2017ash传达-急性髓性白血病简单版

AML-如何提高“标准治疗”？医院主要内容AML分类和风险评估：细胞遗传学和分子表达谱AML

：表观遗传学治疗和化疗如何选择？AML

：靶向治疗主要内容AML分类和风险评估：细胞遗传学和分子表达谱AML

：表观遗传学治疗和化疗如何选择？AML

：靶向治疗AML患者的组学不稳定性AML重排

非整倍体突变重排20%非整倍体32%突变46%3%未知重排20%非整倍体32%突变46%重排AML： 组学简单、低突变负荷信号传导通路活化重排20%非整倍体32%突变46%非整倍体AML与TP53突变高度相关重排20%非整倍体32%突变46%突变AML：突变数量大、共突变复杂、设及特定的

组重排20%非整倍体32%突变46%30-50岁>50岁>50-60岁随着 增加，突变的多样性和复杂性增加！2008WHO2016WHO填补WHO分类的空隙DÖhner

H,

et

al.

Blood,2017;129:424-4472017

ELN-AML建议未来对AML

分层需要考虑的标志：SRSF2, MLL-PTD,SF3B1,U2AF1，STAG22016WHO和2017ELN-单突变对预后的影响主要内容AML分类和风险评估：细胞遗传学和分子表达谱AML

：表观遗传学治疗和化疗如何选择？AML

：靶向治疗AML

front-Iine

treatment

decision-makingInitial

treatment

-Intensiveversusless-intensive

therapy?Intensive

chemotherapy（ICT）DNR/IDA+cytarabine±GO±

ed

agentsLower

Intensity

therapyLow-dose

cytarabineHypomethylating

agents(HMAs,including

azacytidine

and

decitabine)Age＆HealthStatusAML

RiskResults

of

ICT

in

older

fit

patientsAraC

1.5g/m2/12h※

D1/3/5※reduced

to

lg/m2/12h

ifage≥70yClinical

Trial.

ID,NCT01966497Patients,

N509Median

age,

years(range)68

years

(60-85)Patients

aged

＞70years,

N

(%)162

(32%)ECOG-PS0/1/2/3/NA,N219/219/57/9/5HCT-CI0/1/2/3/4+/NA,N226/92/66/61/54/10Secondary

AML,N(%)88

(17%)ELN-2010risk,

N(%)favorable76(15%)Intermediate347(68%)Adverse86

(17%)The

recent

ALFA-1200

studyIDA

12mg/m2

D1-3AraC

200mg/m2

D1-7AraC

1.5g/m2/12h※

D1/3/5CR

orCRpResults

of

HMAs

in

older

unfit

patientsHMA

versus

low-dose

cytarabine/best

supportive

careDecitabine

AzacitidineCR+CRi

28%

CR16%

CR+CRi28%

CR20%JC0

2012，30：2670-77Blood

2015：126:291-99Results

of

azacitidine

in

WHO-MRC

AMLA

subgroup ysis

of

the

AZA-AML-001

studyDecitabine

in

TP53-mutated

AML116

patients

with

AML

or

MDS

treated

with

10-day

courses

of

decitabine-Higher

response

rates

in

patientswith

an

unfavorable-risk

cytogenetic

profile

(67%

vs.

34%,

P<0.

001)with

TP53

mutations

(100%

vs.

41%,

P<0.

001).N

EnglJ

Med

2016

,375:2023-2036How

to

decide

between

ICTand

HMAs?HMAs

vs

ICT-Treatment

decision-makingFactors

in

favor

of

intensive

chemotherapyFactors

in

favor

of

epigenetic

therapyAge

<70

yearsAge

≥80

yearsECOG-PS

<2ECOG-PS≥2Low

CCI,

HCT-Cl

（＜3）High

CCI,

HCT-Cl

（≥3）Higher

WBCLower

WBCde

novo

AMLSecondary

AML(post-MDS,

post-MPN)AML

not

classified

as

WHO

MRC-AMLAML

classified

as

WHO

MRC-AMLFavorable

genetics-Favorable

ELN

categoryUnfavorable

genetics-Monosomy5

or

7,del(5q)-complex,

monosomal

karyotype-TP53

gene

mutationFLT3-ITDNo

FLT3-ITDNo

epigeneticgene

mutation?Epigenetic

gene

mutations

(TET2,

DNMT3A)

?New

agents and

combinations主要内容AML分类和风险评估：细胞遗传学和分子表达谱AML

：表观遗传学治疗和化疗如何选择？AML

：靶向治疗AML突变发现的时间Grimwade

D

et

al.Blood

2016FDA批准非M3-AML更新版1.Midostaurin2.Enasidenib3.CPX-351(Vyxeos)FLT3突变启动信号转导ITD25-30%High

relapse,poor

prognosisTKD5-10%Clinically

associated

withNormal/intermediate

risk

karyotypeNPM1

and/orDNMT3A

mutationsHigh

WBC,highmarrow

blast%Litzow

MR,Blood.2005;106:3331-3332Levis

MJ

et

al.Blood.2002

Jun

1;99(11):3885-91Ley

TJ,et

al.

N

Engl

J

Med

2013;368:2059-2074RATIFY/C10603Stone

RM,et

al.NEJM

2017RATIFY/C10603

OSHazard

Ratio*:0.771-sided

log

rank

p-value*:0.0074Stone

RM,et

al.NEJM

2017新型FLT3抑制剂DrugHalf

life(dosing)D835activitySelectivitySingle

agentRelapse/refractoryChemocombinationsQuizartinib(AC220)Long(once

daily)NONarrow,inhibits

KITPhase

3Enrollment

completePh1/2

completed1，Ph3ongoingCrenolanibShort(TID)YesNarrow,spares

KITN/A(Phase

3

withchemo

ongoing)Ph2

completed2Ph3

to

open

2018Gilteritinib(ASP2215)Long(once

daily)YesNarrow,spares

KITPhase

3ongoingPh1/2

ongoing3Altman

JK,et

al

ASH s

2013;Burnett

AK,et

al

ASHWang

ES,et

al.#566

Monday

7:15

AMPratz

KW,et

al.#722

Monday

3:00

PMs

2013IDH突变的功能AML

cellIDH

mutations

occur

in

20%

of

AML

andproduce2-hydroxyglutarate(2HG)2HG

inhibits

multiple

αKG

dependent

enzymesTET

2(cytosine

methylation)Jumonji-Chistone

lysinedemethylasesCytochrome

C

oxidaseIDH1/IDH2

mutations

induce

BCL-2dependence(Chan,Nature

Medicine,2015)R-2HG

suppresseshomologousbination(Sulkowski,Science

TranslationalMedicine,2017)Prensner

and

Chinnaiyan

Natuer,2011IDH

2抑制剂Enasidenib½期试验Advanced

hememalignancies

withIDH2

mutationContinuous

28

daycyclesCumulative

dailydoses

of

50-650mgRR-AML

age≥60，or

any

ageif relapsed

post-BMT

RR-AML

age＜60，excluding

pts relapsed

post-BMT

Untreated

AML

pts

age≥60

whodecline

standard

of

careAny

hematologic

malignancyineligible

for

otherarmsEnasidenib100mg

POQDRR-AML（N≈125）DoseEscalation Expansion

Phase

1Phase

2KeyEndpoints:Safety，tolerability，MTD，DLTsResponse

ratesas

assessed

bylocal

investigator

per

IWG

criteriaAssessment

of

clinical

activityStein

EM,Dinardo

CD

,et

al.Blood

2017Enasidenib

phase

1/2

R/R

AML100mg

once

daily

N=109CR22(20%)CRi

or

CRp7(6%)PR3(3%)“marrowCR”/MLFS10(9%)Stable

disease58(53%)Progressivedisease5(5%)Not

evaluable2(2%)Median

survival=9.3

monthsMediansurvival

of

CR

patients=19.7

monthsStein

E，Dinardo

CD，et

al，Blood

2017IDH抑制剂：分化综合征Seen

in

~10%

of

patients

on

IDHinhibitorsCan

precede

marrow

responseSymptoms

include:Fever，respiratory

distress，pulmonaryinf

，effusions，weight

gain，renal

insufficiency，

itant

leukocytosisEssential

Management:Prompt

initiation

of

corticosteroids，furosemide，hydroxyurea，consider

temporary

hold

of

IDH

inhibitorSlide

courtesy

of

Courtney

DinardoIDH抑制剂：批准和试验IDH2

inhibitorEnasidenib(approved)IDH1

inhibitorsLvosidenibIDH-305FT-2102BAY1436032GOAccelerated

approval

in

2000at9

mg/m2dose(full

approvalrequired

confirmatory

Ph3data)Initial

ph3

suggested

highertoxicityand

induction

mortalityConcerns

re：hepatotoxicityWithdrawn

from

market

in

2010Schrama

D,et

al

Nat

Rev

Drug

Dev2006GOALFA

0701

study

280

patients

age50-70Dauno

60

mg/m2

D1-3AraC

200mg/m2

D1-7CI+/-

GO

3mg/m2

d1,4,7NoGO

if

2nd

cycle

neededPost-remission

Dauno/IDAC

+/-

GOEquivalent

CRratesFewer

relapses

with

GOCastaigne

S,et

al.Lancet

2012VENETOCLAX+LDAC

or

HMAAML

blasts

overexpress

the

anti-apoptotic

proteinBCL2BCL2

promotes

survivalby

sequestering

BH3-only

anti-apoptotic

proteinsVenetoclax(VEN)is

a

small-molecule

BH3-mimetic

with

selectivity

for

BCL2BCL2

preferentially

binds

VEN,leading

to

releaseof

BH3-onlypro-apoptotic

proteins

thatinitiateapoptosisVEN

combination

studies

ongoing

in

order

AMLpatients

who

are

unfit

for,or

refused

inductionSpierings,et

al.Science

2005Phase

1/2

Study

of

Venetoclax

with

Low-Dose

Cytarabine

inTreatment-Naive,

Elderly

Patients

with

AML

Unfit

forIntensive

Chemotherapy:

1-Year

es

890#特性VEN600mg

(n=61)中位74

(66-87)>75岁,n(%)30(49)细胞遗传学,n(%)中等预后37(61)不良预后19(31)无

象5(8)继发AML,n(%)27(44)HMA治疗史,n(%)17(28)研究结果CR/CRi

:

62%-达到反应的中位时间：1个月在获得CR/CRi

的患者中-中位OS 18.4个月-1年OS

70.4%早期 率（30天内）：3%，n=2(进展1例，肺部

1例）在不同遗传学亚型AML中的效果*7例NPM1中4例伴FLT3突变，ITD3例，TKD1例SO

HOW

DO

WE

TREAT

AML

IN

2017？Like

most

veterinary

students，Doreenbreezes

through

Chapter

9Treatment

approach

prior

to2017:Proposed

treatment

approach

in

2017t-AML

OR

AML-MRC(e.g.

COMPLEX

KARYOTYPE)CD33+(NON-ADVERSE

RISK

KARYOTYPE)FLT3

MUTATION+IDH

MUTATION+ALL

OTHERS“QUADRUPLE

NEGATIVE”FIT：CPX-351（esp.AGE＞60）UNFIT：HMAFIT：7+3+MIDOSTAURINUNFIT:HMAFIT：