12 MILESTONES IN APL THERAPY 1972 Exquisite sensitivity to anthracyclines1987 Differentiative response to RA1993 RA + CHT > CHT93-99 Optimization of RA +CHT combination97-99 ATO, other RA derivatives2000 Anti-CD33, HDAC inhibitors
13 APL AS A MODEL FOR TARGETED Rx RA + anthracycline CHTArsenic & other RA derivativesAnti-CD33 MoAbsHDAC inhibitorsFLT3 inhibitors
14 TARGETED TREATMENT OF APL RA + anthracycline CHTArsenic & other RA derivativesAnti-CD33 MoAbsHDAC inhibitorsFLT3 inhibitors
16 Disease-Free Survival AIDA 0493 vs AIDA 2000 (all risks)1AIDA2000: 86% (CI 95%: ).75AIDA0493: 72% (CI 95%: ).50.25p=0.09The actuarial event-free survival is 73% at 5 years for the LPA96, and 85% at two years for the LPA99.1234567years
17 TARGETED TREATMENT OF APL RA + anthracycline CHTArsenic & other RA derivativesAnti-CD33 MoAbsHDAC inhibitorsFLT3 inhibitors
19 US Multicenter trial with A2O3 Molecular Response by Cycle PCR Responsen=45
20 Molecular remission as a therapeutic goal in APL - Molecular remission in PML-RARa positive APL by combinedATRA and idarubicin. Mandelli et al 1997- Presenting WBC count and kinetics of molecular remissionpredict prognosis in APL treated with ATRA. Burnett et al. 1999- Molecular remission by liposomal encapsulated ATRA in newlydiagnosed APL. Estey et al. 1999- Molecular remission induction with ATRA and anti-CD33 MoAbHuM195 in APL. Jurcic et al. 2000
21 US Multicenter trial with As2O3 for relapsed APL 61218243036Months0%20%40%60%80%100%18-Month OS estimate: 66%Median Follow-up: 18.3 months
22 TARGETED TREATMENT OF APL RA + anthracycline CHTArsenic & other RA derivativesAnti-CD33 MoAbsHDAC inhibitorsFLT3 inhibitors
23 RATIONALE FOR MYLOTARG IN APL - Homogeneous CD33 staining in 100% cases- Striking sensitivity to anthracyclines- Absent / minimal gp170 (MDR) expression
24 ATRA (A) + Mylotarg (M) Trial In Untreated APL (MD Aderson) Induction ATRA until CRM 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 offM 9 mg/m2 Q 4-5 weeks (X 8)Ida 12 mg/m2 X 3 only if PCR +
25 MYLOTARG FOR MOLECULAR RELAPSE (Gimema) Dose 1*Dose 2*PCRPCR+vePCR-veDose 3* and successivedoses until PCR-negativity(max 3 further doses)Dose 3*( final dose)* 6mg/m2 i.v.
26 Mylotarg for molecular relapse (GIMEMA) Mos from Pts PtsMy doses Tested PCR NegativeAfter 2ndAfter 3rd4-6 m8-10 m12-14 m
27 Mylotarg per la recidiva molecolare Sopravvivenza globale (N=16)74% ± 14%Lo Coco, Blood 2004
28 TARGETED TREATMENT OF APL RA + anthracycline CHTArsenic & other RA derivativesAnti-CD33 MoAbsHDAC inhibitorsFLT3 inhibitors
33 FINDING THE NEXT GLEEVEC: FLT3 TARGETED KINASE INHIBITOR THERAPY FOR AMLSawyers, Cancer Cell 2002
34 Survival of FLT3-ITD+ mice treated with/wo (P) PKC412 0.80.60.40.2PP=0.0005d.Weisberg, Cancer cell 2002
35 Combined Modality Therapy for APL (MSKCC) DifferentiationTherapyAll-TransRetinoic AcidImmunotherapyHuM195ArsenicTrioxideTranscriptionModulationChemotherapyIdarubicinRT-PCR**Adaptive Regulation: Number of idarubicin courses determined by RT-PCR results.
36 Type I lesions(point mutations)Type II lesions(fusion genes)prolif./survival advantagedifferentiationblockAPL(AML)Transcriptionaltargeting(ATRA, ATO,HDAC inhib.)Targeting prolif.(e.g. FLT3 inhib.)
37 ACKNOWLEDGMENTS Daniela Diverio Miguel A. Sanz David Grimwade Andrea Biondi Pascual Bolufer Alan K. BurnettPier G. Pelicci Guillermo Martin Antony GoldstoneFranco Mandelli Eva BarraganGIMEMA (Italy) PETHEMA (Spain) MRC (UK)Steve Soignet Elihu EsteyDavid Scheinberg Hagop KantarjianMSKCC, NY MDACC, Houston
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