Speed-Date: Agressive und Indolente NHL - lymphome · Speed-Date: Agressive und Indolente NHL....
Transcript of Speed-Date: Agressive und Indolente NHL - lymphome · Speed-Date: Agressive und Indolente NHL....
Speed-Date:
Agressive und Indolente NHL
Prof. Dr. M. DreylingMed. Klinik III
Klinikum GrosshadernLMU/München
internet: www.lymphome.de • email: [email protected]
Symposium des KML * DGIM 2020 * 24. April 2020
MZL5%
LPL1%
LL2%
ALCL2%
PMLBCL2%
Burkitt-like2%
PTCL6%
MCL6%
SLL6%
Composite13% DLBCL
31%
FL22%
Armitage, JCO 1998
Aggressive und indolente NHL LymphomeHsitologische Subtypen
McKelvey et al. 1976
• 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
Klinische Charakteristika Diffus großzelliges B-Zell Lymphom
93,94Dunleavy, Hematology 2014
Double Hit LymphomeDiffus großzelliges B-Zell Lymphom
>60 years(fit)
<60 yearsaaIPI=0No Bulk
<60 yearsaaIPI2,3
<60 yearsaaIPI=1
and/or Bulk
4xR-CHOP21 8xR-CHOEP14± RTx Bulk
6xR-CHOP14+2xR
± RTx Bulk
6xR-CHOP21± RTx Bulk
old(non-fit)
R±Vinbl.R±Benda
R-MiniCHOP
Chemotherapie (Erstlinie)Diffus großzelliges B-Zell Lymphom
46Pöschl, Lancet 2020
FLYER: Progressions-freies ÜberlebenDiffus großzelliges B-Zell Lymphom
Treatment plan
7
Copa–R-CHOP: (Phase II)Diffus großzelliges B-Zell Lymphom
Lenz, Leukemia 2020
3 yrs EFS 21%
Coral Trial:relapse after 1st line rituximab
3 yrs PFS 11%
British Columbia Cancer Agency Lymphoid Cancer database:
DLBCL Peripheral T cell Lymphoma
Gisselbrecht, JCO, 2010 Mak, JCO, 2013
Progressions-freies ÜberlebenReziziviertes DLBCL
Safety run-in Randomized Phase
• Safety analysis• Substantial amendment
• Safety analysis after 30 pts in experimental arm
• Interim analysis for efficacy
Reziziviertes DLBCLProgressions-freies Überleben
10
Niveau: R-GemOx +/- NivolumabReziziviertes DLBCL
Held, ASH 2019
Corvid-19: Empfehlungen der Med. Klinik IIIDiffus großzelliges B-Zell Lymphom
Agressive Lymphome: -Chemotherapie zeitgerecht durchführen
Dreyling, ESMO CR 2017
Two kind of diseasesMantle cell lymphoma
Dreyling, ASH 2019
Blastoid, Ki-67>30% oder p53 mutMCL Risikofaktoren
Hermine, Lancet 2016
Time to treatment failureMCL younger
Dreyling, ESMO CR MCL 2017
young patient (<65) elderly patient (>65) compromised patientFirst line treatment
conventionalimmuno-chemotherapy
(e.g. R-CHOP, VR-CAP, BR, R-BAC)
Rituximab maintenance
Best supportive care?R-Chlorambucil
BR (dose-reduced)R-CVP
1. relapseimmuno-chemotherapy
(e.g. R-BAC, BR)or targeted approaches
discuss: - allogeneic SCT
immuno-chemotherapy(e.g. BR, R-BAC)
or targeted approaches
discuss: - Rituximab maintenance- radioimmunotherapy
Immuno-chemotherapy(e.g. BR)
or targeted approaches
higher relapseTargeted approaches: Ibrutinib, Lenalidomide,
Temsirolimus, Bortezomib (preferable in combination)Alternatively: repeat previous therapy (long remissions)
dose-intensifiedimmuno-chemotherapy
(e.g. R-CHOP, high dose Ara-C) ⇒ Autologous SCT
⇒ Rituximab maintenance
Observation3x R-CHOP/ 3x R-DHAP ASCT
2 yrs I-maintenance
2 yrs I-maintenance
R 3x R-CHOP + I/ 3x R-DHAP
3x R-CHOP + I/3x R-DHAP
ASCT Observation
Observation
A:
A + I:
I:
superiority/non-inferiority: time to treatment failureHR: 0.60; 65% vs. 77% vs. 49% at 5 years
R maintenance (3 years)
R maintenance (3 years)
R maintenance (3 years)
TRIANGLE: +/-IbrutinibMCL younger 2
0306090
120150180210240270300330360390420450480510540570600630660690720750780810840870
Jun.
16
Jul.
16Au
g. 1
6Se
p. 1
6O
kt. 1
6N
ov. 1
6De
z. 1
6Ja
n. 1
7Fe
b. 1
7M
rz. 1
7Ap
r. 17
Mai
. 17
Jun.
17
Jul.
17Au
g. 1
7Se
p. 1
7O
kt. 1
7N
ov. 1
7De
z. 1
7Ja
n. 1
8Fe
b. 1
8M
rz. 1
8Ap
r. 18
Mai
. 18
Jun.
18
Jul.
18Au
g. 1
8Se
p. 1
8O
kt. 1
8N
ov. 1
8De
z. 1
8Ja
n. 1
9Fe
b. 1
9M
rz. 1
9Ap
r. 19
Mai
. 19
Jun.
19
Jul.
19Au
g. 1
9Se
p. 1
9O
kt. 1
9N
ov. 1
9De
z. 1
9Ja
n. 2
0Fe
b. 2
0M
rz. 2
0Ap
r. 20
Mai
. 20
Jun.
20
Jul.
20Au
g. 2
0Se
p. 2
0O
kt. 2
0N
ov. 2
0De
z. 2
0Ja
n. 2
1Fe
b. 2
1M
rz. 2
1Ap
r. 21
Mai
. 21
Jun.
21
Jul.
21
Planned randomization Actual randomization
Patients randomized: 563
TRIANGLE: +/-Ibrutinib
MCL younger 2
PFS OS
Group5-year rate 95% CI
R 79% 67%-86%IFN 59% 48%-69%
Group5-year rate 95% CI
R 51% 40%-62%
IFN 22% 14%-32%
Kluin-Nelemans, JCO 2019
R-CHOP +/- R maintenaceMCL elderly
Ruan, Blood 2019
36 33 30 28 23 16 12 2Number at risk
0 10 20 30 40 50 60 70Months from Treatment
Progression-Free Survival
0.00
0.25
0.50
0.75
1.00
Prob
abilit
y of
pro
gres
sion
free
surv
ival
36-month PFS = 80.3% (95% CI = 63.0%, 90.1%)48-month PFS = 70.6% (95% CI = 52.0%, 83.1%)
Median follow-up = 61 months (range 21-74)
38 37 36 34 33 26 19 7 0Number at risk
0 10 20 30 40 50 60 70 80
Months from Treatment
Overall Survival
36-month OS = 91.9% (95% CI = 76.9%, 93.7%)48-month OS = 83.0% (95% CI = 65.9%, 92.0%)
Median follow-up = 61 months (range 21-74)
Rituximab-LenalidomidMCL Erstlinientherapie
1st line induction: 8x R-CHOP
PR/CR~80% ®
Rituximab maintenance
Rituximab maintenance+ Lenalidomide
15 mg daily d1-21, q28 days
Treatment: max. 2 years
sponsor: LYSARCcentral pathology: W. KlapperMRD diagnostics: M. Ladetto, C. Pott, MH Delfau
1st line induction: 6x R-CHOP/Ara-C
®
StudiendesignMCL elderly R2
RekrutierungMCL elderly R2
22
European MCL NetworkStudy generation 2019
< 65 years > 60 years
R-HAD +/- Bortezomib
RelapseIbrutinib +/-
ABT-199Ibrutinib/
Bortezomib
MCL elderly R2:R-CHOP vs R-CHOP/Ara-C
=> Rituximab M+/- Lenalidomide
MCL younger:R-CHOP/DHAP =>ASCT
R-CHOP/DHAP+I =>ASCT => IR-CHOP/DHAP + I => I
MCL elderly I:BR +/- Ibrutinib=> Rituximab M
+/- Ibrutinib
> 65 years
Corvid-19: Empfehlungen der Med. Klinik IIIMantelzell-Lymphom
Mantelzell-Lymphom: - Chemotherapie zeitgerecht durchführen (agressiv) oder - 1-2 Monate verschieben (indolent)
• 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
Chemotherapie
Follikuläres LymphomKlinisches Bild
Pastore, Lancet Oncology 2015
Follikuläres Lymphomm7FLIPI Risiko Score
26
Benda: EZH2 wt
CHOP/CVP: EZH2 wt
CHOP/CVP: EZH2 mut
Benda: EZH2 mut
CHOP/CVP: EZH2 wt
CHOP/CVP: EZH2 mut
Benda: EZH2 mutBenda: EZH2 wt
Rituximab (R) arm: Obinutuzumab (G) arm:
CHOP/CVP for EZH2 mut vs wt: HR=0.29, p=0.035
EZH2 wt for Benda vs CHOP/CVP: HR=0.58, p=0.041
CHOP/CVP for EZH2 mut vs wt: HR=0.15, p=0.032
EZH2 wt for Benda vs CHOP/CVP: HR=0.46, p=0.011
Jurinovic, ASH 2019
Follikuläres LymphomRisikoparameter EZH2
Therapie-Richtlinien beim FL (Erstlinie)
Dreyling, EHA/ESMO Guidelines FL 2020
Therapiealgorithmus
R-Chemotherapie (n=474)G-Chemotherapie (n=476)GR
Launonen, ICML 2019
Gallium: G-Chemo vs R-ChemoProgressions-freies Überleben (FLIPI 2-5)
GABE STUDIE
GaBe: G +/- Chemo)Studiendesign (Phase II)
Dreyling, Am J Hematol 2020
Rezidiviertes FL: CopanlisibAnsprechrate
Alternative CStudiendesign (Phase II)
BeRT:R-BendaTemsirolimus
ReBeL:R2 +/- Benda
R-maintenance
Relapse
GaBe:G +/- Bendamustine
G maintenance
Follicular lymphomaGLA Studies 2020
Alternative 2:G-Copanilisib
G-Copanlisibmaintenance
FLAZ:ASCT vs. RIT
Alternative 1:G-Ibru
G-Ibrumaintenance
Corvid-19: Empfehlungen der Med. Klinik IIIFollikuläres Lymphom
Follikuläres Lymphom:- 1-2 Monate verschieben (indolent)
Acknowledgements