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Severe coagulopathy

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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Severe coagulopathy

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

  2. M2 M1 M5 M3

  3. PML/RAR RAR/PML fusion gene fusion gene PML locus RAR locus 15 17 15q+ 17q-

  4. 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

  5. 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

  6. PML/RARa as Ideal Marker for Disease Diagnosis and Monitoring • Causally related to disease pathogenesis • Targeted by specific therapy • Predicts response to retinoids

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

  8. 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%

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

  10. 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

  11. 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

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

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

  14. Acute Promyelocytic Leukemia + RA

  15. 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

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

  17. Dual response of APL cells to arsenic trioxide

  18. US Multicenter trial with A2O3Molecular Response by Cycle PCR Response n=45

  19. 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

  20. 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

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

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

  23. 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 +

  24. 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.

  25. 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

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

  27. TARGETED TREATMENT OFAPL • RA + anthracycline CHT • Arsenic & other RA derivatives • Anti-CD33 MoAbs • HDAC inhibitors • FLT3 inhibitors

  28. 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

  29. Transcriptional therapy with HDAC inhibitors

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

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

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

  33. 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

  34. 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.

  35. 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.)

  36. 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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