Outcome of children with newly diagnosed ALL treated with CCLG-

2008 ALL Study

Chi-kong LI, MBBS, MDProfessor, Department of Paediatrics

Division of Haem/Onc/BMTPrince of Wales Hospital, Hong Kong Children’s Hospital

The Chinese University of Hong Kong

대한혈액학회 Korean Society of Hematology

COI disclosureName of author ： LI Chi-kong

I currently have, or I have had in the past two years, an affiliation or financial interest with business corporation(s):

(1) Consulting fees： Yes, Amgen Asia Ltd

(2) Research fundings： No

(3) Others No

Overall survival probability by treatment era for patients enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005.

Hunger S P et al. JCO 2012;30:1663-1669

Large number of patients recruited into

various clinical trials

83.7%

90.4%

80.1%

83.9%;COG

Conter, V. et al. Blood 2010;115:3206-3214

AEIOP-BFM ALL 2000 Trial” EFS (A) and cumulative incidence of relapse (B) according to PCR-MRD classification in pB-ALL patients

3184 patients treated in the AIEOP-BFM-ALL 2000 trial.

Stratified into 3 risk groups according to MRD as detected by q-PCR

Standard Risk

Intermediate risk

High Risk

Relapse Risk

EF Survival

European Study

Reports of Childhood ALL from China Centers: Single centres

year Center No. outcome report

1998-2006

Changsha 188 5 yr EFS 75% SR, 47% HR

Ch J Ped 2008

2003-2006

Tianjin 225 5 yr OS 72.6% Ch J Hematol 2008

1998-2003

Shanghai 158 5 yr EFS 66.9% Leuk Lymphoma 2008

1998-2004

Hangzhou 248 5 yr EFS 70.7% Ped Blood Cancer 2008

1999-2006

Guangzhou 169 5 yr EFS 72.8-83.8% (SR, IR)

Ped Blood Cancer 2008

ALL Clinical Trials Hong Kong by HKPHOSG

Clinical trialDate of commencement

Date of closure Total case No. 5 year survival

Local trial

ALL93 (HK) Jan, 1993 Oct, 1997 152 78.9%ALL 97 (Singapore, HK) Nov, 1997 Dec, 2002 265 86.4%

ALL IC-BFM 2002 Jan, 2003 May, 2008169 (5060)

(Global) 88.1%EsPhALL Jan, 2006 2015 7Interfant 99 Jan, 2000 Dec, 2005 11

Interfant 06 Jan, 2006 201516 (385) (Global)

Small number of patients participated in above clinical studies though including whole Hong Kong (7 million population)

Li CK, et al. Treatment of Acute Lymphoblastic Leukaemia in Hong Kong Children: HKALL 93 Study. Hematological Oncology, Hematol Oncol 2003, 21:1-9.Li CK et al. Improved outcome of acute lymphoblastic leukaemia treated by delayed intensification in Hong Kong children: HKALL 97 study. Hong Kong Medical Journal, 2006; 12:394-400.Intensive Chemotherapy for Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Intercontinental Trial ALL IC-BFM 2002. J Clin Oncol. 2014; 20;32:174-84.

Opportunity of developing national clinical trial in China in late 2000

Improvement of economy and started to have insurance coverage: more patients could receive proper anti-cancer treatment

Hospitals were not competing for more patients but working for better results

Clinical leaders in many hospitals understood the need for cooperation and concentrating strength

Hong Kong could bring in international experience of multicenter trials

Challenges of participating in the multi-national RCT

No experience on multicenter clinical trial

Requirement on the quality of data collection: completeness, accuracy, timely submission to central data center,

No financial support from government or industry, need to apply grant by each participating national groups

Management of clinical problems related to the protocol.

15 countries in 3 continents, 5060 subjects,130 centersArgentina (1,270), Chile (558), Croatia (122), Cuba (151), Czech Republic (291), Hong Kong (155), Hungary (259),Israel (292), Poland (908), Serbia (266), Slovakia (137), Slovenia (36), Ukraine (421), Uruguay (96), Moscow(98).

I

SR: 標危 Pred-GR + WBC = 2 yrs

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Reg 方案

97A

97B

97C

35 31 42 44

HSCT

HK-SG ALL 97 - Overall View

Induction/

Early Intensification Consolidation Delayed

Intensification Maintenance

MTX 2g/m2 x 4

From Single arm study to Randomized Control Trial:Randomization rate 67%

Delayed Intensification

Induction/

Early Intensification

Consolidation

file:diagram\call97.doc

Revised on 4/11/98

Maintenance

Weeks 星期

Reg 方案

HK-SG ALL 97 - Overall View

HSCT

42

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HR: 高危

( Pred-PR

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( t(9;22)/BCR-ABL

( t(4;11)/MLL-AF4

IR: 中危

Pred-GR and

(WBC ( 20

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Key components of clinical trial:during conduct of trial

Registration of new recruits at Data Center Up to date data collection Report of Serious Adverse Events (SAE) Monitoring Interim analysis, need for amendment of protocol Regular Group meeting Close of trial: final analysis, manuscript preparation Plan for next clinical trial based on early result of

current trial

Chinese Childhood Leukemia Group (CCLG): 17 hospitals from 8 cities

Coordinating hospital：Beijing Children Hospital, Capital Medical

UniversityParticipating hospitals：

Hong Kong (5 hospitals)Children’s Hospital, Suzhou UniversityChildren Hospital, Capital Research InstituteInstitute of hematology and Blood Diseases

Hospital, CAMS , TianjinPeople Hospital, Peking University,Children Hospital, Chongqing Medical UniversityUnion Hospital Tongji Medical School, Central

ChinaPLA General Hospital, BeijingNaval General Hospital, BeijingShanghai Children Hospital, Fudan UniversityChildren Hospital, West China University

From 2008: 2231 patients recruited in CCLG 2008 Study

Objectives of CCLG 2008 Study Establish the first large multicenter study

across the country : as baseline for future development

Standardized ALL stratification based on MICM,

Randomized study on 2 maintenance arms treatment

Pilot the MRD for stratification and treatment modification

CCLG ALL 2008 Protocol opened Feb 2008, 17 hospitals from 8 cities

Risk stratification : NCI Risk, Prednisone 7-Day response, Day 15 BM response,

cytogenetics, Day 33 remission. (MRD in 2 centers: HK, BCH)

BFM based induction, early intensification (CAM), consolidation (mM, M, HR blocks),

COG Delayed intensification, maintenance with 4 wkly pulse.

Reduced intensity for Standard Risk: Reduced intensity of Early intensification (50%) COG DI also reduced intensity c.f. BFM PII (~70%)

Randomised maintenance: 4 vs 3 wk 6MP/MTX in 4 wkcycle

No prophylactic cranial RT for all except CNS 3.

Minimal residual disease (MRD) MRD piloted at Beijing Children’s Hospital, Hong Kong .

BM tested for MRD on Day 33 and Week 12 of treatment

by Flow cytometry and / or polymerase-chained reaction (PCR) quantitative method for immunoglobulin and T-cell receptor antigen gene rearrangements

The required sensitivity and quantitative range of MRD testing was 0.01%.

SR patients D33 MRD ≥ 0.01% and < 1% upstaged to IR, D 33 MRD ≥ 1% or Wk 12 MRD ≥ 0.1% upstaged to HR.

Cheng SH, et al. Minimal residual disease-based risk stratification in Chinese childhood acute lymphoblastic leukemia by flow cytometry and plasma DNA quantitative polymerase chain reaction. PLoS One 2013;8:e69467. Cui L,. Combined analysis of minimal residual disease at two time points and its value for risk stratification in childhood B-lineage acute lymphoblastic leukemia. Leuk Res 2010;34:1314-9.

Supp. Table I Treatment Protocol Treatment Element/Drug Single or Daily dose Days of Administration

Induction Protocol VDLD

Prednisone (PO) 60 mg/m2 per day 1-7 Dexamethasone (PO) 6 mg/m2 per day 8-28, then taper over 9 days Vincristine (IV) 1.5 mg/m2 per dose (max. 2

mg) 8, 15, 22, 29

Daunorubicin (PI over 1 hour) 25 mg/m2 per dose 8, 15, 22a, 29a L-asparaginase (PI over 1 hour) 5000 IU/m2 per dose 8, 11, 14, 17, 20, 23, 26, 29 Methotrexate (IT) b, Methotrexate + Cytarabine + steroid (IT) c Doses according to age 1, 15, 33d

Early Intensification

Protocol CAMe Cyclophosphamide (PI over 1 hour) 1000 mg/m2 per dose 36 Cytarabine (IV) 75 mg/m2 per dose 38-41, 45-48 6-mercaptopurine (PO) 60 mg/m2 per day 36-50 Methotrexate (IT) b, Methotrexate + Cytarabine + steroid (IT) c Doses according to age 38, 45

Consolidation Protocol mM (SR)

6-mercaptopurine (PO) 25 mg/m2 per day 1-56 Methotrexate (PI over 24 hours) f 2 g/m2 per dose 8, 22, 36, 50 Methotrexate (IT) doses according to age 8, 22, 36, 50

Protocol M (IR) 6-mercaptopurine (PO) 25 mg/m2 per day 1-56 Methotrexate (PI over 24 hours) 5 g/m2 per dose 8, 22, 36, 50 Methotrexate + Cytarabine + Steroid (IT) Doses according to age 8, 22, 36, 50

Supp. Table I Treatment Protocol

Treatment Element/Drug

Single or Daily dose

Days of Administration

Induction

Protocol VDLD

Prednisone (PO)

60 mg/m2 per day

1-7

Dexamethasone (PO)

6 mg/m2 per day

8-28, then taper over 9 days

Vincristine (IV)

1.5 mg/m2 per dose (max. 2 mg)

8, 15, 22, 29

Daunorubicin (PI over 1 hour)

25 mg/m2 per dose

8, 15, 22a, 29a

L-asparaginase (PI over 1 hour)

5000 IU/m2 per dose

8, 11, 14, 17, 20, 23, 26, 29

Methotrexate (IT) b, Methotrexate + Cytarabine + steroid (IT) c

Doses according to age

1, 15, 33d

Early Intensification

Protocol CAMe

Cyclophosphamide (PI over 1 hour)

1000 mg/m2 per dose

36

Cytarabine (IV)

75 mg/m2 per dose

38-41, 45-48

6-mercaptopurine (PO)

60 mg/m2 per day

36-50

Methotrexate (IT) b, Methotrexate + Cytarabine + steroid (IT) c

Doses according to age

38, 45

Consolidation

Protocol mM (SR)

6-mercaptopurine (PO)

25 mg/m2 per day

1-56

Methotrexate (PI over 24 hours) f

2 g/m2 per dose

8, 22, 36, 50

Methotrexate (IT)

doses according to age

8, 22, 36, 50

Protocol M (IR)

6-mercaptopurine (PO)

25 mg/m2 per day

1-56

Methotrexate (PI over 24 hours)

5 g/m2 per dose

8, 22, 36, 50

Methotrexate + Cytarabine + Steroid (IT)

Doses according to age

8, 22, 36, 50

Supp. Table I Treatment Protocol

Treatment Element/Drug Single or Daily dose Days of Administration Block HR-1’(HR)

Dexamethasone (PO/IV) 20 mg/m2 per day 1-5 Vincristine (IV) 1.5 mg/m2 (max. 2 mg) 1, 6 Methotrexate (PI over 24 hours) f 5 g/m2 per dose 1 Cyclophosphamide (PI over 1 hour) 200 mg/m2 per dose 2-4 (5 doses, 12 hour intervals) Cytarabine (PI over 3 hours) 2 g/m2 per dose 5 (2 doses, 12 hour intervals) L-asparaginase (PI over 2 hours) 25 000 IU/m2 per dose 6, 11 Methotrexate/cytarabine/steroid (IT) Doses according to age 1g

Block HR-2’(HR) Dexamethasone (PO/IV) 20 mg/m2 per day 1-5 Vincristine (IV) 3 mg/m2 (max. 5 mg) 1, 6 Methotrexate (PI over 24 hours) f 5 g/m2 per dose 1 Ifosfamide (PI over 1 hour) 800 mg/m2 per dose 2-4 (5 doses, 12 hour intervals) Daunorubicin (PI over 24 hours) 30 mg/m2 per dose 5 L-asparaginase (PI over 2 hours) 25 000 IU/m2 per dose 6, 11 Methotrexate/Cytarabine/steroid (IT) Doses according to age 1g

Block HR-3’(HR) Dexamethasone (PO/IV) 20 mg/m2 per day 1-5 Cytarabine (PI over 3 hours) 2 g/m2 per dose 1-2 (4 doses, 12 hour intervals) Etoposide (PI over 1 hour) 100 mg/m2 per dose 3-5 (5 doses, 12 hour intervals) L-asparaginase (PI over 2 hours) 25 000 IU/m2 per dose 6, 11 Methotrexate/Cytarabine/Steroid (IT) Doses according to age 1g

Supp. Table I Treatment Protocol

Treatment Element/Drug

Single or Daily dose

Days of Administration

Block HR-1’(HR)

Dexamethasone (PO/IV)

20 mg/m2 per day

1-5

Vincristine (IV)

1.5 mg/m2 (max. 2 mg)

1, 6

Methotrexate (PI over 24 hours) f

5 g/m2 per dose

1

Cyclophosphamide (PI over 1 hour)

200 mg/m2 per dose

2-4 (5 doses, 12 hour intervals)

Cytarabine (PI over 3 hours)

2 g/m2 per dose

5 (2 doses, 12 hour intervals)

L-asparaginase (PI over 2 hours)

25 000 IU/m2 per dose

6, 11

Methotrexate/cytarabine/steroid (IT)

Doses according to age

1g

Block HR-2’(HR)

Dexamethasone (PO/IV)

20 mg/m2 per day

1-5

Vincristine (IV)

3 mg/m2 (max. 5 mg)

1, 6

Methotrexate (PI over 24 hours) f

5 g/m2 per dose

1

Ifosfamide (PI over 1 hour)

800 mg/m2 per dose

2-4 (5 doses, 12 hour intervals)

Daunorubicin (PI over 24 hours)

30 mg/m2 per dose

5

L-asparaginase (PI over 2 hours)

25 000 IU/m2 per dose

6, 11

Methotrexate/Cytarabine/steroid (IT)

Doses according to age

1g

Block HR-3’(HR)

Dexamethasone (PO/IV)

20 mg/m2 per day

1-5

Cytarabine (PI over 3 hours)

2 g/m2 per dose

1-2 (4 doses, 12 hour intervals)

Etoposide (PI over 1 hour)

100 mg/m2 per dose

3-5 (5 doses, 12 hour intervals)

L-asparaginase (PI over 2 hours)

25 000 IU/m2 per dose

6, 11

Methotrexate/Cytarabine/Steroid (IT)

Doses according to age

1g

Supp. Table I Treatment Protocol Treatment Element/Drug Single or Daily dose Days of Administration

Delayed Intensificationh

DI-I Dexamethasone (PO/IV) 10 mg/m2 per day 1-7, 15-21 (SR,IR); 1-21,9 days taper(HR) Vincristine (IV) 1.5 mg/m2 per dose (max. 2 mg) 1, 8, 15 (SR,IR); 8, 15, 22, 29(HR) Doxorubicin (PI over 1 hour) 25 mg/m2 per dose 1, 8, 15 (SR,IR); 8, 15, 22, 29(HR) L-asparaginase (PI over 1 hour) DI-IIi

10 000 IU/m2 per dose 1, 4, 8, 11 (SR,IR); 8, 11, 15, 18(HR)

Maintenance therapyk SR/IR Methotrexate (PO/IM) 20 mg/m2 per dose Weekly, week 1-4 or 2-4l 6-Mercaptopurine (PO) 50 mg/m2 per dose Daily, week 1-4 or 2-4l Vincristine (IV) 1.5 mg/m2 per dose (max. 2 mg) 1, 29 Dexamethasone (PO) 6 mg/m2 per day 1-5, 29-33 Methotrexate (IT) b, Methotrexate + Cytarabine + steroid (IT) c Doses according to age 1m HR Methotrexate 20 mg/m2 per dose 1, 8 6-Mercaptopurine 50 mg/m2 per dose 1-14 Cyclophosphamide (PI over 1 hour) 300 mg/m2 per dose 15 Cytarabine (PI over 1 hour) 300 mg/m2 per dose 15 Vincristine (IV) Dexamethasone

2 mg/m2 per dose (max. 2 mg) 6 mg.m2 per dose

22 22-26

Methotrexate + Cytarabine + Steroid (IT) 15, 4 weekly x 23

Supp. Table I Treatment Protocol

Treatment Element/Drug

Single or Daily dose

Days of Administration

Delayed Intensificationh

DI-I

Dexamethasone (PO/IV)

10 mg/m2 per day

1-7, 15-21 (SR,IR); 1-21,9 days taper(HR)

Vincristine (IV)

1.5 mg/m2 per dose (max. 2 mg)

1, 8, 15 (SR,IR); 8, 15, 22, 29(HR)

Doxorubicin (PI over 1 hour)

25 mg/m2 per dose

1, 8, 15 (SR,IR); 8, 15, 22, 29(HR)

L-asparaginase (PI over 1 hour)

DI-IIi

10 000 IU/m2 per dose

1, 4, 8, 11 (SR,IR); 8, 11, 15, 18(HR)

Maintenance therapyk

SR/IR

Methotrexate (PO/IM)

20 mg/m2 per dose

Weekly, week 1-4 or 2-4l

6-Mercaptopurine (PO)

50 mg/m2 per dose

Daily, week 1-4 or 2-4l

Vincristine (IV)

1.5 mg/m2 per dose (max. 2 mg)

1, 29

Dexamethasone (PO)

6 mg/m2 per day

1-5, 29-33

Methotrexate (IT) b, Methotrexate + Cytarabine + steroid (IT) c

Doses according to age

1m

HR

Methotrexate

20 mg/m2 per dose

1, 8

6-Mercaptopurine

50 mg/m2 per dose

1-14

Cyclophosphamide (PI over 1 hour)

300 mg/m2 per dose

15

Cytarabine (PI over 1 hour)

300 mg/m2 per dose

15

Vincristine (IV)

Dexamethasone

2 mg/m2 per dose (max. 2 mg)

6 mg.m2 per dose

22

22-26

Methotrexate + Cytarabine + Steroid (IT)

15, 4 weekly x 23

Data Collection

A web-based data network established All participating group will have designated

staff to input data through internet Statistician will monitor data annually Study Group will have Group meeting

2x/year to monitor progress Central review of pathology slides

Progress April 1, 2008 and December 31, 2012,

a total of 2231 patients under age of 18 years with newly diagnosed ALL recruited

Patients were treated with the same chemotherapy regimen

Only the two MRD pilot centers adjusted treatment intensity according to MRD, all the other centers treated according to morphology response (Day 15 BM and D33 BM)

All 2231 %

SexMale 1337 59.9Female 894 40.1

Age(years)< 1 15 0.71 -< 6 1393 62.46 -< 10 492 22.1≥ 10 331 14.8

Initial WBC(×109/L)< 20 1425 63.920 -< 50 348 15.650 -< 100 211 9.5100 -< 200 129 5.8≥ 200 118 5.3

CNS statusCNS1 2145 96.1CNS2 55 2.5CNS3 31 1.4

ImmunophenotypePrecursor B 2041 91.6T 188 8.4

BCR-ABL1 Number %Negative 2078 95.5Positive 99 4.5

TEL-AML1Negative 1787 83.7Positive 349 16.3

E2A-PBX1Negative 2014 94.3Positive 121 5.7

MLL rearrangementNegative 2071 97.0Positive 64 3.0

Prednisone responseGood 2000 90.5Poor 210 9.5

Day 15 BMM1 1647 75.5M2 294 13.5M3 241 11.0

Day 33 nonremissionNo 2155 96.6Yes 76 3.4

Recruitment Rate Among 10 hospitals, 4 hospitals recruited 100% of

patients (high recruitment group, n=1574), 6 hospitals enrolled 70.2% to 84.7% of patients (low

recruitment group, 657/853=77%).

The reason for incomplete recruitment was due to financial reason, and related to the insurance scheme with variable reimbursement rate.

Comparing the high and low recruitment groups, there was no difference in the patients’ characteristics: age, gender, initial WBC counts, immunophenotyping, genetic fusion products and survivals

Supp. Table III Comparison of patients’ characteristics in high recruitment group or low recruitment group in this study

Variables High recruitment (n=1574) Low recruitment

(n=657) P

Sex, male/female 958/616 379/278 0.169 Age (years), median (range) 4.6(0.4-18.6) 4.6(0.5-15.6) 0.967 WBC(×109/L), median (range) 11.0(0.2-1365.0) 10.8(0.6-915.2) 0.161 Immunophenotype, BCP/T 1434/140 607/48 0.242 Fusion gene, n (%)

TEL-AML1 255(16.2) 92(14.0)

0.519 BCR-ABL1 72(4.6) 27(4.1) E2A-PBX1 82(5.2) 37(5.6) MLL rearrangement 40(2.5) 18(2.7) T-ALL 140(8.9) 48(7.3) Other BCP-ALL 985(62.6) 435(66.2)

Treatment Outcome, n (%) Induction failure 61(3.9) 15(2.3) 0.072 Death in induction 27(1.7) 9(1.4) 0.713 Death in complete remission 50(3.2) 14(2.1) 0.211 5y-OS(%) 84.9±1.0 86.3±1.4 0.421 5y-EFS(%) 79.8±1.1 80.1±1.7 0.945 5y-CIR(%) 14.7±1.0 16.6±1.6 0.160

Supp. Table III Comparison of patients’ characteristics in high recruitment group or low recruitment group in this study

Variables

High recruitment

(n=1574)

Low recruitment

(n=657)

P

Sex, male/female

958/616

379/278

0.169

Age (years), median (range)

4.6(0.4-18.6)

4.6(0.5-15.6)

0.967

WBC(×109/L), median (range)

11.0(0.2-1365.0)

10.8(0.6-915.2)

0.161

Immunophenotype, BCP/T

1434/140

607/48

0.242

Fusion gene, n (%)

TEL-AML1

255(16.2)

92(14.0)

0.519

BCR-ABL1

72(4.6)

27(4.1)

E2A-PBX1

82(5.2)

37(5.6)

MLL rearrangement

40(2.5)

18(2.7)

T-ALL

140(8.9)

48(7.3)

Other BCP-ALL

985(62.6)

435(66.2)

Treatment Outcome, n (%)

Induction failure

61(3.9)

15(2.3)

0.072

Death in induction

27(1.7)

9(1.4)

0.713

Death in complete remission

50(3.2)

14(2.1)

0.211

5y-OS(%)

84.9±1.0

86.3±1.4

0.421

5y-EFS(%)

79.8±1.1

80.1±1.7

0.945

5y-CIR(%)

14.7±1.0

16.6±1.6

0.160

WBC indicates white blood cell; BCP, Precursor B; OS, Overall survival; EFS, Event-free survival; CIR, cumulative incidence of relapse

58% 34% 7.4%

47% 31% 22%

D8PR, D15BM D33BM

26% 55% 19%

1,8%

s

All (%) Risk group SR (%) IR (%) HR (%) N 2231(100) 868(100) 893(100) 470(100)

Induction remission 2100 (94.1) 853 (98.3) 875 (98.0) 372 (79.1)

Induction failure 76 (3.4) 0 0 76 (16.2)

Resistant disease 22 (1.0) 0 0 22(4.7)

Induction Death 36 (1.6) 10 (1.2) 14 (1.6) 12 (2.6)

Give up in induction 19 (0.9) 5 (0.6) 4 (0.4) 10 (2.1)

CCR 1725 (77.3) 752 (86.6) 719 (80.5) 254 (54.0)

Remission Death 64 (2.9) 13 (1.5) 30 (3.4) 21 (4.5)

Relapse 284 (12.7) 75 (8.6) 102 (11.4) 107 (22.8)

BM relapse 230 (10.3) 61 (7.0) 76 (8.5) 93 (19.8)

CNS relapse 31 (1.4) 7 (0.8) 16 (1.8) 8 (1.7)

TEST relapse* 15 (1.1) 7 (1.4) 3 (0.6) 5 (1.6)

Secondary malignancy 1 (0.04) 0 1 (0.1) 0

Give up in CCR 80(3.6) 13 (1.5) 23 (2.6) 44 (9.4)

s

All (%)

Risk group

SR (%)

IR (%)

HR (%)

N

2231(100)

868(100)

893(100)

470(100)

Induction remission

2100 (94.1)

853 (98.3)

875 (98.0)

372 (79.1)

Induction failure

76 (3.4)

0

0

76 (16.2)

Resistant disease

22 (1.0)

0

0

22(4.7)

Induction Death

36 (1.6)

10 (1.2)

14 (1.6)

12 (2.6)

Give up in induction

19 (0.9)

5 (0.6)

4 (0.4)

10 (2.1)

CCR

1725 (77.3)

752 (86.6)

719 (80.5)

254 (54.0)

Remission Death

64 (2.9)

13 (1.5)

30 (3.4)

21 (4.5)

Relapse

284 (12.7)

75 (8.6)

102 (11.4)

107 (22.8)

BM relapse

230 (10.3)

61 (7.0)

76 (8.5)

93 (19.8)

CNS relapse

31 (1.4)

7 (0.8)

16 (1.8)

8 (1.7)

TEST relapse*

15 (1.1)

7 (1.4)

3 (0.6)

5 (1.6)

Secondary malignancy

1 (0.04)

0

1 (0.1)

0

Give up in CCR

80(3.6)

13 (1.5)

23 (2.6)

44 (9.4)

85.3%

79.9%

15.3%

median follow-up of 47.3 months (range 0 - 85.8 months),

SR:OS 91.5%EFS 87.9%

IR:OS 87.7%EFS 81.6%

HROS 68.1%EFS 59.9%

T-ALL (8.4%)OS 73.3%, EFS 66%

TEL-AML1 fusion (16.3%)OS: 93.0% , EFS: 89.5% .E2A-PBX (5.7%)OS 86.9%, EFS 86.2%

MLL rearrangement (3%)OS 68.2%, EFS 64.4%.

BCR-ABL1+ (4.5%)OS 53.7%, EFS 48.0%

Day 33 MRD No. % 5 yr EFS

< 0.01% 298 37.8 91.9(1.6)

< 0.0010.01% -< 0.1% 326 41.3 87.8(2.3)

0.1% -< 1% 93 11.8 72.6(5.2)

≥ 1% 72 9.1 51.8(6.2)

Week 12 MRD

< 0.01% 617 85.2 89.8(1.4)

< 0.0010.01% -< 0.1% 66 9.1 78.2(5.6)

≥ 0.1% 41 5.7 55.5(8.3)

MRD and outcome in 2 hospital pilot MRD

No difference in overall survival in MRD and non-MRD groups86.5% vs 84.6%

MRD group had better Event-free survival than non-MRD group82.4% vs 78.3%

MRD group had lower relapse rate than non-MRD group10.7% vs 18%

Variable Total MRD group non-MRD group P 5y-OS SR 91.5±1.0 93.2±1.7 90.8±1.2 0.354 IR 87.7±1.2 87.5±1.7 87.6±1.7 0.763 HR 68.1±2.3 72.2±3.7 65.7±3.0 0.320

Total 85.3±0.8 86.5±1.2 84.6±1.0 0.273 5y-EFS SR 87.9±1.2 91.8±1.9 86.5±1.4 0.057 IR 81.6±1.5 83.1±2.0 79.7±2.1 0.122 HR 59.9±2.6 65.0±4.0 56.9±3.3 0.278

Total 79.9±0.9 82.4±1.4 78.3±1.2 0.038 5y-CI of relapse SR 9.7 ± 1.1 2.8±1.3 11.9±1.4

High risk group:Chemotherapy vs Stem cell Transplant1. Overall survival no significant difference2. Better event-free survival for SCT group3. Higher relapse risk in chemotherapy group

Randomisation of maintenance arms in SR and IR groups:No difference in overall survival, event-free survival and relapse rate

Hong Kong GroupN=206OS 93%EFS 87%

CCLG whole GroupN=2231 (MRD)OS 85.3% (86.5%)EFS 79.9% (82.4%)

Conclusion

large-scale multicenter trial for pediatric ALL feasible in China,

Induction death and remission death low dose reduction in SR group could achieve a

high EFS. (87.9%) MRD-based risk stratification might improve the

treatment outcome for childhood ALL. CNS relapse rate low by chemotherapy CNS

directed treatment

New study

CCCG 2015 study started in 2015 20 hospitals participated > 1200 patients recruited per year Chemotherapy backbone St Jude Total XV Flow MRD as stratification criteria for all

patients Randomised BCR-ABL patients into Imatinib

arm vs Dasatinib arm

Acknowledgement The National Key Technology R&D Program of China

(grant number 2007BAI04B03); the National Natural Science Foundation of China (grant

numbers 81200392, 81170504); the Beijing Natural Science Foundation (grant number

7152054); the Beijing Municipal Administration of Hospitals Clinical

Medicine Development of Special Grant (grant number ZY201404);

the Tianjin Science and Technology Program (grant number 12ZCDZSY18100);

the Children Cancer Foundation of Hong Kong and New Sunshine Charity Foundation of China.

Thank you

VariablesTotal (N = 2231)

N* % 5y-EFS,%(SE) P5y-

OS,%(SE) PSR, %

(n=868)IR, %

(n=893)HR, %

(n=470)All 2231 100 79.9(0.9) 85.3(0.8) 100 100 100Sex

Male 1337 59.9 78.5(1.2) 0.143 84.2(1.1) 0.130 56.9 60.4 64.7Female 894 40.1 81.9(1.4) 86.8(1.2) 43.1 39.6 35.3Age(years)

< 1 15 0.7 77.8(11.4)

< 0.001

71.8(12.0)

0.001

0 0.8 1.71 -< 6 1393 62.4 82.9(1.1) 87.3(1.0) 79.8 55.4 43.66 -< 10 492 22.1 75.2(2.1) 82.1(1.8) 20.2 19.8 29.8≥ 10 331 14.8 74.1(2.6) 81.3(2.2) 0 24.0 24.9

Initial WBC< 20 1425 63.9 85.3(1.0) 90.5(0.8) 85.4 59.4 32.820 -< 50 348 15.6 77.3(2.5) 79.3(2.4) 14.6 14.1 20.450 -< 100 211 9.5 66.4(3.6) < 0.001 73.7(3.4) < 0.001 0 14.2 17.7100 -< 200 129 5.8 69.7(4.2) 79.3(3.8) 0 7.4 13.4≥ 200 118 5.3 55.4(5.0) 62.8(4.6) 0 4.9 15.7

CNS statusCNS1 2145 96.1 80.8(0.9)

< 0.00185.9(0.8)

< 0.00197.5 95.4 95.1

CNS2 55 2.5 63.8(6.9) 72.9(6.2) 2.5 2.5 2.3CNS3 31 1.4 47.5(9.9) 57.7(8.9) 0 2.1 2.6

Immuno-phenoPrecursor B 2041 91.6 81.2(0.9) < 0.001 86.2(0.8) < 0.001 100 88.7 81.4T 188 8.4 66.0(3.7) 73.3(3.4) 0 11.3 18.6

BCR-ABL1Negative 2078 95.5 81.3(0.9) < 0.001 86.3(0.8) < 0.001 100 100 78.6Positive 99 4.5 48.0(5.5) 53.7(5.8) 0 0 21.4

TEL-AML1Negative 1787 83.7 78.3(1.1) < 0.001 83.5(0.9) < 0.001 77.1 84.7 93.6Positive 349 16.3 89.5(1.8) 93.0(1.5) 22.9 15.3 6.4

E2A-PBX1Negative 2014 94.3 79.8(1.0) 0.175 84.9(0.8) 0.650 100 87.9 96.2Positive 121 5.7 86.2(3.2) 86.9(3.2) 0 12.1 3.8

MLLrearrangement

OS : % (± SE) GlobalBy Treatment Arm

SR IR HR

at 24 months 95.9% (1) 97.7% (2) 98.7% (1) 89.7% (4)

at 48 months 93.5% (2) 96.4% (2) 96.1% (2) 86.0% (5)

at 60 months 93.0% (2) 96.4% (2) 96.1% (2) 83.8% (5)

EFS % (± SE) GlobalBy Treatment Arm

SR IR HR

at 24 months 93.2% (2) 96.5% (2) 94.8% (3) 86.2% (5)

at 48 months 88.1% (2) 93.0% (3) 88.1% (4) 81.0% (5)

at 60 months 87.0% (2) 93.0% (3) 85.0% (4) 81.0% (5)

HKPHOSG

Outcome of children with newly diagnosed ALL treated with CCLG-2008 ALL Study 대한혈액학회 Korean Society of Hematology��COI disclosure�　�Name of author ：　LI Chi-kongSlide Number 3Slide Number 4Reports of Childhood ALL from China Centers: Single centresALL Clinical Trials Hong Kong by HKPHOSGOpportunity of developing national clinical trial in China in late 2000Challenges of participating in the multi-national RCTSlide Number 9Slide Number 10Key components of clinical trial:�during conduct of trialSlide Number 12Objectives of CCLG 2008 Study CCLG ALL 2008Slide Number 15Minimal residual disease (MRD)Slide Number 17Slide Number 18Slide Number 19Data CollectionProgressSlide Number 22Slide Number 23Recruitment RateSlide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36ConclusionNew studySlide Number 39AcknowledgementThank youSlide Number 42Slide Number 43