Mantelzell-Lymphom-

Aktuelle Standards

und Studienkonzepte

M. Dreyling, Dept. of Medicine III

Klinikum GrosshadernLMU/München

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

Symposium des KML * DGHO 2008 * Wien, 13. Oktober 2008

Mantle cell lymphoma (MCL)

• Morphology: small to intermediate size lymphoidcells with irregular, cleaved nuclei,cave: round cell, blastoid and pleomorphic variants

• Immunphenotype: sIg++, l > k , CD19/20/22+, CD5+, CD10-, CD23-, CD11c-, HLA-DR++, CD43+

• molecular/cytogenetics: t(11;14)(q13;q32); overexpression of cyclin D1

• clinical outcome: predominantly elderly, male patients,extranodal involvement,late stage, poor outcome

20%

83%

W. Ludwig, Berlin

Clinical risk factors: MIPI clinical

(PALL: PS, age, LDH, leucocyte count) Hoster, Blood 2008

young patient (<65) elderly patient (>65) compromised patient

First line treatment

conventionalimmuno-chemotherapy

(e.g. R-CHOP)

Rituximab maintenance ?radioimmunotherapy ?

watch & wait ?Rituximab

monotherapyChlorambucilBendamustin

1. relapse

high tumor load:immuno-chemotherapy

(e.g. R-FC)

allo-transplant ?radioimmunotherapy ?

Rituximab maintenance ?

immuno-chemotherapy(e.g. R-FC,

R-Bendamustin)

molecular approaches ? autologous PBSCT

radioimmunotherapy ? Rituximab maintenance ?

immuno-chemotherapy

(e.g. R-Bendamustin)

molecular approaches

higher relapse

molecular approaches: Bortezomib, CCI-779, Thalidomide/Lenalidomide, Flavopiridol (preferable in combination)

repeat previous therapy (long remissions)

dose-intensifiedimmuno-chemotherapy

(either sequential: e.g. R-CHOP =>PBSCT

or R-Hyper-CVAD)

Dreyling ASCO 2006

day 1 day 21

Rituximab + HyperCVAD/M-A in MCL

alternate cycles 1 and 2 every 21 days

Rituximab 375mg/m2 (day 1)

Methotrexate 200mg/m2 i.v. 2 hours (day 2)

Methotrexate 800mg/m2 i.v.continuous 22 h (day 2)

Cytarabine 1,000/3,000mg/m2 i.v. 2x 2h (days 3–4)

cycle 1, 3, 5, 7

R-hyperCVADcycle 2, 4, 6, 8

R-M-A

antifungal, antibacterial, antiviral prophylaxis: G-CSF !!!

Romaguera, JCO 2005

Mantle cell lymphoma

R-Hyper-CVAD

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5Years from Registration

At Risk

49

Progression

or Death

13

1-Year

Estimate

89%

Progression-free survival

Epner ASH 2007 #387

Mantle cell lymphoma

R-CHOP/High dose Ara-C => ASCT

B: Survival

0.0 2.5 5.0 7.5 10.00

20

40

60

80

100

MCL1 (n=41)P<0.001

MCL2 (n=160)

Years

Per

cen

t su

rviv

al

A: Event-free Survival proportions

0.0 2.5 5.0 7.5 10.00

20

40

60

80

100

MCL1 (n=41)

MCL2 (n=160)

P<0.0001

Years

Per

cen

t su

rviv

al

Geisler Blood 2008

European MCL Network

patients <65 years

PR, CR!

Cyclo 120mg/kg+ TBI 12 Gray

PBSCT

PR, CR!

3 x R-CHOP3 x R-DHAPalternating

(stem cell mobilization after

course 4)

PBSCT

TBI 10 GrayAra-C 4 x 1.5 g/m2

Melphalan 140 mg/m2

3 x R-CHOP

DexaBEAM(stem cell mobilization)

3 x R-CHOP

MCL Younger Response rate of induction

Documented response 189 55%

Abort without staging 2

CR 59 31%

CRu 40 21% CR+CRu: 52%

PR 73 39% CR+CRu+PR: 91%

SD 8 4%

PD 9 5%

ED 0 0%

MCL younger

Time to treatment failure

young patient (<65) elderly patient (>65) compromised patient

First line treatment

conventionalimmuno-chemotherapy

(e.g. R-CHOP)

Rituximab maintenance ?radioimmunotherapy ?

watch & wait ?Rituximab

monotherapyChlorambucilBendamustin

1. relapse

high tumor load:immuno-chemotherapy

(e.g. R-FC)

allo-transplant ?radioimmunotherapy ?

Rituximab maintenance ?

immuno-chemotherapy(e.g. R-FC,

R-Bendamustin)

molecular approaches ? autologous PBSCT

radioimmunotherapy ? Rituximab maintenance ?

immuno-chemotherapy

(e.g. R-Bendamustin)

molecular approaches

higher relapse

molecular approaches: Bortezomib, CCI-779, Thalidomide/Lenalidomide, Flavopiridol (preferable in combination)

repeat previous therapy (long remissions)

dose-intensifiedimmuno-chemotherapy

(either sequential: e.g. R-CHOP =>PBSCT

or R-Hyper-CVAD)

Dreyling ASCO 2006

European MCL network studies

patients >60 years

4 x R-CHOP

PR, CR

IFN-α maintenance(3 x 3 M IU/week)

or Peg-IFN(1mg/kg week)

4 x R-CHOP

PR, CR

3 x R-FC

Rituximabmaintenance

(all 2 months)

3 x R-FC

MCL Elderly

Response rate of induction

Documented Response 164 50%

Abort without staging 6

CR 55 35%

CRu 26 16% CR+CRu: 51%

PR 51 32% CR+CRu+PR: 84%

SD 5 3%

PD 19 9%

ED 6 4%

MCL elderly

Time to treatment failure

51 events

MCL elderly

Response duration in CR

4 events

young patient (<65) elderly patient (>65) compromised patient

First line treatment

conventionalimmuno-chemotherapy

(e.g. R-CHOP)

Rituximab maintenance ?radioimmunotherapy ?

watch & wait ?Rituximab

monotherapyChlorambucilBendamustin

1. relapse

high tumor load:immuno-chemotherapy

(e.g. R-FC)

allo-transplant ?radioimmunotherapy ?

Rituximab maintenance ?

immuno-chemotherapy(e.g. R-FC,

R-Bendamustin)

molecular approaches ? autologous PBSCT

radioimmunotherapy ? Rituximab maintenance ?

immuno-chemotherapy

(e.g. R-Bendamustin)

molecular approaches

higher relapse

molecular approaches: Bortezomib, CCI-779, Thalidomide/Lenalidomide, Flavopiridol (preferable in combination)

repeat previous therapy (long remissions)

dose-intensifiedimmuno-chemotherapy

(either sequential: e.g. R-CHOP =>PBSCT

or R-Hyper-CVAD)

Dreyling ASCO 2006

Bortezomib: Mechanism of action

26S proteasome:

degrades tagged proteins

Bortezomib:

reversible inhibitor

of the proteasome

Inhibition:prevents proteolysis of tagged proteins

Clinical studies: bortezomib cytotoxic to a variety of lymphomas !

Weigert Leukemia 2007

Bortezomib Ara-C combination in MCL

Efficacy in vitro

Weigert, ASH 2006

Bortezomib Ara-C combination in MCL

Pilot phase

European MCL network

relapsed MCL (DHAB = R-HAD)

Patients: n=250, relapsed MCL after/not appropriate for autologous PBSCT

Therapy: Dexamethasone 40 mg day 1-4 Rituximab 375 mg/m2 day 1 Ara-C 2 x 1–2 g/m2 day 2+/-Bortezomib 1,5 mg/m2 day 1, 4

Study aim: - Response rate- Progression-free/overall survival- Toxicity/feasability

Mantle cell lymphoma

Lenalidomide

HistologyPT

InitiBest

ResponseDay 4

Day 5

Day 20

Day 30

Day 50

Day 51

Day 53

Day 54

Day 58

Day 75

Day 89

Day 91

Day 104

Day 106

Day 108

Day 116

Day 117

Day 122

Day 135

Day 140

Day 170

Day 190

Day 222

Day 229

Day 239

Day 272

Day 373

FCL SB CRu 15 10

DLC BS Cru

DLC TP Cru 20

DLC KJS Cru 20

MCL SLR PR 20 15 10

MCL VFG PR 20 15

FCL GO PR

MCL BMF PR 20

DLC CD PR 20 15 10

MCL JMP PR 20

MCL LMM PR

TSF RE PR 20

MCL ERD PR

TSF KBA SD 20

DLC RA SD

DLC BP SD

DLC LG SD

MCL ET SD 20 15

DLC GAW SD

MCL GHM XPD 20

DLC OWF XPD 20 15

DLC JET XPD

DLC PC XPD

DLC RB XPD

MCL MR XPD

MCL TF XPD

DLC JAL XPD

MCL JES XPD

DLC RF XPD

DLC AD XPD

FCL RCS XPD

MCL FG XPD

CruPRSDPD

Wiernik ASH 2006

Feasability and efficacy of Lenalidomide maintenance after prior immuno-chemotherapy induction in relapsed

or refractory mantle cell lymphoma

Inclusion Criteria• Histologically proven MCL

• Not eligible / relapse after ASCT

• > 1 prior chemotherapy

RecruitmentN=60

Response

PD or Toxicity

Endpoints• Feasability• Duration of Response• TTP and PFS• OS• Safety

Salvage Therapy

R-FC(M)R-DHA(P)R-GemOx

Lenalidomide 15mg p.o/d

daily

Staging PR, CR

National centers: Essen, Homburg, Kiel, Mainz, GH-LMU, Tübingen, Ulm

European MCL Network

clinical intergroup working party

molecular markers

pathological review

virtual tumor bank

WHO/ Kiel criteria

pathology panel

phase III studies (first line)

phase II studies (relapse)

remission/survival data

immunostaining ofmolecular markers

central data base:analysis of predictive and prognostic risk factors

MRD/cytogenetics

pharmacogenomics

expression profiling

new molecular markers

patientblood sample

molecularanalysis

signal pathway of resistance

MRD

www.european-mcl.net

R-CHOP vs. R-FC

anti-CD20 vs. IFN

„Mini“ transplant

< 65 years > 65 years

R-CHOP vs. R-CHOP/DHAP

PBSCT

R-chemo +/- Bortezomib

1. Relapse < 65 years> 65 years

European MCL Network: Clinical studies 2008/9

2. Relapse (or not qualifying for R-HAD)

First line

Bendamustin/Temsirolimus

Radio-immuno

consolidation

Lenalidomide consolidation

Rad 001(mTOR)

www.european-mcl.net