severe coagulopathy specific genetic specific genetic lesion lesion response to differentiating...

Severe coagulopathySevere coagulopathy

Specific genetic Specific genetic lesion lesion

Response to differentiatingResponse to differentiating agents (RA, ATO)agents (RA, ATO)

Striking sensitivityStriking sensitivityto anthracyclinesto anthracyclines

TAILORED DIAGNOSIS AND TAILORED DIAGNOSIS AND MANAGEMENTMANAGEMENT

Acute promyelocytic leukemiaAcute promyelocytic leukemia

M2

M1

M3M5

15 17

15q+ 17q-

PML locus RAR locus

PML/RARfusion gene

RAR/PMLfusion gene

Co-repressor

NCor HD

ACSin3

NCor

HDACSin3

Represión

PML

RARE

RA

R

RA

PML/RAR

transcriptionalactivation

Co-activators(HAT)

Pharmacologic doses(10-6 M)

PML RAR

RT-PCR amplification of the PML/RARRT-PCR amplification of the PML/RAR hybrid hybrid

3 4 5 6 3 bcr 1

3 4 5 6 3 bcr 2

3 3 bcr 3

PML/RARPML/RAR as Ideal Marker for Disease as Ideal Marker for Disease Diagnosis and Monitoring Diagnosis and Monitoring

• Causally related to disease pathogenesisCausally related to disease pathogenesis

• Targeted by specific therapyTargeted by specific therapy

• Predicts response to retinoidsPredicts response to retinoids

Clinical relevance of genetic studies in APLClinical relevance of genetic studies in APL

• DiagnosisDiagnosis

• Response to front-line therapyResponse to front-line therapy

• Follow-up monitoring and therapy of Follow-up monitoring and therapy of molecular relapsemolecular relapse

PML/RARa predicts response to R.A.PML/RARa predicts response to R.A.Miller et al, PNAS 1992Miller et al, PNAS 1992

N. casesN. cases CytogeneticsCytogenetics PML/RARa R.A. responsePML/RARa R.A. response

2424 24 +ve24 +ve 24 +ve24 +ve 100%100%

44 4 not evaluable 4 not evaluable 4 +ve 4 +ve 100%100%

4 +ve4 +ve 100%100%88 8 normal8 normal

4 -ve4 -ve 0% 0%

PCR-monitoring studiesPCR-monitoring studies in large clinical trialsin large clinical trials

• GIMEMAGIMEMA• MRCMRC• PETHEMAPETHEMA• AMLCGAMLCG• MDACCMDACC• US IntergroupUS Intergroup• MSKCCMSKCC• JALSGJALSG

PCR-Adapted Therapy in APL PCR-Adapted Therapy in APL

DDIIAAGGNNOOSSIISS

RA + CHTRA + CHTInductionInduction

Salvage RxSalvage Rx

RA + CHTRA + CHTConsolidationConsolidation

MaintenanceMaintenance

Further intensificationFurther intensification

PML-RARa neg.PML-RARa neg.

PML-RARa pos.PML-RARa pos.(sensitivity 10(sensitivity 10-4-4))

MILESTONES IN APL THERAPYMILESTONES IN APL THERAPY

19721972 Exquisite sensitivity to anthracyclinesExquisite sensitivity to anthracyclines

19871987 Differentiative response to RADifferentiative response to RA

19931993 RA + CHT > CHTRA + CHT > CHT

93-9993-99 Optimization of RA +CHT combinationOptimization of RA +CHT combination

20002000 Anti-CD33, HDAC inhibitorsAnti-CD33, HDAC inhibitors

97-9997-99 ATO, other RA derivativesATO, other RA derivatives

APL AS A MODEL FOR TARGETED RxAPL AS A MODEL FOR TARGETED Rx

• RA + anthracycline CHTRA + anthracycline CHT

• Arsenic & other RA derivativesArsenic & other RA derivatives

• Anti-CD33 MoAbs Anti-CD33 MoAbs

• HDAC inhibitorsHDAC inhibitors

• FLT3 inhibitorsFLT3 inhibitors

TARGETED TREATMENT OF APLTARGETED TREATMENT OF APL

• RA + anthracycline CHTRA + anthracycline CHT

• Arsenic & other RA derivativesArsenic & other RA derivatives

• Anti-CD33 MoAbs Anti-CD33 MoAbs

• HDAC inhibitorsHDAC inhibitors

• FLT3 inhibitorsFLT3 inhibitors

Acute Promyelocytic Leukemia

+ RA

Disease-Free SurvivalDisease-Free SurvivalAIDA 0493 vs AIDA 2000 (all risks)AIDA 0493 vs AIDA 2000 (all risks)

Disease-Free SurvivalDisease-Free SurvivalAIDA 0493 vs AIDA 2000 (all risks)AIDA 0493 vs AIDA 2000 (all risks)

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

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

yearsyears

p=0.09

1

.75

.50

.25

01 2 3 4 5 6 70

TARGETED TREATMENT OF APLTARGETED TREATMENT OF APL

• RA + anthracycline CHTRA + anthracycline CHT

• Arsenic & other RA derivativesArsenic & other RA derivatives

• Anti-CD33 MoAbs Anti-CD33 MoAbs

• HDAC inhibitorsHDAC inhibitors

• FLT3 inhibitorsFLT3 inhibitors

Dual response of APL cells to arsenic trioxide

US Multicenter trial with A2O3

Molecular Response by Cycle

78%

51%

0

50

100

Baseline Induction Consolidation

Pro

po

rtio

n N

eg

ati

ve

n=45n=45

PCR ResponsePCR Response

Molecular remission as a therapeutic goal in APLMolecular remission as a therapeutic goal in APL

- - Molecular remissionMolecular remission in PML-RARa positive APL by combined in PML-RARa positive APL by combinedATRA and idarubicin. Mandelli et al 1997ATRA and idarubicin. Mandelli et al 1997

- Presenting WBC count and kinetics of - Presenting WBC count and kinetics of molecular remissionmolecular remission predict prognosis in APL treated with ATRA. Burnett et al. 1999predict prognosis in APL treated with ATRA. Burnett et al. 1999

-- Molecular remissionMolecular remission by liposomal encapsulated ATRA in newlyby liposomal encapsulated ATRA in newly diagnosed diagnosed APL. Estey et al. 1999APL. Estey et al. 1999

- - Molecular remissionMolecular remission induction with ATRA and anti-CD33 MoAb induction with ATRA and anti-CD33 MoAbHuM195 in APL. Jurcic et al. 2000HuM195 in APL. Jurcic et al. 2000

US Multicenter trial with As2O3 for relapsed APL

00 66 1212 1818 2424 3030 3636MonthsMonths

0%0%

20%20%

40%40%

60%60%

80%80%

100%100%18-Month OS estimate: 66%18-Month OS estimate: 66%

Median Follow-up: 18.3 monthsMedian Follow-up: 18.3 months

TARGETED TREATMENT OF APLTARGETED TREATMENT OF APL

• RA + anthracycline CHTRA + anthracycline CHT

• Arsenic & other RA derivativesArsenic & other RA derivatives

• Anti-CD33 MoAbsAnti-CD33 MoAbs

• HDAC inhibitorsHDAC inhibitors

• FLT3 inhibitorsFLT3 inhibitors

RATIONALE FOR MYLOTARG IN APLRATIONALE FOR MYLOTARG IN APL

- Absent / minimal gp170 (MDR) expressionAbsent / minimal gp170 (MDR) expression

- Homogeneous CD33 staining in 100% casesHomogeneous CD33 staining in 100% cases

- Striking sensitivity to anthracyclinesStriking sensitivity to anthracyclines

ATRA (A) + Mylotarg (M) Trial ATRA (A) + Mylotarg (M) Trial

In Untreated APL (MD Aderson)In Untreated APL (MD Aderson)

InductionInduction ATRA until CR ATRA until CR

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

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

In CRIn CR ATRA 2 weeks on/2 weeks off ATRA 2 weeks on/2 weeks off

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

Ida 12 mg/m2 X 3 Ida 12 mg/m2 X 3 only if PCR +only if PCR +

PCR+ve PCR-ve

Dose 3* and successivedoses until PCR-negativity (max 3 further doses)

Dose 3*( final dose)

MYLOTARG FOR MOLECULAR RELAPSE (Gimema)MYLOTARG FOR MOLECULAR RELAPSE (Gimema)

Dose 1*

Dose 2*

PCR

* 6mg/m2 i.v.

Mos fromMos from Pts Pts Pts Pts My dosesMy doses TestedTested PCR NegativePCR Negative After 2After 2ndnd 88 8 8 After 3After 3rdrd 6 6 6 6 4-6 m4-6 m 4 4 2 2

8-10 m8-10 m 2 2 2 2 12-14 m12-14 m 22 2 2

Mylotarg for molecular relapse (GIMEMA)Mylotarg for molecular relapse (GIMEMA)

0

0,2

0,4

0,6

0,8

1

0 12 24

Months

Prob

abilit

y

0

0,2

0,4

0,6

0,8

1

0 12 24

Months

Prob

abilit

y

74% ± 14%74% ± 14%

Mylotarg per la recidiva molecolareSopravvivenza globale (N=16)

Mylotarg per la recidiva molecolareSopravvivenza globale (N=16)

Lo Coco, Blood 2004Lo Coco, Blood 2004

TARGETED TREATMENT OFTARGETED TREATMENT OF APLAPL

• RA + anthracycline CHTRA + anthracycline CHT

• Arsenic & other RA derivativesArsenic & other RA derivatives

• Anti-CD33 MoAbs Anti-CD33 MoAbs

• HDAC inhibitorsHDAC inhibitors

• FLT3 inhibitorsFLT3 inhibitors

Co-repressor

HDAC

Sin3NCor

NCor HD

ACSin3

NCor

HDACSin3

Co-activators(HAT)

PLZF

PLZF

RARE

RA

R

RA

PLZF/RAR

Pharmacologic doses(10-6 M)

Differentiationinduction

TSA

Transcriptional therapy with HDAC inhibitorsTranscriptional therapy with HDAC inhibitors

TARGETED TREATMENT OF APLTARGETED TREATMENT OF APL

• RA + anthracycline CHTRA + anthracycline CHT

• Arsenic & other RA derivativesArsenic & other RA derivatives

• Anti-CD33 MoAbs Anti-CD33 MoAbs

• HDAC inhibitorsHDAC inhibitors

• FLT3 inhibitorsFLT3 inhibitors

STAT

JAKRAS

MAD

P

P

P

P

P

PP

P

= Ig-like

= TM

= JM

= TK

= FL

Sawyers, Cancer Cell 2002

FINDING THE NEXT GLEEVEC: FLT3 TARGETED KINASE INHIBITOR THERAPY FOR AML

1

0.8

0.6

0.4

0.2

0

0 20 40 60 80 100 d.

P=0.0005

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

Weisberg, Cancer cell 2002

P

Combined Modality Therapy for APL (MSKCC)

Immunotherapy

HuM195

Chemotherapy

IdarubicinArsenicTrioxide

TranscriptionModulation

DifferentiationTherapy

All-TransRetinoic Acid

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

RT-PCR*

Type I lesions(point mutations)

Type II lesions(fusion genes)

differentiation block

APL(AML)

prolif./survival advantage

Transcriptional targeting (ATRA, ATO, HDAC inhib.)

Targeting prolif. (e.g. FLT3 inhib.)

Daniela Diverio Miguel A. Sanz David GrimwadeAndrea Biondi Pascual Bolufer Alan K. BurnettPier G. Pelicci Guillermo Martin Antony GoldstoneFranco Mandelli Eva Barragan

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

Steve Soignet Elihu EsteyDavid Scheinberg Hagop Kantarjian

MSKCC, NY MDACC, Houston

ACKNOWLEDGMENTSACKNOWLEDGMENTS