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 APL / Molecular genetics

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

Induction Therapy APL / Induction Therapy

 Anthracycline sensitive Ara – C role ?  P – glycoprotein expression  APL / Induction Therapy

Induction Therapy After-ATRA APL / Induction Therapy

1) ATRA : ATRA 45 mg/m 2 /day  Course I until CR (or 90ds) 2) Chemo : Course I DNR 60 mg/m 2 /d 1-3 Ara C 200 mg/m 2 /d 1-7 APL 91 ( ) Course II DNR 60 mg/m 2 /d 1-3 AraC 200 mg/m 2 /d 1-7 Course III DNR 45 mg/m 2 /d 1-3 AraC 1 gm/m 2 /12hs/ d 1-4 Induction Consolidation Blood 1997; 82: 3241 APL / Induction Therapy

1) ATRA : 45 mg/m 2 /d ( Until CR ) 2) DNR 45 mg/m 2 /d 1-3 Ara-C 200 mg/m 2 /d 1-7 North America Intergroup ( ) ( I ) DNR 45 /m 2 /d 1-3 Ara-C 100 /m 2 /d 1-7 InductionConsolidation ( II ) DNR 45 /m 2 /d 1-3 Ara-C 2 gm/m 2 /d 1-4 ATRA 45 mg/m 2 /d for 1 year or observation Maintenance NEJM 1997; 337: 1021 APL / Induction Therapy

1) ATRA + Course I 2) ATRA  Course I APL 93 ( ) Course II InductionConsolidation Course III ATRA 6MP + MTX ATRA + Chx None Maintenance Blood 1999; 94: 1192 APL / Induction Therapy

1) ATRA 5 days  chemotherapy (Short course ATRA) 2) ATRA  chemotherapy (Extended course ATRA) MRC ( ) Heterogenous InductionConsolidation Blood 1999; 93: 4131 APL / Induction Therapy

Prospective randomized trials of all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL) TrialnInduction CR (%) ED (%) DFS/EFS, 2-3yrs,(%) APL91 7) APL93 9) No.Am.Inter- group 8) MRC 10) ATRA(+Chemo) Chemo ATRA  Chemo ATRA+Chemo ATRA Chemo ATRA(5d) Chemo ATRA  Chemo 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 APL / Induction Therapy

Consolidation Therapy APL / Consolidation therapy

AIDA : Pilot Study GIMEMA (1993) Induction : ATRA 45 mg/m 2 /duntil CR Ida 12 mg/m 2 /d days 2, 4, 6, 8 Consolidation :I. AraC 1 gm/m 2 /d1-4 Ida 5 mg/m 2 /d1-4 II. Mitoxanthrone 10 mg/m 2 /d1-5 Etoposide 100 mg/m 2 /d1-5 III. Ida 12 mg/m 2 /d1 Ara-C 150 mg/m 2 /8hrs/d1-5 6TG 210 mg/m 2 /d1-5 BMT, Observation CR : 90% (18/20) OS : 85% (27 months) EFS : 69% (27 months) Blood 1996; 88: 1390 APL / Consolidation therapy

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 APL / Consolidation therapy

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 APL / Consolidation therapy

Maintenance Therapy APL / Maintenance Therapy

1) ATRA + Course I 2) ATRA  Course I APL 93 ( ) Course II InductionConsolidation Course III ATRA 6MP + MTX ATRA + Chx None Maintenance Blood 1999; 94: 1192 APL / Maintenance Therapy

1) ATRA : 45 mg/m 2 /d ( Until CR ) 2) DNR 45 mg/m 2 /d 1-3 Ara-C 200 mg/m 2 /d 1-7 North America Intergroup ( ) ( I ) DNR 45 /m 2 /d 1-3 Ara-C 100 /m 2 /d 1-7 InductionConsolidation ( II ) DNR 45 /m 2 /d 1-3 Ara-C 2 gm/m 2 /d 1-4 ATRA 45 mg/m 2 /d for 1 year or observation Maintenance NEJM 1997; 337: 1021 APL / Maintenance Therapy

PETHEMA LPA 96 ( ) Induction : ATRA 45 mg/m 2 /duntil CR Ida 12 mg/m 2 /d days 2, 4, 6, 8 Consolidation : I. Idarubicin 5 mg/m 2 /d (day 1-4) II. Mitoxanthrone 10 mg/m 2 /d (day 1-5) III. Idarubicin 12 mg/m 2 /d (day I) Monthly 3 cycles Maintenance : ATRA 45 mg/m 2 /d /3month for 15 days. 6-MP 90 mg/m 2 /day MTX 15 mg/m 2 /wk For 2 years Blood 1999; 94: 3015 APL / Maintenance Therapy

Maintenance therapy in acute promyelocytic leukemia(APL) StudynMaintenanceRelapse Rate(%) No.Amer. Intergroup 8) APL93 9) PETHEMA 6) ATRA Observation ATRA ATRA+CT CT Observation ATRA+CT Abbreviations: ATRA,all-trans retinoic acid; CT,chemotherapy (6-mercaptopurine plus methotrexate) ASH. Education program book 2003; 92 APL / Maintenance Therapy

Long-Term outcome with ATRA-based Regimen APL / Long-Term outcome

Long-term outcome with all-trans retinoic acid (ATRA)-based regimens StudyNRegimenDFS/EFS/RFS, 3-5yrs,(%) Randomized APL91 North American Intergroup Nonrandomized GIMEMA PETHEMA ATRA+DNR+Ara-C ATRA+DNR+Ara-C+maint. ATRA+IDA+maint. ATRA+IDA+maint.(no Ara-C) 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 ASH. Education program book 2003; 90 APL / Long-Term outcome

CRRelapseSurvival Pre ATRA60-80%50-60%30-40% After ATRA90%10-20%80-90% APL / Long-Term outcome Long-term outcomes of APL

Retinoic Acid Syndrome (RAS) APL Syndrome (APLS) APL / RAS

Mainfestations of the retinoic acid syndrome Manifestation% of patients Respiratory distress Fever Pulmonary edema Pulmonary infiltrates Pleural/pericardial effusion Hypotension Bone pain Headache Congestive heart failure Acute renal failure Blood 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

WBCplatelet6yr CIR(LPA 96) High risk Intermediate Low risk >10.000/uL  /uL  /uL >40.000/uL 34% 14% 6.1% CIR: Cumulative incidence of relapse PETHEMA and GIMEMA Blood 2000; 1247 APL / Prognostic Factors

Female – good px PML/RAR-  break point short : poor px CD56 expression : poor px HLA B13 : relapse  Additional cytogenetic abnormality(?) APL / Prognostic Factors

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/m 2  15 days ② Idarubicine 용량 증가 I : Ida 5 mg/m 2  7 mg/m 2  4 days II : Mitoxanthrone 10 mg/m 2  5 days III : Idarubicine 12 mg/m 2  1 days  2 days Risk-adapted Therapy PETHEMA LPA 99 ( ) : Blood 2004; 103: 1237 APL / Prognostic Factors

3year cumulative Relapse ; (CIR) 17.2%  7.5% ( p =0.008 ) Low risk 제외한 3years CIR 20.1%  8.7% ( p =0.004 ) Low riskintermediatehigh risk 6yr CIR (LPA96)6.1%14%34% 3yr CIR(LPA99)3%2.5%21% Results : LPA 96 (157), LPA 99 (227) APL / Prognostic Factors

Treatment in Relapsed APL Arsenic Trioxide (AS 2 O 3 )

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 (AS 2 O 3 ) in APL

▪ Mechanism : 0.1 – 0.5 micromole/L (low) Partial differentiation 0.5 – 2.0 micro mole/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-CRelapse 3/4 - ATO groupRelapse 12/18 - ATO+Chemotherapy groupRelapse 2/11 * Duration of ATO-induced CR was related to the post- remission therapy Blood 1999; 94: 3315 APL / ATO

ATO therapy in relapsed APL CR/NCR (%)MoCR Soignet (USA) 1998 Soignet (USA) 2001 Shen (china) 1997 Chao(china) /12 34/40 9/10 8/11(de novo) 40/47(relapse) 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 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 Analysis GIMEMA 0493 ( ) APL /Molecular relapse

Salvage Therapy in Molecular Relapse Reinduction : ATRA 45mg/m 2  30days (14 명 ) Consolidation: Mitoxanthrone 6mg/m 2 /day 1-4 Ara-C 1g/m 2 /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) APL /Molecular relapse

100 months after relapse P < 0.05 probability 92% in molecular relapse 44% in hematologic relapse APL /Molecular 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 APL /Molecular relapse

Mylotarg in molecular relapsed APL Mylotarg : Caliceamicin – conjugated anti-CD33 (Gemtuzumab Ozogamicin) N=16 / 8 (1 st line), 5(2 nd line ), 2(3 rd line ), 1(4 th 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/m 2 /d, until CR  Next 2 주간격 (on,off) Mylotarg 9mg/ m 2 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/dayInduction (1) Consolidation (1) Maintenance (6) Results: Children 11 명 CR: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 : ATRA 17: de novo APL 5: Relapsed APL CR: 19/22(86.4%) (16/17 and 3/5) group II : ATRA +ATO 15: de novo APL 4: Relapsed APL CR: 17/19 (89.5%) (15/15 and 2/4) median time to CR : 23 일, 26 일 Coagulopathy 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 II Trentinoin 투여 후 CR 온 APL  MOAB HUM –195  ATO  Idarubicin  Trentinoin 3) phase III : de novo APL Induction: Trentinoin Daunorubicin + Ara-C Consolidation: Arm I: Trentinoin Arm II: ATO  Trentinoin + Daunorubicin Maintenance: 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 cytarabine or allogenic SCT or autologous SCT (PCR(-) 시 harvest 한 경우 ) 3) Maintenance ATRA 45mg/ ㎡ /day for 15 days (3 개월 간격 ) + 6MP 100mg/ ㎡ /day + MTX 10mg/ ㎡ /week for 2years

Current recommendations for treatment of APL APL / Conclusion 4) Molecular monitering · PCR for PML/RAR α 처음 2 년간 3 ∼ 6 개월 간격, 다음 2 년간 6 개월 간격 2. 재발시 ATO 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 (As 4 S 4 ) Realgan  p.o ( blood 2002; 99: 3136) Liposomal ATRA (IV) Future Directions