recent results from the prospective studies on apl in the

Akihiro Takeshita The Japan Adult Leukemia Study Group (JALSG)

Recent results from the prospective studies on APL in the Japan Adult Leukemia Study Group (JALSG)

J A L S G Japan Adult Leukemia Study Group

2018 Korean Society of Hematology International Conference

1

COI disclosure

Name of First Author : Akihiro Takeshita

I have no personal or financial interests to declare

in relation to this paper.

2

Summary of the studies for APL in JALSG APL92 APL97 APL204 APL212

Mar 92 - Aug 96 May 1997 - Jun

2002 Jun 2004 - Dec 2010 July 2012 -

Study design Pilot Phase 3 Phase 3 Phase 2

Pts registered 198 302 347 220

New Drugs or Strategies Applied

ATRA Multi-agent

chemotherapy for maintenance

New retinoid Am80

for maintenance

ATO & GO for consolidation

Am80 for

maintenance

Endpoint CR rate & EFS RFS after

maintenance period

RFS after maintenance period

EFS

Results Improved

CR rate & EFS

Multi-agents maintenance Cx is not effective

Am80 during maintenance

improved EFS in high risk group

In follow-up period

The combination of ATRA and ATO has been eagerly awaited, but it has not been approved in Japan, yet.3

Significance of heavier chemotherapy in maintenance for newly diagnosed APL

JALSG APL97 study

May 1997 - Jun 2002

J A S G Japan Adult Leukemia Study Group

L 4

ATRA/6-MP/MTX was the most effective,

especially in WBC>5,000μl group.

AIDA 0493 : Italy APL93: France

12 years DFS was equivalent.

ATRA + 6MP/ MTX for Maintenance therapy

CIR (%)

ATRA ATRA 6MP MTX

6MP MTX

None

WBC > 5,000 53.1 20.6 32.8 68.4

WBC ≦ 5,000 22.9 11.5 21.0 29.2

Blood 2010;115:1690 Blood 2011; 117(18):4716

Both ATRA and 6MP/MTX were effective.

Relapse in late period is important.

July/1993 〜Feb1997〜 May/2000

6-MP/MTX

ATRA

ATRA/6-MP/MTX

None

ATRA

ATRA/6-MP/MTX

√

From 1997, as age adjusted consolidation

regimen was adopted for patients ≧ 60yrs,

protocol was amended.

5 The role of maintenance therapy for the patients of APL in molecular remission is still undetermined.

JALSG APL97 protocol

Induction Consolidation Maintenance/ Intensification (A) WBC < 3.0 x 109/L

& APL < 1.0 x 109/L

ATRA 45 mg/m2/day

(B) 3.0 < WBC < 10.0 x 109/L or APL > 1.0 x 109/L

ATRA IDR 12 mg/m2x2 Ara-C 80 mg/m2x5

(C) WBC > 10.0 x109/L

ATRA IDR 12 mg/m2x3 Ara-C 100 mg/m2x5

(D) During induction, APL > 1.0 x109/L

add IDR 12 mg/m2x2/Ara-C 80 mg/m2x5

I. MIT/Ara-C II. DNR/ETP/Ara-C III.IDR/Ara-C

no therapy

I. BHAC-DM II. BHAC-M III.BHAC-AM IV.BHAC-EV V. BHAC-DM VI.BHAC-EV

ATRA

PML-RARA (-)

(+)

6

283 patients had t(15;17) and/or the PML-RARA transcript at the time of diagnosis.

230 patients were negative for PML-RARA at the end of 3 courses of consolidation .

175 patients who showed absence of PML-RARA transcript were randomized either to receive 6 courses of intensified maintenance chemotherapy or to observation.

JALSG-APL97 Study design


Asou N, et al. Blood, 2007

7

DFS and OS of randomized patients in the maintenance phase in the JALSG APL97

estimated from the date of randomization.

Disease-free survival

Overall survival


Asou N, et al. Blood, 2007

8

Tamibarotene as Maintenance Therapy for APL: Phase III Randomized Controlled Trial

Results of Long Time (7-year) Observation

JALSG APL204L study

Jun 2004 - Dec 2010

J A S G

Japan Adult Leukemia Study Group

L 9

Back Ground and Purpose

• A phase III study, designated APL204, was started with the aim of clarifying advantage of tamibarotene to ATRA in maintenance therapy for newly diagnosed APL.

• The 4-year-relapse free survival (RFS) did not significantly differ between patients treated with ATRA or tamibarotene (Sinagawa et al, JCO, 2014). However, the efficacy in maintenance therapy needs longer observation period to be accurately evaluated.

• Here, we evaluate the long-term outcome of the study.

10 J A L S G Japan Adult Leukemia Study Group

10

Tamibarotene (Am80)

• New synthetic retinoid invented by Shudo K et al (University of Tokyo) in 1984.

• Differentiation potential is several times more than ATRA.

• Low affinity to CRABP and no binding to RAR-.

• More stable to light, heat, and oxidation than ATRA.

• No decrease of Cmax and AUC even in daily administration, even at end of the treatment.

• Second CR was achieved in 58% of relapsed APL patients by the single treatment of tamibarotene (Ann Intern Med 1996; Blood, 1997).

• Tamibarotene was approved in Japan in 2005.

Am80

ATRA

11

JALSG APL204 Study Phase III Randomized Controlled Trial

Induction

Consolidation

A: IDA x 3, Ara-C x 7 B: IDA x 1, Ara-C x 2 C: IDA x 1

Group A WBC3,000 & APL cells1,000

Group B 3000WBC10,000 or APL cells1,000

Group C WBC10,000

Group D If number of APL cells1,000

ATRA 45

ATRA 45 IDA 12 x 2 AraC 100 x 5

ATRA 45 IDA 12 x 3 AraC 100 x 7

MIT 7× 3 Ara-C 200 × 5

DNR 50× 3 Ara-C 200 × 5

IDA 12 × 3 Ara-C 140 × 5

CR

Maintenance

A J L S G Japan Adult Leukemia Study Group

mCR Randomize

IT: MTX, AraC, PSL

12

Follow up

(2 years)

Maintenance

(2 years)

JALSG APL204 Study

Primary endpoint:

hematological or molecular

relapse

(relapse-free survival)


ATRA 45 mg/m2/d

t.i.d × 14 days q 3 mos X 8 courses

Am80 6 mg/m2/d

b.i.d × 14 days q 3 mos X 8 courses

PML/RARα

MRD

Monitoring

Molecular

CR

( Japan UMIN-CTR Registration ID : C000000154 )

Randomize

13

Characteristics No. of Patients (n = 344)

Age, years

median 48

range 15-70

Sex

male 183

female 161

Performance status

0 188

1 126

2 19

3 11

Leukocyte count x109

median 1.4

range 0.1-127

Platelet count x109

median 31

range 1-471

Sanz' risk category

low 117

intermediate 157

high 70

Morphology

M3 323

M3v 21

Induction therapy group

A 112

B 48

C 70

D 114

Abbreviations: M3v, M3 variant

Patients characteristics of 344 cases


14

Consort diagram and treatment schema


Complete remission (n = 319)

Consolidation #1: MIT + AraC (n = 308)

Consolidation #2: DNR + AraC (n = 305)

Consolidation #3: DNR + AraC (n = 288)

Randomized (n = 269)

Maintenance by ATRA (n = 135)

Maintenance by Am80 (n = 134)

Group A WBC < 3,000

(122)

Group B 3,000≦ WBC＜10,000

(48)

Group C WBC≧10,000

(70)

Group D APL cells≧1,000

A→D (104) B→D (10)

15

Enrollment:347; evaluable:344, Median age (range): 48 (16-68)

Number of patients achieving CR and CR rates


Risk Group N Death during

Induction, N (%) CR rate

(%)

A WBC < 3000

112 2 109 (97.3)

B 3000≦ WBC＜10000

48 4 44 (91.7)

C WBC≧10000

70 9 61 (87.1)

D Add Cx in case of APL cells≧1000

114 A→D 104 B→D 10

6 104 (91.2)

Total 344 21 318 (92.4)

16 patients died within 30 days after starting the treatment. 14 patients died of hemorrhagic complications.

DS: grade 1-, 59 (17.2%), grade 3- (5,2%) [ ex: grade 1, 14, grade 2, 27; grade 3, 12, grade 4, 6 ]

16

Consort diagram and treatment schema


Randomized (269)

Maintenance by ATRA (135) Maintenance by Am80 (134)

Discontinued maintenance (22)

Relapse (12)

Adverse event (4)

Withdrew consent (2)

Investigator decision (0)

Other neoplasms (3)

Lost to follow-up (0)

Unknown reason (1)

Discontinued maintenance (22)

Relapse (5)

Adverse event (7)

Withdrew consent (6)

Investigator decision (1)

Other neoplasms (1)

Lost to follow-up (2)

Unknown reason (0)

Late relapse and complications

Relapse (9)

Other neoplasms (5)

Secondary MDS/AML (4)

Death (1)

Alive after HSCT (1)

Death from other reason (1)

Apoplexy in second CR (1)

Cardiac comorbidities (> grade 3) (2)

Late relapse and complications

Relapse (4)

Other neoplasms (2)

Secondary MDS/AML (5)

Death (1)

Alive after HSCT (1)

Death from other reason (0)

Cardiac comorbidities (> grade 3) (1)

HSCT for relapsed patients (18)

CR after HSCT (13)

CR after two courses of HSCT (1)

Relapse (4)

HSCT for relapsed patients (6)

CR after HSCT (3)

CR after two courses of HSCT (1)

Relapse (2)

17

No. of patients ATRA Am80

Characteristic (n = 135) (n = 134) Age (years) 0.597

median 46 46 range 16-76 16-69

Gender 0.807 male 70 72 female 65 62

Performance status 0.840 0 72 78 1 50 43 2 8 8 3 5 5

WBC 0.841 median 1.3 1.4 range 0.2 - 111 0.2 - 88.5

Platelet count 0.343 median 28 33 range 2 - 208 1 - 470

Sanz's risk category 0.636 low 46 44 intermediate 59 63 high 26 26 unkown 4 1

Morphlogy 0.597 M3 126 128 M3v 9 6

Indction treatment group 0.986 A 47 45 B 18 20 C 26 26 D 44 43

Clinical Characteristics of Patients Randomly Assigned for Maintenance Therapy

Abbreviations: ATRA, all-trans-retinoic acid; Am80, tamibarotene; M3v, M3 variant


18

Results of JALSG APL204L Study 7-year RFS


Kaplan-Meier curves for relapse-free survival in relation to maintenance therapy random

assignment for all patients (N = 269). Significance was calculated by the ITT analysis

Comparison between patients treated ATRA and tamibarotene

HR 0.44 (0.21-0.93), p=0.027

Rel

apse

-Fre

e S

urv

ival

(

pro

po

rtio

n)

Tamibarotene: 93% ATRA: 84%

Patients (n)

Observed events (n)

Expected events (s)

ATRA 135 22 16.1

Tamibarotene 134 10 16.0

Time after random assignment (years)

Median follow-up of 7.3 years (range, 1.8 to 12.3 years)

19

Cu

mu

lati

ve In

cid

en

ce o

f R

elap

se

(pro

port

ion)

Patients (n)

Observed events (n)

Expected events (s)

ATRA 135 21 15.1


Time After Random Assignment (years)

HR 0.42 (0.19-0.92), p=0.031

Tamibarotene: 7% ATRA: 16%

Results of JALSG APL204L Study (4) 7-year CIR




20


Rel

apse

-Fre

e

Surv

ival

(p

rop

ort

ion

)

p=0.005

Patients (n)

Observed events (n)

Expected events (s)

A 92 8 10.95

B 38 3 4.52

C 52 13 6.19

D 87 8 10.35

RFS: comparison among treatment group (ABCD, ITT)

Group A: 91%

Group B: 92%

Group C: 75%

Group D: 91%

Results of JALSG APL204L Study



21


7-year RFS in ‘low & intermediate risk group’ and ‘high risk group’

WBC < 10.0 x 109 /µL WBC 10.0 x 109 /µL



Kaplan-Meier curves RFS in relation to maintenance therapy random assignment for with an initial WBC count of ≥ 10.0 x 109/L (n = 52), and for patients with an initial WBC count less than 10.0 x 109/L (n = 217). Significance was calculated by the ITT analysis.

Tamibarotene ATRA

Tamibarotene: 88.5% (N=26)

ATRA: 63.6% (N=26)

P = 0.034 Rel

apse

Fre

e Su

rviv

al (

%)


Rel

apse

Fre

e Su

rviv

al (

%)

Tamibarotene: 93.5% (N=108)

ATRA: 89.0% (N=109)

Tamibarotene ATRA P = 0.263



22

OS EFS


7-year OS, EFS for all patients

N=344 OS率 87.2%

years

Surv

ival

(%

)

Even

t Fr

ee S

urv

ival

(%

)

years

N=344 EFS率 79.4%


Median follow-up of 7.1 years (0 - 12.7 years)

23

Years

EFS of the 5 previous JALSG-APL studies

0 1 2 3 4 5 6

0.2

0.4

0.6

0.8

7

APL97 (n=283) [65%]

APL92 (n=369) [52%]

AML87 (n=45) [32%]

AML89 (n=64) [32%]

1.0


APL204 (n=344) [79%]


7-year OS according to Age ( 60 vs 60 )

OS

years

Surv

ival

(%

)

P = 0.001

years

Surv

ival

(%

)

EFS

P = 0.048

60 y.o.: 90.5% (N=283)

60 y.o.: 72.1% (N=61) 60 y.o.: 81.3% (N=283)

60 y.o.: 70.5% (N=61)


25

Ove

rall

Surv

ival

(p

rop

ort

ion

)


Patients (n)

Observed events (n)

Expected events (s)

ATRA 135 6 5.02


HR 0.66 (0.19-2.35), p=0.520

Tamibarotene: 97.0%

ATRA: 95.6%

Results of JALSG APL204L Study OS-after randomization in ‘low-/intermediate risk group’ and ‘high risk group’

Comparison between patients treated ATRA and tamibarotene Median follow-up of 7.3 years (range, 1.8 to 12.3 years)


26

Relapse or Died After Randomization for Maintenance Therapy

N Relapse (after R) Death (after R)

ATRA 135

21

(15.5%)

A (47) WBC < 3000

5

6

A 1

B 1 B (18) 3000≦ WBC＜10000

2

C (26) WBC≧10000

10 C 3

D (44) Add Cx in case of APL cells≧1000

4 D 1

Am80 134 8

(5.9%)

A (45) 1

3

A 0

B (20) 1 B 1

C (26) 3 C 2

D (43) 3 D 0

Total 269 29 (10.8%) 9 (3.3%)


27

Longer Term Complications in Patients Treated with APL204

Secondary AMD/AML

Secondary neoplasms

Cardiac complications (grade 3-)

3 cases developed heart failure. (2 in the ATRA arm and one in the

tamibarotene arm)

9 patients (4 in the ATRA arm and 5 in the tamibarotene arm)

developed 2 AML, 4 RAEB-I, one RAEB-II, one refractory cytopenia

with multilineage dysplasia and one 5q- syndrome.

Median time from randomization to the onset of MDS/AML was 2.8

years (0 - 7.2 years).

11 patients (8 in the ATRA arm and 3 in the tamibarotene arm)

developed 12 malignancies: 2 lung cancers, 2 prostate, 2 breast, and

one each in stomach, pharynx, bowel, bladder, esophagus and

pancreas.

Median time from randomization to the onset of these neoplasms was

5.5 years (1.0 - 7.9 years).

28

Results of APL204L study

Totally, CR rate was 92%, but 87% in high risk group mainly due to hemorrhagic events.

7-year analysis revealed that the maintenance therapy with tamibarotene was effective to decrease relapse compared with ATRA (92% vs 84%. P = 0.027).

Tamibarotene is significantly also effective in high risk group as an initial leukocyte count > 10,000/μl (88% vs 63%. p = 0.042).

These results are the first to show that a new synthetic retinoid, tamibarotene, is superior to ATRA, and may lead to a new strategy for the treatment of APL including the high-risk group.

29

Molecular Target Therapy including Arsenic Acid and GO as Consolidation Therapy for

APL: Phase II Historical Control Study

JALSG APL212 study

July 2012 – Oct 2016

J A S G Japan Adult Leukemia Study Group

L 30

JALSG APL212 (schema)

Am80: (ATRA mg/m2, 14 days/3M, 8 courses)

A群: WBC<3,000/l and APL<1,000 /l

B群: 3,000≦WBC＜10,000 or APL≧1000

ATRA 45mg/m2 ATRA 45 mg/m2 IDA 12 mg/m2× 2 Ara-C 100 mg/m2× 5

Consolidation

Maintenance

Induction

D群: (in case: APL≧1,000) C群: WBC≧10,000

A群；IDA x3, Ara-C x7 B群；IDA x1, Ara-C x2 C群；IDA x1

Followed up by PCR (2 years) 2 years

ATRA 45 mg/m2 IDA 12 mg/m2× 3 Ara-C 100 mg/m2× 5

CR

molecular CR

Age: 16-65

Age: ≤60: 83.8% 60-70: 16.2% 65-70: 5.0%

C1: ATO 0.15mg/kg (5 days, 5 weeks) C2: DNR/AraC C3: ATO 0.15mg/kg (5 days, 5 weeks)

( IT: MTX/Ara-C) C4: GO 4mg (day1, 15)

(30%)

(24%) (18%) (25%)

AD(23%) BD( 1%)

Single arm historical control study (risk adopted)

31

Molecular Target Therapy including Arsenic Acid as Consolidation Therapy for APL: Phase

II Historical Control Study (For 65y.o. or more)

JALSG APL212-G study

July 2012 – Oct 2016

J A S G

Japan Adult Leukemia Study Group

L 32

Am80: (Am80 6mg/m2, 14days/3M, 8 courses)

A群: WBC<3,000/l and APL<1,000 /l

B群: 3,000≦WBC＜10,000 or APL≧1000

ATRA 45mg/m2

IDA 8 mg/m2× 2

Consolidation

Maintenance

Induction

D群: (in case: APL≧1,000) C群: WBC≧10,000

A群；IDA x3 B群；IDA x1 C群；IDA x1

Followed up by PCR (2 years) 2 years

IDA 8 mg/m2× 3

CR

molecular CR

ATRA ATRA ATRA

Age: 65 – no limit PII study for consolidation by ATO

ATO ( IT: MTX/Ara-C)

ATO

< registration

JALSG APL212-G (schema)

33

Financial support: • Health and Labor Sciences Research Grants • Grant-in-Aid for Cancer Research from the

Ministry of Health, Labor and Welfare • Japan Agency for Medical Research and

Development.

Acknowledgements

Contributions: • Conception and design: Shinagawa K, et al. • Data analysis and interpretation: Atsuta Y, et al. • Data confirmation: Asou N, et al. • Collection and assembly of data: Ohtake S, et al. • JALSG President: Miyazaki Y. • Supervision and Suggestion: Ohno R and Naoe T.

and all JALSG members from 225 institutions.

A J L S G Japan Adult Leukemia Study Group

34

The 30th Anniversary International Symposium of JALSG was held on June, 2017. We have

been supported by many people. We would like to express our sincere appreciation to the

people having supported us continuously.


Japan Adult Leukemia Group (JALSG) was established in 1987

35

recent results from the prospective studies on apl in the

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