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