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Linfoma di Hodgkin:La miglior strategia terapeutica iniziale
43° Congresso Nazionale SIENapoli 16-19- 2011
Ercole BrusamolinoClinica EmatologicaFondazione IRCCS Policlinico San Matteo, PaviaE-mail: [email protected]
Masaccio:“L’ombra di San Pietro guarisce il cieco”Cappella Brancacci, Firenze
Hodgkin lymphomaA success story
3
Today:
CompleteRemissionrate:85‐95%Relapserate:‐5%inearlystage‐25‐30%inadvancedstage
Rates of death from Hodgkin’s disease1935-2000
Cause di morte nel linfoma di Hodgkin
Causes of death according to stage
0
20
40
60
80
100
I-IIA IIB-IV
Not-relatedRespiratory eventsCardiac eventsSolid tumorsLeukemiaHD progression
Ematologia, Pavia
Late effects to avoidas cures increase
• Secondary MDS/AML from alkylating agents
• Solid tumours from extended field radiation
• Pulmonary fibrosis from bleomycin
• Ischaemic heart disease from mediastinalirradiation and doxorubicin
• Infertility from alkylating agents
Prognosi del Linfoma di Hodgkin
Fattori prognostici
• Età• Sesso• Istotipo (LD, NS)• Genotipo (GST)
• Sintomi B• VES• Hb, WBC, Ly• Albumina• IL-1, IL-6, IL-10
Biologia
Traffico citochinico
Fattori prognostici
• Bulk• Tumor burden• Numero linfonodi• sCD30• LDH
• Tipo di terapia• Chemiosensibilità
Massa tumorale
Terapia
Initial stage : Prognostic factors
EORTC/GELAEORTC/GELA GHSGGHSG USA/CanadaUSA/Canada
Bulky mediastinum Bulky mediastinum
Age ≥ 50 Age > 40
ESR ≥ 50 ESR > 50 ESR > 50
≥ 4 nodes ≥ 3 nodes ≥ 3 nodes
B and ESR > 30 B or extranodal site
Hodgkin lymphomaHD7 trial (GHLSG)
12
In early stage disease, CT+RT is superior to RT alone
ABVD x 4 + IF-RT: RFS
Brusamolino CCR 2006
Limited disease: EFS
Brusamolino CCR 2006
ABVD x 4 + IF-RT: EFS
Limited disease: OS
Brusamolino CCR 2006
ABVD x 4 + IF-RT: OS
Late events: 22 (18%)
Events No. %Cardiovascular 9 7Second neoplasia 6 5Hypothyroidism 5 4Mediastinal fibrosis 3 2
Brusamolino CCR 2006
GHSG-HD10 trial: Early favorableGHSG-HD10 trial: Early favorableCR % 5-yr PFS % 5-yr OS %
ABVD x 2 97 91.2 96.6ABVD x 4 97 93.5 97.1RT 20 Gy 97 93.2 97.5RT 30 Gy 99 93.7 97.6
More adverse events for 4 ABVD vs 2 ABVD (52% vs 33%)and for 30 Gy vs 20 Gy RT (9% vs 3%)
2 ABVD + 20 Gy RT is the new standard2 ABVD + 20 Gy RT is the new standard
Engert et al, NEJM 363: 640; 2010
•• ABVD + 20 Gy is inferior to ABVD + 30 GyABVD + 20 Gy is inferior to ABVD + 30 Gy•• BEACOPP + 20 or 30 Gy is not superior to ABVD + 30GyBEACOPP + 20 or 30 Gy is not superior to ABVD + 30Gy
Therapy arms
4 ABVD + 30 Gy
4 ABVD + 20 Gy
4 BEACOPP base + 30 Gy
4 BEACOPP base + 20 Gy
Results in the whole group
CR rate 94.1%
5 yr-PFS 86 %
5 yr OS 94.5 %
In terms of 5-yr FFTF
GHSG-HD11 trial: Early unfavorableGHSG-HD11 trial: Early unfavorable
4 ABVD + 30 Gy RT is the new standard4 ABVD + 30 Gy RT is the new standard
Eich et al, JCO 28: 4199; 2010
Prognosi Linee Guida SIE 2009 2011
Favorevole ABVD x 3 + RT (30 Gy) ABVD x 2 + RT (20 Gy)
Sfavorevole ABVD x 4 + RT (30 Gy) ABVD x 4 + RT (30 Gy)
Terapia di prima linea:Stadi inziali
Hasenclever D. NEJM 1988; 339:1506
HD prognostic score
7% or the patients
Advanced HL prognostic score: 7y-FFP & OS
Hasenclever D. NEJM 1988; 339:1506
HD9 trial:(GHLSG)
Anni
Advanced stage disease
FFP at 10 years:
(A) COPP/ABVD: 64%;(B) BEACOPP baseline: 70%;(C) BEACOPP escalated: 82%
Diehl et al, NEJM 2003
Advanced stage:ABVD vs BEACOPP
Studio IIL-GITIL-Michelangelo
Study Outline
HL diseaseStage IIB-IV
Stratify: Site; IPS ≤ 2 vs ≥ 3 Random 1:1
ABVDx 6-8
BEACOPP exc x 4BEACOPP std x 4
CR, CRU, PR > 80%RT on bulk
or residual mass(30 Gy)
CR, CRU, PR > 80%RT on bulk
or residual mass(30 Gy)
R< 80%, PD, RelapseHigh-dose
Salvage + RT(20-25 Gy)
R< 80%, PD, RelapseHigh-dose
Salvage + RT(20-25 Gy)
Main patient characteristics in %
Total(321 patients)
ABVD(166 patients)
BEACOPP(155 patients)
IPS 1-2 45 46 45IPS ≥ 3 55 54 55Males 59 60 57Nodal extent only 54 54 55Bulky disease mediastinum
5846
5544
6148
NS Histology 80 78 81Systemic symptoms 84 84 85Age ≤ 45 78 77 80
Viviani et al, NEJM 2011
ABVDABVD(166 pts)(166 pts)
BEACOPPBEACOPP (155 pts) (155 pts)
CR after CT 65 73CR after CT + RT 77 85PR > 80% 8 4No response 5 2PD 10 4
Response rate after first-line treatment
Viviani et al, NEJM 2011
Freedom from first progression
.25
1.00
.75
.50
1 5432 Years
PROBABILITY
BEACOPP
Pts Events HR p
ABVD
155 18 0.43 0.01
166 42
86% 85%
70% 69%
Viviani et al, NEJM 2011
Event-free survival
.25
1.00
.75
.50
1 5432 Years
PROBABILITY
BEACOPP
Pts Events HR p
ABVD
155 29 0.69 0.12
166 43
80% 78%
72% 69%
Viviani et al, NEJM 2011
ABVD BEACOPP
Evaluable patients 37 16
Median time to furtherprogression/death
17 mo(1-65)
6.5 mo(1-38)
CR 22 (59%) 6 (38%)
In continuous CR atcut-off date
17/37(46%)
3/16(18%)
Effects of salvage therapy
Viviani et al, NEJM 2011
Freedom from second progression1.00
.25
.75
.50
1 5432 Years
PROBABILITY
BEACOPP
Pts Events HR p
ABVD
155 11 0.61 0.17
166 20
91% 88%
85% 82%
Viviani et al, NEJM 2011
Overall survival
.25
1.00
.75
.50
1 5432 Years
PROBABILITY
BEACOPP
ABVD
90% 87%89%
86%
Pts Events HR p
155 14 1.03 0.94
166 15
Viviani et al, NEJM 2011
GISL HD2000 trialGISL HD2000 trial
Random
ABVD x 3 CEC x 3 BEACOPP x 3
CR/PR
<PR IGEV + HDT
ABVD x 3 CEC x 3 BEACOPP
X 1 escalated+ 2 standard
Federico, M. et al. J Clin Oncol; 27:805-811 2009
FFS, PFS, RFS, OS by intention to treat
Ovarian toxicity after BEACOPP
Regular menses at dx 90%
Amenorrhea(8 BEACOPP escalated)
57%
Age > 30 years p = 0.006
Advanced stage p < 0.0001
No estro-progestinics p = 0.0002
GHLSG
Gonadal toxicity after ABVD
4 to 6 cycles
Oligospermia 5-8%Amenorrhea< 25 yrs> 25 yrs
2-4%4-8%
Recovery in male > 90%
Recovery in female < 25 yrs 85%
INT-MI and Pavia
Terapia di prima linea:Malattia avanzata
Linee Guida 2009 2011
ABVD x 6-8 ABVD x 6-8
How can we target patients at ahigh chance of failure?
PET - CT
CT-PET: Last-born imaging technique in lymphoma
CT: anatomic detail PET: viability of cells
CT-PET= high-specificity (CT), high-sensitivity (PET)
Interim PET as indicator in advanced diseaseInterim PET as indicator in advanced disease
543210
Time in years
1
0,8
0,6
0,4
0,2
0
Failu
re-fr
ee su
rviv
al
IPS 3-7, PET2posIPS 3-7, PET2negIPS 0-2, PET2posIPS 0-2, PET2neg
IPSandPET
log rank, p ~ 0
Gallamini, Blood 2007
Rigacci, Cologne 2010
months
100806040200
Prog
ress
ion
free
surv
ival
1,0
,8
,6
,4
,2
0,0
PET2-negative
PET2-positive
P < 0.001
Interim FDG-PET in early-stage HL
PET-oriented trials
• H10 trial (EORTC-GELA-IIL)• GHSH HD16• RAPID trial (UK)• HD 0801 (IIL)• GITIL 06/07
Si può omettere la RT negli stadi iniziali?
STUDIO EORTC-GELA-IIL H10
H10: Study design
2 ABVD
2 ABVD
2 BEACOPPesc+INRT 30(+6)
FPET
2 ABVD
1 ABVD+INRT 30 GyPET
-
+
2 ABVD
4 ABVD
2 BEACOPPesc+INRT 30(+6)
PET
2 ABVD
2 ABVD+INRT 30 GyPET
-
+
R
Hodgkin - CS I/II – untreated - 15-70 yrs - no NLPHL
U R
2 ABVD
4 ABVD
H10: Study emendment(August 2010)
2 ABVD
2 ABVD
2 BEACOPPesc+INRT 30(+6)
FPET
2 ABVD
1 ABVD+INRT 30 GyPET
-
+
2 ABVD
4 ABVD
2 BEACOPPesc+INRT 30(+6)
PET
2 ABVD
2 ABVD+INRT 30 GyPET
-
+
R
Hodgkin - CS I/II – untreated - 15-70 yrs - no NLPHL
U R
1 ABVD+INRT 30 Gy
2 ABVD+INRT 30 Gy
GHSG HD16 trial: Early favorableGHSG HD16 trial: Early favorable
ABVD x 2ABVD x 2
Standard arm Experimental arm
ABVD x 2 ABVD x 2
PET neg PET pos
No RTNo RT
PET neg or pos
RTRT RT (30 Gy)RT (30 Gy)
Initial treatment: ABVD x 3Re-assessment with PET in CR/PR patients
4th cycle ABVD + IFRT Random
IFRT No further Tx
PET pos PET neg
RAPID trial design: Early stages (no bulky)RAPID trial design: Early stages (no bulky)
RandomRandom
RT bulkyRT bulky No RTNo RT
SalvageSalvageIIL-HD0802IIL-HD0802
Stage IIB-IVStage IIB-IV
Baseline CT/PETBaseline CT/PET
2 ABVD2 ABVD
PETPET
IIL-HD0801 OutlineIIL-HD0801 Outline
- +
PETPET- +
4 ABVD4 ABVD
ABVD x 2
CT/PET
+ -ABVD x 4
IIB-IV; IPS 0-7
CT/PET- +
Follow up
HD0607
RT
CT/PET
+ -
ASCT
RNo RT
RR-BEACOPP-esc. x 4BEACOPP-esc. x 4
R-BEACOPP-bas. x 4BEACOPP-bas. x 4
- Biopsy +
CT/PET
Shared featuresShared features
• ABVD as first-line therapy• Early FDG-PET evaluation (PET-2)• Switch of therapy in PET-2 positive pts• RT vs no RT in pts in CR with prior bulk
FDG-PET Fstand
Fexper
Ustand
Uexper Total
negative (%) 85 88 73 77 80
positive (%) 15 12 27 23 20
Total patients 212 218 316 334 1080
PET after 2 ABVD
André, ASH 2009
Accrual:305
ABVDx2
PET-2: 263
ABVDx4 SalvageaFerPET‐2:50
PET‐6:147
IIL‐HD0801
RT:28 NoRT:30
R
SalvageaFerPET‐6:12
As of September 2011
199 neg (76%) 64 pos (24%)
13 PET pos134 PET neg
Interim Analysis
Interim PET during ABVD in HLInterim PET during ABVD in HL
• Nearly 70-75% of patients show anegative interim-PET
• Nearly 20% of patients show a positiveinterim-PET
• Nearly 5-10% of patients show a minimalresidual uptake (MRU) at interim-PET
PET 0
PET 6
PET 2
MRU: SUV Max=2.8
What is Minimal Residual Uptake (MRU) ?
Cut-off for positivity
The Deauville score: Sensitive
1 no uptake2 uptake ≤ mediastinum
3 uptake > mediastinum but ≤ liver4 moderately increased uptake compared to liver5 markedly increased uptake compared to liver
The Deauville score: Specific
1 no uptake2 uptake ≤ mediastinum3 uptake > mediastinum but ≤ liver
4 moderately increased uptake compared to liver5 markedly increased uptake compared to liver
It may not be a perfect wheel, but it’s a state-of–the-art wheel