悪性リンパ腫治療の変遷と展望archive.jsco.or.jp/data/jp/detail_images/51/ess20.pdf ·...

417JSCO 第48巻第2号

21

43

65

Arm difference in 5y-FFTF = -0,5%

95% CI [-3,6%; 2,6%]

p=0,90

Time [months]

30 Gy RT 20 Gy RT

Free

dom

from

Tre

atm

ent F

ailu

re

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

GHSG HD10 StudyRadiotherapy (FFTF)

Engert A, et al.: N Engl J Med 2010;363;640-52

Time [months]

4xABVD 2xABVD

Free

dom

from

Tre

atm

ent F

ailu

re

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

5y-FFTF difference -1,9%;

95% CI [-5,2%; 1,4%]

p=0,39

GHSG HD10 StudyChemotherapy (FFTF)


CS I/II without risk factors*

2 x ABVD

30 Gy IF

2 x ABVD

4 x ABVD

4 x ABVD

30 Gy IF20 Gy IF 20 Gy IF

*Large mediastinal mass; extranodal disease; high ERS; 3 or more areas involved

GHSG HD10 StudyEarly favorable HL

Engert A, et al.: N Engl J Med 2010;363;640-52Time to 2nd neoplasm (y)

403020100

1.0

.8

.6

.4

.2

0.0

Chemo + RT

RT alone

Chemo alone

(n = 1340)

Connors J, Vancouver, Canada, JCOG-SWOG Joint Sympo., 2002

ABVD x 4 IFRT [30-40Gy](Fav: ABVD x 2 IFRT [20Gy])

I, IIB

III, IVB or I, II

ABVD x 6 - 8

512013 10 24 26

B

T/NK

（国立がん研究センター中央病院　血液腫瘍科）飛　内　賢　正

悪性リンパ腫治療の変遷と展望ESS20

教育セッション「悪性リンパ腫」

418 JSCO 第48巻第2号

1211

109

87

PETHodgkin lymphoma

Italian - Danish Study

Gallamini A, et al.: J Clin Oncol 2007;25:3746-52

ABVD ABVD ABVD ABVD ABVD ABVD

SUV 2.0 3.5minimum residual uptake PET negative

ABVD versus BEACOPP for Hodgkin Lymphoma When High-Dose Salvage Is Planned

Viviani S, et al.: N Engl J Med 2011;365:203-12

7-yr freedom from 1st progression was 85% in BEACOPP and 73% in ABVD (P=0.004), whereas 7-yr OS was 89% and 84%, respectively (P=0.39). Severe AEs were more frequent in BEACOPP.

Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term outcome did NOT differ significantly.

GHSG HD9 trial FFTF by treatment arm

Diehl V, et al.: N Engl J Med 2003;348:2386-95 / Engert A, et al.: J Clin Oncol 2009;27:4548–54

p <0,001

Years

COPP/ABVD (64%)

BEACOPP (70%)

escBEACOPP (82%)

Perc

enta

ge

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

18%

BEACOPP

BEACOPP

COPP/ABVD

BEACOPP BLM, ETP, DOX, CPA, VCR, PCZ, PSL

ABVd JCOG 9305

5 I, II 63 98%III, IV 65 87%

Days after registration

Ogura M, Tobinai K, et al.: Int J Hematol 2010;92:713-24

Time [months]

4xABVD 2xABVD

Ove

rall

Surv

ival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

5y-FFTF difference 0,5%

95% CI [-2,6%; 1,6%]

p=0,92

GHSG HD10 StudyOverall Survival



第51回　日本癌治療学会学術集会Educational Book

1817

1615

1413

CVP Rituximab in Untreated Follicular Lymphoma: TTP, Relapse or Death

R-CVP: median, 34 months

CVP: median, 15 months

Study month

Even

t-fre

e pr

obab

ility

1.00.90.80.70.60.50.40.30.20.1

00 6 12 18 24 30 36 42 48 54 60 66 72

p < 0.0001

Patients at risk:CVP 159 130 88 65 52 40 31 27 23 15 7 1 0R-CVP 162 145 133 113 106 85 78 69 58 42 15 3 0

Median follow-up: 53 months

Marcus R, et al.: J Clin Oncol 2008;26:4579-86

C: Overall Survival

Time to Treatment Failure (A), Duration of Response (B) and Overall Survival (C) after CHOP and R-CHOP in Patients with Advanced-Stage Follicular Lymphoma

German Lymphoma Study Group(Hiddemann W, et al.:

Blood 2005;106:3725-32)

Time to Treatment Failure

Duration of Response

P = 0.016

P < 0.001

P = 0.001

R-CHOP

CHOP

1995-present

1980s

1970s

Fisher RI, et al.: J Fisher RI, et al.: J ClinClin OncolOncol 2005;23:84472005;23:8447--5252

4-YearN Death Estimate

1995-present 179 18 91%1980s 425 189 79%1970s 356 226 69%

SWOGFollicular Lymphoma (FL)Follicular Lymphoma (FL)Most common indolent B-NHL in the worldVariable presentation and prognosis, but typicallyadvanced stage at presentationOften asymptomaticAdvanced stage FL, not curable with conventional TxMST was about 10 years in the pre-rituximab era, buthas increased with the advent of rituximab and RITMultiple options: no standardMany novel therapies in development

Modified from Skarin and Dorfman. CA Cancer J Clin. 1997;47:351

Follicular Lymphoma

TransformedAccelerated Indolent10% to 15% 40% to 65% 20% to 60%

Younes A, et al.: J Clin Oncol 2012;30:2183-9


2423

2221

2019

PRIMA: Rituximab maintenance for 2 years prolongs PFS

HR = 0.5595% CI: 0.44–0.68p < 0.0001

Time (months)

Rituximab maintenance

Observation

60 12 24 30 42 48 60

Even

t-fre

e ra

te

0.8

0.6

0.4

0.2

0

1.0

Patients at risk505513

472 445 423 307 207 17469 415 367 247 161 16

00

18 36 54

404334

8470

––

RituximabObservation

Salles G, et al.: Lancet 2011;377:42–51

PRIMA: Assessing R-chemo induction and R-maintenance concept in first-line

PDSD

off study

Maintenance12 x rituximab(q2mo for 24 mo)

Observation

Untreatedfollicular NHLHigh tumour

burden

Induction8 x rituximab

Chemotherapy(8 x CVP

or 6 x CHOPor 6 x FCM)

+CR

CRuPR

1,217 pts

1,018 pts

Salles G, et al.: Lancet 2011;377:42–51

FIT Study: Progression-free Survival

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66

PFS time from randomization (months)

Prop

ortio

n re

mai

ning

pr

ogre

ssio

n fr

ee (%

)

Log rankP < 0.0001HR 0.463

Zevalin: median 37 mon = 208

Control: median 13.5 mon = 206

*Median observation period was 3.5 years.

Morschhauser F, et al.: J Clin Oncol 2008;26:5156-64 / J Clin Oncol. 2013 Apr 1. [Epub ahead of print]

Rituximab-containing therapy as induction; 14% (59/409)

JCOG 0203: Conclusions

R-CHOP is highly effective as an initial treatmentfor indolent B-NHL in terms of ORR (97%) and OS(88% at 6 years).

However, long-term PFS is not good enough (42%at 6 years). Dose-dense strategy with the immunomodulatory agent G-CSF did NOT improve the PFS.

Further improvement of front-line treatment or investigations on post-remission therapy following R-CHOP are warranted.

JCOG-LSG

Watanabe T, Tobinai K, et al.: J Clin Oncol 2011;29:3990-8

0.00.10.20.30.40.50.60.70.80.91.0

0 1 2 3 4 5 6 7 8Time after Enrollment (years)

Ove

rall

Sur

viva

l(P

roba

bilit

y)

No. of patients at riskR-CHOP-21R-CHOP-14

148 145 142 139 120 86 51151 148 148 144 122 79 49

2627

R-CHOP-14R-CHOP-21Arm n Median

151148

not reachednot reached

88%87%

6-year

One-sided stratified long-rank test P = .65HR, 1.15 (95% CI, .57 to 2.30)

96%95%

3-year

Overall Survival (OS) (N = 299)

JCOG-LSG


median follow-up time; 5.2 years

Progression-Free Survival (PFS) (N = 299)

JCOG-LSG

R-CHOP-14R-CHOP-21Arm n Median (95% CI)

151148

4.7 (3.1-not estimable)3.7 (3.0-5.1)

43%41%

6-year

58%57%

3-year

One-sided stratified long-rank test P = .30

Pro

gres

sion

-Fre

e S

urvi

val

(Pro

babi

lity)

Time after Enrollment (years)

HR, .92 (95% CI, .68 to 1.25)

No. of patients at riskR-CHOP-21R-CHOP-14

148 135 98 83 56 34 23151 135 104 87 65 34 18

96


median follow-up time; 5.2 years



3029

2827

2625

Lenalidomide: Putative Mechanism of Action

Fowler N. et al.: ICML 2011. Abst#137. Rummel MJ, et al.: Lancet 2013;381(9873):1203-10

In untreated indolent B-NHL, B-R can be considered as a preferred first-line treatment approach to R-CHOP because of increased PFS and fewer toxic effects.

120 mg/m2 1 1 2 30 6019 1 Cycle 6 12 Cycles

77 CR 34 PR 43 PFS 7.1

66 6267 79%

ORR 77%

CR/CRu34%

ORR 66%

ORR 62%

ORR 67%

ORR 79%

Friedberg JW, et al.: J Clin Oncol 2008;26:204-10(Ohmachi K, Tobinai K, et al.: Cancer Sci 2010;101:2059-64 – Japanese phase II study)

Indolent B-NHLBendamustine IITREAKYSIM®)

1963

DNADNA

p53mitotic

catastrophe

C16H21Cl2N3O2 HCl

394.72N

NCH3

COOHN

ClH2C

ClH2C Bendamustine

Carboxylic acidCarboxylic acidBenzimidazole ring

Nitrogen mustardNitrogen mustard

Global Phase III: G-Chemo vs. R-Chemo

Previously

untreated

indolent B-NHL

Stage III, IV,

Stage II bulky

FL Grade 1-3a

MZL

n=1,400!

R

A

N

D

O

M

I

Z

E

Primary endpoint: PFS

Secondary endpoints: OS, EFS, DFS, ORR, CRR, safety, etc.

Study duration: 2011.7 - ?

R-Chemo*

CR/PR

Maintenance Rq2 months x 2 years

GA101-Chemo* Maintenance GA101 q2 months x 2 years

*CHOP, CVP: per center basis

CR/PR

type II

– Increased direct cell death induction

– Enhanced ADCC

Obinutuzumab (GA101): a glycoengineered, type II anti-CD20 Ab

Mössner E, et al.: Blood 2010;115:4393-402Salles G, et al.: Blood 2012;119:5126-32 [Phase I study]

Heavy chainCD20 peptide

Glycoengineering

Light chain


36

Duodenal Follicular Lymphoma (DFL)

months

0 12 24 36 48 60 72 84 96

Initial treatment group(n = 14)

No initial treatmentgroup (n = 13)

Median follow-up: 28 months (5 – 100 months

IGH/BCL2 fusion by FISH: 20/24 (83%)

Mori M, Kobayashi Y, Maeshima A, Tobinai K, et al.: Ann Oncol 2010;21:1500-5

The prognosis of pts with primary DFL was excellent. A watchful waiting policy might be an acceptable approach for a significant fraction of DFL pts.

Progression-free survivalOverall survival

35

3433

3231

clinicaloptions.com/oncologyLymphomas

Ibrutinib in de Novo DLBCLRel/ref de novo DLBCL (median number of previous systemic therapies: 3); ibrutinib 560 mg PO QD; CT and PET scanning pretreatment and every 2 cycles; primary endpoint: ORR, categorized by molecular subtype

Ibrutinib showed a clinically meaningful response rate in rel/ref ABC DLBCL, but not in other molecular subtypes

Wilson WH, et al. ASH 2012. Abstract 686, Oral Session

ResponseABC

Subtype(n = 29)

GCBSubtype(n = 20)

Unclassifiable* (n = 16)

Unknown* (n = 5)

Total(N = 70)

Not evaluable for response, n 4 1 3 2 10

ORR (CR + PR, per protocol), n (%) 10 (40%) 1 (5%) 0 2 (67%) 13 (22%)

CR, n (%) 2 (8%) 0 0 1 (33%) 3 (5%)

PR, n (%) 8 (32%) 1 (5%) 0 1 (33%) 10 (17%)

*GEP performed, but not assignable to ABC or GCB subtypes, or GEP not yet performed or tissue not available.

clinicaloptions.com/oncologyLymphomas

Ibrutinib for rel/ref MCL: Response Rates

Responses to Ibrutinib increased with increased time on treatment

Wang M, et al.: ASH 2012. Abstract 904, Oral Session

Best Response, %[1] Bortezomib Naive(n = 63)

BortezomibExposed(n = 47)

Total(N = 110)

ORR 65% 72% 68%PR 44% 49% 46%CR 21% 23% 22%

Best Response, %Bortezomib

Naive(n = 30)

BortezomibExposed(n = 21)

Total(N = 51)

Median follow-up 3.7 mos[2]

PR 55% 50% 53%CR 16% 15% 16%

Median follow-up 14.7 mosPR 37% 33% 35%CR 40% 38% 39%

The Future:

Rational combinations

Overcoming challenges to

new agent development

Friedberg JW: Clin Cancer Res

2011;17:6112-7

1st lineFL

N=1,000

Rituximab - Lenalidomide

R-Chemo x 6-8 then Rituximab (2 yrs)R

2.5 yrs

Control Arm: Investigator choice of one of the following R-chemo regimens:R-CHOP or R-CVP or R-Bendamustine

Followed by 2 years of R maintenance in responding ptsvs.

Experimental Arm: Rituximab - Lenalidomide

RELEVANCE Study(LYSA / GELA - international study)

Courtesy of Morschhauser F

Follicular Lymphoma Response: Tumor Burden, Molecular Response

BY GELF CRITERIA N=46GELF(+) HIGH TUMOR BURDEN

N=22 (48%)GELF(-) HIGH TUMOR BURDEN

N=24 (52%)SD PR CR/CRu ORR SD PR CR/CRu ORR0 1 (5%) 21 (95%) 100% 1 (4%) 4 (17%) 19 (79%) 96%

BY BULK OF DISEASE N=46BULKY N=13 (28%) NON-BULKY N=33 (72%)

SD PR CR/CRu ORR SD PR CR/Cru ORR0 1 (8%) 12 (92%) 100% 1 (3%) 4 (12%) 28 (85%) 97%

MOLECULAR RESPONSE N=44 (eval)PCR POSITIVE PCR NEGATIVE

PRETREATMENT 17 (41%) 26 (59%)POST CYCLE 3 5 (11%) 39 (89%)POST CYCLE 6 2 (5%) 42 (95%)

Bone marrow and peripheral blood for major or minor breakpointFowler N, et al.: ASH 2012, Abstract #901



39

3837

Overall survival of pts with the common subtypes of PTCL

International T-Cell Lymphoma Project: J Clin Oncol 2008;26:4124-30

ATL PTCL-NOS

AITL

NK/T

Sur

viva

l pro

babi

lity

(%)

Years0

100

90

80

70

60

50

40

30

20

10

01 2 3 4 5 6 87 9 10

Survival of 15 Pts with Burkitt & Burkitt-like Lymphoma Treated with CODOX-M/IVAC R at NCCH

5-year progression-free survival: 87%

5-year overall survival: 87%

Median follow-up duration: 74 months [range 16-126]

Maruyama D, Watanabe T, Tobinai K, et al.: Int J Hematol 2010;92:732-43

41

40

7 days

REGISTRATION

w 1 2 3 4 5 6 7 8 9 10RT*

Concurrent chemoradiotherapy (RT-2/3DeVIC)

2/3DeVIC†

†, Recommended dose determined in the phase I portion

(Yamaguchi M, Tobinai K, et al.: ASH 2005, #2685)

JCOG0211: Treatment details

* High-dose RT (50 - 50.4 Gy; 1.8 - 2.0 Gy / fx.)CT based 3 dimensional RT planning confirmed by RT QAClinical target volume: entire nasal cavities, nasopharynx, and the volume + 2 cm to gross tumor

CBDCA 200 mg/m2 IV day 1ETP 67 mg/m2 IV days 1-3IFM 1.0 g/m2 IV days 1-3DMS 40 mg/day IV days 1-3

MDR-non-related agentsEtoposide is effective for EBV-associated diseases

Nasal NK/T-cell Lymphoma

MDR1 (ABCB1)

42

Long-term follow-up results of a phase I/II study of concurrent chemoradiotherapy for localized nasal NK/T-cell lymphoma (NKTCL): JCOG0211

Yamaguchi M, Tobinai K, et al., Japan Clinical Oncology

Group - Lymphoma Study Group (JCOG-LSG)

ASCO Annual Meeting, 2012, #8050JSH Annual Meeting, 2012, PlenaryJ Clin Oncol. 2012 Oct 8. [Epub ahead of print] Correspondence


4847

46

Untreated Indolent ATL< 75 years old

IFN 6 muAZT 600 mg

Continue until PD

Allo-HSCT for aggressive ATL(pII: JCOG0907)

Untreated Aggressive ATL< 56 years old

VCAP/AMP/VECP

Sibling donor + Sibling donor -

Allo-SCT

UBMT donor + Donor -

Continue ChemoSearch for UBMT donor

Allo-SCT Chemotherapy

Current & Next ATL Trials by JCOG-LSG

Randomization

Watchful wait

IFN/AZT v Watchful waitfor indolent ATL (pIII: JCOG1111)

Courtesy of Dr. Tsukasaki, NCCHE

Bazarbachi A, et al.: J Clin Oncol 2010;28:4177-83

Meta-Analysis on Zidovudine and Interferon-alfa in ATLChronic and smoldering Lymphoma

AcuteJCOG9801

Tsukasaki K, et al.: J Clin Oncol 2007;25:5458-64

Although the authors claimed the high efficacy of AZT & IFN in leukemic subtypes of ATL, one of the limitations of this retrospective study is potential selection bias.

Takasaki Y, Iwanaga M, Tsukasaki K, et al.: Blood 2010;115:4337-43Long-term Follow-up Study of Indolent ATL

The prognosis of indolent ATL pts in this study was poorer than expected. Further studies are required to develop better management for indolent ATL.

45

4443

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7

Hazard ratio = 0.751 (95% CI, 0.50–1.13)One sided p = 0.085

p = 0.029 by adjustment by Cox regression

VCAP-AMP-VECP(n=57)CHOP-14 (n=61)

MST, 11M3 yr-OS, 13%

MST, 13M3 yr-OS, 24%

Years after randomization

Proportion OS

Tsukasaki K, Tobinai K, et al.: J Clin Oncol 2007;25:5458-64

Overall Survival of ATL Pts in JCOG 9801

Conclusion: JCOG0211

Concurrent chemoradiotherapy with RT and a two-thirds dose of DeVIC(RT - 2/3DeVIC) is a recommendable first-line treatment for localized nasal NKTCL.

Yamaguchi M, Tobinai K, et al.: J Clin Oncol 2009;27:5594-600 / J Clin Oncol. 2012 Oct 8. [Epub ahead of print] Correspondence

Survival (All pts, N=33)

5-yr %PFS 67%(90% CI, 51-78%)

Overall survival Progression-free survival

5-yr %OS 73% (90% CI, 57-83%)

Median follow-up time: 69 months (range, 62-96)

Time (months)

0

20

40

60

80

100

12 24 36 48 8460 72 96

(%)

Time (months)

0

20

40

60

80

100

12 24 36 48 8460 72 96

(%)

J Clin Oncol. 2012 Oct 8. [Epub ahead of print] Correspondence



51

5049

Efficacy of Mogamulizumab for Relapsed ATL * (n=26)

*�Determined�according�to�the�criteria�described��by�Tsukasaki et�al.�(J�Clin�Oncol,�2009)

Best response by disease site

Best overall response (ORR)

Ishida T, Tobinai K, et al.: J Clin Oncol 2012;30:837-42

KW-07611.0 mg/kg/day (iv)

weekly x 8

KW-07611.0 mg/kg/day (iv)

weekly x 8

CCR4assessmentBy FCM /

IHC

CCR4assessmentBy FCM /

IHC

RegistrationCCR4+

D1 8 15 22 29 36 43 50

Mogamulizumab , 1.0 mg/kg

1 mo 2 mos1 mo

Efficacy assessment

Design of Phase II Study of Mogamulizumab

Dosing and assessment schedule

Endpoints: Primary; Overall response rate (ORR)Secondary; PFS, OS, Response by disease site

RelapsedATL

RelapsedATL

Ishida T, Tobinai K, et al.: J Clin Oncol 2012;30:837-42

Mogamulizumab (KW-0761),a defucosylated humanized anti-CCR4 antibody

A humanized monoclonal antibody that targets CC

chemokine receptor (CCR4) expressing cells such as T-cell

subset (Th2, T-reg) and T-cell malignancies (PTCLs, CTCL, ATL).

Has enhanced ADCC activity (appr. 100 fold) through defucosylation

by the POTELLIGENT® Technology.

Does NOT exhibit CDC or neutralizing activity.

5453

52

UntreatedATL

( 20yo)

UntreatedATL

( 20yo)RRR

mLSG15(VCAP/AMP/VECP)

x 4 cycles

mLSG15(VCAP/AMP/VECP)

x 4 cycles

mLSG15 x 4 cycles+

Mogamulizumab(Bi-weekly x 8)

mLSG15 x 4 cycles+

Mogamulizumab(Bi-weekly x 8)

CCR4ASSESSCCR4CCR4

ASSESSASSESS

Primary endpoint: CR rate

CCR4+

(n=44)

ClinicalTrials.gov ID:NCT01173887 ATL 1st line

Relapsed T/NK cell lymphoma( 20 yo)

Relapsed T/NK cell lymphoma( 20 yo)

Mogamulizumab1.0 mg/kg/day (iv)

weekly x 8

Mogamulizumab1.0 mg/kg/day (iv)

weekly x 8CCR4

ASSESSCCR4CCR4

ASSESSASSESSCCR4+

(n=35)

T/NK cell lymphoma(including CTCL)

Primary endpoint: Overall response rate (ORR)

Subsequent Studies of Mogamulizumab

Tobinai K, et al.: Curr Hematol Malig Rep 2012;7:235-40

悪性リンパ腫治療の変遷と展望archive.jsco.or.jp/data/jp/detail_images/51/ess20.pdf ·...

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