Mantle Cell LymphomaMantle Cell LymphomaJan 7 2009林建廷

台灣血液癌症發生率在增加台灣血液癌症發生率在增加

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正常淋巴器官正常淋巴器官 // 組織組織 約有 600個淋巴結

只有少數位於表淺處可摸到，例如：頸部、腋下和鼠蹊部

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淋巴癌 分期淋巴癌 分期若只有一群淋巴節受侵犯則為第一期有多群淋巴節受侵犯但皆在橫膈膜的同一側則為第二期

若受侵犯的淋巴結分佈跨越橫隔膜則為第三期而若有肝臟，骨髓或兩個以上之非淋巴器官受侵犯則為第四期

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淋巴癌的分期要做哪些檢查淋巴癌的分期要做哪些檢查 ??

抽血X 光

CT骨髓

( 正子攝影 PET/CT)

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淋巴癌 分類淋巴癌 分類

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淋巴癌

何杰金淋巴癌~10% 非何杰金淋巴癌~90%

T/NK 淋巴癌~20% B 淋巴癌~80%

低惡性度B 淋巴癌 中惡性度B 淋巴癌 高惡性度B 淋巴癌

Follicular lymphomaMALToma

SLVLCLLMM

DLBCLMantle cell lymphoma Burkitt lymphoma

非何杰金淋巴癌的治療非何杰金淋巴癌的治療——簡要版簡要版低惡性度 中惡性度 高惡性度

容易消但不易根治所以常反覆覆發

不容易消但一旦消了表示根治機會大

治療效果差危險性高

要懂得與病和平共存

追求治癒 治療大致上比照急性白血病

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Lymphoma Response Lymphoma Response CriteriaCriteria

Invisible: CRVery small but no biopsy: CRu <0.7: PR

0.7~1.2: SD

>1.2: PD

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Mantle cell lymphomaMantle cell lymphoma6% of NHL (2-3/100,000yrs)~3,000 new cases/yr

in USM:F=3:1, Median age 63

B-symptoms 33%Generalized LAD 90%

Extranodal involvement 80%, ~GI tract 9-20%80-90% stage III/IV, ~BM involved 64%,

~Splenomegaly 60%

Median OS: 3 - 4 yrsWHO classified as indolent and aggressive

◦ 25% behavior as indolent (unable to predict)◦ 75% behavior as aggressive

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5-yr Overall Survival5-yr Overall Survival

Blood 1997 Jun 1;89(11):3909-18

T-ALCLMALTomaFL

Marginal zone, nodalLymphoplasmacytoidSLL

BurkittsDLBC

MCL (27%)T-lymphoblasticPTCL

30-49%

>70% 50-70%

<30%

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HistologyHistology Lymphocytes in the primary

lymphoid follicles and mantle zones of secondary follicles

Histologic progression is common, transformation rare

Express◦ Cyclin D1◦ CD19, CD20, CD22◦ CD5◦ BCL-2◦ CD79a, FMC7◦ Surface IgM / IgG

Negative ◦ CD10◦ CD23

Palutke M et al. Blood 1996 June;87(11):4483

Diffuse~45%Diffuse~45%

Harris, N. L. ASH Image Bank 2002;2002:100367

Nodular~30%Nodular~30%

JCO 1997;15 (4):1664

Mantle Zone~25%Mantle Zone~25%

CD148 is a potential marker D/D MCL(+)/CLL(-)ASH 2008, Miguet et al, Abstract 1766 11

Blastoid Variant CytologyBlastoid Variant CytologyClassic MCL CytologyClassic MCL Cytology

HistologyHistology

Blastoid variant LNBlastoid variant LN

Kadin, M. ASH Image Bank 2003;2003:100610Maslak, P. ASH Image Bank

2004;2004:101031

Blastoid Variant BloodBlastoid Variant Blood

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CytogeneticsCytogenetics t(11;14)(q13;q32): deregulated expression of

cyclin D1.MM~20-30% of casesMCL~virtually all cases

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Mantle Cell Lymphoma: Mantle Cell Lymphoma: BiologyBiology

Cell cycleDNA damage response

(> 80% MCL have secondary alterations)

INK4/ARF

DNArepair

Apoptosis

Deletion 11q22-23Mutations ATM locus

ATMATR

p21 G1/S arrestDeletion 17q/mutation p53

G1

S

G2

M

RB1

RB1 P

cdk4/cyclin D1

p16

p14 Stabilization of p53

Deletion 9q21

G1/S arrest

p53p27

MDM2

CHK1-2

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Clinical risk factors: MIPI clinical

(PALL: PS, age, LDH, leucocyte count) Hoster, Blood 2008 15

Mantle cell lymphoma Mantle cell lymphoma treatmenttreatment

Rituximab (Meta-analysis)Rituximab (Meta-analysis)

J Natl Cancer Inst 2007;99: 706 – 14

Response rateResponse rate

Overall survivalOverall survival

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First Line Induction First Line Induction RegimensRegimens

Standard ~R-CHOP ◦ Woward, CR=48%, PFS=16.6m◦ GLSG, CR=34%, PFS=15m

Intensive ~ R-HyperCVAD/R-MTX-AC◦ MDACC, CR=87%, FFS=not reached (67%@3yr)

~Maxi-CHOP/HDAC (Nordic-2) CR=54%, PFS=not reached

(66%@6yr)

Purine analog ~R-FCM

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Lenz, G. et al. J Clin Oncol; 23:1984-1992 2005

Time to Treatment Failure

R-CHOP vs CHOP (GLSG R-CHOP vs CHOP (GLSG trial)trial)

CR (%)ORR (%)

TTF (m) 2 yr PFS 2 yr OS

CHOP 7 75 14~25% 77%

R-CHOP 34 94 21

P value 0.00024 0.0054 0.0131 0.31 0.93

OS

86% vs 82%@2yrs

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OS of GLSG OS of GLSG (1996-2004) (1996-2004) vs KLSG vs KLSG (1975-(1975-1986)1986)

4.8 yrs vs 2.7 yrs

Hermann et al, Published Ahead of Print on December 15, 200820

Phase 2 R-HyperCVAD/R-MTXAC Phase 2 R-HyperCVAD/R-MTXAC (MDACC)(MDACC)

29% pts not complete scheduled C/T cyclesPoor prognostics = >65yo, high LDH, lack of GI involvement,

B2>3mg/L8 deaths and 4 t-AML/MDS

Romaguera et al. JCO 2005 Oct 1;23(28):7013-2321

day 1 day 21

alternate cycles 1 and 2 Q21D

Romaguera, J. E. et al. J Clin Oncol; 23:7013-7023 2005

R-HyperCVAD/R-MTXAC R-HyperCVAD/R-MTXAC (MDACC)(MDACC)

OS 82%@3 yrs FFS 64%@3 yrs

CR=87%, ORR=97%

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R-HyperCVAD/R-MTXAC R-HyperCVAD/R-MTXAC (MDACC)(MDACC)Too toxic! TRM~8%

Romaguera, J. E. et al. J Clin Oncol; 23:7013-7023 200523

Mantle cell lymphoma Mantle cell lymphoma and transplantationand transplantation

Upfront ASCT: European MCL Upfront ASCT: European MCL NetworkNetworkPhase 3 trialPhase 3 trial

Dreyling et al, Blood, 2005, Vol. 105, No. 7, pp. 2677-2684

61% CHOP; 26% R-CHOP

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PFS Benefit, no OS BenefitPFS Benefit, no OS Benefit

Dreyling et al, Blood, 2005, Vol. 105, No. 7, pp. 2677-268426

Upfront ASCT: Nordic-1 vs Upfront ASCT: Nordic-1 vs Nordic-2Nordic-2Phase 2CR=54%, ORR=96%NRM~5%

Geisler et al, Blood. 2008;112:2687-269327

Upfront ASCT: Nordic-1 vs Upfront ASCT: Nordic-1 vs Nordic-2Nordic-2PFS: 66%@6yrs, No relapse after

5 yrsOS: 70%@6yrs

Geisler et al, Blood. 2008;112:2687-269328

Retrospective EBMT and ABMT Registry Retrospective EBMT and ABMT Registry supports ASCT in CR1supports ASCT in CR1

195 patients (new diagnosis and relapsed)Chemotherapy: varied/not reportedConditioning regimens: variedPts not transplanted in CR1 were 3x more likely to

die from MCLMedian survival 59 months

*Vandenberghe, E., Ruiz, C., et al., BJH 2002120:793

2yr PFS 2yr OS 5yr PFS 5yr OS

All patients 55% 76% 33% 48%

CR1 Patients

65% 88% 52% 65%

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EBMT Registry ASCT improves OS in EBMT Registry ASCT improves OS in CR1CR1

*Vandenberghe, E., Ruiz, C., et al., BJH 2002120:793

Patients transplanted in CR12 year PFS: 65% 5 year PFS: 52%2 year OS: 88% 5 year OS: 65%

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ASCT in CR1: OS by BASCT in CR1: OS by B22 Microglobulin Microglobulin

0 10 20 30 40 50 60 70 80Months Post Transplant

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cu

mu

lati

ve

Pro

po

rtio

n

Su

rviv

ing

P = 0.0001

B2 > 3 (N=9)

B2< 3 (N=18)

Khouri et al. Cancer 98:2630-2635, 200331

The MD AndersonThe MD Anderson11 and Fred and Fred HutchinsonHutchinson22 Experience Experience

Allo may have a role as salvage in MCL

Differed by conditioning regimen

1. Khouri, I., Lee,M., et al., JCO 2003;21(3):44072. Maris, M., Sandmaier, B., et al., Blood 2004;104(12):3535

nMedian f/u

(Months)ORR CR

Measurable dz

at transplantOutcome

MDA1 18 26 89% 94% 9Est 3yr OS 86%

Est 3yr PFS 82%

FHCRC2 33 24.6 85% 75% 202yr OS 64%

2yr PFS 60%

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Novel AgentsNovel Agents•Proteosome inhibitors•Mammalian target of rapamycin (mTOR) inhibitors•Thalidomide

Relapsed MCLRelapsed MCLRegimen N % CR % PR %

ORRForan[19] Rituximab 35 14 23 37Gressin[20] VAD +Chlorambucil* 30 43 30 73Kaufmann[21] Rituximab+thalidomide 16 31 50 81Dang[22] Ontak 8 12.5 25 37.5Cohen[23] Cyclophosphamide+fludarabine 30 30 33 63Goy[24] Bortezomib 29 21 21 42O'Connor[25] Bortezomib 11 9 36 45McLaughlin[26] Fludarabine+mitoxantrone+dexamethason

e5 20 80 100

Seymour[27] Fludarabine+cisplatin+cytarabine 8 88

Forstpointner[28] Fludarabine+cyclophosphamide+mitoxantrone

24 0 46 46

Forstpointner[28] Fludarabine+cyclophosphamide+mitoxantrone+rituximab

24 29 29 58

Levine[29] Fludarabine+mitoxantrone+rituximab 5 80 0 80Rummel[30] Bendamustine+rituximab 16 50 25 75Fisher[31] Bortezomib 141 8 25 33Robak[32] 2-CdA+rituximab or rituximab with

cyclophosphamide9 22 45 67

Rupolo[33] Rituximab+oxaliplatin+cytarabine 9 NA NA 100Drach[34] Rituximab+bortezomib+dexamethasone 12 25 50 75Wang R-HyperCVAD/R-MTXAC 29 45 48 93

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2 Line-- Single Agent 2 Line-- Single Agent BortezomibBortezomib

Phase 2 studies in relapsed MCLVelcade 1.3~1.5mg/m2 days 1,4,8,11

Q21DN CR PR SD PD Outcome

Median follow-

up

PINNACLE1 141 8% 25% 40% 10%OS NR

DOR 9.2mTTP 6.2m

13.4m

MSKCC2 10 10% 40% 40% 10% DOR 6-19m

MDACC3 29 20.5% 20.5% 20.5% 38% PFS 42%@6m 9.3m

Strauss4 24 4% 25%

Belch5 28 4% 42% TTP 12.5m

1. Fisher R et al. JCO 2006;24:early release online 10.1200/JCO.2006.07.9665

2. O’Connor, O., Wright, J., et al., JCO 2005; 23(4):6763. Goy, A., Young, A., et al., JCO 2005;23(4):6674. Strauss et al, JCO 20065. Belch et al, Ann Onc 2007

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Bortezomib 1.3 mg/m2 D1, 4, 8, 11

Q21D

CR or CRuContinue treatment

for 4 cycles beyond initial documentation, up to 17 cycles

PR or SDmaxi 17 cycles

PDDiscontinue

EVALUATE

PINNACLE

Enroll completed in June 2005 (N = 155)35 centers in the US, UK and Germany

Fisher et al. JCO 2006; 24: 4867-4874

Phase 2 PINNACLEPhase 2 PINNACLE

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(%)

(5/19)8/29Prior radioimmunotherapy / radiation therapy

(37)

(91)

(100)

(96)

(97)

(98)

(4)

(42)

(54)

NParameter

58Prior high intensity therapy*

141 All 3 of the above

155 At least 2/3 of the above

149 Rituximab

150 Alkylating agents

152 Anthracycline/mitoxantrone

Received prior regimen containing

6 3

65 2

84 1

No. of prior lines of therapy for MCL

*High-intensity regimens defined as stem cell transplant, Hyper-CVAD/ICE/ESHAP/DHAP; all ± rituximab

Fisher et al. JCO 2006; 24: 4867-4874

Phase 2 PINNACLEPhase 2 PINNACLE

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Important ThingsImportant ThingsCR rate=8%ORR rate=33%Median time to response: 1.3m (2

cycles)

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

MCL All Patients

Follicular Lymphoma

Median Time to First Response

MCL = 5 weeks (~2 cycles)

Follicular = 11 weeks (~ 4 cycles)% P

ts R

esp

on

din

g

Time (weeks)

Time to First Response

O’Connor et al. JCO 2005O’Connor et al. ICML 2005

Fisher et al. JCO 2006; 24: 4867-4874

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Weigert et al, Germany, Leukemia (2007) 21, 524–528

Bortezomib is Synergistic with Bortezomib is Synergistic with CytarabineCytarabine

Case 1: B 1.5mg/m2, D1, D4

Ara-C 1000mg/m2, D2, D3 /Q21D

Case 2: B 1.5mg/m2, D1, D4

Ara-C 1000mg/m2, D2, D3

Rituximab 375mg/m2, D0 /Q28D

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Bortezomib is Synergistic with Bortezomib is Synergistic with Rituximab/ Cyclophosphamide in Rituximab/ Cyclophosphamide in vitro and in vivovitro and in vivo

Wang et al, MDACC, Leukemia (2008) 22, 179–18540

Bortezomib Combination in Bortezomib Combination in MCLMCL

Study Bortezomib RegimenEvaluable

Patients (n) CR PR ORR Outcome

Blum(ASH 2006)

Bortezomib + Rituximab 6 33% - 33%

Drach

(ASH 2006)

Bortezomib + Rituximab + Dex

(BoRiD))16 19%* 56% 75% PFS 9m

Weigert(ASH 2006)

Bortezomib + Cytarabine + Dex +/-

Rituximab4† 25% 75%

100%

* All PET- negative; †evaluable following 4 cycles

Blum et al. ASH 2006, abstract # 2768

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2-Line Single Agent Temsirolimus 2-Line Single Agent Temsirolimus (Torisel)(Torisel)Phase 2

Dose N CR PR SD PD Outcome

Witzig (Mayo Clinic)1

250mgweekly

34 3% 35% 40%TTP=6.5mDOR=6.9m

Ansell (Mayo Clinic)2

25mg weekly

27 4% 37%TTP=6mDOR=6m

1.JCO. 2005 Aug 10;23(23):5347-562. Cancer. 2008 Aug 1;113(3):508-14

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2-Line Single Agent Temsirolimus 2-Line Single Agent Temsirolimus (Torisel)(Torisel)

Phase 3N CR PR SD PD Outcome

T 175mg QW*3, then 75mg QW

54 2% 20% PFS=4.8mDOR=7.1mOS=13.6m

T 175mg QW*3, then 25mg QW

54 0 6% PFS=3.4mDOR=3.6mOS=10.0m

Investigator’s choice

54 2% 0 PFS=1.9mNAOS=9.7m

ASCO 44th annual meeting, 2008 Jun 43

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

First line

conventionalR-chemo

(e.g. R-CHOP)

Rituximab maintenance ?radioimmunotherapy ?

watch & wait ?Rituximab

monotherapyChlorambucilBendamustin

First relapse

High tumor load:R-chemo

(e.g. R-FC)

allo-transplant ?radioimmunotherapy ?

Rituximab maintenance ?

R-chemo(e.g. R-FC,

R-Bendamustin)

molecular approaches ASCT

radioimmunotherapy ? Rituximab maintenance ?

R-chemo(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-intensifiedR-chemo

(either sequential:

e.g. R-CHOP =>ASCTor R-HyperCVAD/MTXAC)

Dreyling ASCO 2006 44

NCCN 2008 V3NCCN 2008 V3

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