高級別B細胞淋巴瘤高級別B細胞淋巴瘤Definition：High

Grade

BCellLymphoma

by

2016WHO

High-gradeB-cell

lymphoma,

withMYCandBCL2and/orBCL6rearrangements伴MYC和BCL2和(或)BCL6重排的“double

or

triplehitlymphoma，但需要除外FL和LBL

High-gradeB-cell

lymphoma,

NOS沒有MYC和BCL2和(或)BCL6重排，但形態學介于DLBCL和BL之間，具有原始細胞樣特征高級別B細胞淋巴瘤HGBL

CategoriesStevenH.Swerdlow

et

al.

Blood2016;127:2375-2390高級別B細胞淋巴瘤CytologicspectrumofHGBLStevenH.Swerdlow

et

al.

Blood2016;127:2375-2390高級別B細胞淋巴瘤Double-Hit

andDouble-expressorBlood

Rev.

2017

March

;31(2):

37–42.高級別B細胞淋巴瘤DH和TH細胞來源比例高級別B細胞淋巴瘤診斷建議

HGBL-DHL病理診斷主要依賴于FISH檢測，需要同時檢測出Myc和BCL-2或BCL-6重排陽性

關于FISH檢測，兩種看法：

所有DLBCL均應進行MYC、BCL2和BCL6重排檢測

GCB型和/或形態學高侵襲性伴MYC+細胞>40%的患者中進行FISH檢測

HGBL-NOS丌能簡單地依靠Ki67來進行診斷，其細胞形態學必須符合HGBL的特征

HGBL-NOS異質性強，存在很多未知因素，后續可能對這一分類進一步細化分層高級別B細胞淋巴瘤Mechanisms：Double-Hit

and

Double-expressor高級別B細胞淋巴瘤Mechanisms：

MYC

deregulation

inaggressive

lymphomasPierre

Sesques,andNathalie

A.

JohnsonBlood2017;129:280-288高級別B細胞淋巴瘤Alyssa

Bouskaet

al.

Blood2017;130:1819-1831高級別B細胞淋巴瘤NGS

found

tobe

recurrentlymutated

in52mBL

casesAlyssa

Bouskaet

al.

Blood2017;130:1819-1831高級別B細胞淋巴瘤HGBL與Burkitt淋巴瘤比較：基因組特征和潛在的治療靶點

成人高級別B細胞淋巴瘤不伯基特淋巴瘤(BL)分子特征相似

不兒童-mBL相比，成人-mBL攜帶明顯而又高頻的基因異常(del13q14，

del17p，

gain8q24和gain18q21)

基因組分析揭示MYC-ARF-p53軸是主要的信號通路

成人-mBL的一個子集攜帶BCL2異位和突變，上調BCL2mRNA和蛋白質表達

在50%的成人-mBL患者中觀察到MIR17HG和它的旁系同源位點的獲得/擴增。miR-17~92在BCR信號通路的活性和對依魯替尼的敏感性中發揮作用Alyssa

Bouskaet

al.

Blood2017;130:1819-1831高級別B細胞淋巴瘤HGBL

的臨床特征

中老年發病

(51-65

years)

高LDH,

疾病呈進展狀態,

高IPI評分

BM/CNS

受累

(9-50%)

細胞遺傳學

Double

Hit/

TripleHit(MYC、BCL2、BCL6

rearrangements)

可同時伴有

IG-MYC,

或

Non-IG-MYC

（常見于HBCL，NOS）

免疫表型表達全B抗原（CD20、PAX5、CD79a），Bcl-6+，CD10+/-，Bcl-2+/-，分裂指數80-100%。TdT-，CD34-，cyclinD1-。

預后很差，中位

OS

<2年，不DHL相比，HGBL-NOS預后可能相對較好高級別B細胞淋巴瘤DLBCL：雙打擊(DHL)和雙表達(DEL)患者預后更差R-CHOP治療DLBCL患者OSMYC和BCL2易位或MYC和BCL2蛋白表達1.00.8其他DLBCL

(n=236)0.6MYC+/BCL2+

(n=55)0.4DHL

(n=14)0.2P<0.001*P=0.014(MYC+/BCL2+

vs.

其它)358100時間

(年)通過對2個R-CHOP治療的DLBCL患者隊列進行IHC檢測分析MYC和BCL2蛋白表達不患者生先期納入10個國際機構的167例患者的FFPET樣本。驗證隊列納入140例BCCA患者FFPE樣本DunleavyK,

et

al.

CurrTreat

Options

Oncol

2015;16:58.Johnson

NA,

et

al.

J

Clin

Oncol

2012;

30(28):3452-9.高級別B細胞淋巴瘤novel

ECOGscoreIPI7%R-IPIECOG

DHL預后積分：白細胞增多>10X10

/L9Ann

Arbor

III-IV期LDH>3x

ULN,中樞侵犯Adam

M.

Petrich

et

al.

Blood2014;124:2354-2361高級別B細胞淋巴瘤Clinical

risk

according

to

MYC

andBCL2

status

inDLBCLPierre

Sesques,andNathalie

A.

JohnsonBlood2017;129:280-288高級別B細胞淋巴瘤Translocation

partner：對EFS無影響patientsreceiving

IDall

patientspatientsachieving

CRCancer.

2016

February

15;

122(4):

559–564.高級別B細胞淋巴瘤多中心回顧性分析：DHLR-強化療方案延長PFS,

但OS未獲益100強化誘導

(N=136)：mPFS

21.6月?

強誘導方案治療DHL患者PFS顯著優于R-CHOP，各方案都顯著延長PFS806040200R-CHOP

(N=63)：mPFS

7.8月R-CHOP(n=63)10080R-HyperCVAD

(n=38)：P=0.001DA-EPOCH-R

(n=57)：P=0.0463R-CODOX-M/IVAC(n=41)

：P=0.036其他

(n=24)P=0.00011224364860時間

(月)100806040200強化誘導

(N=171)R-CHOP(N=100)6040200P=0.001625P=0.5605075100125401224364時間

(月)時間

(月)回顧性多中心研究入組311例DHL患者分析Petrich

AMet

al.Blood,2014,124(15):2354-61.高級別B細胞淋巴瘤MDACC：R-EPOCH方案治療DHL療效顯著?

MDACC經驗結果：R-hyperCVAD/MA不R-CHOP治療生存相似，而R-

EPOCH治療較R-CHOP治療EFS和OS更長（持續輸注）RCHOP(n=57)100806040200100REPOCHR(

nH=C2V8A)

D

/

M

A

(n=34)80其他

(n=10)3y：76%603y：67%3y：40%3y：35%402003y：32%3y：<12%P=0.0573y：<10%3y：20%P=0.0040

6

12

18

24

300

6

12

18

24

30

36

42

4836

42

48時間

(月)時間

(月)EFSOS多因素分析95%CIP值0.00895%CI0.19-1.14

0.031P值HR0.37HR0.47R-EPOCHvs

R-CHOP0.18-0.77R-HCVAD

vs

R-CHOP0.611.920.36-1.050.91-4.010.0740.0840.672.860.37-1.211.28-6.3900其他

vs

R-CHOP回顧性研究分析129例DHL患者的數據Oki

Y,et

al.

BrJ

Haematol

2014;

166(6):891-901.高級別B細胞淋巴瘤11項研究薈萃分析：R-EPOCH及劑量增強的免疫化療方案是DHL一線有效治療策略?

首個DHL患者治療結果薈萃分析結果表明：R-EPOCH較R-CHOP顯著改善DHL患者PFS，降低進展風險，但OS相似100806040200100806040R-EPOCHDI(R-Hyper-CVAD/R-CODOX-M/IVAC)R-CHOPR-EPOCHDI(R-Hyper-CVAD/R-CODOX-M/IVAC)

20R-CHOP12002436

486001224364860時間

(月)時間

(月)治療中位OS，月21.4OSHR(95%

CrI)參照P值-中位PFS，月12.1PFSHR(95%

CrI)參照P值R-CHOPR-EPOCHDI-31.40.77(0.51-1.13)0.89(0.62-1.27)0.1860.53122.20.66(0.44-0.96)0.74(0.51-1.05)25.218.9Howlett

C,

et

al.BrJ

Haematol

2015;

170(4):504-14.高級別B細胞淋巴瘤MDACC:

R-DA-EPOCH優化治療DHL?

DA-EPOCH-R治療DHL(GCB)，無MYC和BCL2表達的DLBCL(GCB)以及DEL(GCB和非GCB)患者OS相似?

DA-EPOCH-R治療高危患者療效顯著，可能克服R-CHOP治療時的丌良預后因素1.0變量年齡結果DHL(GCB)DEL(GCB)DELP≤60>607(31.8%)15(68.2%)30(65.2%)16(34.8%)6(37.5%)10(62.5%)0.020.80.60.40.2BM-+12(68.2%)10(45.5%)41(89.1%)5(10.9%)14(93.3%)1(6.7%)0.0020.730.21DHL(E/N=4/22)DEL

(E/N=3/16)DLBCL(E/N=4/46)P=0.2617ki67<80%≥80%4(21.1%)15(78.9%)7(16.3%)36(83.7%)4(25%)12(75%)結外部位0/1≥211(50%)11(50%)31(68.9%)14(31.1%)8(50%)8(50%)0.01.0012243648)607284時間

月(低

0-1中

2高

3-55(22.7%)2(9.1%)15(68.2%)21(45.7%)9(19.6%)16(34.8%)2(12.5%)4(25%)10(62.5%)IPI0.030.80.60.4DA-EPOCH-R治療應答<CRCR6(27.3%)16(72.7%)5(10.9%)41(89.1%)4(26.7%)11(73.3%)NS0.31年OS

(95%

CI)1年PFS

(95%CI)DHL(E/N=6/22)DEL

(E/N=6/16)DLBCL(E/N=7/46)P=0.08480.79(0.62-1)0.91(0.84-1)0.86(0.69-1)0.20.00.72(0.56-0.94)0.87(0.78-0.97)0.65(0.44-0.95)0.080122436486時間

(月)回顧性分析納入2010-2014年MD

Anderson癌癥中心233例接受DA-EPOCH-R治療的新診斷高危DLBCLSathyanarayanan

V,et

al.

2016

ASH

106.高級別B細胞淋巴瘤CR后給予ASCT一線鞏固治療：并沒有提高EFS/OSP=0.17P=0.56Oki

etal.

BrJHaematol.

2014

Sep;166(6):891-901高級別B細胞淋巴瘤復發/難治DHL:

ASCT二線治療療效差117patients

wereincluded;

44%had

DEL

and

10%had

DHL.J

ClinOncol

35:24-31.高級別B細胞淋巴瘤Risk

of

CNSinvolvement

建議所有患者CR都應進行中樞神經系統預防治療

尚無充足的研究結果證實全身CNS預防比傳統的鞘內注射對中樞侵犯的預防效果更好Oki

et

al.BrJ

Haematol.

2014

Sep;166(6):891-901Adam

M.Petrichet

al.

Blood

2014;124:2354-2361高級別B細胞淋巴瘤Intensive

Chemo

+Allo-HSCT

DHL

doverypoorly

with

SDalone.

DIstrategies

with

allogeneic

SCT

leadtosignificantly

longer

PFSand

OS.Christina

Howlett,

Blood

2013

122:2141;高級別B細胞淋巴瘤研發中的新藥和新方法分類BTK

抑制劑PI3K抑制劑IbrutinibIdelalisibBCL-2抑制劑MYC

抑制劑ABT-199BET

結構域蛋白BCL-6

抑制劑Aurora酶

抑制劑CART細胞免疫治療高級別B細胞淋巴瘤1555Objective

Responses

Achieved

inPatientswithMYC-AlteredRelapsed/Refractory

Diffuse

LargeB-CellLymphoma

Treated

withthe

Dual

PI3KandHDAC

InhibitorCUDC-907(NCT02674750)DanielJ.Landsburg,

MD,

et

al.AbramsonCancer

Center,UniversityofPennsylvania,Philadelphia,

PA高級別B細胞淋巴瘤Contents

CUDC-907,

a

first-in-classoral

dual

inhibitor

ofHDACandPI3Kenzymes,hasdemonstrateddownregulation

ofMYC

mRNAandproteinlevels

Phase2study

isdesigned

tofurther

explore

theefficacyof

CUDC-907

inDHL

andDELpatients

Patientswith

confirmedMYC-altereddisease

bycentralimmunohistochemistry

(IHC)testing

Patientsreceive

60mgofCUDC-907

orally

onceadayon

a5days

on/2days

off

schedule

in21-daycycles

3CRand4PR.TheORRwas

19.4%(7/36)

AEwerediarrhea,

nausea,

fatigue,thrombocytopenhypokalemia,

andvomiting高級別B細胞淋巴瘤4035

Assessment

of

CD52Expressionin

"Double-Hit"

and

"Double-Expressor"

Lymphomas:

Implicationsfor

Clinical

Trial

Eligibility(ID:NCT03132584)Jeffrey

W.Craig,etal.Departmentof

Pathology,Brigham

andWomen'sHospital,Boston,MA高級別B細胞淋巴瘤Contents

PhaseI

trial

investigating

theuseofalemtuzumabandlow-doseCTXfor

thetreatment

ofDHL/THL

andDEL

Study

included

35DHL,5THL,7HGBCL,NOS,and

51DLBCL,NOS

75%ofDHL/THL

andDELexhibited

convincingcytoplasmicand/ormembranous

CD52

expression

Results

suggesting

that

alemtuzumab-based

therapymay

beappropriate

formost

patients

Target

validation

mustbe

performedonacase-by-casebasis高級別B細胞淋巴瘤577

JULIET:

Phase

IIPrimaryAnalysisof

CART-Cell

TherapyTisagenlecleucel

inAdult

Patients

WithRelapsed/Refractory

DLBCL(NCT02631044)StephenJ.

Schuster,

MD,

etal.Lymphoma

Program,

AbramsonCancerCenter,UniversityofPennsylvania,Philadelphia高級別B細胞淋巴瘤JULIET:

Study

DesignInternational,single-arm,

open-label

phaseIItrialTisagenlecleucelinfusion(0.6-6.0

x108CAR+viableT-cells)?Screening,apheresis,cryopreservationRestaging,lymphodepletionAdult

DLBCL

ptswithcentrallyconfirmedhistology;

≥2prior

tx

lines

forDLBCL;

PD(n

=99?)PosttreatmentFollow-up§(n

=81Tisagenlecleucelevaluable)manufacturing*following

orineligible

forautoHSCT;

noprior

anti-CD19tx;noactive

CNSinvolvement(N

=147)Day-2

toDay-14Bridgingchemotherapy*Centralized

inUSorGermany.

?Ptsreceived

US-made

tisagenlecleucelinpatient

or

outpatient,

with26%receiving

outpatient

infusion,

77%

ofwhomremained

outpatient

≥3dayspost

infusion;

1pt

infused

with<0.6

x

108

CAR+viable

T-cells;

?D/cbefore

preinfusion:

n=43

(inability

to

manufacture,related

topt

status,

n=34);

infusion

pending

for

additional

5pts.

Ima3

mos.

Data

cutoff:

March

2017.Schuster

SJ,

et

al.

ASH2017.

Abstract

577.高級別B細胞淋巴瘤JULIET

PrimaryAnalysis:BaselinePtCharacteristicsPts(n

=99)Pts(n=99)Baseline

CharacteristicsBaselineCharacteristics,

%Median

age,

yrs

(range).

≥

65

yrs,%56

(22-76)23No.priorlines

ofantineoplastic

tx.

2443119ECOG

PS0/1,

%55/45.

3.

4-6Histology,%.

DLBCL.

Transformed

FL8019Response

tolasttx.

Refractory.

RelapsedDouble/triple

hits

inCMYC/BCL2/BCL6,*

%524815Cell

of

origin,

%PriorautoHSCT47.

Germinal

center

B-cell

type.

Nongerminal

center

B-celltype5242

90%of

pts

received

bridgingchemotherapy,

93%of

pts

receivedlymphodepleting

chemotherapy*CMYC/BCL2,

n=4;

CMYC/BCL6,n=3;CMYC/BCL2/BCL6,

n=8.Schuster

SJ,

et

al.

ASH2017.

Abstract

577.高級別B細胞淋巴瘤JULIET:

Best

ORR(PrimaryEndpoint)3-MoResponse(n

=81)6-MoResponse(n

=46)Best

ORR(n

=

81)Response,

%ORR

(CR

+PR)533837.

CR.

PR4014326307

Studymetprimaryendpoint

with

ORRof53%

(95%CI:42%to64%)?

Significantly

greaterthan

null

hypothesis

ORR≤20%(P<.0001)?

No

relationship

apparent

between

tisagenlecleucel

doseand

3-moresponse?

Responses

observed

acrossentire

dose

rangeSchuster

SJ,

et

al.

ASH2017.

Abstract

577.高級別B細胞淋巴瘤JULIET:

ORRby

SubgroupsNull

Hypothesis

of

ORR≤

20%ORR,n/N

(%)95%

CI43/81

(53.1)

41.7-64.3All

PtsAge,

yrs<

6532/64

(50.0)

37.2-62.811/17

(64.7)

38.2-85.8≥

65SexFemaleMale18/29

(62.1)

42.3-79.325/52

(48.1)

34.0-62.4Prior

antineoplastic

therapy≤

2lines>

2lines22/41

(53.7)

37.4-69.321/40

(52.5)

36.1-68.5Cell

of

origin*19/34

(55.9)

37.9-72.819/41

(46.3)

30.7-62.6Nongerminal

centerGerminal

centerRearranged

MYC/BCL2/BCL6Double/triple

hitsOther5/12

(41.7)15.2-72.338/69

(55.1)

42.6-67.160708090100ORR

(%)*Data

missing

for

6pts

ORR

consistent

across

subgroupsSchuster

SJ,

et

al.

ASH2017.

Abstract

577.

Reprinted

withpermission.高級別B細胞淋巴瘤193CAR

T-Cell

Therapy

JCAR017

inR/RDLBCL

FromTRANSCEND

NHL

001:CorrelationBetween

Patient

CharacteristicsandClinical

Outcomes(NCT02631044)JeremyS.

Abramson,

MD,

MMSc1,Massachusetts

General

HospitalCancerCenter,Boston,MA高級別B細胞淋巴瘤TRANSCEND

NHL001:

Study

Design

Multicenter,

multicohort,

open-label

phase

I

trial?

DLBCLCORE(n=67):high-grade

B-celllymphoma

(double/triple

hit),DLBCLNOSdenovo

ortransformedfromFL?

DLBCLFULL(n=91):CORE+ptswith

DLBCL

transformedfromCLL/MZL,PMBCL,orFL3BEnrollment,apheresis,JCAR017Pts

withR/RmanufacturingDLBCL

Dose-FindingDLBCL

Dose-ExpansionCohortCohortJCAR017?

IVDL1S:

5x107

cellssingledose,

D1;DL1D:

5x107

cellsdoubledose,

D1,D14;DL2S:

1x108

cellssingledose,

D1DLBCL

after2

lines

of

txor

R/RMCLafter

1

lineof

tx*Pivotal

DLBCL

cohortenrollment

ongoing(JCAR017?

IVDL2S)JCAR017?

IVDL1S,

DL2S*Pts

could

receivelow-dose

CT

for

disease

control

during

JCAR017