Linfomi: Report del gruppo di lavoro - Ematologialasapienza.it · Linfomi: Report del gruppo di...
Transcript of Linfomi: Report del gruppo di lavoro - Ematologialasapienza.it · Linfomi: Report del gruppo di...
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Maurizio Martelli
Dip. Biotecnologie Cellulari ed Ematologia
Università “Sapienza” Roma
Linfomi:
Report del gruppo di lavoro
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Nadia Bisso Genova
Catello Califano Salerno
Tullio Calzamiglia Sanremo
Andrea Camera Caserta
Angela Lorenzi Verbania
Laura Paris Bergamo
Rossella Ribolla Brescia
Anna Maria Bugli San Marino
Linfomi: gruppo di lavoro
Francesca Rossi Milano
Pietro Terrizzi Messina
Daniela Venditti Roma
Falcinelli Flavio Perugia
Maria Pina Cabras Cagliari
Marco Ladetto Alessandria
Maurizio Martelli Roma
Umberto Vitolo Torino
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Is ASCT still the golden standard for MCL? how to challenge it
in the future?
Linfomi: Report del gruppo di lavoro
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YOUNG PATIENTS PROBABLY NOT DESERVING ASCT
Patients with major comorbidities
Patients with limited stage MCL
Indolent MCL ????
Primary refractory patients
For specific prognostic subgroups….
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Patients in whom treatment may be
postponed (indolent MCL)
• Long history of asymptomatic disease
• Non-nodal leukemic disease (++ spleen)
• Low proliferation rate
• Hypermutated IGHV
• Noncomplex karyotypes
• SOX11-negative
Fernandez V, Cancer Res 2010Seto M, Blood 2013Ferrando A, Blood 2013Vegliante et al, Blood 2013
Linfomi: Report del gruppo di lavoro
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15-YEAR FOLLOW-UP OF THE NORDIC MCL2-TRIAL:DESPITE LONG-TERM RESPONSES LATE RELAPSES STILL OCCUR.
Eskeund CW S437 oral presentation
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on behalf of European MCL Network
TRIANGLE Phase III Trial
observation
ASCT
R-CHOP/
R-DHAP x 6ASCT
I-maintenance
I-maintenance
RR-CHOP/
R-DHAP x 6 + I
R-CHOP/
R-DHAP x 6 + I
QuickTime™ and aGIF decompressor
are needed to see this picture.
MCL, 18 to 65 years old
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•NPP program to allow access to ibrutinib for eligible patients R/E MCL This program provides
real-world data on estimated outcomes with ibrutinib across a large, global MCL population.
REAL-WORLD EXPERIENCE OF IBRUTINIB IN >700 PATIENTS WITH MCL:DATA FROM A GLOBAL NAMED PATIENT PROGRAM
Rule S et al S438 poster presentation
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Outcome, %iBTK
(n = 139)
Tems
(n = 141)P Value
ORR by IRC
CR
PR
SD
71.9
18.7
53.2
10.8
40.4
1.4
39.0
30.5
< .0001
23% of pts treated with temsirolimus
crossed over to ibrutinib at progression
Median DoR:
Not reached (95% CI: 16.2-NE) with
ibrutinib vs 7.0 mos (95% CI: 4.2-9.9)
for temsirolimus.
Open-Label, Phase 3 Study (MCL3001 Ray):Response and survival curves
PFS
OS
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OVERALL SURVIVAL OUTCOMES IN PATIENTS WITH MCL TREATEDWITH IBRUTINIB IN A POOLED ANALYSIS OF 370 PATIENTS
FROM 3 INTERNATIONAL OPEN-LABEL STUDIES
Rule S et al S438 oral presentation
>1 line >1 line
BlastoidBlastoid
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Best Response
12 5 1 34 15 19 50 24 20
***Ki67 N/A for 4 patients***
p = 0.0001
50%
42%
8%
100%
44%
56%
88%
48%
40%
Wang ML et al. ASH 2014; Oral/Abstract 627
Ibrutinib And Rituximab Are An Efficacious And Safe Combination In Relapsed Mantle Cell Lymphoma: Preliminary
Results From A Phase II Clinical Trial
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Progression Free Survival
12 5 1 34 15 19 50 24 200 3 6 9 12 15
0.0
0.2
0.4
0.6
0.8
1.0
P-value < .0001
<50% ( E / N = 2 / 34 )
>=50% ( E / N = 6 / 12 )
Progression Free Survival by Ki67
Time (months)
Pro
ba
bil
ity
Progression Free Survival
Time (Months)
Pro
ba
bil
ity
0 3 6 9 12 15
0.0
0.2
0.4
0.6
0.8
1.0
Overall PFS (N=50) PFS by Ki67
Months
Pro
ba
bil
ity
Months
Pro
ba
bil
ity
Median = 13.6 months
Median follow up 11 months (4-16 months)
Wang ML et al. ASH 2014; Oral bstract 627
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Ibrutinib può essere considerato il gold standard della
terapia di salvataggio del paziente con MCL refrattario o in
prima recidiva di malattia?
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Is ASCT still the golden standard for MCL? how to challenge it
in the future?
What is new in relapsed follicular lymphoma? Is benda-
obinotuzumab a major step forward? Which are the alternatives?
Linfomi: Report del gruppo di lavoro
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Obinutuzumab 1000 mg i.v. Days 1, 8 and 15 Cycle 1; Day 1 Cycle 2–6 (28 day cycles)
Bendamustine 90 mg/m2/day i.v. Days 1 and 2 Cycles 1–6 (28 day cycles)
GADOLIN: Study design (NCT01059630)
G-B
B
Rituximab-refractory CD20+ iNHL
(incl FL, MZL and SLL)
(N=413)
G-maintenanceCR/ PR/ SD
R1:1
Obinutuzumab 1000 mg i.v. every 2 months for 2 years or until progression
Bendamustine120 mg/m2/day i.v. Days 1 and 2 Cycles 1–6 (28 day cycles)
Stratification factors:• NHL subtype (FL vs other) • Prior therapies (≤2 vs >2)• Refractory type (R-mono vs R-chemo)• Geographic region
• International, randomized, open-label study
• Response monitored by CT scan post-induction, then every 3 months for 2 years, then every 6 months
OBINUTUZUMAB PLUS BENDAMUSTINE VERSUS BENDAMUSTINE ALONE IN PATIENTS WITH RITUXIMAB-REFRACTORY FOLLICULAR LYMPHOMA:
RESULTS FROM THE GADOLIN STUDY
Trneny abs 440 Oral presentaion
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11.7 18.59.0
9.010.19.5
58.0 50.8
11.2 12.2
0
20
40
60
80
100
G-Bn=188
Bn=189
Pati
en
ts (%
)GADOLIN: Response to therapy
69.263.0
End-of-induction response (IRF)
5.7 7.64.7 4.1
10.9 11.7
62.0 59.4
16.7 17.3
0
20
40
60
80
100
G-Bn=192**
Bn=197**
Pa
tie
nts
(%
)
CR
PR
SD
PD
NE/missing78.7 76.7
Best overall response to 12 months (IRF)
• 19 patients still in induction (G-B, n=6; B, n=13)*
Sehn et al ASCO oral session
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GADOLIN primary outcome: IRF-assessed PFS
IRF, independent radiology facility; HR, hazard ratio; CI, confidence interval; NR, not reached.
IRF-assessed PFS G-B (n=194) B (n=202)
Events, n 71 (37%) 104 (51%)
Median PFS, months (95% CI)
NR (22.5–NR)14.9 (12.8–
16.6)
Stratified HR (95% CI) 0.55 (0.40–0.74)
Log-rank p-value p=0.0001
14.9
1.0
0.8
0.6
0.4
0.2
0 6 12 18 24 30 36 42 48 54
Time (months)
Pro
ba
bili
ty o
f P
FS
0.0
194202
157149
10686
7542
4726
2713
74
21
1
No. at riskG-B
B
Median follow-up: 21 months
G-BBCensored
+
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Median follow-up: 21 months
0 6 12 18 24 30 36 42 48 54
Pro
ba
bili
ty o
f O
S
194202
169167
146139
117111
8177
5548
2427
99
11
1.0
0.8
0.6
0.4
0.2
0.0
No. at riskG-B
B
Time (months)
G-B
B
Censored
OS G-B (n=194) B (n=202)
Events, n 34 (18%) 41 (20%)
Median OS, months (95% CI) NR (NR–NR) NR (39.8–NR)
Stratified HR (95% CI) 0.82 (0.52–1.30)
Log-rank p-value p=0.4017 (NS)
• 34 (18%) patients died in the G-B arm vs 41 (20%) in the control arm
– In the G-B arm, 22 (65%) deaths were due to disease progression vs 29 (71%) deaths in the B arm
GADOLIN primary outcome: OS
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ANALYSIS OF SECONDARY NEOPLASIAS AFTER HIGH DOSE THERAPY SUPPORTED BY ASCTIN FOLLICULAR LYMPHOMA PATIENTS.
A LONG TERM FOLLOW-UP ANALYSIS FROM THE GELTAMO REGISTRY.
CONCLUSIONSPts undergoing and ASCT are at an increased risk of developing a second malignancy, however, the incidence is not higher than that reported in other series.
We suggest that, given the favorable survival obtained by HDT/ASCT makes not evident to what extent incidence of secondary neoplasia will diminish the benefit of HDT/ASCT in FL.
Ubieto et al 441 oral presentation
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CONCLUSIONS
The interim analysis of this surveillance confirms 90YIT is a tolerable and efficacious treatment option for pts with R/R B-cell NHL or MCL in Japan, demonstrating good benefit-risk balance consistent with the currently available international and Japanese data. (NCT01448928)
INTERIM ANALYSIS OF POST MARKETING SURVEILLANCE OF YTTRIUM-90 IBRITUMOMAB TIUXETANIN JAPANESE PATIENTS WITH RELAPSED
OR REFRACTORY INDOLENT B-CELL NHL OR MCL
Hatake et al P686
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3 R-CHEMO REGIMENS
(CHOP-like, DHAP-like, ICE-like, fludarabin or bendamustine-based)
RANDOMIZATIONStratify (PR, CR PCR+,PCR-, no marker)
SD - PD
ARA-C 2g/sqm b.i.d. for two days
with Rituximab in vivo purging
CR - PR
Arm A
consolidation with
Zevalin
Arm B:
consolidation with
ASCT (BEAM)
Any salvage
treatment
MRD
PBSC harvest
MRD
MRDRituximab maintenance every three months for 8 courses
(starting three months after consolidation)
At relapse
Rituximab maintenanceevery three months for 8 courses
(starting three months after consolidation)
At relapse
ASCT With
Previously collected PBSC
FLAZ12
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Relapsed FL: Renoir
Rituximab 375 mg/m2 day 0 or 1 (day 8 on cycle 1)
Bendamustine 90 mg/m2 iv days 1-2
R-Bendamustine x 4 once a month
RELAPSED/REFRACTORY FOLLICULAR LYMPHOMANEED TO THERAPY
CR/PR
NR OFF
Random
Rituximab 375 mg/m2 day 1 q 90 days (8 cycles)Lenalidomide (10 mg dd 1-21 q 28) (24 cycles)
R2
Rituximab 375 mg/m2 day 1 q 90 days (8 cycles)
R alone
Rituximab 375 mg/m2 day 0 or 1 (day 8 on cycle 1)Bendamustine 90 mg/m2 iv days 1-2
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Is ASCT still the golden standard for MCL? how to challenge it
in the future?
What is new in relapsed follicular lymphoma? Is benda-
obinotuzumab a major step forward? Which are the alternatives?
Ultra high-risk lymphoma patients: Can we identify them? and
where shall we go for treatment?
Linfomi: Report del gruppo di lavoro
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MYC and BCL2 expression, determined by IHC or Nanostring GEP, are independent poor prognostic factors for rrDLBCL, and dual expression predicts dismal prognosis.
A BIOCLINICAL PROGNOSTIC MODEL INCORPORATING MYC AND BCL2 PREDICTS OUTCOME TO SALVAGE THERAPY IN RELAPSED/REFRACTORY DLBCL:
AN NCIC CTG LY12 CORRELATIVE SCIENCE STUDY.
Stewart et al 479 oral presentation
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Diffuse large B-cell lymphoma
Burkittlymphoma
High-grade B-cell lymphomaswith Myc, Bcl-2 Bcl-6
Translocation
MYC/BCL2 HICDouble expressor
lymphoma
20-30%
5-10 %
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Rearrangement of MYC in R-CHOP treated DLBCL
303 DLBCL previously untreated no follicular evidence.
MYC, BCL6, t(14;18)/ BCL2 rearrangements
245 evaluable, 35 (14%) MYC rearrangements of these 26 (74%) double HIT
Barrans S. et al JCO 2010
IPI +MYC +
IPI +MYC +
MYC -
MYC+
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MYC> 40%
MYC> 40%
BCL2 < 70%
BCL2 > 70%
DHS 1
DHS 2
Green T.M et al JCO 2012
DHS 2 = 29%
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Hu et al. Blood 2013
700 de novo DLBCL : 466 pts training and 234 validation set treated with R-CHOP
Prognostic impact ofMYC or BCL2 proteinexpression wasapparently due to theconfounding effect ofcases with MYC/BCL2coexpression; when allcases with MYC/BCL2were excluded neitherMYC nor BCL2 proteinexpression significantlyimpacted OS
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Overall survival of patients with DLBCL according MYC and BCL2 translocation (DHIT) or MYC and BCL2 protein expression (DE)
20-25% “dual protein expressor (DE)”
5-10% “ double-hit”
Other DLBCL
Johnson et al J.Clin. Oncol 2012
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First step:Identification of patient at poor prognosis
Screen all new DLBCLIHC : Myc, Bcl-2, Bcl-6indipendent of Ki-67
IHC : Myc > 40%Bcl-2 > 50 %
FISH breakpoint: Myc,Bcl-2, Bcl-6
neg
posDouble expressor Lymphomas (DE)
Myc +Single Hit Lymphoma
Myc+ & Bcl-2/Bcl6 + Double hit Lymphoma
Myc+ & Bcl-2+ & Bcl6 + Triple hit Lymphoma
What we propose doing in Myc/DH pos DLBCL ?
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Nella vostra pratica clinica quale work-up nella diagnostica dei
DLBCL viene impiegato ?
Linfomi: Report del gruppo di lavoro
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Petrich M, Gandhi M et al 2014
R-CHOP
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Petrich M, Gandhi M et al 2014
R-CHOP
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Petrich M, Gandhi M et al 2014
SCT in CR
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Nella vostra pratica clinica quale work-up nella diagnostica dei
DLBCL viene impiegato ?
Il trattamento dei DLBCL-DE e dei DLBCL-DH è diversificato rispetto
al classico DLBCL (R-CHOP) ?
Nei DLBCL-DH impiegate ASCT come terapia di consolidamento?
Linfomi: Report del gruppo di lavoro
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GCB=189 (55%)ABC=108 (31%) Unclassicable=38 (11%)
Pts 344 R-CHOP
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20% “dual protein expressor (DE)”
5% “ double-hit” and aggressive DLBCL NOS
Other DLBCL
Intensive regimens +/- ASCTCNS prophylaxis with HD-MTX and HD-ARAC and IT
R-CHOP +XR2-CHOP; R-CHOP+IBR; R-CHOP +?
R-CHOP
How I treat Myc/DH and DE pos DLBCL ?
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BASELINE TOTAL METABOLIC VOLUME (TMTV) PREDICTS THE OUTCOMEOF PATIENTS WITH ADVANCED HODGKIN LYMPHOMA (HL) ENROLLED
IN THE AHL2011 LYSA TRIAL
Olivier Casasnovas Abstract: S105 Oral Presentation
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• Assessment of the prognostic value of⁻ maximum Standard Uptake Value (SUVmax)⁻ metabolic tumor volume (MTV) ⁻ total lesion glycolysis (TLG)
⁻ SUV max, MTV and TLG were measured following a standard protocoL
Functional and quantitative PET parameters
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The combination of MTV and PET2 allows identifying 3 subsets of HL pts with
significantly different outcome that may help clinician to better tailor therapy.
High TMTV Low TMTV PET-2 pos PET- 2 neg
2yrs PFS 81% 93% 76% 92%
Low TMTV
PET2 neg
High TMTV
PET 2 pos
Low TMTV HighT MTV
PET-2 pos PET- 2 neg
2yrs PFS 94% 61% 88%
Olivier Casasnovas Abstract: S105 Oral Presentation
BASELINE TOTAL METABOLIC VOLUME (TMTV) PREDICTS THE OUTCOMEOF PATIENTS WITH ADVANCED HODGKIN LYMPHOMA (HL) ENROLLED
IN THE AHL2011 LYSA TRIAL
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PFS ---- 64% vs 97%Logrank test, p < .0001
PFS ---- 55% vs 94%Logrank test, p < .0001
PFS ---- 64% vs 97%Logrank test, p = .007
OS ---- 80% vs 100%Logrank test, p = .0001
OS ---- 86% vs 100%Logrank test, p = .004
OS ---- 83% vs 98%Logrank test, p = .003
Prognostic value of the baseline functional PET
parameters in PMBCL26
Ceriani L, Martelli M, Zinzani PL et al Blood 2015
An high value of SUVmax, MTV and TLG showed a significant prognostic impact for PFS at univariate analysis
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Nella vostra pratica clinica I parametri quantitativi SUV max,
MTV,TLG vengono riportati nella valutazione della PET basale ?
Questi parametri potranno essere considerati nel futuro un valido e
riproducibile fattore prognostico nella pratica clinica del paziente
con HD e LNH?
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DISCUSSION
Allo-HCT is a feasible and effective option
for RR HL. In our series, the disease status
at HCT was the main predictor of outcomes,
primarily relapse. Furthermore, BV showed
efficacy as a bridge to allo- HCT as well as
post allo-HCT rescue.
Festuccia M et al 796 oral presentation
ALLOGENEIC STEM CELL TRANSPLANTATION ANDBRENTUXIMAB VEDOTIN
IN RELAPSED/REFRACTORY HODGKIN LYMPHOMA:A MULTICENTER EXPERIENCE
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Linfomi: Report del gruppo di lavoro
Allo ASCT è la terapia standard del paziente con HD recidivato
post ASCT?
Aplo vs allo ASCT ?
Brentuximab è considerato terapia bridge o post Allo ASCT ?
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Grazie per la cortese attenzione ……
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Frontline
therapy MCL;
age > 65 years
R
A
N
D
O
M
I
Z
E
Bendamustine (90 mg/m2 IV Days 1-2) Rituximab (375 mg/m2 Day 1)
Study drug:Oral placebo (starting on Cycle 1, Day 1)
until PD or unacceptable toxicity
Bendamustine (90 mg/m2 IV Days 1-2) Rituximab (375 mg/m2 Day 1)
Study drug:Oral ibrutinib 560 mg (starting on Cycle 1, Day 1) until PD or unacceptable toxicity
1:1
N=520
MCL3002 - study design ( SHINE study)
Phase 3, randomized, double-blind, placebo-controlled study
CR/PR
Rituximab 375 mg/m2
every 2 months
2 years
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