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New agents and strategies in AML and high-risk MDS

New agents and strategies in AML and high-risk MDS. 연세의대 내과학교실 민 유 홍. Advances in understanding the cell biology, molecular abnormalities Development of novel targeted therapy Understanding mechanisms of drug resistance, synergistic actions Reinforcement of existing therapy

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New agents and strategies in AML and high-risk MDS

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  1. New agents and strategies in AML and high-risk MDS 연세의대 내과학교실 민 유 홍

  2. Advances in understanding the cell biology, molecular abnormalities Development of novel targeted therapy Understanding mechanisms of drug resistance, synergistic actions Reinforcement of existing therapy Better definition of leukemias based on biology and prognostic Indicators Innovation of treatment strategy

  3. MDS therapeutic agentsA wide variety of new agents are in clinical trials Allogeneic HSCT Risk AML-type chemotherapy Biologic therapy Benefit

  4. Myelodysplastic syndrome

  5. Novel therapeutics in MDS Mechanism modulated Agent Survival signals FT inhibitor R115777 (Zarnestra, tipifarnib), SCH66336 Anti-angiogenic Thalidomide, Revimid, Bevacizumab RTK inhibitors SU5416, SU11248,PTK787, AG13736 PKC inhibitor PKC412 MMP inhibitor AG3340 (Prinomastat) Hemopoietic growth factors EPo, G-CSF, IL-11 Arsenicals Arsenic trioxide, As4S4 Genetic integrity Immunoconjugate Mylotarg MDR/PGP antagonist CSA, LY335979 Epigenetic therapy Azacitidine and decitabine SAHA, depsipeptide, valproic acid Immunomodulation ATG, cyclosporine Leukemia regimen HSCT NST

  6. Phase II Study of R115777 (Zarnestra) in MDSM.D. Anderson, 2004 • 600mg (PO) bid in cycles of 4 weeks (2-week rest & total 12 weeks) • 3 (high-risk) /27 responded (2, CR) • Dose reduction/discontinuation: 41% • Optimal dose and schedules ?

  7. Thalidomide trials Low-dose trial ? CC5013 (RevimidTM) Phase I/II study, 2003 88% responded: 64% erythroid response major cytogenetic response, 65% Near complete suppression of plasma VEGF in responding cases FDA pivotal trial in early stage MDS RA, low/intermediate-1, del(5q)

  8. Darbepoietin ?

  9. Epigenetic gene silencingDNA hypermethylation, histone methylation/acetylation • DNA methyltransferase inhibitor: 5-azacitidine (VidazaR) (p15INK4B), Decitabine, Zebularine • Histone deacetylase inhibitors: SAHA, valproic acid, apicidin

  10. 5-Azacitidine (Vidaza)Randomized controlled trial for MDS (CALGB, 2002) • 191 patients with MDS • Aza C (75mg/m2/d SC for 7 days q 28 days) vs supportive Median time to LK transformation: 21 m vs 13m (P = 0.007) Significantly improved quality of life FDA approval for MDS, 2004

  11. Phase II Multicenter Study of Decitabine, 2000 Median response duration: 7.4 m Myelosuppression: common 2002 Update: overall-response – 49% Median response duration: 9.5 m (survival, 15 m)

  12. AML-type chemotherapy for high-risk MDS CR ~ 50% Post-remission biologic therapy ?

  13. Targeted therapy of acute myeloid leukemia

  14. Targets for new agents in AML Targets Agents FLT3R tyrosin kinase CEP-701, PKC-412, SU11248, CT53518 Ras family, FTase BMS-214662, R115777 Epigenic silencing SAHA, trapoxin, VA, Decitabine Bcl-2 Bcl-2 antisense S-phase checkpoints UCN-01 20S proteasome PS-341 MDR1/Pgp Cyclosporine, PS833 Angiogenesis/ VEGF Thalidomide, SU-5416,Bevacizumab Kinases MAPK, Akt inhibitors CD33 Gemtuzumab ozogamicin CD45 131I-anti-CD45

  15. FLT3 inhibitor • Constitutive, ligand-independent activation of FLT3R (FLT3R-ITD, point mutation) to Ras, PI3-K activation observed in 15 – 30% AML cases • Recently reported trials of FLT3R inhibition (Cancer 100:446, 2004)

  16. FLT3 inhibitor early clinical trials Combination therapy ?

  17. Farnesyltransferase inhibitor Combination therapy ?

  18. Agents that reverse multidrug resistanceABC superfamily (Pgp, MRP, BCRP, LPR) • Cyclosporine A or PSC-833(GALGB;Blood 100:1224, 2002)

  19. Constitutively active kinases • Translocations Bcr-Abl, TEL-PDGFR • RTKs PDGFR, CSF-1R, Kit, FLT3R • Serine/threonine cascades PI3-K, Akt/PKB, MEK/ERK

  20. Constitutive activation of PI3-K and Akt/PKB in AML. Leukemia 17:995, 2003

  21. Constitutive activation of extracellular signal-regulated Kinase in human acute leukemia. BLOOD 93:3893, 1999

  22. CD33 monoclonal antibodies CFU-GEMM AML >90% Naked humanized CD33 antibody (HuM195) CD33-calicheamicin conjugate (Gemtuzumab ozogamicin; Mylotarg)

  23. Mylotarg Study Group (2001) GO 9mg/m2 on Days 1 and 15 for relapsed older AML • CR rate 16%; CRp rate 14.8% • G III/IV hyperbilirubinemia 23% (median time to onset, 8D) • VOD 12% (comparable to younger AML) RFS: 6.8m (CR) vs 2.2m (CRp) Preliminary CRp CR NR Elderly (60) AML in first relapse (FDA approval, 2000)

  24. Mylotarg Study Group (2002) GO 9mg/m2 on Days 1 and 15 for relapsed older AML • CR rate 13% (overall response, 28%) • Median RFS for CR (6.8m) vs CRp (2.2m) • G III/IV neutropenia, trombocytopenia (99%) • Hyperbilirubinemia (24%) • Mucositis (4%), infection (27%) • Comparable to younger AML

  25. Strategy for expanding GO place • Minimum CD33 expression ? High CD33-Ag load ? • Dose and intervals ? Successive treatment of GO? Not to be feasible due to hepatic, hematologic toxicity • Combination therapy with chemoRx for induction or consolidation ? Comparative study required • HSCT matters ?

  26. GO Plus Chemotherapyas first line treatment for AML (Age < 60) • ADT, or FLAG-IDA Plus GO (3mg/m2 6mg/m2 on D1): CR, 85% (higher toxicity with 6-TG) (UK, 2003) • AD with GO (6mg/m2 on D4): CR rate 83% with no VOD (DFCI, 2003) • MACE or HiDAC consolidation Plus GO (3mg/m2 on D1): virtually no increased hepatotocivity; non-6TG-containing, non-consecutive therapy, 78% remain in CCR at a median of 8 months (UK, 2003)

  27. Increased VOD (SOS) with GO in the setting of HSCT FHCRC, 2002 DFCI, 2003 Prior GO 3.5m 9/10 vs 0/4

  28. Identify further relevant pathophysiologic pathways • Better define disease subgroups • Develop new drugs based on a clearer understanding • of disease biology

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