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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
4
淋巴癌 分類淋巴癌 分類
6
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
7
Lymphoma Response Lymphoma Response CriteriaCriteria
Invisible: CRVery small but no biopsy: CRu <0.7: PR
0.7~1.2: SD
>1.2: PD
8
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
9
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%
10
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
12
CytogeneticsCytogenetics t(11;14)(q13;q32): deregulated expression of
cyclin D1.MM~20-30% of casesMCL~virtually all cases
13
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
14
Rituximab (Meta-analysis)Rituximab (Meta-analysis)
J Natl Cancer Inst 2007;99: 706 – 14
Response rateResponse rate
Overall survivalOverall survival
17
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
18
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
19
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%
22
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
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
25
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%
29
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%
30
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%
32
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
34
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
35
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
36
(%)
(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
37
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
38
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
39
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
41
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
42
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
Recommended