대한혈액학회 Korean Society of Hematologyplan.medone.co.kr/70_icksh2019/data/SS12-3_Yasuhiro... · 2019-06-27 · I have no financial support from an industry source at the

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.


DFS by sentinel genomic alterations


Outline


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


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


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





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


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





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


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





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



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%

Documents

대한혈액학회 Korean Society of Hematologyplan.medone.co.kr/70_icksh2019/data/SS12-3_Yasuhiro... · 2019-06-27 · I have no financial support from an industry source at the