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 locus RAR locus 15 17 PML/RAR fusion gene RAR/PML fusion gene 15q+ 17q-
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
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
PML/RARa as Ideal Marker for Disease Diagnosis and Monitoring Causally related to disease pathogenesis Targeted by specific therapy Predicts response to retinoids
Clinical relevance of genetic studies in APL Diagnosis Response to front-line therapy Follow-up monitoring and therapy of molecular relapse
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%
PCR-monitoring studies in large clinical trials GIMEMA MRC PETHEMA AMLCG MDACC US Intergroup MSKCC JALSG
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
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
APL AS A MODEL FOR TARGETED Rx RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
TARGETED TREATMENT OF APL RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
Acute Promyelocytic Leukemia + RA
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 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
TARGETED TREATMENT OF APL RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
Dual response of APL cells to arsenic trioxide
US Multicenter trial with A2O3 Molecular Response by Cycle PCR Response n=45
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
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
TARGETED TREATMENT OF APL RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
RATIONALE FOR MYLOTARG IN APL - Homogeneous CD33 staining in 100% cases - Striking sensitivity to anthracyclines - Absent / minimal gp170 (MDR) expression
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 +
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.
Mylotarg for molecular relapse (GIMEMA) Mos from Pts Pts My doses Tested PCR Negative After 2nd 8 8 After 3rd 6 6 4-6 m 4 2 8-10 m 2 2 12-14 m 2 2
Mylotarg per la recidiva molecolare Sopravvivenza globale (N=16) 74% ± 14% Lo Coco, Blood 2004
TARGETED TREATMENT OF APL RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
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
Transcriptional therapy with HDAC inhibitors
TARGETED TREATMENT OF APL RA + anthracycline CHT Arsenic & other RA derivatives Anti-CD33 MoAbs HDAC inhibitors FLT3 inhibitors
= Ig-like = TM = JM = TK P P P P = FL P STAT JAK RAS MAD
FINDING THE NEXT GLEEVEC: FLT3 TARGETED KINASE INHIBITOR THERAPY FOR AML Sawyers, Cancer Cell 2002
Survival of FLT3-ITD+ mice treated with/wo (P) PKC412 0.8 0.6 0.4 0.2 P P=0.0005 0 20 40 60 80 100 d. Weisberg, Cancer cell 2002
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.
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.)
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