영남대학교 의과대학 혈액종양내과 현 명 수 curative strategies in acute...

영남대학교 의과대학 혈액종양내과

현 명 수

Curative Strategies in Acute Promyelocytic Leukemia

APL 의 특징

1. Morphology

2. Bleeding tendency

3. t(15:17), PML/RAR

4. Vit A 유도체 에 의한 분화

5. AML 중 완치율 (70-80%) 이 가장 높음

6. AML 중 백혈병 발생기전이 밝혀짐

APL / Introduction

Molecular Genetics & Pathogenesis

APL / Molecular genetics

t (15:17)

PML/RAR

inhibit myeloid differentiation

Variant translocation

PLZF (promyelocytic leukemia zinc finger gene)

NMP (nucleophosmin)

NUMA (nuclear mitotic apparatus)

STAT5b


A model for the interactions of APL fusion proteins with the N-Co-R-mSin3-histone deacetylase complex Nature 1998;391:815


Induction Therapy

APL / Induction Therapy

Anthracycline sensitive

Ara – C role ?

P – glycoprotein expression


Induction TherapyAfter-ATRA


1) ATRA :

ATRA 45 mg/m2/day Course I

until CR (or 90ds)

2) Chemo :

Course I

DNR 60 mg/m2/d1-3

Ara C 200 mg/m2/d1-7

APL 91 (1991-1992)

Course II

DNR 60 mg/m2/d1-3

AraC 200 mg/m2/d1-7

Course III

DNR 45 mg/m2/d1-3

AraC 1 gm/m2/12hs/ d

1-4

Induction Consolidation

Blood 1997; 82: 3241


1) ATRA :

45 mg/m2/d

( Until CR )

2) DNR 45 mg/m2/d1-3

Ara-C 200 mg/m2/d1-7

North America Intergroup (1992-1995)

( I )

DNR 45 /m2/d1-3

Ara-C 100 /m2/d1-7


( II )

DNR 45 /m2/d1-3

Ara-C 2 gm/m2/d1-4

ATRA 45 mg/m2/d

for 1 year or

observation

Maintenance

NEJM 1997; 337: 1021


1) ATRA + Course I

2) ATRA Course I

APL 93 (1993-1996)

Course

II


Course

III

ATRA6MP + MTXATRA + ChxNone

Maintenance

Blood 1999; 94: 1192


1) ATRA 5 days

chemotherapy

(Short course ATRA)

2) ATRA chemotherapy

(Extended course

ATRA)

MRC (1993-1997)

Heterogenous


Blood 1999; 93: 4131


Prospective randomized trials of all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL)

Trial n InductionCR(%)

ED(%)

DFS/EFS,

2-3yrs,(%)

APL917)

APL939)

No.Am.Inter- group8)

MRC10)

5447

10999

172174119120

ATRA(+Chemo)Chemo

ATRAChemoATRA+Chemo

ATRAChemo

ATRA(5d) Chemo

ATRAChemo

9181959472697087

9887

11142312

7950758669295978

Abbreviations:CR, complete response:ED,early death:DFS,disease-free survival:EFS,event-free survival :ATRA,all-trans retinoic acid;chemo, chemo-herapy:MRC, Medical Research Council.

ASH. Education program book 2003; 90


Consolidation Therapy

APL / Consolidation therapy

AIDA : Pilot StudyGIMEMA (1993) • Induction : ATRA 45 mg/m2/d until CR

Ida 12 mg/m2/d days 2, 4, 6, 8 • Consolidation : I. AraC 1 gm/m2/d1-4

Ida 5 mg/m2/d1-4II. Mitoxanthrone 10 mg/m2/d1-5 Etoposide 100 mg/m2/d1-5III. Ida 12 mg/m2/d1 Ara-C 150 mg/m2/8hrs/d1-5 6TG 210 mg/m2/d1-5

• BMT, Observation CR : 90% (18/20)OS : 85% (27 months)EFS : 69% (27 months) Blood 1996; 88: 1390


PETHEMA LPA 96 (without ARA-C)

• Induction : ATRA + IDA

CR : 89% RT-PCR (-) : 51%

• Consolidation : I. Idarubicin II. Mitoxanthrone III. Idarubicin

RT-PCR (-) : 93% • Maintenance :

ATRA , 6-MP , MTX For 2 years

CR 환자의 2 year DFS : 92 3 %Blood 1999; 94: 3015


1. Most important goal : PCR negative status 2. How many cycles ? : at least 2 cycles

3. Regimen : Anthracycline (IDA or DNR) with Ara-C without Ara-C

Consolidation : conclusion


Maintenance Therapy

APL / Maintenance Therapy

1) ATRA + Course I

2) ATRA Course I

APL 93 (1993-1996)

Course II


Course III

ATRA

6MP + MTX

ATRA + Chx

None

Maintenance

Blood 1999; 94: 1192


1) ATRA :

45 mg/m2/d

( Until CR )

2) DNR 45 mg/m2/d1-3

Ara-C 200 mg/m2/d1-7

North America Intergroup (1992-1995)

( I )

DNR 45 /m2/d1-3

Ara-C 100 /m2/d1-7


( II )

DNR 45 /m2/d1-3

Ara-C 2 gm/m2/d1-4

ATRA 45 mg/m2/d

for 1 year

or

observation

Maintenance

NEJM 1997; 337: 1021


PETHEMA LPA 96 (1996-1998)

• Induction : ATRA 45 mg/m2/d until CR

Ida 12 mg/m2/d days 2, 4, 6, 8• Consolidation :

I. Idarubicin 5 mg/m2/d (day 1-4)II. Mitoxanthrone 10 mg/m2/d (day 1-5)III. Idarubicin 12 mg/m2/d (day I) Monthly 3 cycles

• Maintenance : ATRA 45 mg/m2/d /3month for 15 days.6-MP 90 mg/m2/dayMTX 15 mg/m2/wk

For 2 yearsBlood 1999; 94: 3015


Maintenance therapy in acute promyelocytic leukemia(APL)

Study n Maintenance

Relapse Rate(%)

No.Amer.

Intergroup8)

APL939)

PETHEMA6)

94

105

63

64

63

67

123

ATRA

Observation

ATRA

ATRA+CT

CT

Observation

ATRA+CT

32

57

20

9

22

32

5Abbreviations: ATRA,all-trans retinoic acid; CT,chemotherapy(6-mercaptopurine plus methotrexate)



Long-Term outcomewith

ATRA-based Regimen

APL / Long-Term outcome

Long-term outcome with all-trans

retinoic acid (ATRA)-based regimens

Study N Regimen DFS/EFS/RFS,

3-5yrs,(%)

Randomized APL91 North American IntergroupNonrandomized GIMEMA PETHEMA

5449

108109

ATRA+DNR+Ara-CATRA+DNR+Ara-C+maint.

ATRA+IDA+maint.ATRA+IDA+maint.(no Ara-C)

6374

9090

Abbreviations: DFS, disease-free survival;EFS,event-free survival;RFS, relapse-free survival; ATRA, all-trans retinoic acid; ENR, daunorubicin;Ara-C, Cytosine arabinoside;IDA, idarubicin



CR Relapse Survival

Pre ATRA 60-80% 50-60% 30-40%

After ATRA 90% 10-20% 80-90%


Long-term outcomes of APL

Retinoic Acid Syndrome

(RAS)

APL Syndrome (APLS)

APL / RAS

Mainfestations of the retinoic acid syndromeManifestation % of patients

Respiratory distress

Fever

Pulmonary edema

Pulmonary infiltrates

Pleural/pericardial effusion

Hypotension

Bone pain

Headache

Congestive heart failure

Acute renal failure

84

81

54

52

36

18

14

14

11

11Blood 2000; 95: 90

APL / RAS

Incidence :

ATRA 단독 : 25%

ATRA + Chemo : 4~15%

Differential Diagnosis :

Sepsis, Pneumonia

Chemotherapy Toxicity

Heart Failure etc.

APL / RAS

Prevention and Treatment

1) Prophylactic prednisolone (?)

2) Concurrent ATRA and Chemotherpay

3) Early treatment with Dexamethasone

APL / RAS

Prognostic Factors

APL / Prognostic Factors

WBC platelet 6yr CIR(LPA 96)

High risk

Intermediat

e

Low risk

>10.000/

uL

10.000/

uL

10.000/

uL

40.000/

uL

>40.000/

uL

34%

14%

6.1%

CIR: Cumulative incidence of relapse

PETHEMA and GIMEMA

Blood 2000; 1247


Female – good px

PML/RAR- break point

short : poor px

CD56 expression : poor px

HLA B13 : relapse

Additional cytogenetic abnormality(?)


• High risk : (WBC > 10,000 /uL)

Intermediate risk : (WBC 10,000/uL, PLT 40,000/uL)

• LPA 96 Consolidation 에

① ATRA 추가 : 45 mg/m2 15 days

② Idarubicine 용량 증가

I : Ida 5 mg/m2 7 mg/m2 4 days

II : Mitoxanthrone 10 mg/m2 5 days

III : Idarubicine 12 mg/m2 1 days 2 days

Risk-adapted Therapy

PETHEMA LPA 99 (1996-2002) : Blood 2004; 103: 1237


• 3year cumulative Relapse ; (CIR)

17.2% 7.5%

( p=0.008 )

• Low risk 제외한 3years CIR

20.1% 8.7%

( p=0.004 ) Low risk intermediate

high risk

6yr CIR (LPA96)

6.1% 14% 34%

3yr CIR(LPA99)

3% 2.5% 21%

Results : LPA 96 (157), LPA 99 (227)


Treatment in Relapsed APL

Arsenic Trioxide (AS2O3)

• 공업용 화공약품

• 1970 년초 하얼빈의대

APL, Hepatoma, Lymphoma

• China report (92, 96) ; CR 65.6% ~ 84%

10yr SR 9/32 (28.

2%)

APL / ATO

Arsenic Trioxide (AS2O3) in APL

▪ Mechanism : • 0.1 – 0.5 micromole/L (low)

Partial differentiation

• 0.5 – 2.0 micromole/L (high)

Apoptosis (Programmed cell death)

Caspase pathway activation

* CD33 (immature myeloid element)

CD 11b (mature myeloid element)

Clinically CR ; Coexpression RT PCR(+)

Later in Remission ; Coexpression RT PCR(-)

APL / ATO

▪ Adverse effects : - Skin ; (rash, erythema, itching)

- GIT ; (nausea, vomiting, diarrhea)

- Liver ; severe hepatotoxicity(China : de novo APL)

mild hepatotoxicity(USA, china : relapsed APL)

- Nervous system ; Neuropathy

- Myeloskeletal system ; Musculo skeltal pain, Fatigue

- Heart ; QTc interval prolongation

- Hyperglycemia & Hypokalemia

- APL Syndrome ; (31%, 8/26)

- dose 증가시 ; renal failure, flaccid paralysis

APL / ATO

Soignet et al. (U.S.A)

• 대상환자 (12 명 )multiple relapse

ATRA resistance

Chemo resistance

Allo BMT relapse

• Induction :

0.15 mg/kg IV until CR (maximum 60 dose)

• Additional 6 cycle :

0.15 mg/kg IV 25 dose/cycle

NEJM 1998; 339: 1341

APL / ATO

Soignet et al. (U.S.A)

• Induction: 0.15mg/kg IV until CR (maximum 50dose) • Consolidation : CR 후 3~4 주 뒤

0.15mg/kg IV (daily or 5ds/wk) total 25 dose • Maintenance : optional 4 cycle (same as consolidation)

- Allogeneic (8) - Autologous (3) - additional ATO (18)

OS : 66% (18 Months) RFS : 56% (18 Months) * 50 만 175 8000~9000 만원

JCO 2001; 19: 3852

APL / ATO

Chao et al. (in China)

• Induction : ATO 10 mg IV for 6wks ( 필요시 2nd course 1 번 )

• Consolidation : - Chemotherapy group

DNR or Mito + Ara-C Relapse 3/4- ATO group Relapse 12/18

- ATO+Chemotherapy group Relapse 2/11* Duration of ATO-induced CR was related to the post-remissi

on therapyBlood 1999; 94: 3315

APL / ATO

ATO therapy in relapsed APL

CR/N CR

(%)

MoCR

Soignet (USA)

1998

Soignet (USA)

2001

Shen (china)

1997

Chao(china)

1999

11/12

34/40

9/10

8/11(de

novo)

40/47(relap

se)

91%

85%

90%

72.7%

85.1%

8/11(77%)

25/29(86%) after induction

14

after

Consolidation 11

4/5 after CR 1

after

consolidation 3

1/15(?) CR 후 14 명 (+)

APL / ATO

• Relapsed APL

• ATO 단독으로

CR (85 –90%)

Molecular CR (77 –86%)

• 이후 maintenance role (?)

• if PCR(+) Allo SCT

PCR (-) Auto SCT

APL / ATO

ATO therapy in APL : Conclusion

Treatment in Molecular Relapse

Autologous HSCT in second CR

Relapsed(<14 months)

CCR(>14

months)

PCR +

PCR -

7

1

0

7

Meloni.et al. Blood 1997;90:1321

APL /Molecular relapse

After consolidation RT-PCR(-) : 163 명

• RT-PCR(+) : 21 명

20/21 : 평균 3 개월 내 hematologic relapse

17/21 (85%) : Consolidation 후 6 개월 내 (+)

• RT-PCR Persistent(-) : 142 명

134/142 : CCR

8/142 : Hematologic relapse

Blood 1998; 92: 784

Prospective RT-PCR AnalysisGIMEMA 0493 (1993-1997)


Salvage Therapy in Molecular Relapse

Reinduction : ATRA 45mg/m2 30days (14 명 )

Consolidation: Mitoxanthrone 6mg/m2/day 1-4

Ara-C 1g/m2/day 1-4

Maintenance : ATRA + 6MP+MTX (4 명 )

ABMT (8 명 )

RT-PCR(-) : 12/14 (85%)ATRA 후 7 명

Consolidation 후 5 명

Blood 1999; 94: 2225 (Italy)


100

months after relapse0 12 24 36 48 60

0

25

50

75

P < 0.05

pro

bab

ilit

y

92% in molecular relapse

44% in hematologic relapse


Overall Survival from relpase

Molecular level 에서 치료 시 장점

• Clinical relapse 전 치료

Fetal complication 예방

• MRD 상태에서 치료

Better long term survival

• 외래치료가능


Mylotarg in molecular relapsed APL

• Mylotarg : Caliceamicin – conjugated anti-CD33

(Gemtuzumab Ozogamicin)

• N=16 / 8 (1st line), 5(2nd line ), 2(3rd line ), 1(4th line )

• Method :

6mg/m2 (IV) : 2cylce

Molecular CR 오면 1cycle more

APL / Mylotarg

• after 2 cycle : 9/11 (91%)

after 3 cycle : 13/13 (100%)

- 1 명 : 1 cycle 후 CR (hepatotoxicity), No further tx

- 2 명 : disease progression

• 7/14 : Molecular CR (Mean 15mo) (7~31mo)

7/14 : Molecular relapse (3~15mo)

retry Mylotarg

2/2 new molecular CR

Blood 2004; 104: 1913 (Italy)

APL / Mylotarg

Mylotarg in molecular relapsed APL

Other Treatment in New APL

APL / Other treatment

ATRA+Mylotarg in de novo APL

• ATRA 45mg/m2/d, until CR Next 2 주간격 (on,off)

• Mylotarg 9mg/ m2 on D1-5 then q 4~5wks additional 8 cycle

• 3cycle 후 PCR(+) Idarubicin ATRA

CR : 16/19 (84%) • 14/16 : ATRA + Mylotarg • 2 /16 : + Idarubicin

3 명 사망 MOF (1) Hemorrhage (2)

PCR (-) 12/12 Mylotarg appears active in APL

APL / ATRA + Mylotarg

Blood 2002; 99: 4222 (U.S.A)

ATO (de novo APL)

• 0.15mg/kg/day Induction (1)

Consolidation (1)Maintenance (6)

• Results:

Children 11 명CR:10/11(91%)Molecular CR 10/10 (100%)OS : 91% (30 months)RFS : 81% (30 months )

Leukemia 2004; 18; 1587 (India)

APL / Other treatment

Treatment ATRA and ATO in APL

group I : ATRA17: de novo APL 5: Relapsed APL

CR: 19/22(86.4%) (16/17 and 3/5)

group II : ATRA +ATO15: de novo APL 4: Relapsed APL

CR: 17/19 (89.5%) (15/15 and 2/4)

median time to CR : 23 일 , 26 일Coagulopathy normolize : 7 일 , 4 일

ATRA +ATO Combination 이 CR 유도 시간 , Coagulopathy 가 좀 더 빨리 호전

APL / ATO+ATRA

Ai Zheng 2004; 23: 430 (China)

1) Phase I/II

ATO in Refractory /Relapsed APL

• MTD (maximum tolerated dose)

MED (minimum effective dose )

• Determine the efficacy

• Determine the acute and chronic toxicity

APL / ongoing trial

Ongoing Trial

2) Phase IITrentinoin 투여 후 CR 온 APL

MOAB HUM –195 ATO Idarubicin

Trentinoin

3) phase III : de novo APLInduction: Trentinoin

Daunorubicin + Ara-CConsolidation:

Arm I: Trentinoin Arm II: ATO

Trentinoin + DaunorubicinMaintenance:

Arm I: Trentinoin ArmII: Trentinoin + 6MP + MTX

APL / ongoing trial

Conclusion

APL / Conclusion

Current recommendations for treatment of APL

APL / Conclusion

1. 초치료 1) Induction

ATRA 45mg/ ㎡ /day until CR + anthracycline anthracycline : daunorubicin 50-60mg/ ㎡ /day for 3 days or idarubicin 12mg/ ㎡ /day for 4 days (2 일에 1 번

4 회 ) 2) Consolidation

anthracycline based chemotherapy (2-3 cycle) consolidation 후 PCR(+)

high dose cytarabineor allogenic SCTor autologous SCT (PCR(-) 시 harvest 한

경우 ) 3) Maintenance

ATRA 45mg/ ㎡ /day for 15 days (3 개월 간격 )+ 6MP 100mg/ ㎡ /day + MTX 10mg/ ㎡ /week fo

r 2years

Current recommendations for treatment of APL

APL / Conclusion

4) Molecular monitering· PCR for PML/RARα 처음 2 년간 3∼6 개월 간격 , 다음 2

년간 6 개월 간격

2. 재발시ATO 0.15mg/kg/day ( 혹은 월∼금 5 회 )

CR 올때까지 → if PCR(-) : autologous SCT

PCR(+) : allogeneic SCT (for young pts)

• Induction Mortality 를 줄일 수 있는 방법은 ?

• Other Prognostic factor?

Risk adapted therapy (blood 2004; 103: 1237)

• Molecular relapse 에서 치료

• ATO, Mylotarg, ATRA 등 Combination

• Tetra-arsenic tetra-sulfide (As4S4)

Realgan p.o (blood 2002; 99: 3136)

• Liposomal ATRA (IV)

Future Directions

영남대학교 의과대학 혈액종양내과 현 명 수 curative strategies in acute...

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