alla dose di 10µg/kg/die dopo il 4° ciclo

per raccolta cellule staminali

Se massa residua, eseguire SL

chirurgico: in caso di tumore vitale,

eseguire TMO

Uso facoltativo di G-CSF: l’uso è consigliato dopo il primo ciclo AA(z) e il primo ciclo BB(z)

AIEOP LNH 97 B: PIANO TERAPEUTICO

Cycle Daily dose Administration Days

PREPHASE

Prednisone 30 mg/m²/day Orally (in 3 fractions) 1-5

Cyclophosphamide 200 mg/m²/day IV (1 h) 1,2

Mtx+ARA-C+Pdn 12 mg +30mg+10mg* IT 1

CYCLE A

Dexamethasone 10 mg/m²/day Orally or IV (in 3 fractions) 1-5

MD-Methotrexate 500 mg/m²/day IV (1/10 in 30 min, 9/10 in 23,5 h) 1

Ifosfamide 800 mg/m²/day IV (1 h) 1-5

Etoposide 100 mg/m²/day IV (1 h) 4,5

Cytarabine 150 mg/m² every 12 h IV (1 h) 4,5

Mtx+ARA-C+Pdn 12 mg +30mg+10mg* IT 1

CYCLE B

Dexamethasone 10 mg/m²/day Orally or IV (in 3 fractions) 1-5

MD-Methotrexate 500 mg/m²/day IV (1/10 in 30 min, 9/10 in 23,5 h) 1

Cyclophosphamide 200 mg/m²/day IV (1 h) 1-5

Adriamycin 25 mg/m²/day IV (4 h) 4,5

Mtx+ARA-C+Pdn 12 mg +30mg+10mg* IT 1

CYCLE AA

Dexamethasone 10 mg/m²/day Orally or IV (in 3 fractions) 1-5

HD-Methotrexate 5 g/m²/day IV (1/10 in 30 min, 9/10 in 23,5 h) 1

Ifosfamide 800 mg/m²/day IV (1 h) 1-5

Etoposide 100 mg/m²/day IV (1 h) 4,5

Cytarabine 150 mg/m² every 12 h IV (1 h) 4,5

Vincristine 1.5 mg/m²/day (max 2 mg) IV 1

Mtx+ARA-C+Pdn 12 mg +30mg+10mg* IT 1

CYCLE BB

Dexamethasone 10 mg/m²/day Orally or IV (in 3 fractions) 1-5

HD-Methotrexate 5 g/m²/day IV (1/10 in 30 min, 9/10 in 23,5 h) 1

Cyclophosphamide 200 mg/m²/day IV (1 h) 1-5

Adriamycin 25 mg/m²/day IV (4 h) 4,5

Vincristine 1.5 mg/m²/day (max 2 mg) IV 1

Mtx+ARA-C+Pdn 12 mg +30mg+10mg* IT 1

CYCLE CC

Dexamethasone 20 mg/m²/day Orally or IV (in 3 fractions) 1-5

Etoposide 150 mg/m²/day IV (1 h) 3,4,5

HD-Cytarabine 2 gr/m² every 12 h IV (3 h) 1,2

Vindesine 3 mg/m²/day (max 5 mg) IV 1

Mtx+ARA-C+Pdn 12 mg +30mg+10mg* IT 5

* Dose of intrathecal (IT) chemotherapy was age-adjusted for children less than 3 years. CNS

positive patients were administered IT therapy daily intraventricularly or by lumbar puncture.

Pdn=prednisolone; MD=medium dose; HD= high dose; IV=intravenously; h=hours.

OS: 90% 258 pz - 20 eventi EFS: 84% 258 pz - 36 eventi

AIEOP LNH 97

LNH 97 B: SOPRAVVIVENZA

349 patients B-NHL without PMLCL

5-year EFS by Risk Group

N EVENTS EFS (SE) p

R1 17 0 100 < 0.0012

R2 136 7 94.3 (2.1)

R3 73 8 89.0 (3.7)

R4 123 24 79.8 (3.7)

Tempi mediani tra blocchi - R4

Fine AA1 - Inizio BB1: 17 gg (range 8 - 37 gg)

Fine BB1 - Inizio CC1: 16 gg (range 6 - 48 gg)

Fine CC1 - Inizio AA2: 16 gg (range 10 - 31 gg)

Fine AA2 - Inizio BB2: 17 gg (range 12 - 42 gg)

Fine BB2 - Inizio CC2: 16 gg (range 9 - 48 gg)

AIEOP LNH 97

Day 0 1 2 3 4 5 6

Rituximab i.v.

375 mg/m2

Evaluation of response:

Extent of 1-3 index manifestation(s)

And/or % blastrs in BM/PB

Chemotherapy according to

Protocol B-NHL BFM 04

Study Design: Rituximab window prior to chemotherapy

Meinhardt A et al. J Clin Oncol, 2010, Published ahead of print June 1, 2010

RESULTS

87 of 136 enrolled patients were evaluable for response (41 low-risk; 43 high-risk)

31/87 were responders (CR+PR+OR) and 51 non-responders: response rate 41%

Toxicity: infusion related toxicity (frequent); TLS 8%; no SAE

R-ICE in Recurrent B-cell NHL and B-ALL of childhood 20 eligible pts:12 BL; 6 DLBCL; 2 B-ALL

Griffin TC et al (for COG): Pediatr Blood Cancer 2009; 52: 177-81

HIGH RISK B-NHL AND B-AL: PHASE III • For children/adolescents with B-cell lymphoma (except PMLBL) and stage III + LDH > Nx2, Stage IV or B-AL.

• Treatment according to LMB scheme.

• Randomisation assignment to not receive rituximab or to receive rituximab, 2 doses during the 2 first induction courses (COPADM) and one

dose during the 2 consolidation courses (CYM or CYVE).

Pts Ev 5-y EFS% SE% P

BL/BL-like 358 37 89 2 <0.0001

Other 78 10 86 4

PMLBL 40 17 56 8

Pts Ev 5-y EFS% SE% P

Other 436 47 89 1 <0.0001

PMLBL 40 17 56 8

Characteristics Categories #

Pts

Events 5-y EFS %

(SE%)

Univariate

p-value

Multivariate

p-value

Hazard Ratio

(95% CI)

Age < 8.9 y

> 8.9 y

238

238

21

43

91 (2)

82 (3)

0.004 0.0290 Age>8.9 y

1.87 (1.1-3.3)

LDH < 591 IU/L

> 591 IU/L

239

237

8

56

97 (1)

76 (3)

< 0.0001 0.0001 LDH >591 IU/L

6.3 (2.5-15.9)

PMLBL Yes

No

40

436

47

17

56(8)

89 (1)

<0.0001 0.0039 PMLBL

2.51 (1.3-4.7)

Unpublished data

PMLBL show a worse prognosis

PMLBL: PHASE II

All patients receive rituximab

Lymphoblastic lymphoma

IND CONS MANT II ciclo

MANT III ciclo

MANT II

STADI I e II

IND CONS REIND MANT II ciclo

MANT III ciclo

MANT II

STADI III e IV

Durata totale 1 anno

Durata totale 2 anni

SNC+: cRT

AIEOP LNH 97 per linfomi linfoblastici

PIANO TERAPEUTICO

AIEOP LNH 97

Linfomi linfoblastici

73 pz 56 censored 17 events

73 pz 61 censored 12 events OS

EFS

AIEOP LNH 97

OS - EFS

Median Follow-up : 4.2 years (range 1 - 7.8)

Years from diagnosis

Su

rviv

al

82 9 %

75 10 %

Stage

Induction Protocol M Maintenance 6-MP/MTX

III+IV Induction Protocol M Re-Induction Maintenance

I+II

Cranial RT

104

Therapy Strategy for T-cell Lymphoblastic Lymphoma

1 9 11 19 28 21 Week

NHL-BFM 90

30

P

I/1-PRED

I/1-DEXA

M Prot. II

6-MP/MTX

18 months

24 months

I/2 Random 1 Random 2

Precursor-T-cell-LBL: Randomization 1+2

Precursor-B-LBL: Reference arm

EURO-LB-02

Induction Re-Induction

Not stage I+II

Maintenance

6-MP/MTX

Consoli-

dation

EFS in base al livello di MMD misurata in citofluorimetria

Coustan-Smith, JCO 2009

89%

52%

91%

68%

Inferiore 5% Inferiore 1%

P=0.009 P=0.03

•Classico

•A cellule giganti

•A piccole cellule

•Linfoistiocitico

•A cellularità mista

•Hodgkin-like

• Forte reattività per il CD30

•CD3

•CD5

•CD43

•CD2

•CD7

•ALK

•TIA1

•Granzyme

•Perforina

Marcatori immunoistochimici

ALCL Aspetti morfologici

CD30 ALK

Author N. of

patients

Treatment regimen RT on

primary site

CNS

prophylaxis

Overall

survival (%)

Event free

survival (%)

Therapy

duration

(months)

Vecchi, 1993 13 modified LSA2-L2 Yes Yes 100 (4-yrs) 62.9 (4-yrs) 24

Sandlund, 1994 18 CHOP or

MACOP-B +

maintenance

Yes na 84 (5-yrs) 57 (5-yrs)

Reiter, 1994 62 BFM83, 86, 90 No Yes 83 (9-yrs) 81 (9-yrs) 2-5

Brugieres,

1998

82 COP-COPADM No No 83 (3-yrs) 66 (3-yrs) 7-8

Massimino,

1995

27 institutional

protocol for LBL

Yes No 84 (8-yrs) 72 (8-yrs) 8-24

Seidemann,

2001

89 BFM90 No Yes na 76 (5-yrs) 2-5

Williams, 2002 72 COP-COPADM No Yes 65 (5-yrs) 59 (5-yrs) 5

Mora, 1999 19 LSA2-L2 Yes Yes 84 (5-yrs) 56 (5-yrs) 24

Laver, 2005 86 APO+maintenance Yes Yes 88 (4-yrs) 72 (4-yrs) 12

Rosolen, 2005 34 modified LSA2-L2 Yes Yes 85 (10-yrs) 65 (10-yrs) 24

Characteristics and treatment results of pediatric ALCL patient series published

Prefase: P

Randomizzazione

Braccio 1

MTX 1g/m2 - 24 h

+ IT

Braccio 3

MTX 3g/m2 - 3h

senza IT

Ciclo A: A1 AM1

Ciclo B: B1 BM1

Ciclo A: A2 AM2

Ciclo B: B2 BM2

Ciclo A: A3 AM3

Ciclo B: B3 BM3

Valutazione della Remissione

“M”: MTX 3g/m2 in 3 ore senza rachicentesi

ALCL 99

PIANO TERAPEUTICO

Rischio Standard

Prefase: P

Prima Randomizzazione

MTX 1g/m2- 24 h

+ IT

MTX 3g/m2 - 3h

senza IT

Ciclo A: A1 AM1

Se non c’è progressione

Seconda Randomizzazione

Braccio 1 Braccio 2

(V)

Braccio 3

(M)

Braccio 4

(MV)

Ciclo B: B1 BV1 BM1 BMV1

Ciclo A: A2 AV2 AM2 AMV2

Ciclo B: B2 BV2 BM2 BMV2

Ciclo A: A3 AV3 AM3 AMV3

Ciclo B: B3 BV3 BM3 BMV3

Valutazione della Remissione

Se RC raggiunta 1 anno diMantenimnto ?

No

Vinblastinasettimanale

No

Vinblastinasettimanale

Alto Rischio

ALCL 99

ALCL99 Trial MTX-Random

J Clin Oncol 2009; 27:897

Two-year EFS and OS rates were 71%

(95% CI, 75% to 77%) and 94% (95%

CI, 89% to 96%), respectively, for the

whole trial population (217 patients).

(A) Event-free survival (EFS) by

treatment group. (B) Overall survival

(OS) by treatment group. VLB,

vinblastine.

Malattia Minima Disseminata (MMD)

52 biopsie tumorali

25/41 t(2;5) positivi nel BM in RT-PCR

90% 47/52 t(2;5) positivi in RT-PCR

61%

6/41 t(2;5) positivi nel BM al microscopio 15%

MMD

• Midollo osseo

• Sangue periferico

MMD (RT-PCR)

• plasma

Titolo anticorpale anti-ALK

(ICC)

Test biologici

Diluizioni crescenti del plasma (1/50, 1/250...)

patients events pr 5y (s.e.) log-rango

PFS BM+Titer LR 51 5 90 (4) <0.0001

IR 52 17 65 (7)

HR 28 19 27 (9)

HR

IR

LR

AIEOP-BFM

study

Patients Events OS% (SE%) p-value

bHR 26 7 71 9 0.02

bIR 62 10 83 5

bLR 40 1 97 2

bLR

bIR

bHR

Patients Events OS% (SE%) p-value

bHR 26 7 71 9 0.02

bIR 62 10 83 5

bLR 40 1 97 2

bLR

bIR

bHR

LR

IR

HR

Overall Survival

Mussolin et al, 2013

P< 0.0001

Brentuximab Vedotin Mechanism of Action

Brentuximab vedotin antibody-drug

conjugate (ADC)

Anti-CD30 monoclonal antibody conjugated to

An auristatin (MMAE), a highly potent antitubulin agent, by

A linker that is stable in plasma but labile in the presence of lysosomal enzymes

Selectively induces apoptosis in HL and ALCL cells:

Binds to CD30

Becomes internalized

Releases MMAE

Brentuximab vedotin ADC

ADC binds

CD30

Endocytosis

ADC traffics to

lysosome

Enzymatic

linker cleavage

releases MMAE

from ADC

MMAE binds

tubulin

G2/M cell

cycle arrest

& apoptosis

CD30

ALCL 2012

ALCL 2013

Conclusioni