Curative Strategies in Acute Promyelocytic Leukemia

1
Curative Strategies in Acute Promyelocytic
Leukemia

• ????? ???? ??????
• ? ? ?

2
APL? ??
APL / Introduction

1. Morphology
2. Bleeding tendency
3. t(1517), PML/RAR?
4. Vit A ??? ? ?? ??
5. AML? ???(70-80)? ?? ??
6. AML? ??? ????? ???

3
Molecular Genetics Pathogenesis
APL / Molecular genetics
4
APL / Molecular genetics

• ? t (1517)
• PML/RAR?
• ? inhibit myeloid differentiation
• ? Variant translocation
• ? PLZF (promyelocytic leukemia
  zinc finger gene)
• ? NMP (nucleophosmin)
• ? NUMA (nuclear mitotic
  apparatus)
• ? STAT5b

5
APL / Molecular genetics
A model for the interactions of APL fusion
proteins with the N-Co-R-mSin3-histone
deacetylase complex
Nature 1998391815
6
Induction Therapy
APL / Induction Therapy
7
APL / Induction Therapy

• ? Anthracycline sensitive
• Ara C role ?
• ? P glycoprotein expression ?

8
Induction TherapyAfter-ATRA
APL / Induction Therapy
9
APL / Induction Therapy
APL 91 (1991-1992)

• 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

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/ d1-4
Induction
Consolidation
Blood 1997 82 3241
10
APL / Induction Therapy
North America Intergroup (1992-1995)

• 1) ATRA
• 45 mg/m2/d
• ( Until CR )
• 2) DNR 45 mg/m2/d1-3
• Ara-C 200 mg/m2/d1-7

( 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
Induction
Consolidation
Maintenance
NEJM 1997 337 1021
11
APL / Induction Therapy
APL 93 (1993-1996)

• 1) ATRA Course I
• 2) ATRA ? Course I

ATRA 6MP MTX ATRA Chx None
Course III
Course II
Induction
Consolidation
Maintenance
Blood 1999 94 1192
12
APL / Induction Therapy
MRC (1993-1997)

• 1) ATRA 5 days ? chemotherapy
• (Short course ATRA)
• 2) ATRA ? chemotherapy
• (Extended course ATRA)

Heterogenous
Induction
Consolidation
Blood 1999 93 4131
13
APL / Induction Therapy
Prospective randomized trials of all-trans
retinoic acid (ATRA) in acute promyelocytic
leukemia (APL)
Trial n Induction CR () ED () DFS/EFS, 2-3yrs,()
APL917) APL939) No.Am.Inter- group8) MRC10) 54 47 109 99 172 174 119 120 ATRA(Chemo) Chemo ATRA?Chemo ATRAChemo ATRA Chemo ATRA(5d) Chemo ATRA?Chemo 91 81 95 94 72 69 70 87 9 8 8 7 11 14 23 12 79 50 75 86 69 29 59 78
AbbreviationsCR, complete responseED,early deathDFS,disease-free survivalEFS,event-free survival ATRA,all-trans retinoic acidchemo, chemo-herapyMRC, Medical Research Council. AbbreviationsCR, complete responseED,early deathDFS,disease-free survivalEFS,event-free survival ATRA,all-trans retinoic acidchemo, chemo-herapyMRC, Medical Research Council. AbbreviationsCR, complete responseED,early deathDFS,disease-free survivalEFS,event-free survival ATRA,all-trans retinoic acidchemo, chemo-herapyMRC, Medical Research Council. AbbreviationsCR, complete responseED,early deathDFS,disease-free survivalEFS,event-free survival ATRA,all-trans retinoic acidchemo, chemo-herapyMRC, Medical Research Council. AbbreviationsCR, complete responseED,early deathDFS,disease-free survivalEFS,event-free survival ATRA,all-trans retinoic acidchemo, chemo-herapyMRC, Medical Research Council. AbbreviationsCR, complete responseED,early deathDFS,disease-free survivalEFS,event-free survival ATRA,all-trans retinoic acidchemo, chemo-herapyMRC, Medical Research Council.
ASH. Education program book 2003 90
14
Consolidation Therapy
APL / Consolidation therapy
15
AIDA Pilot Study
APL / Consolidation therapy

• GIMEMA (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/d1-4
• II. Mitoxanthrone 10 mg/m2/d1-5
• Etoposide 100 mg/m2/d1-5
• III. 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
16
PETHEMA LPA 96 (without ARA-C)
APL / Consolidation therapy

• 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 ??? 2 year DFS 92 ? 3

Blood 1999 94 3015
17
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
APL / Consolidation therapy
Consolidation conclusion
18
Maintenance Therapy
APL / Maintenance Therapy
19
APL / Maintenance Therapy
APL 93 (1993-1996)

• 1) ATRA Course I
• 2) ATRA ? Course I

ATRA 6MP MTX ATRA Chx None
Course III
Course II
Induction
Consolidation
Maintenance
Blood 1999 94 1192
20
APL / Maintenance Therapy
North America Intergroup (1992-1995)

• 1) ATRA
• 45 mg/m2/d
• ( Until CR )
• 2) DNR 45 mg/m2/d1-3
• Ara-C 200 mg/m2/d1-7

( 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
Induction
Consolidation
Maintenance
NEJM 1997 337 1021
21
PETHEMA LPA 96 (1996-1998)
APL / Maintenance Therapy

• 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/day
• MTX 15 mg/m2/wk
• For 2 years

Blood 1999 94 3015
22
APL / Maintenance Therapy

• 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 ATRACT CT Observation ATRACT 32 57 20 9 22 32 5
Abbreviations ATRA,all-trans retinoic acid CT,chemotherapy (6-mercaptopurine plus methotrexate) Abbreviations ATRA,all-trans retinoic acid CT,chemotherapy (6-mercaptopurine plus methotrexate) Abbreviations ATRA,all-trans retinoic acid CT,chemotherapy (6-mercaptopurine plus methotrexate) Abbreviations ATRA,all-trans retinoic acid CT,chemotherapy (6-mercaptopurine plus methotrexate)
ASH. Education program book 2003 92
23
Long-Term outcomewith ATRA-based Regimen
APL / Long-Term outcome
24
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 Intergroup Nonrandomized GIMEMA PETHEMA 54 49 108 109 ATRADNRAra-C ATRADNRAra-Cmaint. ATRAIDAmaint. ATRAIDAmaint.(no Ara-C) 63 74 90 90
Abbreviations DFS, disease-free survivalEFS,event-free survivalRFS, relapse-free survival ATRA, all-trans retinoic acid ENR, daunorubicinAra-C, Cytosine arabinosideIDA, idarubicin Abbreviations DFS, disease-free survivalEFS,event-free survivalRFS, relapse-free survival ATRA, all-trans retinoic acid ENR, daunorubicinAra-C, Cytosine arabinosideIDA, idarubicin Abbreviations DFS, disease-free survivalEFS,event-free survivalRFS, relapse-free survival ATRA, all-trans retinoic acid ENR, daunorubicinAra-C, Cytosine arabinosideIDA, idarubicin Abbreviations DFS, disease-free survivalEFS,event-free survivalRFS, relapse-free survival ATRA, all-trans retinoic acid ENR, daunorubicinAra-C, Cytosine arabinosideIDA, idarubicin
ASH. Education program book 2003 90
25
APL / Long-Term outcome
Long-term outcomes of APL
CR Relapse Survival
Pre ATRA 60-80 50-60 30-40
After ATRA 90 10-20 80-90
26
Retinoic Acid Syndrome (RAS)APL Syndrome (APLS)
APL / RAS
27
Mainfestations of the retinoic acid syndrome
APL / RAS
Manifestation 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 11
Blood 2000 95 90
28
APL / RAS

• Incidence
• ATRA ?? 25
• ATRA Chemo 415
• Differential Diagnosis
• Sepsis, Pneumonia
• Chemotherapy Toxicity
• Heart Failure etc.

29
Prevention and Treatment
APL / RAS

• 1) Prophylactic prednisolone (?)
• 2) Concurrent ATRA and Chemotherpay
• 3) Early treatment with Dexamethasone

30
Prognostic Factors
APL / Prognostic Factors
31
APL / Prognostic Factors
PETHEMA and GIMEMA
WBC platelet 6yr CIR(LPA 96)
High risk Intermediate Low risk gt10.000/uL ?10.000/uL ?10.000/uL ?40.000/uL gt40.000/uL 34 14 6.1
CIR Cumulative incidence of relapse
Blood 2000 1247
32
APL / Prognostic Factors

• ? Female good px
• ? PML/RAR-? break point
• short poor px
• ? CD56 expression poor px
• ? HLA B13 relapse ?
• ? Additional cytogenetic abnormality(?)

33
APL / Prognostic Factors
Risk-adapted Therapy

• High risk (WBC gt 10,000 /uL)
• Intermediate risk (WBC ? 10,000/uL, PLT?
  40,000/uL)
• LPA 96 Consolidation?
• ? ATRA ?? 45 mg/m2 ? 15 days
• ? Idarubicine ?? ??
• 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

PETHEMA LPA 99 (1996-2002) Blood 2004 103
1237
34
APL / Prognostic Factors
Results LPA 96 (157), LPA 99 (227)

• 3year cumulative Relapse (CIR)
• 17.2 ? 7.5 ( p0.008 )
• Low risk ??? 3years CIR
• 20.1 ? 8.7 ( p0.004 )

Low risk intermediate high risk
6yr CIR (LPA96) 6.1 14 34
3yr CIR(LPA99) 3 2.5 21
35
Treatment in Relapsed APL
Arsenic Trioxide (AS2O3)
36
Arsenic Trioxide (AS2O3) in APL
APL / ATO

• ??? ????
• 1970?? ?????
• APL, Hepatoma, Lymphoma
• China report (92, 96) CR 65.6 84
• 10yr SR
  9/32 (28.2)

37
APL / ATO

• ? 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(-)

38
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 ??? renal failure, flaccid paralysis

39
Soignet et al. (U.S.A)
APL / ATO

• ???? (12?)
• 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
40
Soignet et al. (U.S.A)
APL / ATO

• Induction 0.15mg/kg IV until CR (maximum
  50dose)
• Consolidation CR ? 34? ?
• 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??175 ? 80009000??

JCO 2001 19 3852
41
Chao et al. (in China)
APL / ATO

• Induction ATO 10 mg IV for 6wks
• ( ??? 2nd course 1? )
• Consolidation
• - Chemotherapy group
• DNR or Mito Ara-C Relapse 3/4
• - ATO group Relapse 12/18
• - ATOChemotherapy group Relapse 2/11
• Duration of ATO-induced CR was related to the
  post-remission therapy

Blood 1999 94 3315
42
ATO therapy in relapsed APL
APL / ATO
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(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? 14?()
43
ATO therapy in APL Conclusion
APL / ATO

• Relapsed APL
• ATO ????
• CR (85 90)
• Molecular CR (77 86)
• ?? maintenance role (?)
• if PCR() ? Allo SCT
• PCR (-) ? Auto SCT

44
Treatment in Molecular Relapse
45
Autologous HSCT in second CR
APL /Molecular relapse
Relapsed (lt14 months) CCR (gt14 months)
PCR PCR - 7 1 0 7
Meloni.et al. Blood 1997901321
46
Prospective RT-PCR AnalysisGIMEMA 0493
(1993-1997)
APL /Molecular relapse

• After consolidation RT-PCR(-) 163?
• RT-PCR() 21?
• 20/21 ?? 3?? ? hematologic relapse
• 17/21 (85) Consolidation ? 6?? ? ()
• RT-PCR Persistent(-) 142?
• 134/142 CCR
• 8/142 Hematologic relapse

Blood 1998 92 784
47
Salvage Therapy in Molecular Relapse
APL /Molecular relapse

• Reinduction ATRA 45mg/m2 ?30days (14?)
• Consolidation Mitoxanthrone 6mg/m2/day 1-4
• Ara-C 1g/m2/day 1-4
• Maintenance ATRA 6MPMTX (4?)
• ABMT (8?)
• RT-PCR(-) 12/14 (85)

ATRA ? 7?
Consolidation ? 5?
Blood 1999 94 2225 (Italy)
48
APL /Molecular relapse
Overall Survival from relpase
100
49
Molecular level ?? ?? ? ??
APL /Molecular relapse

• Clinical relapse ? ??
• Fetal complication ??
• MRD ???? ??
• Better long term survival
• ??????

50
Mylotarg in molecular relapsed APL
APL / Mylotarg

• Mylotarg Caliceamicin conjugated anti-CD33
  
• (Gemtuzumab Ozogamicin)
• N16 / 8 (1st line), 5(2nd line ), 2(3rd line
  ), 1(4th line )
• Method
• 6mg/m2 (IV) 2cylce
• ? Molecular CR ?? ? 1cycle more

51
Mylotarg in molecular relapsed APL
APL / Mylotarg

• after 2 cycle 9/11 (91)
• after 3 cycle 13/13 (100)
• - 1? 1 cycle ? CR (hepatotoxicity), No further
  tx
• - 2? disease progression
• 7/14 Molecular CR (Mean 15mo) (731mo)
• 7/14 Molecular relapse (315mo)
• ? retry Mylotarg
• 2/2 new molecular CR

Blood 2004 104 1913 (Italy)
52
Other Treatment in New APL
APL / Other treatment
53
ATRAMylotarg in de novo APL
APL / ATRA Mylotarg

• ATRA 45mg/m2/d, until CR
• ? Next 2???(on,off)
• Mylotarg 9mg/ m2 on D1-5
• ? then q 45wks
• ? additional 8 cycle
• 3cycle ? PCR() ? Idarubicin
• ATRA
• CR 16/19 (84)
• 14/16 ATRA Mylotarg
• 2 /16 Idarubicin
• 3? ?? ? MOF (1)
• Hemorrhage (2)
• PCR (-) 12/12
• ? Mylotarg appears active in APL

Blood 2002 99 4222 (U.S.A)
54
ATO (de novo APL)
APL / Other treatment

• 0.15mg/kg/day Induction (1)
• Consolidation (1)
• Maintenance (6)
• Results
• Children 11?
• CR10/11(91)
• Molecular CR 10/10 (100)
• OS 91 (30 months)
• RFS 81 (30 months )

Leukemia 2004 18 1587 (India)
55
Treatment ATRA and ATO in APL
APL / ATOATRA

• 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 ?, 26? Coagulopathy
normolize 7?, 4? ATRA ATO Combination ? CR
?? ??, Coagulopathy ? ? ? ?? ??
Ai Zheng 2004 23 430 (China)
56
Ongoing Trial
APL / ongoing trial

• 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

57
APL / ongoing trial

• 2) Phase II
• Trentinoin ?? ? CR ? 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

58
Conclusion
APL / Conclusion
59
Current recommendations for treatment of APL
APL / Conclusion
1. ??? 1) Induction ATRA 45mg/?/day until CR
anthracycline anthracycline daunorubicin
50-60mg/?/day for 3 days or idarubicin
12mg/?/day for 4 days (2?? 1? 4?) 2)
Consolidation anthracycline based chemotherapy
(2-3 cycle) consolidation ? PCR() high dose
cytarabine or allogenic SCT or autologous SCT
(PCR(-)? harvest? ??) 3) Maintenance ATRA
45mg/?/day for 15 days (3?? ??) 6MP
100mg/?/day MTX 10mg/?/week for 2years
60
Current recommendations for treatment of APL
APL / Conclusion
4) Molecular monitering PCR for PML/RARa ??
2?? 36?? ??, ?? 2?? 6?? ?? 2. ??? ATO
0.15mg/kg/day (?? ?? 5?) CR ????
? if PCR(-) autologous SCT
PCR() allogeneic SCT (for young pts)
61
Future Directions

• Induction Mortality? ?? ? ?? ????
• Other Prognostic factor?
• Risk adapted therapy (blood 2004 103 1237)
• Molecular relapse ?? ??
• ATO, Mylotarg, ATRA ? Combination
• Tetra-arsenic tetra-sulfide (As4S4)
• Realgan? p.o (blood 2002 99 3136)
• Liposomal ATRA (IV)