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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
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M2 M1 M5 M3
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PML locus RAR locus 15 17 PML/RAR fusion gene RAR/PML fusion gene 15q+ 17q-
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PML/RAR Pharmacologic doses Co-repressor (10-6 M) RAR Co-activators
NCor HDAC Sin3 Pharmacologic doses (10-6 M) Co-repressor NCor HDAC Sin3 RAR Co-activators (HAT) RA RARE PML transcriptional activation Represión
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RT-PCR amplification of the PML/RAR hybrid
3 4 5 6 3 bcr 1 3 4 5 6 3 bcr 2 3 3 bcr 3
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PML/RARa as Ideal Marker for Disease Diagnosis and Monitoring
Causally related to disease pathogenesis Targeted by specific therapy Predicts response to retinoids
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Clinical relevance of genetic studies in APL
Diagnosis Response to front-line therapy Follow-up monitoring and therapy of molecular relapse
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PML/RARa predicts response to R.A.
Miller et al, PNAS 1992 N. cases Cytogenetics PML/RARa R.A. response ve 24 +ve 100% not evaluable ve 100% 4 +ve 100% 8 8 normal 4 -ve %
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PCR-monitoring studies
in large clinical trials GIMEMA MRC PETHEMA AMLCG MDACC US Intergroup MSKCC JALSG
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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
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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
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APL AS A MODEL FOR TARGETED Rx
RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
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TARGETED TREATMENT OF APL
RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
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Acute Promyelocytic Leukemia
+ RA
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Disease-Free Survival
AIDA 0493 vs AIDA 2000 (all risks) 1 AIDA2000: 86% (CI 95%: ) .75 AIDA0493: 72% (CI 95%: ) .50 .25 p=0.09 The actuarial event-free survival is 73% at 5 years for the LPA96, and 85% at two years for the LPA99. 1 2 3 4 5 6 7 years
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TARGETED TREATMENT OF APL
RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
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Dual response of APL cells to arsenic trioxide
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US Multicenter trial with A2O3 Molecular Response by Cycle
PCR Response n=45
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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 remission by 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
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US Multicenter trial with As2O3 for relapsed APL
6 12 18 24 30 36 Months 0% 20% 40% 60% 80% 100% 18-Month OS estimate: 66% Median Follow-up: 18.3 months
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TARGETED TREATMENT OF APL
RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
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RATIONALE FOR MYLOTARG IN APL
- Homogeneous CD33 staining in 100% cases - Striking sensitivity to anthracyclines - Absent / minimal gp170 (MDR) expression
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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 +
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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.
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Mylotarg for molecular relapse (GIMEMA)
Mos from Pts Pts My doses Tested PCR Negative After 2nd After 3rd 4-6 m 8-10 m 12-14 m
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Mylotarg per la recidiva molecolare
Sopravvivenza globale (N=16) 74% ± 14% Lo Coco, Blood 2004
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TARGETED TREATMENT OF APL
RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
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PLZF/RAR Pharmacologic doses Co-repressor (10-6 M) RAR Co-activators
NCor HDAC Sin3 Pharmacologic doses (10-6 M) Co-repressor Differentiation induction NCor HDAC Sin3 RAR Co-activators (HAT) RA RARE PLZF HDAC Sin3 NCor TSA
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Transcriptional therapy with HDAC inhibitors
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TARGETED TREATMENT OF APL
RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
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= Ig-like = TM = JM = TK P P P P = FL P STAT JAK RAS MAD
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FINDING THE NEXT GLEEVEC: FLT3 TARGETED KINASE
INHIBITOR THERAPY FOR AML Sawyers, Cancer Cell 2002
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Survival of FLT3-ITD+ mice treated with/wo (P) PKC412
0.8 0.6 0.4 0.2 P P=0.0005 d. Weisberg, Cancer cell 2002
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Combined Modality Therapy for APL (MSKCC)
Differentiation Therapy All-Trans Retinoic Acid Immunotherapy HuM195 Arsenic Trioxide Transcription Modulation Chemotherapy Idarubicin RT-PCR* *Adaptive Regulation: Number of idarubicin courses determined by RT-PCR results.
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Type I lesions (point mutations) Type II lesions (fusion genes) prolif./survival advantage differentiation block APL (AML) Transcriptional targeting (ATRA, ATO, HDAC inhib.) Targeting prolif. (e.g. FLT3 inhib.)
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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
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