aggressive b-celllymphomas in theelderly · 2019. 6. 7. · aggressive lymphomas in theelderlysiog...
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Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09
Lorenz Trümper – Universitätsmedizin Göttingen
„ Treatment of aggressive B-Cell Lymphomas in the Elderly “
Lorenz TrümperAbteilung Hämatologie & Onkologie
Göttingen Comprehensive Cancer Center Universitätsmedizin Göttingen
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Centroblastic Immunoblastic
Diffuse large B-cell lymphoma, not otherwise specified (NOS)
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NHLim Alter NHL – 10 most frequent
DiagnoseH
äufig
keit
in %
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NHLim Alter Lymphoma Characteristics
Diagnose
0
20
40
60
80
100
Chronische lymphatische
Leukämie
Follikuläres LymphomDiffus großzelliges Lymphom
Burkitt-Lymphom
Therapieerfolg Überleben
5 Ja
hre
nach
Dia
gnos
e %
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NHLim Alter Treatment strategies
Therapie
Indolent Lymphoma
CLLAggressive Lymphoma
Limited Radiation Watch & waitChemotherapy
± Moab± RadiationAdvanced
Chemotherapy± Moab
± Radiation
Chemotherapy(+) Moab
Trials/singlecases
TransplantationRadioimmunthx
MoabTransplantation
TransplantationRadioimmunthx
Lymphoma
Involvement
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Risk Score CR (%) 5-year OS (%)
International Prognostic Factors Group NEJM 1993
Prognosis of aggressive 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
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Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09
Lorenz Trümper – Universitätsmedizin Göttingen
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25Years from Registration
ProMACE-CytaBOMm-BACODCHOPMACOP-B
At Risk233223225218
Events173164175170
10-YearEstimate
37%35%34%32%
Fisher et al. NEJM 1993
Primary Treatment of aggressive B-NHL: CHOP
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NHLim Alter Life expectancy – RKI data
Basis
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Sonnen & Kuse, DMW 1998
Aggressive NHL in elderlyTreatment outcome and prognosis
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Autor, JahrGruppe
Therapie n AlterMedian
CR%
OAS%
nach
Tirelli, 1998 EORTC CHOPVMP
6060
70-93 75
4527
65*30 2 J
Bastion, 1997GELA
CTVPCVP
233220
> 6975
47*32
27*19 5 J
Sonneveld, 1995 DHOSG
CHOPCNOP
7276
60-84 70
49*31
42*26 3 J
Meyer, 1995 Ontario CHOPCHOPw
1919
> 6571
6874
74*51
2 J
Osby, 2003 (NLG) CHOPCNOP
203205
7171
60*34
57*32 3J
Treatment of aggressive lymphomas in the elderlyTx with less intensity – no anthracycline?
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NHLim Alter CHOP: Bad in old age?
Therapie
"Alters-CHOP"CHOP0
20
40
60
80
100
VMP CHOPw CNOP
2-3
J-Ü
berle
ben
%
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Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09
Lorenz Trümper – Universitätsmedizin Göttingen
12–2004
07–2000: Interim analysis (ASH 2000)05–2001: Update of interim analysis (EHA 2001)09–2001: Analysis at end of study (NEJM 2002)12–2002: 3-year follow-up analysis12–2004: 5-year analysis (Feugier JCO)
09–200105–2001
07–2000
12–2002
Years
1.0
0 1 2 3 4 5 6 70.0
0.2
0.4
0.6
0.8
Even
t-fre
e su
rviv
alImprovement 1 over CHOP: Rituximab – CHOP (elderly)
GELA / Coiffier et al.
LN98-5
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Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09
Lorenz Trümper – Universitätsmedizin Göttingen 14
Improvement 2: Dose density,G-CSF supported (CHOP-14)
9080706050403020100
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
CHOEP-14 (n=169)
CHOEP-21 (n=170)
CHOP-21 (n=178)
CHOP-14 (n=172)
months
Pfreundschuh, Trümper et al (Blood 2004)
CHOP-14 56%
CHOP-21 42%
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6 x CHOP-14+ 30-40 Gy (Bulk, E)
Random2x2
FactorialDesign
8 x CHOP-14+ 30-40 Gy (Bulk, E)
8 x CHOP-14+ 36 Gy (Bulk, E)
+ 8 x Rituximab
6 x CHOP-14+ 36 Gy (Bulk, E)
+ 8 x Rituximab
Study Design RICOVER-60
CD20+ DLBCLStages I-IV
61 to 80 years
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RICOVER-60 - Event-free survival -
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=0.0371, 3: p<0.0011, 4: p<0.0013, 4: p=0.561
Months
Prop
ortio
n
3-years rate:
66.5%
63.1%
53.0%
47.2%
6x R-CHOP 14
8x R-CHOP 14
8x CHOP 14
6x CHOP 14
Pfreundschuh et al. Lancet Oncology 2008
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NHLim Alter Pre-Phase Treatment
Diagnose
„Sick due toNHL“
Pre PhaseTreatment
Re-assessment⇨ ⇨
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Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09
Lorenz Trümper – Universitätsmedizin Göttingen 18
RICOVER-60: Conclusion
• CHOP-14 plus Rituximab is safe and feasible
• EFS – significant increase !
• No significant difference between 6 or 8 cycles of R-CHOP-14
• 6 x CHOP-14 + 8 x Rituximab is the new standard– less toxicityand cost, same efficacy as 8 cycles
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III. Elderly Patients
Is further
Improvement
possible ?
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Study Design DENSE-R-CHOP-14
CD20+ DLBCLStages I-IV
61 to 80 years
CHOP
CHOP
CHOP
CHOP
CHOP
CHOP
12 141086420
W e e k s
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Study Design DENSE-R-UP-CHOP-14
CD20+ DLBCLStages I-IV
61 to 80 years
121086420
121086420
W e e k s
Rituximab 375 mg/m2
Rituximab 500 mg/m2
♀
♂
121086420 14
121086420 14
1
2
2
1
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R-CHOP-14+ 36 Gy IN-RT*
Random2x2
FactorialDesign
DENSE-R-CHOP-14+36 Gy IN-RT*
DENSE-R-CHMP-14+ 36 Gy IN-RT*
R-CHMP-14+ 36 Gy IN-RT*
Study Design DENSE-R-CHO/MP-60UNFAVORABLE
CD20+ DLBCLIPI 2-4
IPI 1 Bulky61 to 80 years
* Except Interim-PET-neg.
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Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09
Lorenz Trümper – Universitätsmedizin Göttingen
„ Denser“ RituximabConclusion
• Pharmakokinetics ….. Also important forMoAb Tx
• Phase III for early densification planned• Significant sex-related differences• Increased rate of opportunistic
infections – prophylaxis in the elderlylike in AML etc !!!
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Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09
Lorenz Trümper – Universitätsmedizin Göttingen
m o n t h s
Prop
ortio
n
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
6xR-CHOP-14 / no Rxbulk(n=47)
6xR-CHOP-14 + Rxbulk(n=117) 68%
43%
p=0.002
RICOVER-Trials Follow up: EFS of patients in PR
Depending on Consolidative Radiation
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Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09
Lorenz Trümper – Universitätsmedizin Göttingen
RICOVER-Follow up Trial: PFS of patients in CR
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
Months
Prop
ortio
n
p=0.512
6xR-CHOP-14 + Rxbulk(n=33)
6xR-CHOP-14 / no Rxbulk(n=20)
Median time of observation: 18/34 months
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Aggressive Lymphomas in the Elderly SIOG Berlin Oct 09
Lorenz Trümper – Universitätsmedizin Göttingen
Role of Radiation Tx in elderlyAggressive NHL pts
• Consolidation (36-40 Gy GHD)– In initial bulky disease pts only when
remaining lymphoma on CT– Dto. In extranodal– Contralateral testis in testis lymphoma
• Palliative• Decreased Chemo-Tx + Radiation – not
superior to full dose chemotherapy
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Radioimmuntherapie bei Lymphomen – Onkologische Aspekte
Lorenz Trümper – Universitätsmedizin Göttingen
Bias in clinical trials: KML results
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Radioimmuntherapie bei Lymphomen – Onkologische Aspekte
Lorenz Trümper – Universitätsmedizin Göttingen
DSHNHL Elderly Trial - BR
• Open, non-randomized phase II• Elderly non-fit pts (not fit for R-CHOP-14)• Geriatric assessment• Dose-dense Rituximab + Bendamustin• PI U. Wedding / DSHNHL trial office
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Radioimmuntherapie bei Lymphomen – Onkologische Aspekte
Lorenz Trümper – Universitätsmedizin Göttingen 29
Acknowledgements
• DSHNHL – M. Pfreundschuh, N. Schmitz, L. Trümper B. Glaß, G. Wulf, M. Ziepert, S. Zeylanova, M. Loeffler
• UMG – C. Binder, K. Hohloch, G. Wulf, E. Stitz, J. Hasenkamp, A. Borgerding
D S H N H L