Speed-Date: Agressive und Indolente NHL - Prof. Dr. M. Dreyling Med. Klinik III Klinikum Grosshadern LMU/München
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internet: www.lymphome.de • email: lymphome@medizin.uni-koeln.de
Symposium des KML * DGIM 2020 * 24. April 2020
Speed-Date:
Agressive und Indolente NHL
Prof. Dr. M. Dreyling
Med. Klinik III
Klinikum Grosshadern
LMU/München
Aggressive und indolente NHL
Lymphome
Hsitologische Subtypen
Burkitt-like
LL 2%
LPL
2% 1%
Composite
ALCL 13%
2% DLBCL
PMLBCL 31%
2%
MZL
5%
PTCL FL
6% 22%
MCL
6%
SLL
6%
Armitage, JCO 1998
Diffus großzelliges B-Zell Lymphom
Klinische Charakteristika
• schnell wachsend = aggressiv
• unbehandelt in wenigen Wochen tödlich
• häufig in frühen Stadien entdeckt
(ausgeprägte Symptomatik !)
• häufig Befall außerhalb der Lymphknoten
• hohe Wachstumsfraktion =
prinzipiell heilbar durch Chemotherapie
McKelvey et al. 1976
Diffus großzelliges B-Zell Lymphom
Double Hit Lymphome
Dunleavy, Hematology 2014
93,94
Diffus großzelliges B-Zell Lymphom Chemotherapie (Erstlinie)
Diffus großzelliges B-Zell Lymphom
FLYER: Progressions-freies Überleben
Pöschl, Lancet 2020
46
Diffus großzelliges B-Zell Lymphom
Treatment plan (Phase II)
Copa–R-CHOP:
Lenz, Leukemia 2020
7
Reziziviertes DLBCL
Progressions-freies Überleben
DLBCL Peripheral T cell Lymphoma
Coral Trial: British Columbia Cancer Agency
relapse after 1st line rituximab Lymphoid Cancer database:
3 yrs PFS 11%
3 yrs EFS 21%
Gisselbrecht, JCO, 2010 Mak, JCO, 2013
Reziziviertes DLBCL
Progressions-freies Überleben
Safety run-in Randomized Phase
• Safety analysis • Safety analysis • Interim analysis
• Substantial amendment after 30 pts in for efficacy
experimental
arm
Reziziviertes DLBCL
Niveau: R-GemOx +/- Nivolumab
Held, ASH 2019
10Diffus großzelliges B-Zell Lymphom Corvid-19: Empfehlungen der Med. Klinik III Agressive Lymphome: -Chemotherapie zeitgerecht durchführen
Mantle cell lymphoma Two kind of diseases Dreyling, ESMO CR 2017
MCL Risikofaktoren Blastoid, Ki-67>30% oder p53 mut Dreyling, ASH 2019
MCL younger Time to treatment failure Hermine, Lancet 2016
young patient (65) compromised patient
First line treatment
dose-intensified conventional
immuno-chemotherapy Best supportive care?
immuno-chemotherapy
(e.g. R-CHOP, high dose Ara-C) (e.g. R-CHOP, VR-CAP, BR, R-BAC) R-Chlorambucil
⇒ Autologous SCT BR (dose-reduced)
⇒ Rituximab maintenance R-CVP
Rituximab maintenance
1. relapse
immuno-chemotherapy immuno-chemotherapy Immuno-chemotherapy
(e.g. R-BAC, BR) (e.g. BR, R-BAC) (e.g. BR)
or targeted approaches or targeted approaches or targeted approaches
discuss: discuss:
- allogeneic SCT - Rituximab maintenance
- radioimmunotherapy
higher relapse
Targeted approaches: Ibrutinib, Lenalidomide,
Temsirolimus, Bortezomib (preferable in combination)
Alternatively: repeat previous therapy (long remissions)
Dreyling, ESMO CR MCL 2017MCL younger 2
TRIANGLE: +/-Ibrutinib
A:
3x R-CHOP/
ASCT Observation
3x R-DHAP
R maintenance (3 years)
A + I:
R 3x R-CHOP + I/
ASCT 2 yrs I-maintenance Observation
3x R-DHAP
R maintenance (3 years)
I:
3x R-CHOP + I/
2 yrs I-maintenance Observation
3x R-DHAP
R maintenance (3 years)
superiority/non-inferiority: time to treatment failure
HR: 0.60; 65% vs. 77% vs. 49% at 5 years0
30
60
90
120
150
180
210
240
270
300
330
360
390
420
450
480
510
540
570
600
630
660
690
720
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780
810
840
870
Jun. 16
Jul. 16
Aug. 16
Sep. 16
Okt. 16
Nov. 16
Dez. 16
Jan. 17
Feb. 17
Mrz. 17
Apr. 17
Mai. 17
Jun. 17
Jul. 17
Aug. 17
Sep. 17
Okt. 17
Nov. 17
Dez. 17
Jan. 18
Feb. 18
Mrz. 18
Apr. 18
Mai. 18
MCL younger 2
Jun. 18
Jul. 18
Aug. 18
Planned randomization
Sep. 18
Okt. 18
Nov. 18
Dez. 18
Patients randomized: 563
Jan. 19
Feb. 19
Mrz. 19
Apr. 19
Mai. 19
TRIANGLE: +/-Ibrutinib
Jun. 19
Jul. 19
Aug. 19
Sep. 19
Okt. 19
Nov. 19
Dez. 19
Jan. 20
Feb. 20
Mrz. 20
Apr. 20
Mai. 20
Jun. 20
Jul. 20
Aug. 20
Sep. 20
Actual randomization
Okt. 20
Nov. 20
Dez. 20
Jan. 21
Feb. 21
Mrz. 21
Apr. 21
Mai. 21
Jun. 21
Jul. 21MCL elderly
R-CHOP +/- R maintenace
PFS OS
5-year
Group rate 95% CI
R 79% 67%-86%
IFN 59% 48%-69%
5-year
Group rate 95% CI
R 51% 40%-62%
IFN 22% 14%-32%
Kluin-Nelemans, JCO 2019MCL Erstlinientherapie
Rituximab-Lenalidomid
Progression-Free Survival Overall Survival
1.00
Probability of progression free survival
0.75
0.50
36-month PFS = 80.3% (95% CI = 63.0%, 90.1%) 36-month OS = 91.9% (95% CI = 76.9%, 93.7%)
48-month PFS = 70.6% (95% CI = 52.0%, 83.1%) 48-month OS = 83.0% (95% CI = 65.9%, 92.0%)
0.25
Median follow-up = 61 months (range 21-74)
Median follow-up = 61 months (range 21-74)
0.00
0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 80
Months from Treatment
Months from Treatment
Number at risk Number at risk
36 33 30 28 23 16 12 2 38 37 36 34 33 26 19 7 0
Ruan, Blood 2019MCL elderly R2
Studiendesign
Rituximab maintenance
1st line induction: + Lenalidomide
8x R-CHOP 15 mg daily d1-21,
q28 days
® PR/CR
~80% ® Treatment: max. 2 years
1st line induction:
6x R-CHOP/Ara-C Rituximab maintenance
sponsor: LYSARC
central pathology: W. Klapper
MRD diagnostics: M. Ladetto, C. Pott, MH DelfauMCL elderly R2 Rekrutierung
European MCL Network
Study generation 2019
< 65 years > 60 years > 65 years
MCL younger: MCL elderly R2: MCL elderly I:
R-CHOP/DHAP =>ASCT R-CHOP vs R-CHOP/Ara-C BR +/- Ibrutinib
R-CHOP/DHAP+I =>ASCT => I => Rituximab M => Rituximab M
R-CHOP/DHAP + I => I +/- Lenalidomide +/- Ibrutinib
Relapse
Ibrutinib/ Ibrutinib +/-
Bortezomib
R-HAD +/- Bortezomib ABT-199
22Mantelzell-Lymphom Corvid-19: Empfehlungen der Med. Klinik III Mantelzell-Lymphom: - Chemotherapie zeitgerecht durchführen (agressiv) oder - 1-2 Monate verschieben (indolent)
Follikuläres Lymphom
Klinisches Bild
• ca. 25% aller Lymphome
• mittleres Alter 60-65 Jahre
• ca. 85% Stadium III/IV
• schleichender Verlauf
(mittleres Überleben 15-20 Jahre)
• auch im Rückfall empfindlich auf
ChemotherapieFollikuläres Lymphom m7FLIPI Risiko Score Pastore, Lancet Oncology 2015
Follikuläres Lymphom
Risikoparameter EZH2
Rituximab (R) arm: Obinutuzumab (G) arm:
CHOP/CVP: EZH2 mut
CHOP/CVP: EZH2 mut
Benda: EZH2 wt
Benda: EZH2 mut Benda: EZH2 wt
Benda: EZH2 mut
CHOP/CVP: EZH2 wt
CHOP/CVP: EZH2 wt
CHOP/CVP for EZH2 mut vs wt: HR=0.29, p=0.035 CHOP/CVP for EZH2 mut vs wt: HR=0.15, p=0.032
EZH2 wt for Benda vs CHOP/CVP: HR=0.58, p=0.041 EZH2 wt for Benda vs CHOP/CVP: HR=0.46, p=0.011
Jurinovic, ASH 2019
26Therapie-Richtlinien beim FL (Erstlinie) Therapiealgorithmus Dreyling, EHA/ESMO Guidelines FL 2020
Gallium: G-Chemo vs R-Chemo
Progressions-freies Überleben (FLIPI 2-5)
G
R-Chemotherapie (n=474)
G-Chemotherapie (n=476)
R
Launonen, ICML 2019GaBe: G +/- Chemo)
Studiendesign (Phase II)
GABE STUDIERezidiviertes FL: Copanlisib Ansprechrate Dreyling, Am J Hematol 2020
Alternative C Studiendesign (Phase II)
Follicular lymphoma
GLA Studies 2020
Alternative 1: Alternative 2: GaBe:
G-Ibru G-Copanilisib G +/- Bendamustine
G-Ibru G-Copanlisib G maintenance
maintenance maintenance
Relapse
ReBeL:
FLAZ: BeRT: R2 +/- Benda
ASCT vs. RIT R-BendaTemsirolimus
R-maintenanceFollikuläres Lymphom Corvid-19: Empfehlungen der Med. Klinik III Follikuläres Lymphom: - 1-2 Monate verschieben (indolent)
Acknowledgements
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