Speed-Date:

Agressive und Indolente NHL

Prof. Dr. M. DreylingMed. Klinik III

Klinikum GrosshadernLMU/München

internet: www.lymphome.de • email: lymphome@medizin.uni-koeln.de

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

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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