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