DLBCL, FL

1

• DLBCL, FL
• ??????????
• ?????????? ???
• ?????????

2
WHO???????? (2008)
????
HL?PTLD

• B ????????/???
• B ????????/???,NOS
• B ????????/???,????????????
• B ????????/???,??t(922)(q34q11.2) BCR-ABL1
• B ????????/???,??t(v11q23) MLL ??
• B????????/???,??t(1221)(p13q22) TEL-AML1
  (ETV6-RUNX1)
• B ????????/???,??????
• B ????????/???,??????(????ALL)
• B ????????/???,??t(514)(q31q32) IL3-IGH
• B ????????/???,??t(119)(q23p13.3) E2A-PBX1
  (TCF3-PBX1)
• T????????/???

???B??
??T/NK??
??B??

• ?????????/????????
• ?B?????
• ???????
• ??????
• ????/???,???
• ???????B?????
• ??????-???
• ????????
• ????????
• ???
• Alpha???
• Gamma???
• Mu???
• ????
• ?????????
• ??????
• ???????????????? (MALT???)
• ????????
• ??????????

• ??????
• ???B????? (DLBCL),NOS
• ??T/??????B?????
• ??????????DLBCL
• ??????DLBCL,??
• ???EB?????DLBCL
• ????????DLBCL
• ???????
• ?????(??)??B?????
• ????B?????
• ALK????B?????
• ????????
• HHV8????B????? ? ??Castleman ?
• ?????????
• ??????
• B?????,?????,,???????B?????????????????
• B?????,?????,???????B?????????????????

• ?T?????
• ???T???????
• NK??????????????
• ???NK?????
• ?????EB?????T?????????
• ???????
• ??T?????/???
• ??NK/T?????,??
• ??????T?????
• ??T?????
• ??????T?????
• ?????
• Sézary ???
• ??????CD30???T???????
• ???????
• ???????????????
• ???????d T?????
• ??????CD8?????????????T?????
• ??????CD4???/??T?????

• ??????
• ???????????????
• ????????
• ?????????????
• ???????????????
• ?????????????
• ???????????????
• ???????????? (PTLD)
• ????
• ?????
• ??????????PTLD
• ??? PTLD
• ????? PTLD (B- ?T/NK-???)
• ??????????PTLD

3
??10?8?NHL-B?????????
??????????????
4
Major subtypes , SYSUCC

• DLBCL 39.5
• PTCL 18.6
• NK/T 5.8
• FL 5
• MCL 2.7
• total 71.6

5
NHL ??

• ????
• ?????
• ??
• ????????
• ???? (??)
• ???????????
• ????????
• ???????
• ?????????
• ?????????????
• ????????/FISH???????

FISH ?????? National Comprehensive Cancer
Network. Practice Guidelines in Oncology. v.2.
2006.
6
?????

• ??????,???????????
• ???? (FNA) ????????????,???????????????
• ???????
• ???????,????????????
• FNA???????????????

7
????????????

• ????
• CD20?CD79?CD10?BCL2?BCL6?MUM1?CD21?CD23?CyclinD1
  (??????D1)
• CD2?CD3?CD5?CD7?CD4?CD8?CD56
• MIB1(Ki67)?kappa/lambda?CD138?CD30?ALK-1?EBER
• ?????
• CD45?CD19?CD20?CD23?CD5?CD3?CD10?FMC7
• CD3?CD4?CD8?CD56
• ZAP70?CD38?CD30

8

• 1.???B?????

9
???B?????(DLBCL)

• ??????NHL,???NHL?30-40
• ??????????
• ??????50-60?
• ???????40
• ??????,?50???

10

• ????

11
?????? (IPI)
?????
????? ?????
5?DFS ()
5? OS ()
??
????
??
gt60?
??????
2
?
0-1
70
73
LDH
gt??
?/?
2
50
51
??????
2
?/?
3
49
43
?
4-5
40
26
??
III-IV
??????
?????
????? ?????
5?OS ??gt60 ()
5?OS ??60 ()
????
??
??????
2
?
0
56
83
LDH
gt??
?/?
1
44
69
??
III-IV
?/?
2
37
46
?
3
21
32
The International Non-Hodgkin's Lymphoma
Prognostic Factors Project. N Engl J Med.
1993329987-994.
12
DLBCL ???????
13
???????????????

• DNA ????????????????

High
1.0
Level of geneexpression
Low
Germinal-centerB-celllike
0.5
Probability
Type 3
ActivatedB-celllike
0.0
0
2
4
6
8
10
Overall survival (years)
Rosenwald A et al. N Engl J Med.
20023461937-1947.
14
????????B??????
15
DLBCL ??????
Overall Survival
Zucca, IOSI database 2009
16
?????????????
17
???B??????????
?? ????
IPI0 ????
??
?? ????
IPI1 ????
?? ??
IPIgt2
60?
gt60?
18
????
6CHOP? 30-40Gy(???)
CD20DLBCL 18-60? IPI 0?1 II-IV?????????I?
???
6CHOP? ??? 30-40Gy(???)
19
???
?? (n218)
R-?? (n226)
????(CR/CRu)
????(PD)
(Fisher????)
(Fisher????)
??????
20
???????
R-??
????????
??
???????(?)
?????21??
21
???
R-??
??
????
????(?)
?????21??
22
???????TTF
R-??
????
R-??
?/????
????????
???????(?)
23
??????????
R-??
????
R-??
????
????
????(?)
24
???B??????????
???
?? ????
????
?? ????
??
? ???
?????8???????,????????
?? ??
?
?
25
????????aaIPI0, ???? FLYER (6-6/6-4) ????
C H O P
C H O P
C H O P
C H O P
C H O P
C H O P
?? 6R-CHOP21 VS 6R-4CHOP14
R
R
R
R
R
R
Stage I/II aaIPI0 ??? 18-60?
R
d 1
d 64
d 106
C H O P
C H O P
C H O P
C H O P
R
R
R
R
R
R
26
IPI1?/???????
UNFOLDER (21/14) ????
C H O P 21
C H O P 21
C H O P 21
C H O P 21
C H O P 21
C H O P 21
/ - ?? Bulk / E
???
R
R
R
R
R
R
d 1
d 75
d 105
6R-CHOP21 VS 6R-CHOP14
C H O P 14
C H O P 14
C H O P 14
C H O P 14
C H O P 14
C H O P 14
/ - ?? Bulk / E
R
R
R
R
R
R
27
CHOEP-14R ? HDT (MegaCHOEP)R?????????B?????
??????????MegaCHOEP????
CHOEP-14
???????? 1860? aaIPI23
CHOEP-14 8 6R
??
R
MegaCHOEP-21 4 6R
MegaCHOEP-21 4

• ??
• ????vs HDT/ASCT???????????????????R???????HDT?????
  ????
• ????III??????????8CHOEP-146R ? MegaCHOEP6R .
• ????
• ????EFS
• ????PFS,OS,???

Schmitz et al. Blood 2009 114 Abstract 404.
28
????

• ??? 346? 216??? .???? 48?. ????29?.

MegaCHOEP N16 CHOEP-14 8 N15 CHOEP-14 8 6R N91 MegaCHOEP 6R N94
???? ???? ????48 ?, LDH gt N 97 , IIIIV 96, ECOG gt 1 35 ????48 ?, LDH gt N 97 , IIIIV 96, ECOG gt 1 35
?? 3y EFS 3y PFS 3y OS 71 76 83.8 56.7 64.6 75.3
??? ???????, ??, ???
??? ??????? 1/ 94 ( 5.3) 5 / 94 ( 5.3)
p 0.05
p 0.119
p 0.142
p 0.211
29
2009 ESMO Clinical Recommendation
????(IPI0,1)???? 8R
CHOP14
????(IPIgt2)???? 8R
CHOP14
30
? ?

• MInT?? RCHOP??CHOP?
• lt60????????
• ?????? 3 or 4 X CHOP14
• 8R ?????? 6 X CHOP14
• 
  

?? 8 x CHOEP
31
???B??????????
?? ???? 8R 3 or 4CHOP14
IPI0 ????
?? GELA/ RICOVER 60 / LNH03-6B
?? ???? 8R 6CHOP14
IPI1 ????
?? ?? 8R 8CHOEP14
IPIgt2
60?
gt60?
32
8?????? CHOP??????DLBCL (GELA??) ????
??????????-GELA???LNH98-5??,
??????????????DLBCL?????????
??? 375mg/m2 i.v. day 1 ???? 750mg/m2 i.v. day
1 ???? 1 .4mg/m2 i.v. day 1 ??? 50mg/m2 i.v.
day 1 ??? 40mg/m2 p.o. days 15
Coiffier et al. N Engl J Med. 2002346235
Feugier et al. JCO 2005 Vol.231-10
33
8RCHOP?????????
8RCHOP??CR/CRu????CHOP?
100 80 60 40 20 0
76
63
CRCRu()
P0.005
RCHOP (n202)
CHOP (n197)
34
8RCHOP?????????
??10??,8RCHOP?EFS??79
35
8RCHOP???????
??10??,8RCHOP?OS??55
36
8RCHOP????CR???????
??10??,8RCHOP?DFS??49
37
8RCHOP ?8CHOP ??????
8RCHOP
3?4????????1
8CHOP
50
45
40
39
30
???()
25
20
20
20
12
10
10
9
5
8
8
8
5
5
5
2
3
3
2
2
2
1
2
0
??
??
???
???
?? ??
?? ??
???
???
??
??
????
38
???????????????????
39
RICOVER 60??(DSHNHL1999-1) ????
6 x CHOP-14 36 Gy (???, ??)
8 x CHOP-14 36 Gy (???, ??)
1222? 61-80???? DLBCL??
6 x CHOP-14 36 Gy (???, ??) 8 x ???
8 x CHOP-14 36 Gy (???, ??) 8 x ???
??????? 1,15,29,43,57,71,85,99
DSHNHL 09-19-00
40
8R6CHOP14?????????
8R6CHOP14??CR?78
100 50 0
78
76
72
68
????? ()
?6CHOP14?????,P0.0069
41
8R6CHOP14?????????
8R6CHOP14??3?EFS???41
??????()

?6CHOP14?????,Plt0.0001
??????(?)
42
8R6CHOP14???????
8R6CHOP14??3?OS???15
????()
?6CHOP14?????,P0.0181
????(?)
43
8RCHOP14 ??????
3?4????????1
6CHOP14 (n307)
8CHOP14 (n305)
8R6CHOP14 (n306)
8R8CHOP14 (n304)
P?
?????
?????
??
????
?????
????
???
??
?????
?????
?????
P????????????
44
R-CHOP14 vs R-CHOP21 ????DLBCL, ??????
45
LNH03-6B GELA??R-CHOP14 vs R-CHOP21 ????DLBCL
R-CHOP14 q2w8
DLBCL 6080? aaIPI 1 n600
???
R-CHOP21 q3w8
????1?
Delarue et al. Blood 2009 114 Abstract 406.
46
LNH03-6B GELA?? R-CHOP14 vs R-CHOP21 ????DLBCL

• ??
• Gela ??R-CHOP21 ????DLBCL????????2 ?
  ????CHOP14?CHOP21 R-CHOP14 ? CHOP14??????
• LNH03-6B ???? ???, III????, ????,??R-CHOP14
  ?R-CHOP21???, ???? 202?,????2?.
• ????
• ????EFS
• ????OS, PFS, DFS,RR,?????????

47
LNH03-6B GELA????

• 202 ???, 201???.???? 72 ?. ????2y.

RCHOP21 N98 RCHOP14 N103
???? aaIPI 2-3 B ?? ??8????? ??G-CSF 59 43 76 66 67 37 71 90
?? RR(CRCRu) 2y EFS 2y PFS 2y DFS 2y OS 75 61 63 70 70 67 48 49 57 67
??? 3-4 ??? ?? ???? RCHOP14????, ??????????,????????, ???. ??????? RCHOP14????, ??????????,????????, ???. ???????
pNS
pNS
pNS
pNS
Delarue et al. Blood 2009 114 Abstract 406.
48
??????

• ?R-CHOP14??, R-CHOP21????,??????
• ???????DLBCL?

49
???B??????????
? ? ???? 8R 3 or 4CHOP14
IPI0 ????
?? 8R 8CHOP21
?? ???? 8R 6CHOP14
IPI1 ????
?? ?? 8R 8CHOEP14
IPIgt2
60?
gt60?
50
? ? ? ?

• 8???????CHOP
• ????????
• ????????????

51
2 .? ? ? ? ? ?

52
? ?

• 1?FL?????
• 2?FL?????
• EORTC 20981 ?????????FL
• PRIMA?? ?????????FL
• 3???

53
??????????? ???????(19601996)
19871996 19761986 19601975
100 80 60 40 20 0
???? 11?!
?? ()
5-year 80 10-year 60 15-year 45
0 5 10 15 20 25 30
?
Horning. Semin Oncol 199320 (5 Suppl. 5)7588
54
??????FL???

• ??????FL?????1,2

1.0
R-CHOP R-FND R-CVP R-Chlorambucil
0.8
0.6
19982006
OS
0.4
198997
0.2
198088
BCCA data
0
0
10
15
20
25
5
??(?)
1. Fisher R, et al. J Clin Oncol 2005
2384478452.2. British Columbia Cancer Agency
data.
55
FL?????

• ??????? (PR ? CR)
• ???????????
• ????????????
• ?????

56
?????????????????FLEORTC 20981 III?????????????

• van Oers MHJ, Van Glabbeke M, Giurgea L, Klasa R,
  Marcus RE, Wolf M, Kimby E, van t Veer M,
  Vranovsky A, Holte H, Hagenbeek A

J Clin Oncol 2010 May 3 ePub ahead of print.
57
EORTC 20981 ??????? vs ??,????FL
R-CHOP q21dmax. 6 cycles
R A N D O M I S E
R A N D O M I S E
8 x ????? 375 mg/m2 ?3?1?,??2?
CRPR
??/ ??FL
CHOP q21dmax. 6 cycles
??
CR ???? PR ???? CHOP ???? ???, ????, ???
van Oers MHJ, et al. J Clin Oncol 2010 ePub
ahead of print.
58
??????????????FL?PFS
100
PFS ?? gt 2.4 years
80
??????? ?? 3.7?
60
PFS ()
40
?? ?? 1.3?
20
HR, 0.55 p lt 0.0001
0
0
1
2
3
4
5
6
7
8
Time (years)
van Oers MHJ, et al. J Clin Oncol 2010 ePub
ahead of print.
59
??????????????????PFS
CHOP??
R-CHOP??
100
100
80
80
?? 3.1 years
??4.4 years
60
60
PFS ()
40
40
20
20
??1 year
??1.9 years
HR, 0.37 p lt 0.001
HR, 0.69 p 0.043
0
0
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
Time (years)
Time (years)
van Oers MHJ, et al. J Clin Oncol 2010 ePub
ahead of print.
60
??????????????????PFS
CR?
PR?
100
100
??3.4 years
80
80
??4.4 years
60
60
PFS ()
40
40
20
20
??1.2 years
??1.3 years
HR, 0.48 p 0.003
HR, 0.58 p 0.0006
0
0
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
Time (years)
Time (years)
van Oers MHJ, et al. J Clin Oncol 2010 ePub
ahead of print.
61
???????????
5 years
100 80 60 40 20 0
??????? 74.3
??64.7
???? ()
HR 0.70 p 0.07
0
1
2
3
4
5
6
7
8
Time (years)
?????
HR Hazard ratio
van Oers MHJ, et al. J Clin Oncol 2010 ePub
ahead of print.
62
EORTC 20981 ???? ??

• ????????????,6????PFS??????????
• ??????
• ?????? (CHOP?, R-CHOP?, CR?PR?)
• ??5??OS????????????????,????????????,????????
• ??????????????

van Oers MHJ, et al. J Clin Oncol 2010 ePub
ahead of print.
63
Primary RItuximab and MAintenance (PRIMA??)
?????????

• ??FL?????,???????????????????????????????,???????
  ???????
• ????????,???FL???,??????????????????????
• ?????????????????????
• ?????????????????????
• ??,????????????????????,?????????????????????
• PRIMA????III???????

64
PRIMA????
????
????
????????? 375 mg/m2 ?8?1? ?2?
??
???? 8 x ????? 8 x CVP or 6 x CHOP or 6 x FCM
????? ??????? ??????
CR/CRu PR
?11????????
??
PD/SD ????
??????????????????????????
?????????????????CT?????????5?????
65
?????,??????PFS

• ?????????????????????50

1.0
82
????????? N505
0.8
?? N513
0.6
66
??????
0.4
??HR0.50 95 CI 0.39 0.64 plt.0001
0.2
0
6
0
12
18
24
30
36
??????(?)
?????
505
472
443
336
230
103
18
513
469
411
289
195
82
15
66
????????????,???????????????
??
??
HR
N
???(HR)
95 CIs
??
All
1018
0.380.64
0.49
0.330.62
624 394
0.45 0.59
lt 60
??
0.390.90
60
216 370 431
0.190.77
0.38 0.39 0.61
FLIPl 1
FLIPl?? (CRF)
0.250.61
FLIPl 2
0.430.87
FLIPl 3
0.310.59
0.43 0.69 0.51
768 222 28
R-CHOP
????
0.441.08
R-CVP
R-FCM
0.132.07
??????
721 290
0.380.70
0.52 0.45
CR/CRu
PR
0.290.72
2
3
0
1
????
????
Non-stratified analysis Salles G, et al. J Clin
Oncol 2010 28Abstract 8004.
67
???????????
?????????????
?????????
?????????
?????????
1.0
1.0
0.8
0.8
0.6
0.6
??????
??????
HR 0.61 p 0.0003
HR 0.60 p 0.0011
??
??
0.4
0.4
0.2
0.2
0
0
6
0
12
18
24
30
36
0
6
0
12
18
24
30
36
0
??????(?)
??????(?)
?????
505
483
453
349
235
103
18
505
484
457
351
243
108
19
513
487
447
327
218
87
15
513
492
454
332
225
91
17
68
????????
?? n 398 ????????? n 389
???? (PD) 162 (40.7) 79 (20.3)
???? (SD) 1 (0.3) 0 (0)
???? (PR) 29 (7.3) 28 (7.2)
???? (CR/CRu) 190 (47.7) 260 (66.8)
???????????? n 190 n 258
?? CR/Cru??? 153 (56) 209 (75)
?PR/SD??? CR/Cru??? 37 (30) 49 (45)
???????????,???????????????16?22?
???????,????????2?
69
???????????????
100
80
?? (n 508)
????????? (n 501)
60
?? ()
52
40
37
35
20
23
22
16
4
4
lt1
lt1
lt1
0
2? ??
??????
3/4????????
3/4? ??
3/4?????
70
PRIMA ? ?

• ???????FL??,???????????????,??????2???????????,???
  ??PFS?
• ?????????,????????????????
• ????(??EFS?TNLT?TNCT??????ORR?CR?)?????????
• ????????????????????
• ??????,??????????????????????

71
??????

• ???????????????????
• ??????? ??????????1??
• ??????? ???????????
• ??????? ?????????????????
• ??????? ?2??????,??2?

72
???????????????FL????????????
Chemo
Chemo
Chemo
PFS 3 yrs
lt 2 yrs
PFS 56 yrs
2.8 yrs
Chemo
R-??
8 x R
5 yrs
56 yrs
Chemo
Chemo
8 x R
R-??
8 x R
R-??
79 yrs???
?
73
? ?

• ???????????????? / DLBCL,????????,????????
• ???????????FL????????, ?DLBCL??????????
• ?????????????????????????????????