Post on 12-Aug-2019
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
Hämatologie im Wandel 2015Aggressive B-und T Zell Lymphome
Lorenz Trümper, Klinik für Hämatologie und Medizinische Onkologie, UniversitätsKrebszentrum, Georg-August-Universität Göttingen
Für die DSHNHLMichael Pfreundschuh, Gerhard Held, Marita Ziepert, Bertram Glaß,
Maike Nickelsen, Gerald Wulf, Markus Loeffler, Norbert Schmitz
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
Risk Score CR (%) 5-year OS (%)
International Prognostic Factors Group NEJM 1993
Prognose aggressiver NHL: IPI
Risk Group # Factors 5-y OSAge > 60 y Low 0,1 73ECOG PS > 1 Low-Intermed 2 51Stage III or IV High Intermed 3 43Extr sites > 1 High 4,5 26LDH > normal
2
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
IPI Modifikation: NCCN-IPI
Zheng Zhou et al. Blood 2014;123:837-842
©2014 by American Society of Hematology
Stärkere Gewichtungvon Alter undAbsolutem LDH Wert
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
Alizadeh et al. Nature403:503, 2000
Rosenwald et al. NEJM346:1937, 2002
Wright et al. PNAS100:9991, 2003
Prognose aggressiver B NHL: ABC versus GCB
Lenz et al. NEJM359, 2008
w/o rituximab
w rituximab
Aggressive B NHL Erlangen
Lorenz Trümper – Universitätsmedizin Göttingen
51 43 33 20 10 4 3 3 353 49 39 28 23 7 5 1 08 6 4 3 3 0 0 0 0
patients at risk:
p=0.013
GCB (n=66)
non-GCB (n=74)
MYC+ independent of GCB/ non GCB (n=14)
Months
Prop
ortio
n
0 10 20 30 40 50 60 70 80 900
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
51 43 33 20 10 4 3 3 353 49 39 28 23 7 5 1 08 6 4 3 3 0 0 0 0
patients at risk:
p=0.013
GCB (n=66)
non-GCB (n=74)
MYC+ independent of GCB/ non GCB (n=14)
Months
Prop
ortio
n
0 10 20 30 40 50 60 70 80 900
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Clinical Significance of Myc Break Positive NHL
-B1/B2 Trials of DSHNHL
Klapper et al., Leukemia 2009
Johnson et al. (2012) JCO 30: 3452-3459
MYC Expression + BCL2 + BCL6Signifikanter Prädiktor beim DLBCL
Horn et al. (2013) Blood
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.lymphome.de/en/Groups/DSHNHL
7
Aggressive B-NHLPrimärbehandlung: molekulare prognostische Faktoren
Kein signifikanter prognostischer Unterschied in der Cox-Regression für myc-Rearrangement, keine Unterschiede uni- oder multivariat für alle anderen getesteten Marker bzw. Kombinationen (double-hit, MIB1, p53, bcl6, bcl2, GCB vs nGCB)
B-Zell Rezeptor Mutationen
Wilson, Hematology 2013, ASH EDU
Prognose bei DLBCL• IPI nach wie vor „einfach und gut“• Genetische Daten:
– Genexpressions-Subtypen ABC und GCB haben prognostische Signifikanz
– Myc-Bruch hat prognostische Signifikanz– Double/Triple Hit – ?– Vielzahl von Mutationen und Kombinationen– Mutationen im B-Zell-Rezeptor –
Therapeutisch relevant wenn „addicted“• Prospektive Bio-Screens unerlässlich• Keine Änderung der Therapie!
Coiffier et al., N Engl J Med 2002 Pfreundschuh et al., Lancet Oncol 2006
LN98-5 (elderly) MInT (young good risk)
Immunchemotherapie – Standard beim DLBCL15
DLBCL: Strategien zur Optimierung
modulating humoral immunotherapytiming / dose of rituximab
dose escalationHD therapy / autologous tx
MegaCHOEP
TBICy
DexaBEAM
6-8 x R-CHOP-14/21
Rx
early modulation of therapye.g. PET-guided
intensification
addition of novel agents („targeting“) e.g. bortezomib, lenalidomide, ibrutinib
modulating chemotherapy back-bonee.g. CHOEP / ACVBP / DaEPOCH
dees
cala
tion
reduction of chemotherapy
Rx
reduction / omission of radiation
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
< 60 J. 60 - 80 J. > 80 J.
FLYER
OPTIMAL R-BendaUNFOLDER
MegaCHOEPAmendment 2
aaIP
I 1aa
IPI 0
aaIP
I 2 /
3
Risikogruppen der
supported by
CHOP
CHOP
CHOP
CHOP
CHOP
CHOP
R R R R R R
CHOP
R
CHOP
CHOP
R R R
Rando
Low-risk Very Favourable Group:FLYER (6-6/6-4) STUDY
CHOP
R R
506 Patienten rekrutiert
FLYER (6-6/6-4): 2nd PLANNED INTERIM ANALYSIS (07/13)
Months
Prop
ortio
n
0 10 20 30 40 50 60 70 80 90 1000.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
Prop
ortio
n
0 10 20 30 40 50 60 70 80 90 1000.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
P F S O S
CHOP21
CHOP21
CHOP21
CHOP21
CHOP21
CHOP21
R R R R R R
CHOP14
R R R R
R
CHOP14
CHOP14
CHOP14
CHOP14
CHOP14
R R
d 105d 1 d 75
+/- Radiation to Bulky Disease
IPI = 1and/orBulk
+/- Radiation to Bulky Disease
Low-risk Less Favourable Group:UNFOLDER (21/14) STUDY
UNFOLDER Study: Interim AnalysisEFS – Patients randomized to 4 arms (n=285)
65%
R-CHOP 21/14 + Rx
(n=146)R-CHOP 21/14 - Rx
(n=139)
p=0.004
Months
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 800
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Prop
ortio
n
81%
UNFOLDER (21/14) STUDY DESIGN
CHOP21
CHOP21
CHOP21
CHOP21
CHOP21
CHOP21
R R R R R R
CHOP14
R R R R
R
CHOP14
CHOP14
CHOP14
CHOP14
CHOP14
R R
d 105d 1 d 75
+ Radiation to BulkyDisease
IPI = 1and/orBulk
+ Radiation to BulkyDisease Recruited 621 pts
Intensified chemotherapy with ACVBP plus rituximab vs. standard CHOP plus rituximab for the treatment of
diffuse large B-cell lymphoma (LNH03-2B) an open-label randomised phase 3 trial
Recher et al. LANCET 2011; 378:1858-67
60 3 12 15 189 21
R-ACVBP
R-CHOP
RWks
MTX R-IFM-VP16 Ara-C
0 2 4 6 10 14 24 Wks
4 IT-MTX
Progression-Free Survival
3-y PFS: 73% after 8x R-CHOP-21
87% after R-ACVBP
p=0.0015, HR 0.48
Junge Patienten mithohem Risiko (aa IPI = 2, 3)
Conventional chemotherapy (CHOEP-14) with rituximab orhigh-dose chemotherapy (MegaCHOEP) with rituximabfor young, high-risk patients with aggressive B-cell lymphoma
Schmitz et al. The Lancet Oncology Volume 13, Issue 12 2012 1250 - 1259
Event-free survival (A), progression-free survival (B), and overall survival (C)for all patients. Overall survival for the 192 patients with age-adjusted IPI 2 (D).
Schmitz et al. The Lancet Oncology Volume 13, Issue 12 2012 1250 - 1259
FOLLOW UP
PFS OS
HDT conventional HDT conventional
Stiff et al.* 2 yrs. 72% 62% 76% 72%
Vitolo et al. 2 yrs. 71% 59% 82% 80%
Schmitz et al. 4 yrs. 67% 72% 75% 85%
Le Gouill et al. 3 yrs. 37% 56% 82% 85%
* PFS and OS for pts. treated with R-CHOP ± HDT
R-HDT or Conventional Therapy (R-Chemo) in Younger Patients with Poor-risk Aggressive B-cell Lymphoma
Ältere Patienten(60 – 80 Jahre)
0 10 20 30 40 50 60 70 800
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1: 6 x CHOP 14 (n=307)2: 8 x CHOP 14(n=305)
3: 6 x R-CHOP 14(n=306)
4: 8 x R-CHOP 14(n=304)
1, 2: p=0.6161, 3: p<0.0011, 4: p=0.0013, 4: p=0.317
Months
Prop
ortio
n
RICOVER-60- Progression-free Survival -
3-year rates:
73.4%
68.8%
56.9%
56.9%8x CHOP 146x CHOP 14
6x R-CHOP 14
Pfreundschuh et al., Lancet Oncol. (2008)
8x R-CHOP 14
Figure 2 Survival endpoints (A) Event-free survival. (B) Progression-free survival. (C) Disease-free survival. (D) Overall survival. Shaded areas show 95% CIs.
Richard Delarue , Hervé Tilly , Nicolas Mounier , Tony Petrella , Gilles Salles , Catherine Thieblemont , Serge B...
Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial
The Lancet Oncology, Volume 14, Issue 6, 2013, 525 - 533
http://dx.doi.org/10.1016/S1470-2045(13)70122-0
Failure-free survival
R-CHOP14 533 438 355 224 102 25 1
Patients at Risk
R-CHOP21 534 429 358 216 116 25 1
Years from randomisation
R-CHOP21 R-CHOP14
Pro
babi
lity
0.00.10.20.30.40.5
0.60.70.80.9
1.0
0 1 2 3 4 5 6
0.99 (0.79–1.24)HR (95% CI)p=0.94Log-rank test
75%75%2-yr FFS153 (28)155 (29)Events, n (%)
R-CHOP14R-CHOP21
Cunningham et al. The Lancet. Published online April 22, 2013
M o n t h s0 10 20 30 40 50 60 70 80
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Male without Rituximab(n=325); 3 year rate: 55%
Male with Rituximab(n=325); 3 year rate: 68%
Female without Rituximab(n=287); 3 year rate: 60%
Female with Rituximab(n=285); 3 year rate: 75%
Prop
ortio
n
DSHNHL 26.03.09
RICOVER-60 Trial (n=1222)PFS according to Sex and Rituximab
Murawski et al., ASH 2009
Effect of age, gender, tumor load, and IPI on rituximab clearance.
Michael Pfreundschuh et al. Blood 2014;123:640-646
©2014 by American Society of Hematology
SEXIE-R-CHOP-14
P F S O S
Pfreundschuh et al, ASCO 2014
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
„SMARTER“ - CHOP
Pfreundschuh et al., JCO 2014
Phase II Studie, n = 189 Patienten
6+2 Gaben Rituximab mit „Erhaltung“ bisTag + 240
Im Historischen Vergleich zu Ricover 60
1. Verbesserung Ergebnisse Männer2. Verbesserung Ergebnisse High – Risk
Phase III OPTIMAL rekrutiert
Ausserhalb Studien „on label“ bestes Regime
Gesamtüberleben
Alle
IPI 1,2
IPI 3-5
2xR-CHLIP-14+ 2R + 36 Gy*
Study Design OPTIMAL >60
CD20+ DLBCLIPI=1
No bulk61 to 80 years
4xR-CHOP-14PET +
2xR-CHOP-14+ 2R + 36 Gy
4xRPET -
4 x R4xR-CHLIP-14
PET -
PET +
Vitamin-D ≤8 ng/ml Vitamin-D >8 ng/ml
p=0.094
p<0.001
0.00.10.20.30.40.50.60.70.80.91.0
0 10 20 30 40 50 60 70 80
Months
0 10 20 30 40 50 60 70 800.00.10.20.30.40.50.60.70.80.91.0
Prop
ortio
n
0.00.10.20.30.40.50.60.70.80.91.0
0 10 20 30 40 50 60 70 800.0
0.10.2
0.3
0.40.5
0.60.70.8
0.9
1.0
0 10 20 30 40 50 60 70 800 10 20 30 40 50 60 70 800.0
0.10.2
0.3
0.40.5
0.60.70.8
0.9
1.0
0.0
0.10.2
0.3
0.40.5
0.60.70.8
0.9
1.0
p=0.094 p<0.001
Months
Prop
ortio
n
3-Year EFS Improvement by Rituximab in RICOVER-60
16%31%
Bittenbring et al., JCO 2014
R-CHOP-14
R-CHOP-14
CHOP-14 CHOP-14
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
DLBCL & Rituximab
• „one size fits all“ passt nicht !– Clearance Alters- und Geschlechtsabhängig– Dosis / Expositionsdauer lymphom-typspezifisch– Zelluläre Funktion (ADCC) korreliert mit Vit. D
• Empfehlung– Vit. D substituieren (Zielspiegel 65 ng/ml)– SMARTER schedule „on label“ & wirksam– Optimal?
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
Aggressives B-NHL – DLBCL >65 Jahre
pre Treatment CGA, z.b. Staging, IPI, N CCN-IPI Gespräch mit Patient-CIRS Ausführliche Untersuchung Aufklärung-ADL Anamnese .Gespräch mit Angehörigen-IADL Echokardiographie-KPS Lungenfunktion
Evaluation-Entscheidung
FEV1>50%, Diff. Kap>50% CIRS>6EF > 50%, CIRS < 6
Kurative Therapie Unklar Palliativ-lebensv.TherapieVorphasentherapie VorphasentherapieStratifizierung nach IPI! dann Reevluation
6-8 x R-CHOP-21 R-Bendamustin(BRENDAStudie)6 x R-CHOP-14+ 8 x R R-miniCHOPz.B. OPTIMAL Studie Palliativ-supportive Therapie
Entscheidungsbaum – Ältere Patienten
Studie für Patienten ≥ 81 Jahre, oder Alter 61 bis 80 und CIRS >6, die nicht für eine Therapie mit CHOP qualifizieren
InterimStaging(RE1)
Ende
4x
3x Benda
Final-Staging(RE2)
Re-Staging
(RE3)
RTX*
Follow-Up
PR, SD
CR
Benda3xPrednisolon
R i.v. s.c.
s.c.R R
PD
CR, PR, SD
Vorphase * Therapiephase
InterimStaging
(RE1)
Ende
4x
3x Benda
Final-Staging(RE2)
Re-Staging(RE3)
RTX*
Follow-Up
PR, SD
CR
Benda3xPrednisolon
R i.v.i.v.
i.v.
PD
CR, PR, SD
Vorphase * Therapiephase
RR
Run-In Phase (Patient 1-20)* bei Residualbefund nach initialem Bulk
Hauptphase (Patient 21-100)* bei Residualbefund nach initialem Bulk
DSHNHL 2010-1 (BRENDA)
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
Herrera et al. Cancer 2014.
Bedeutung der Referenzpathologie
Bei peripheren T NHL
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
Schmitz et al., Blood 2010;116(18):3418-3425
Periphere T NHL: Ergebnisse CHOP-ähnlicher Primärtherapie
Event-free survival18-60 years, LDH < UNV)
NHL-B1all PTCL
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
5-y OS (%)
CHOEP and HD-therapy w autol. PBSCT: Swedish registry data
Ellin et al., Blood 2014; 124; 1570-1577
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
6x CHOEP-14/21+ / - IFRT
6x CHOP-14+ / - IFRT
HD-therapyautol. SCT
novel compounds / combinations phase II
HDAC-IRomidep
sin
new agentse.g.Aurora KI
allogeneic SCT
prospective trials
PTCL PTCL
< 60 years > 60 years
primary
treatment
salvagetreatm
ent
prospective trials
ABsz.B. CD52
anti folatepralatrexate
CTXmultiple
regimens
specific entities
ALCLNK/T
aspar.„SMILE“
RT+ CT
6x CHOEP+ / - IFRT
ALK neg: HD-therapyautol. SCT
Adcetris
SCT
prospective trials
IITs
pT-NHL: Treatment Strategies
CHOP versus CHP with Brentuximab vedotin as first line therapy: ECHELON2
• O’Connor OA, et al. ASCO 2013; Chicago, US (Abstract #TPS8611)
DSHNHL: http://www.dshnhl.org/
DSHNHL 2006-1B / ACT-2
alemtuzumab 30 mg s.c.30 mg day 1 courses 1-4 of CHOP-14
antibiotic/antimycotic/virostatic prophylaxisCMV and EBV monitoring
1days 15 29 43
R
71
CHOP
CHOP
CHOP
CHOP
CHOP
CHOP
57
T-cell lymphomaexcept ALCL
61-80 yearsall stagesexcept stage I, IPI 0w/o bulk
CHOP
CHOP
CHOP
CHOP
CHOP
CHOP
A AA A
accrual completed 09.2013
ORR results combined with ACT-1 (NLG)2015
DSHNHL 2006-1A
accrual stopped 08.2013
DSHNHL: http://www.dshnhl.org/
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
www.dshnhl.org
Aktuelle Studien und Empfehlungen:
www.dshnhl.org
CHEMO14 according to center decision:- ACVBP14- CHOP14
GAINEDDLBCL, 18-60y, aaIPI = 1-3
Phase III – 2 arms
GA101: 1000mg by injectionD1-D8 cycles 1 -2
MTX BEAM + ASCT
Salvage therapy
∆SUV 0-2> 66%
2-/4-
PET results
PET 0
∆ SUV0-≤ 70%
4+
4
According to randomization arm and CHEMO14 regimen
R
Arm A
Arm B
MTX / GA101-VP-IFOSFAMIDE / Arac
A
B GA101-CHOP-14 x 4
PET 2 PET 4
Induction
∆ SUV0-4>70%
4-
∆SUV 0-2≤ 66%
2+/4-
C1 C2 C3 C4
C1 C2 C3 C4
R-CHEMO14
consolidation
MTX / R-VP-IFOSFAMIDE / AracR-CHOP-14 x 4
GA101-CHEMO14