aml therapy in china by jian xiang wang

Current Status of Acute Myeloid Leukemia in China

Jianxiang WangInstitute of Hematology Hospital of Blood Disease

Chinese Academy of Medical Sciences

Shen Y et al. Blood 2011;118:5593-5603

Characteristics AML without prognostic cytogenetic markers

(group)

CBF leukemias

APL

Sex.no.of patients(%) Male 348(29.4) 104(8.8) 199(16.8) Female 257(21.7) 72(6.1) 189(15.9)Mean age, y 43.2+18.9 31.4+19.5 34.7+17.1 Range 18-86 18-75 18-80 N0.of the patients<60

481 160 354

Median WBC count,109/L

13.35(0.5-453) 10.05(0.8-177.9)

2.9(0.3-205.7)

Median BM blasts,%

69(22.5-97) 60(23.5-91) 64(22.5-91.0)

AML Prognosis Factors(Shang Hai/Zhe Jiang Institute of Hematology ）

Shen Y et al. Blood 2011;118:5593-5603

CR OS EFSvariables P OR(95%CI) P OR(95%CI) P OR(95%CI)Age <.001 0.976(0.966-

0.987)<.00

11.018(1.011-

1.027)<.001 1.013(1.006-

1.02)

WBC count

.02 0.996(0.992-0.999)

.022 1.002(1.000-1.004)

.044

BM balsts NS. NS. NS.FLT ITD/TKD

NS. NS. NS.

C-KIT NS. NS. NS.N-RAS NS. NS. NS.NPM1+/DNMT3A-

.001 2,533(1.43-4.488)

.014 0.626(0.431-0.91)

.012 0.638(0.45-0.906)

Bi-CEBPA 0.005 2.45(1.319-4.553)

<.001

0.396(0.214-0.65)

.001 0.488(0.319-0.746)

WT1 NS. NS. NS.ASXL1 NS. NS. NS.DNMT3A .036 0.486(0.248-

0.953).005 1.753(1.189-

2.583).010 1.638(1.123-

2.388)

MLL NS. .002 1.803(1.240-2.623)

.004 1.642(1.167-2.311)

IDH1 NS. NS. NS.TET2 NS. NS. NS.

CR, OS and EFS- Multivariate Analysis

OS and EFS According to Genotypes -Multivariate Analysis.

Shen Y et al. Blood 2011;118:5593-5603

Homoharringtonine(HHT)- based induction therapy

Induction therapyHAA HHT 2mg/ m2/d d1-7 Acla 20mg /d d1-7 Ara-C 100mg/ m2/d d1-7HAD: HHT 2mg/ m2 /d d1-5/7 DNR 40 mg/ m2 /d d1-3 Ara-C 100 mg/ m2 /d d1-7 DA: DNR 40/45mg/ m2 /d d1-3 Ara-C 100mg/m2/d d1-7

HHT -based induction therapy for patients of de novo AML（ from multicenter randomized controlled trial )

ID-Ara-C*2

DA/HA ， MA ， DA/HA ， AA

CR PR/(reduced blast cells≥60 ％ )

NR/(reduced blast cells<60 ％ )

Continued previous regimen

Salvage therapyPR/NR

Withdraw from the study

CR

Observed for 3-year

Patients were randomly assigned to HAA ， HAD or DA treatment groups

Number(%) P-value

DA(N=202) HAA(N=200) HAD(N=194) HAA:DA HAD:DA

1-cycle 109(54.0%) 135(67.5%) 126(64.9%) 0.005 0.026

2-cycle 125(61.9%) 150(75%) 133(68.6%) 0.005 0.163

CR rate i n i nducti on therapy

00. 10. 20. 30. 40. 50. 60. 70. 8

DA HAA HAD

perc

enta

ge cycl e-1cycl e-2

CR Rate

Group median range Group median range Group median range

HAA 26.0 (16.3-35.7)M HAA 11.7 (8.6-14.8) M HAA 31.3 not reach M HAD 22.6 (12.3-32.9) M HAD 8.6 (5.4-11.8)M HAD 21.7 not reach M DA 21.1 (15.1-27.1)M DA 6.9 (4.0-9.8) M DA 15.5 ( 10.8-20.2)M

OS EFS

HAA:DA P=0.584

HAD:DA P=0.979

HAA:DA P=0.003

HAD:DA P=0.091

HAA:DA P=0.115

HAD:DA p=0.220

RFS

Survival

诱导方案对低 / 中危险组的影响

EFS

os

HAA:DA P=0.017

HAD:DA P=0.814

HAA:DA P=0.001

HAD:DA P=0.368

HAA:DA P=0.030

HAD:DA P=0.530

RFS

Group median range Group median range Group median range HAA not reach not reach M HAA 15.2 (8.7-21.7)M HAA not reach not reach M HAD 20.6 (8.6-32.6)) M HAD 8.0 (5.1-10.9)M HAD 17.8 not reach M DA 18.4 (11.7-25.1) M DA 7.5 (5.0-9.8)M DA 15.9 ( 9.5-22.3) M

Survival Patients with favorable/intermediate

cytogenetic profile

os EFS

HAA:DA P=0.059

HAD:DA P=0.760 HAA:DA P=0.424

HAD:DA P=0.973

RFS

HAA:DA P=0.058

HAD:DA P=0.421

Group median range Group median range Group median range HAA 7.6 (0-15.8) M HAA 2.2 (0.2-4.2) M HAA 3.8 (0.0-13.9) M HAD 17.1 (0-34.5) M HAD 2.1 (0-12.3) M HAD 11.9 not reachM DA 10.9 (4.9-17.0) M DA 1.1 (0.2-2.0) M DA not reach not reach M

Patients with poor cytogenetic profile

DA (n=205) HAA (n=206) HAD (n=198)

No.(%) No.(%) P （ vs.DA ） No.(%) P （ vs.DA ）Hemorrhage 13/193(6.7%) 10/191(5.2%) 0.536 15/186(8.1%) 0.621

Hepatic 3/192(1.6%) 5/189(2.6%) 0.500 4/185(2.2%) 0.719

Renal 0/193(0) 0/187(0) - 0/183(0) -

Cardiac 0/193(0) 3/188(1.6%) 0.119 3/185(1.6%) 0.116

Gastrointestinal 9/184(4.9%) 12/182(6.6%) 0.484 11/172(6.4%) 0.538

Infection (0-4) 144/186(77.4%) 156/188(83.0%) 0.177 141/178(79.2%) 0.678

Adverse Events

ID-Ara-C 、 Homoharringtonine (HHT)- based induction therapy

ID-Ara-C-based induction therapy

Induction of Ara-C dose effect relation

Am. J. Hematol. 2009, 84:422–427.

2010.9.1- 201 de novo<55, AML patients were enrolled follow up to

2012.12.31 ， The median follow-up 8.85 （ 0.33-27.67 ） months Male 105 ， Famale 96 Median age 37 （ 15-54 ） At diagnosis median WBC count 12.7(0.81-275.4) ×109/L,

median HGB 81(36-162)g/l ， median PLT 35(3-415)×109/L

HHT/ID-Ara-C-based inductin therapy for the patients of de novo AML

（ the data of Chinese Academy of Medical Sciences Institute of Hematology)

Induction therapy HAD group HHT 2mg/HHT 2mg/ ㎡㎡ /d d1-7/d d1-7

Ara-c 100mg/Ara-c 100mg/ ㎡㎡ /d d1-7/d d1-7 DNR 40mg/DNR 40mg/ ㎡㎡ /d d1-3/d d1-3

ID-HAD groupID-HAD group HHT 2mg/HHT 2mg/ ㎡㎡ /d d1-7/d d1-7 Ara-c 100mg/Ara-c 100mg/ ㎡㎡ /d d1-4/d d1-4 , , 1g/1g/ ㎡㎡ /q12h d5-7/q12h d5-7 DNR 40mg/DNR 40mg/ ㎡㎡ /d d1-3/d d1-3Early consolidation therapyEarly consolidation therapy

HD-Ara-C group Ara-c 3.0g/Ara-c 3.0g/ ㎡㎡ /q12h d1-3 3/q12h d1-3 3 cycle cycless

ID-Ara-C groupID-Ara-C group DNR DNR 40mg/40mg/ ㎡㎡ /d d1-3/d d1-3 Ara-cAra-c 1.5g/ 1.5g/ ㎡㎡ /q12h d1-3/q12h d1-3

MTZ MTZ 8mg/8mg/ ㎡㎡ /d d1-3/d d1-3 Ara-cAra-c 1.5g/ 1.5g/ ㎡㎡ /q12h d1-3/q12h d1-3

Late consolidation therapyLate consolidation therapy HA HHT HHT 2.5mg/2.5mg/ ㎡㎡ /d/d d1-6 1-6 Ara-c Ara-c 100mg/ ㎡ /d d1-61-6

continuous 2 cyclescontinuous 2 cycles MA MA MTZ MTZ 8mg/8mg/ ㎡㎡ /d d1-3/d d1-3 Ara-c 100mg/ 100mg/ ㎡㎡ /d/d d1-6d1-6

continuous 1-2 cyclescontinuous 1-2 cycles

R

R

Risk category (based on cytogenetics and molecular abnormalities)

Risk status

cytogenetics Molecular abnormalities

better-risk inv(16)t(8;21)t(16;16)

normal cytogenetics: with NPM1 mutation or isolation CEBPA mutation in the absence of FLT3-ITD

Intermediate-risk

Normal+8 、 t(9;11)Other non-defined

t(8;21), inv(16) , t(16;16)

with c-KIT mutation

Poor-risk complex(3 clonal chromosomal abnormalities)－ 5, － 7,5q-7q-,11q23 non t(9;11), Inv(3), t(3;3), t(6;9), t(9;22)

Normal cytogeneticsWith FLT3-ITD mutation

NR n=26(25.2%)death n=1 (0.97%)no evalution n=2

NR n=6 (6.1%)death n=6 (6.1%)no evalution n=2

CR n=74（ 71.8% ） Discontinuen=5 (6.7%)

CR n=84（ 85.7% ）Discontinuen=8 （ 9.5% ）

201 AML patients（≤ 55 years ）

SD-Ara-C induction （ n=103 ）

ID-Ara-C induction （ n=98 ）

HD-Ara-C （ n=75 ）

ID-Ara-C （ n=70 ）

低危组

Poor

Induction therapy for risk stratificationfavorable

induction therapy

SD-Ara-C group ID-Ara-C group

97.4% 94.3% （ 38/39 ）（ 33/35 ） P>0.05

induction therapy

SD-Ara-C group ID-Ara-C group 70.3% 82.1% （ 26/37 ）（ 32/39 ） P<0.05

intermediate

induction therapy

SD-Ara-C group ID-Ara-C group 40.0% 86.4% （ 10/25 ）（ 19/22 ） P<0.05

D. Description of the contents

2 years OS rate 62% 2 years RFS rate70%

Follow up to 2012.12.31, 42patients died.7 patients died during induction therapy,19 patients died because of relapse,16 patients died after NR

Follow up to 2012.12.3124 patients relapse

Survival

Poor

intermediate

低危组 favorable

P=0.0 P=0.015

favorable intermediate PoorDeath(N.) 6/74 18/76 17/47 2 yearsOSrate 80% 58% 43%

favorable intermediate PoorRelapse(N.) 6/70 10/58 8/292 yearsDFS rate 76% 71% 52%

Survival Risk groups

Cum

sur

viva

l

OS(months ）

favorable

intermediate

PoorC

um s

urvi

val

RFS(months ）

D. Description of the contents SD-Ara-c group ID-Ara-c group

Death(N.) 21/101 20/96

2 years OS rate 55% 67%

SD-Ara-c group ID-Ara-c groupRelapse(N.) 11/73 13/84

2 years RFS rate 62% 76%

Cum

sur

viva

l

OS(months ）

ID-Ara-c induction group

SD-Ara-c induction group

P=0.491 P=0.773

ID-Ara-c induction group

SD-Ara-c induction group

Cum

sur

viva

lRFS(months ）

Induction therapy

Survival

C. Description of the contents


SurvivalInduction therapy

Better-risk Intermediate-risk Poor-risk

ID-Ara-C induction group

P=0.815

SD-Ara-C induction group



Cum

sur

viva

l

Os (months)

Cum

sur

viva

l

P=0.75

Cum

sur

viva

l

Os (months)



P=0.11

Os (months)


Survival

HD-Ara-c group

ID-Ara-c group

HD-Ara-c ID-Ara-cDeath (N.) 11/75 8/70

2 years OS rate 71% 76%

HD-Ara-c ID-Ara-c

Replase (N.) 15/75 9/62

2 years DFS rate 61% 78%

consolidation therapy

P=0.404

ID-Ara-c group

HD-Ara-c groupCum

sur

viva

l

Os (months)

P=0.191Cum

sur

viva

l

RFS (months)

Survival


P=0.082 P=0.885P=0.358

consolidation therapy

ID-Ara-c group

HD-Ara-c group ID-Ara-c group

HD-Ara-c group HD-Ara-c group

ID-Ara-c group

Cum

sur

viva

l

Os (months)

Cum

sur

viva

l

Cum

sur

viva

lOs (months) Os (months)

Survival

P=0.108 P=0.014


P=0.83

Induction, consolidation therapy

ID-Ara-C /ID-Ara-C group

ID-Ara-c / HD-Ara-C group

SD-Ara-C / ID-Ara-C group

SD-Ara-C / HD-Ara-C group

Os (months)

Cum

sur

viva

l

Cum

sur

viva

l



SD-Ara-C/ HD-Ara-C group


Os (months)

Cum

sur

viva

l

SD-Ara-C/ HD-Ara-C group




Os (months)

ID-Ara-C（ n=98 ）

SD-Ara-C （ n=103 ）

Induction Related Mortality 6 （ 6.1%) 1(0.97%) P>0.05

the lowest WBC count（ ×109/L ）

0.07（ 0.01-0.38 ）

0.23（ 0.02-1.44 ） P =0.0

WBC< 1×109/Lcontinuous days

15（ 5-28 ）

14.5 （ 6-41 ） P =0.041

infection （ n=89 ）（ n=76 ） P =0.03

3-4Ⅱo intestinal ,crissum infection

17 （ 19.1%) 11(14.5%)

3-4Ⅱo oral cavity ,gingiva infection

2 （ 2.2% ） 3 （ 3.9% ） 4ⅡoSepticemia 18 （ 20.2% ） 9 （ 11.8% ）

Liver infection 3 （ 3.3% ） 1(1.3%)3-4Ⅱolung infection 25(28.1%) 26(34.2%)

Adverse Events

Summary Currently, major hematological centers in China

has been established diagnosis and classification system of AL based cytogenetics and molecular genetics.

The therapy of AML in China has achieved dramatic progress, improved long -term survival of AML patients substantially.

Cooperative groups are required for clinical trials.

Thank you

aml therapy in china by jian xiang wang

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