I have no financial support from an industry source at the

current presentation.

대한혈액학회 Korean Society of Hematology

COI disclosureName of author ： Yasuhiro Okamoto

Recent updates of prospective trials for ALL in Japan

Yasuhiro OkamotoJapan Children’s Cancer Group (JCCG)

ALL committee

Outline

4 Groups• Tokyo Children’s Cancer Study

Group study

～2003

JPLSG• B-12 study

2003～2014

JCCG• B-19 study

2014～

TCCSG

KYCCSG

JCCLSG

JACLS

Japan Association of Childhood Leukemia Study(1996)

Kyushu-Yamaguchi Children’s Cancer Study Group(1984)

Japanese Children’s Cancer and Leukemia Study Group(1980)

Tokyo Children’s Cancer Study Group (1969)

～2003: 4 Groups

Outline

4 Groups• Tokyo Children’s Cancer

Study Group study

～2003

JPLSG• B-12 study

2003～2014

JCCG• B-19 study

2014～

TCCSG L92-13 study• Tokyo Children’s Cancer Study Group• Designed to test the hypothesis;

- “Intensified consolidation might reduce leukemic cell burden sufficiently to allow shortening of maintenance therapy.”

• Conducted in 1992 - 1995• Newly diagnosed ALL （1-15y）• n = 347 (non T-ALL 308, T-ALL 39)

All treatment was discontinued at 1 year after Dx, and duration of maintenance therapy; 4-6 months

Toyoda Y et al. J Clin Oncol 2000

Outcome of L92-13 study

EFS OS

• EFS 59.5%@5.5y (median f/u: 4 years)(6yEFS: 68.7% in L89-12 study)

• Conclusion: maintenance for 6m was not adequate.Toyoda Y et al. J Clin Oncol 2000

• To confirm long-term outcome of ALL with short maintenance therapy.

- true cure or late relapse?

• 347 pts enrolled in L92-13- a median follow-up period of surviving pts;

17.1y（0.25-21.8y）

An extended follow-up study; L92-13E

Kato M et al. Leukemia 2017

Which patients require standard maintenance?

Boys require standard maintenance.

Immunophenotype and early response could not predict those who require standard maintenance.

Kato M et al. Leukemia 2017

DFS by sentinel genomic alterations

Kato M et al. Leukemia 2017

Outline

4 Groups• Tokyo Children’s Cancer Study

Group study

～2003

JPLSG• B-12 study

2003～2014

JCCG• B-19 study

2014～

Japanese Pediatric Leukemia/lymphoma Study Group in 2003

TCCSG

KYCCSG

JCCLSG

JACLS

Keizo Horibe M.D.

T-ALL T11 (n= 290)

BCP-ALL B12 (n= 1577)

Infant MLL03 (n=63) MLL10 (n= 94)

Ph+ Ph04 (n=44) Ph13 (n=44)

03 04 05 06 07 08 09 10 11 12 13 14 15 16 17

Development of protocols for Acute Leukemia in JPLSG

RT-11 RT11 (n=4)

IntReALLSR 14 (n= 60)

Relapsed R08 (n= 163) R14 (n=24 )

AML AML05 (n=484 ) AML12 (n=255 )

18

JPLSG StudiesJPLSG trials Enrollment period Completion Date # of enrollments # of centers Publication

MLL03 2004-2009 2012/1/31 63 128 Leukemia. 2015;29:290-6

B-NHL03 2004-2010 2012/10/31 346 141 Pediatr Blood Cancer. 2014;61:1215-21

B-NHL03 G-CSF 2004-2010 2012/10/31 60 84 Leukemia and Lymphoma, 2015;23:1-8

ALB-NHL03 2004-2010 2013/10/31 154 140 Pediatr Blood Cancer. 2016;63:451-7

Ph+ ALL04 2004-2008 2012/5/31 44 118 Cancer Med. 2015;4:682-9

AML-P05 2006-2011 2014/3/31 46 125 Br J Haematol. 2016 Mar 31

HLH-2004 2006-2011 2014/11/30 90 109 Int J Hematol 2019

AML-05 2006-2010 2012/4/30 484 137 Int J Hematol. 2013;98:578-88Leukemia. 2013;27:2413-6 etc.

AML-D05 2008-2010 2013/12/31 74 112 Pediatr Blood Cancer. 2016;63:248-54

ALL-R08 (I, II) 2009-2013 2016/10/31 163(I:82,II:81) 116 In preparation

AML-R11 2012-2013 2015/6/30 8 37 Submitted

TAM-10 2011-2014 2019/2/28 167 115 Submitted

CML-08 2009-2014 2019/9/30 79 119

MLL-10 2011-2015 2020/12/31 94 120

AML-D11 2012-2015 2018/2/28 82 110

STKI-14 2015-2016 2018/12/31 22 32

JPLSG Studies, continuedJPLSG trials Enrollment period Completion Date Target sample size # of enrollments # of centers

ALCL99 2002- - 400 163 117

LLB-NHL03 2004-2019 2022/10/31 48 37 140

JMML-11 2011-2017 2020/6/30 43 24 84

ALL-RT11 2011-2018 2019/11/30 6-18(P1), 22-25(P2) 4 21ALL-T11 2011-2017 2020/11/30 147 290 131

LCH-12 2012-2020 2023/5/31 130 183 131

ALL-B12 2012-2017 2022/11/30 1560 1577 148

ALL-Ph13 2013-2017 2021/9/30 44 29 105

AML-12 2014-2018 2023/2/28 50(P2),250(P3) 255 125

IntReALL SR 2010 2014-2018 2021/4/30 612 (Japan 60) 20 28

AML-P13 2014-2017 2020/11/30 30 19 89

ALB-R13 2015-2019 2021/2/28 24 4 42

ALB-NHL-14 2015-2019 2022/8/31 145 18 80

HL-14 2015-2020 2025/9/30 50 13 66

ALL-R14 2015-2017 2019/11/30 75 24 50

B-NHL-14 2016-2018 2023/9/30 46 6 60

JPLSG-CHM-14* 2010-2035 - - 8826 146

* Umbrella observational study. Other 16 studies are all interventional.

Outline

4 Groups• Tokyo Children’s Cancer Study

Group study

～2003

JPLSG• B-12 study

2003～2014

JCCG• B-19 study

2014～

JPLSG ALL B-12• Start from Nov 2012

- PI: Katsuyoshi Koh• B-cell precursor ALL in children (<19 years old)

- Excl. • Infant ALL• Mature B-ALL• T-ALL• Ph+-ALL

- Incl.• Down syndrome

• Target enrollment: 1,560 patients

Treatment schema ofJPLSG ALL B-12

Study question:

Can intensification with VCR/DEX pulse during maintenance improve outcome of SR patients?

(n = 800)

Treatment schema of SR

Treatment schema of IR

Study question:Can intensification with L-asp improve outcome of IR patients? (n = 490)

Treatment schema of HR

Study question:Which is better as consolidation for HR patients, Block-type or VCR intensifcation? (n = 270)

Patient accrualPa

tient

s per

mon

th

Patie

nts t

otal

400 patients/year>90% of ALL patients in Japan are enrolled

Closed enrollment in Nov 2017

Aim of ALL T-11

• T-ALL specific trial- Intensification by DEX and L-asp- Nelarabine for HR/VHR- Omit prophylactic CRT for all T-ALL

• CRT only for CNS-3- Indication of SCT is determined by PCR-MRD

• Includes 1-25 years of age- AYA-ALL:

• Collaboration with Japanese Adult Leukemia Study Group (JALSG)

Treatment schema ofJPLSG ALL T-11

Result of B12/T11

Not yet disclosed

Incidence of hematologic malignancy in Japan (2006-2010)

Horibe K et al. Int J Hematol 98:74-88, 2013

Outcome of hematologic malignancy in Japan (2006-2010)

Disease n 2y-OS 4y-OSLeukemia

ALL 2,464 94.2% 89.1%BCP-ALL 2,110 96.2% 91.8%T-ALL 269 81.3% 66.9%

AML 891 83.3% 76.3%MDS 296 92.8% 85.3%

LymphomaNHL 628 92.1% 83.1%HL 345 95.2% -

Horibe K et al. Int J Hematol 98:74-88, 2013

Updated Results 2006-2016

Horibe K, 60th JSPHO meeting, 2018

Years

Ove

rall

Surv

ival

Improved OS in recent years

3y OS Year 1 (2006-2011, n=3,042): 90.9%Year 2 (2012-2016, n=2,356): 93.3%

Horibe K, 60th JSPHO meeting, 2018

Years

Ove

rall

Surv

ival

Japan Children’s Cancer Group in 2014

Study Groups ofSolid Tumors

Outline

4 Groups• Tokyo Children’s Cancer Study

Group study

～2003

JPLSG• B-12 study

2003～2014

JCCG• B-19 study

2014～

JCCG-B19:stratification

• Age and WBC count: NCI criteria• Biology

- Favorable: ETV6-RUNX1, high hyperdploid- Unfavorable: MLL-AF4, hypodiploid, E2A-HLF,

IKZF1 deletion• Treatment response

- Day 8 PSL response/Day 15 BM- Day 33 CR status- TP1(day33) and TP2(day78) PCR-MRD

JCCG ALL-B19 StudyRRCT-L

RRCT-S 18m

24m

24m

30mLR

IIA2 IIBIM2 III

IM RR

HR

IIA4 IIB

IR

B12IR+LIIA4 IIB

SR

B12SRIIA2 IIB

RRRCT-L

RRCT-S 18m

24m

24m

30mHR3

HR2

HR1

HR3

HR2

HR1 BLINBLIN

HR3

HR2

HR1

HR3

HR2

HR1BLINBLIN SCT

SCT group

Chemotherapy group

RRCT-L

RRCT-S 18m

24m

24m

30m

RRCT-L

RRCT-S 18m

24m

24m

30m

Induction: Dex (<10y), PRD(>10y)Randomize of HC for Dex

JCCG-B19: Study Questions

• Test the pediatric based treatment to adult• Treatment reduction for selected LR patients• Test the efficacy and safety of blinatumomab for HR

patients• Optimization of treatment duration

JCCG-B19: patient age• 1-65y: joint study with adult group JALSG

Hayakawa F, et al, Blood Cancer Journal 2015

JCCG-B19: Study Questions

• Test the pediatric based treatment to adult• Treatment reduction for selected LR patients• Test the efficacy and safety of blinatumomab for HR

patients• Optimization of treatment duration

JCCG ALL-B19 StudyRRCT-L

RRCT-S 18m

24m

24m

30mLR

IIA2 IIBIM2 III

IM RR

HR

IIA4 IIB

IR

B12IR+LIIA4 IIB

SR

B12SRIIA2 IIB

RRRCT-L

RRCT-S 18m

24m

24m

30mHR3

HR2

HR1

HR3

HR2

HR1 BLINBLIN

HR3

HR2

HR1

HR3

HR2

HR1BLINBLIN SCT

SCT group

Chemotherapy group

RRCT-L

RRCT-S 18m

24m

24m

30m

RRCT-L

RRCT-S 18m

24m

24m

30m

Induction: Dex (<10y), PRD(>10y)Randomize of HC for Dex

Reduction of therapeutic intensity for low risk

Inclusion criteria: B-ALL & NCI-SR, PGR, (day 15 M1/M2 + TP1 PCR MRD negative) &ETV6-RUNX1 or HHD & no CNS3 & no extramedullary disease

IIA2 IIB

IM2 III Imaintenance

R

B12 SR standard arm

IM R Imaintenance including VP pulse

JACLS SR-02

Day 15 TP1 TP2

Week 13 14 15

Day 1 8 15

6-MP

HD-MTX(3 g/m2) ◆ ◆

LVⅠⅠⅠ ⅠⅠⅠ

TIT ◎ ◎

Protocol Mweek(SR) 16 17 18 19

day 1 8 15 22

PSL

VCR ○ ○ ○

THP ▲ ▲

L-ASP ◇ ◇◇ ◇ ◇◇

TIT ◎

Re-inductionJACLS ALL-02 SR

Results of JACLS ALL-02 SR Reduced intensity regimen for LR-B-ALL in B19

Inclusion criteria: WBC<10K, age<10y, no CNS3day15 M1/M2, PGR

JCCG-B19: Study Questions

• Test the pediatric based treatment to adult• Treatment reduction for selected LR patients• Test the efficacy and safety of blinatumomab for HR

patients• Optimization of treatment duration

JCCG ALL-B19 StudyRRCT-L

RRCT-S 18m

24m

24m

30mLR

IIA2 IIBIM2 III

IM RR

HR

IIA4 IIB

IR

B12IR+LIIA4 IIB

SR

B12SRIIA2 IIB

RRRCT-L

RRCT-S 18m

24m

24m

30mHR3

HR2

HR1

HR3

HR2

HR1 BLINBLIN

HR3

HR2

HR1

HR3

HR2

HR1BLINBLIN SCT

SCT group

Chemotherapy group

RRCT-L

RRCT-S 18m

24m

24m

30m

RRCT-L

RRCT-S 18m

24m

24m

30m

Induction: Dex (<10y), PRD(>10y)Randomize of HC for Dex

Blinatumomab RCT in high risk arm

IA IB + LTP1 TP2

SCT-group

BLIN

Prot II-A,II-BHR3

HR2

HR3

HR2

HR1

HR3

HR2

HR1

HR1

maintenanceBLIN

BLINBLIN HR3

HR2

HR1 SCT

Chemo-group

Immuno-monitoring of the patient lymphocytes will be performed prior to and during binatumomab.

B19 HR: PPR, M3@Day15 in IR, CNS-3, hypodiploid = or <44, MLL-AF4, E2A-HLF, IKZF1, TP2-MRD = or >10-e3

SCT indication: M2/M3@TP1, hypodiploid = or <43, MLL-AF4 and PPR, E2A-HLF, TP2-MRD = or >10-e3

R

JCCG-B19: Study Questions

• Test the pediatric based treatment to adult• Treatment reduction for selected LR patients• Test the efficacy and safety of blinatumomab for HR

patients• Optimization of treatment duration

JCCG ALL-B19 StudyRRCT-L

RRCT-S 18m

24m

24m

30mLR

IIA2 IIBIM2 III

IM RR

HR

IIA4 IIB

IR

B12IR+LIIA4 IIB

SR

B12SRIIA2 IIB

RRRCT-L

RRCT-S 18m

24m

24m

30mHR3

HR2

HR1

HR3

HR2

HR1 BLINBLIN

HR3

HR2

HR1

HR3

HR2

HR1BLINBLIN SCT

SCT group

Chemotherapy group

RRCT-L

RRCT-S 18m

24m

24m

30m

RRCT-L

RRCT-S 18m

24m

24m

30m

Induction: Dex (<10y), PRD(>10y)Randomize of HC for Dex

Kato M et al. Leukemia 2017

B19: therapy duration RCT

RCT-L: Total therapy 24m vs. 30m- Eligible (estimated as 58% of cases)

• Boys (excluding ETV6-RUNX1/TCF3-PBX1)• Girls with HHD

- Superiority of long duration

RCT-S: Total therapy 24m vs. 18m- Eligible (estimated as 42% of cases)

• Girls (excluding HHD)• Boys with ETV6-RUNX1/TCF3-PBX1

- Non-inferiority of short duration

B19: therapy duration RCT

Upcoming Studies in Japan

• B19 for BCP-ALL will start late in 2019• MLL17 for infant ALL will start early in 2019• Ph18 for Ph+-ALL will start mid in 2019• T19 for T-ALL will start late in 2019

Summary

• JPLSG B12 study was closed.- First nation-wide study in children- 2000 patients- improved outcome

• JCCG B19 study will open soon.- Age up to 65- Reduce treatment for selected LR- Blinatumomab in first line treatment- Optimization of duration of maintenance therapy

Acknowledgements- TCCSG

• Atsushi Manabe• Akira Ohara• Masahiro Tsuchida

- JCCGALL committee

• Toshihiko Imamura• Yasuhiro Okamoto• Chihaya Imai• Atsushi Sato• Arata Watanabe• Soichi Suenobu• Hidemi Shimonodan• Hirotoshi Sakaguchi• Sae Ishimaru• Takeshi Inukai• Yuki Arakawa• Motohiro Kato

- JALSG・Fumihiko Hayakawa・Etsuko Yamazaki・ Hitoshi Kiyoi・ Yasushi Miyazaki

MRD based stratification

• In T11 study all patients were stratified by PCR-MRD because patient number was relatively small

• In B12 study PCR-MRD was used only to decide SCT indication in HR patients

• In mid 2018 PCR-MRD was approved by government and will be available for all ALL patients in December

MRD analysis in B12SR/IR 感度 定量域 TP1-MRD TP2-MRD

1.00E-01 0 0 0 01.00E-02 0 0 5 21.00E-03 0 19 20 75.00E-04 5 87 0 01.00E-04 115 232 6 91.00E-05 255 36 2 2

定量域未満陽性 - - 31 48陰性 - - 207 287

NA 0 1 0 0total 375 375 271 355

HR 感度 定量域 TP1-MRD TP2-MRD

1.00E-01 0 0 4 31.00E-02 0 0 11 71.00E-03 0 6 16 95.00E-04 1 31 0 01.00E-04 44 74 12 61.00E-05 81 15 2 0

定量域未満陽性 - - 20 25陰性 - - 35 71

NA 1 1 0 0total 127 127 100 121

positive: less than quantitative areapositive

positive: less than quantitative areapositive

T-ALL• 2006-2010 74.1%• 2006-2016 81.5%• → 2011-2016 = 163-74.1= 88.9%

BCP-ALL• 2006-2010 93.2%• 2006-2016 93.4%• → 2011-2016 = 186.8-93.2= 93.6%