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Acute promyelocytic leukemia. Severe coagulopathy. Striking sensitivity to anthracyclines. TAILORED DIAGNOSIS AND MANAGEMENT. Response to differentiating agents (RA, ATO). Specific genetic lesion. M2. M1. M5. M3. PML/RAR. RAR/PML. fusion gene. fusion gene. PML locus.

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slide2

Acute promyelocytic leukemia

Severe coagulopathy

Striking sensitivity

to anthracyclines

TAILORED DIAGNOSIS AND MANAGEMENT

Response to differentiating

agents (RA, ATO)

Specific genetic

lesion

slide3

M2

M1

M5

M3

slide4

PML/RAR

RAR/PML

fusion gene

fusion gene

PML locus

RAR locus

15

17

15q+

17q-

slide5

Pharmacologic doses

(10-6 M)

HDAC

Sin3

NCor

Sin3

HDAC

NCor

Co-activators

(HAT)

RA

PML

PML/RAR

Co-repressor

RAR

RARE

transcriptional

activation

Represión

slide6

RT-PCR amplification of the PML/RAR hybrid

PML

RAR

bcr 1

3

3

4

5

6

3

bcr 2

3

4

5

6

3

bcr 3

3

slide7

PML/RARa as Ideal Marker for Disease Diagnosis and Monitoring

  • Causally related to disease pathogenesis
  • Targeted by specific therapy
  • Predicts response to retinoids
slide8

Clinical relevance of genetic studies in APL

  • Diagnosis
  • Response to front-line therapy
  • Follow-up monitoring and therapy of molecular relapse
slide9

PML/RARa predicts response to R.A.

Miller et al, PNAS 1992

N. cases Cytogenetics PML/RARa R.A. response

24 24 +ve 24 +ve 100%

4 4 not evaluable 4 +ve 100%

4 +ve 100%

8 8 normal

4 -ve 0%

slide10

PCR-monitoring studies

in large clinical trials

  • GIMEMA
  • MRC
  • PETHEMA
  • AMLCG
  • MDACC
  • US Intergroup
  • MSKCC
  • JALSG
pcr adapted therapy in apl
PCR-Adapted Therapy in APL

PML-RARa neg.

RA + CHT

Induction

RA + CHT

Consolidation

PML-RARa pos.

(sensitivity 10-4)

Maintenance

DIAGNOSIS

Further intensification

Salvage Rx

slide12

MILESTONES IN APL THERAPY

1972 Exquisite sensitivity to anthracyclines

1987 Differentiative response to RA

1993 RA + CHT > CHT

93-99 Optimization of RA +CHT combination

97-99 ATO, other RA derivatives

2000 Anti-CD33, HDAC inhibitors

slide13

APL AS A MODEL FOR TARGETED Rx

  • RA + anthracycline CHT
  • Arsenic & other RA derivatives
  • Anti-CD33 MoAbs
  • HDAC inhibitors
  • FLT3 inhibitors
slide14

TARGETED TREATMENT OF APL

  • RA + anthracycline CHT
  • Arsenic & other RA derivatives
  • Anti-CD33 MoAbs
  • HDAC inhibitors
  • FLT3 inhibitors
slide16

Disease-Free Survival

AIDA 0493 vs AIDA 2000 (all risks)

1

AIDA2000: 86% (CI 95%: 80 - 92)

.75

AIDA0493: 72% (CI 95%: 66 - 78)

.50

.25

p=0.09

0

0

1

2

3

4

5

6

7

years

slide17

TARGETED TREATMENT OF APL

  • RA + anthracycline CHT
  • Arsenic & other RA derivatives
  • Anti-CD33 MoAbs
  • HDAC inhibitors
  • FLT3 inhibitors
slide20

Molecular remission as a therapeutic goal in APL

- Molecular remission in PML-RARa positive APL by combined

ATRA and idarubicin. Mandelli et al 1997

- Presenting WBC count and kinetics of molecular remission

predict prognosis in APL treated with ATRA. Burnett et al. 1999

-Molecular remissionby liposomal encapsulated ATRA in newly

diagnosed APL. Estey et al. 1999

- Molecular remission induction with ATRA and anti-CD33 MoAb

HuM195 in APL. Jurcic et al. 2000

slide21

18-Month OS estimate: 66%

100%

80%

60%

40%

20%

Median Follow-up: 18.3 months

0%

0

6

12

18

24

30

36

Months

US Multicenter trial with As2O3 for relapsed APL

slide22

TARGETED TREATMENT OF APL

  • RA + anthracycline CHT
  • Arsenic & other RA derivatives
  • Anti-CD33 MoAbs
  • HDAC inhibitors
  • FLT3 inhibitors
slide23

RATIONALE FOR MYLOTARG IN APL

-Homogeneous CD33 staining in 100% cases

-Striking sensitivity to anthracyclines

-Absent / minimal gp170 (MDR) expression

atra a mylotarg m trial in untreated apl md aderson
ATRA (A) + Mylotarg (M) Trial In Untreated APL (MD Aderson)

Induction ATRA until CR

M 9 mg/m2 d 5 (d 1 if WBC >10)

Ida 12 mg/m2 d1-3 (if WBC > 30)

In CR ATRA 2 weeks on/2 weeks off

M 9 mg/m2 Q 4-5 weeks (X 8)

Ida 12 mg/m2 X 3 only if PCR +

slide25

MYLOTARG FOR MOLECULAR RELAPSE (Gimema)

Dose 1*

Dose 2*

PCR

PCR+ve

PCR-ve

Dose 3* and successive

doses until PCR-negativity

(max 3 further doses)

Dose 3*

( final dose)

*6mg/m2 i.v.

slide26

Mylotarg for molecular relapse (GIMEMA)

Mos from Pts Pts

My dosesTestedPCR Negative

After 2nd 8 8

After 3rd 6 6

4-6 m 4 2

8-10 m 2 2

12-14 m 2 2

slide27

Mylotarg per la recidiva molecolare

Sopravvivenza globale (N=16)

74% ± 14%

Lo Coco, Blood 2004

slide28

TARGETED TREATMENT OFAPL

  • RA + anthracycline CHT
  • Arsenic & other RA derivatives
  • Anti-CD33 MoAbs
  • HDAC inhibitors
  • FLT3 inhibitors
slide29

HDAC

Pharmacologic doses

(10-6 M)

Sin3

NCor

Sin3

HDAC

Differentiation

induction

NCor

Co-activators

(HAT)

RA

PLZF

HDAC

NCor

Sin3

TSA

PLZF/RAR

Co-repressor

RAR

RARE

slide31

TARGETED TREATMENT OF APL

  • RA + anthracycline CHT
  • Arsenic & other RA derivatives
  • Anti-CD33 MoAbs
  • HDAC inhibitors
  • FLT3 inhibitors
slide32

= Ig-like

= TM

= TK

P

P

P

P

P

P

= JM

P

= FL

P

STAT

JAK

RAS

MAD

slide33

FINDING THE NEXT GLEEVEC:

FLT3 TARGETED KINASE

INHIBITOR THERAPY FOR AML

Sawyers, Cancer Cell 2002

slide34

Survival of FLT3-ITD+ mice treated with/wo (P) PKC412

1

0.8

0.6

0.4

0.2

0

P

P=0.0005

0 20 40 60 80 100 d.

Weisberg, Cancer cell 2002

slide35

Combined Modality Therapy for APL (MSKCC)

Immunotherapy

Differentiation

Therapy

Chemotherapy

Transcription

Modulation

HuM195

All-Trans

Retinoic Acid

Idarubicin

Arsenic

Trioxide

RT-PCR*

*Adaptive Regulation: Number of idarubicin courses determined by RT-PCR results.

slide36

Type I lesions

(point mutations)

Type II lesions

(fusion genes)

differentiation

block

prolif./survival advantage

APL

(AML)

Transcriptional

targeting

(ATRA, ATO,

HDAC inhib.)

Targeting prolif.

(e.g. FLT3 inhib.)

slide37

ACKNOWLEDGMENTS

Daniela Diverio Miguel A. Sanz David Grimwade

Andrea Biondi Pascual Bolufer Alan K. Burnett

Pier G. Pelicci Guillermo Martin Antony Goldstone

Franco Mandelli Eva Barragan

GIMEMA (Italy) PETHEMA (Spain) MRC (UK)

Steve Soignet Elihu Estey

David Scheinberg Hagop Kantarjian

MSKCC, NY MDACC, Houston