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Severe coagulopathy Specific genetic Specific genetic lesion lesion Response to differentiating agents (RA, ATO) agents (RA, ATO) Striking sensitivity.

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Presentation on theme: "Severe coagulopathy Specific genetic Specific genetic lesion lesion Response to differentiating agents (RA, ATO) agents (RA, ATO) Striking sensitivity."— Presentation transcript:

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2 Severe coagulopathy Specific genetic Specific genetic lesion lesion Response to differentiating agents (RA, ATO) agents (RA, ATO) Striking sensitivity to anthracyclines TAILORED DIAGNOSIS AND MANAGEMENT Acute promyelocytic leukemia

3 M2 M1 M3 M5

4 q+17q- PML locusRAR locus PML/RAR fusion gene RAR/PML fusion gene

5 Co-repressor NCor HDAC Sin3 NCor HDAC Sin3 Represión PML RARE RAR RA PML/RAR transcriptional activation Co-activators (HAT) Pharmacologic doses (10 -6 M)

6 PML RAR RT-PCR amplification of the PML/RAR hybrid bcr bcr bcr 3

7 PML/RAR as Ideal Marker for Disease Diagnosis and Monitoring Causally related to disease pathogenesis Causally related to disease pathogenesis Targeted by specific therapy Targeted by specific therapy Predicts response to retinoids Predicts response to retinoids

8 Clinical relevance of genetic studies in APL Diagnosis Diagnosis Response to front-line therapy Response to front-line therapy Follow-up monitoring and therapy of molecular relapseFollow-up monitoring and therapy of molecular relapse

9 PML/RARa predicts response to R.A. Miller et al, PNAS 1992 N. casesCytogeneticsPML/RARa R.A. response ve24 +ve100% 4 4 not evaluable 4 +ve100% 4 +ve100% 4 +ve100% 88 normal 4 -ve 0% 4 -ve 0%

10 PCR-monitoring studies in large clinical trials in large clinical trials GIMEMA MRC MRC PETHEMA PETHEMA AMLCG AMLCG MDACC MDACC US Intergroup US Intergroup MSKCC MSKCC JALSG JALSG

11 PCR-Adapted Therapy in APL PCR-Adapted Therapy in APL DIAGNOSISDIAGNOSISDIAGNOSISDIAGNOSIS RA + CHT Induction Salvage Rx RA + CHT Consolidatio n Maintenance Further intensification PML-RARa neg. PML-RARa pos. (sensitivity )

12 MILESTONES IN APL THERAPY 1972Exquisite sensitivity to anthracyclines 1987Differentiative response to RA 1993RA + CHT > CHT 93-99Optimization of RA +CHT combination 2000Anti-CD33, HDAC inhibitors 97-99ATO, other RA derivatives

13 APL AS A MODEL FOR TARGETED Rx RA + anthracycline CHT RA + anthracycline CHT Arsenic & other RA derivatives Arsenic & other RA derivatives Anti-CD33 MoAbs Anti-CD33 MoAbs HDAC inhibitors HDAC inhibitors FLT3 inhibitors FLT3 inhibitors

14 TARGETED TREATMENT OF APL RA + anthracycline CHT RA + anthracycline CHT Arsenic & other RA derivatives Arsenic & other RA derivatives Anti-CD33 MoAbs Anti-CD33 MoAbs HDAC inhibitors HDAC inhibitors FLT3 inhibitors FLT3 inhibitors

15 Acute Promyelocytic Leukemia + RA

16 Disease-Free Survival AIDA 0493 vs AIDA 2000 (all risks) Disease-Free Survival AIDA 0493 vs AIDA 2000 (all risks) AIDA0493: 72% (CI 95%: ) AIDA2000: 86% (CI 95%: ) years p=

17 TARGETED TREATMENT OF APL RA + anthracycline CHT RA + anthracycline CHT Arsenic & other RA derivatives Arsenic & other RA derivatives Anti-CD33 MoAbs Anti-CD33 MoAbs HDAC inhibitors HDAC inhibitors FLT3 inhibitors FLT3 inhibitors

18 Dual response of APL cells to arsenic trioxide

19 US Multicenter trial with A 2 O 3 Molecular Response by Cycle n=45 PCR Response

20 Molecular remission as a therapeutic goal in APL Molecular remission as a therapeutic goal in APL - Molecular remission in PML-RARa positive APL by combined ATRA and idarubicin. Mandelli et al Presenting WBC count and kinetics of molecular remission predict prognosis in APL treated with ATRA. Burnett et al Molecular remission by liposomal encapsulated ATRA in newly diagnosed APL. Estey et al diagnosed APL. Estey et al Molecular remission induction with ATRA and anti-CD33 MoAb HuM195 in APL. Jurcic et al. 2000

21 US Multicenter trial with As 2 O 3 for relapsed APL

22 TARGETED TREATMENT OF APL RA + anthracycline CHT RA + anthracycline CHT Arsenic & other RA derivatives Arsenic & other RA derivatives Anti-CD33 MoAbs Anti-CD33 MoAbs HDAC inhibitors HDAC inhibitors FLT3 inhibitors FLT3 inhibitors

23 RATIONALE FOR MYLOTARG IN APL Absent / minimal gp170 (MDR) expression - Absent / minimal gp170 (MDR) expression Homogeneous CD33 staining in 100% cases - Homogeneous CD33 staining in 100% cases Striking sensitivity to anthracyclines - Striking sensitivity to anthracyclines

24 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) 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 CR 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 only if PCR + Ida 12 mg/m2 X 3 only if PCR +

25 PCR+vePCR-ve Dose 3* and successive doses until PCR-negativity (max 3 further doses) Dose 3* ( final dose) MYLOTARG FOR MOLECULAR RELAPSE (Gimema) Dose 1* Dose 2* PCR * 6mg/m 2 i.v.

26 Mos from Pts Pts My doses Tested PCR Negative My doses Tested PCR Negative After 2 nd 8 8 After 2 nd 8 8 After 3 rd 6 6 After 3 rd m m m m m2 2 Mylotarg for molecular relapse (GIMEMA)

27 74% ± 14% Mylotarg per la recidiva molecolare Sopravvivenza globale (N=16) Mylotarg per la recidiva molecolare Sopravvivenza globale (N=16) Lo Coco, Blood 2004

28 TARGETED TREATMENT OF APL RA + anthracycline CHT RA + anthracycline CHT Arsenic & other RA derivatives Arsenic & other RA derivatives Anti-CD33 MoAbs Anti-CD33 MoAbs HDAC inhibitors HDAC inhibitors FLT3 inhibitors FLT3 inhibitors

29 Co-repressor HDAC Sin3 NCor HDAC Sin3 NCor HDAC Sin3 Co-activators (HAT) PLZF RARE RAR RA PLZF/RAR Pharmacologic doses (10 -6 M) Differentiation induction TSA

30 Transcriptional therapy with HDAC inhibitors

31 TARGETED TREATMENT OF APL RA + anthracycline CHT RA + anthracycline CHT Arsenic & other RA derivatives Arsenic & other RA derivatives Anti-CD33 MoAbs Anti-CD33 MoAbs HDAC inhibitors HDAC inhibitors FLT3 inhibitors FLT3 inhibitors

32 STAT JAK RAS MAD P P P P P P P P = Ig-like = TM = JM = TK = FL

33 Sawyers, Cancer Cell 2002 FINDING THE NEXT GLEEVEC: FLT3 TARGETED KINASE INHIBITOR THERAPY FOR AML

34 d. P= Survival of FLT3-ITD+ mice treated with/wo (P) PKC412 Weisberg, Cancer cell 2002 P

35 Combined Modality Therapy for APL (MSKCC) Immunotherapy HuM195 Chemotherapy Idarubicin Arsenic Trioxide Transcription Modulation Differentiation Therapy All-Trans Retinoic Acid * Adaptive Regulation: Number of idarubicin courses determined by RT-PCR results. RT-PCR*

36 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.)

37 Daniela Diverio Miguel A. SanzDavid Grimwade Andrea Biondi Pascual BoluferAlan K. Burnett Pier G. Pelicci Guillermo MartinAntony Goldstone Franco Mandelli Eva Barragan GIMEMA (Italy) PETHEMA (Spain)MRC (UK) Steve Soignet Elihu Estey David Scheinberg Hagop Kantarjian MSKCC, NY MDACC, Houston ACKNOWLEDGMENTS


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