Leucemia Mieloide Acuta Terapie Innovative. Adriano Venditti Ematologia Universita Tor Vergata, Roma

Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita Tor Vergata, Roma

Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita Tor Vergata, Roma

AML.Current outcome of therapy Age, y CR % DFS % ED% OS % (med) <60 75 45 10 35 (24 mo) >60 50 20 25 10 (10 mo)

Novel cytotoxic drugs Nucleoside analogues Clofarabine Troxacitabine Ester of ARAc Alkylating agents Cloretazine Inhibitors of Ribonucleotide reductase Triapine New strategies in AML Targeted therapy Cell surface antigens Anti-CD33 MoAbs Drug-resistance MDR1 modulators Cellular signaling pathways Kinase inhibition (FLT3, mtor) FT inhibition (RAS) Induction of apoptosis (anti-bcl-2) Proteasome inhibition Angiogenesis Lenalidomide Bevacizumab Epigenetic events Hypomethylating agents, HDACi Others Vaccines (WT1)

Clofarabine Resistant to Deamination & Phosphorolysis Fludarabine Cladribine Clofarabine

Metabolism and mechanism of action Clofarabine P P P RNR DNA Polymerases dntp pool DNA incorporation Clofarabine P P Clofarabine P dcyd kinase Clofarabine Apoptosome Inhibition of DNA synthesis CELL DEATH

Clofarabine in AML Regimen N Population CR+CRi% Clo 31 Rel/Ref 32 1 Clo (Biov-121) 66 Untreated 44 2 Clo + Id-AC 29 Rel/Ref 41 3 Clo + Id-AC 60 Untreated 60 4 Clo + Ld-AC 42 Untreated 63 5 Clo + Hd-AC 23 Rel/Untreated 61 6 Clo + D + GO 37 Untreated 65 7 1 Kantarjian et al, Blood 2003; 2 Burnett et al, ASH 2006; 3 Faderl et al, Blood 2005; 4 Faderl et al, Blood 2006; 5 Faderl et al, ASH 2005; 6 Agura et al, ASH 2006; 7 Burnett et al, ASH 2006

AML16 intensive: Outline Course 1 Course 2 Demethylation (Azacytidine) D + Ara-C D + Ara-C D + Ara-C + Mylotarg No Treatment vs CR/PR R 2 Demethylation (Azacytidine) D+Clofarabine + Mylotarg D+Clofarabine No Rx No Treatment *Randomise 2 vs 3 courses if at least PR after course 1 Mini-allo after course 2

Cloretazine Novel sulfonylhydrazine alkylating agent Phase I dose-finding study in advanced AML (MDACC) 38 pts (28 AML, 5 MDS) 600 mg/m 2 single iv infusion recommended dose for phase II Minimal extramedullary toxicity 1 CR Phase II study in poor risk relapsed AML (MDACC) 53 pts (1st relapse AML; median age 62y) 600 mg/m 2 single iv infusion 2 CR (4%)

Cloretazine Phase II multicenter study in elderly untreated poor risk patients with de novo AML or High Risk MDS N=104 600 mg/m 2 single iv infusion Risk factors included 60 yrs, ECOG PS, secondary AML, unfavorable cytogenetics, and organ dysfunction Results: Risk Factors Age+0 # of patients 12 CR/CRp (N=33) 7 CR/CRp (%) 58% Age+1 22 7 32% Age+2 41 9 22% Age+ 3 29 10 34% Currently being evaluated in a multicenter phase III trial in combination with Ara-C in 1st relapse AML Giles et al, JCO 2007

MRC AML 15 Schema Course 1 Course 2 Course 3 Course 4 Course 5 ADE 10+3+5 ± GO R I S K ADE 8+3+5 MACE ± GO MidAc Stop therapy R DA 3+10 ± GO FLAG-Ida ± GO A S S E S S M E N T DA 3+8 FLAG-Ida Ara-C 1.5g/m 2 ± GO AraC 3g/m 2 ± GO Ara-C 1.5g/m 2 Ara-C 3g/m 2 R AraC 1.0g/m 2 Burnett AK et al. ASH 2006. Abstract 13

MRC AML 15 trial: study design Patients with untreated AML < 60 years of age (N = 1115) Induction: Course 1 ADE ± GO (n = 160) DA ± GO (n = 474) FLAG-Ida ± GO (n = 479) Risk assessment *Consolidation arms included gemtuzumab + chemotherapy. Burnett AK, et al. ASH 2006. Abstract 13. To compare three induction schedules (namely ADE, DA and FLAG-Ida) Induction: Course 2 ADE DA CR Second randomization, then To assess the value of GO during FLAG-Ida induction when used in combination with ADE or DA or FLAG-Ida consolidation*

MRC AML 15 trial: relapse and DFS No gemtuzumab Gemtuzumab Relapse DFS P =.027 P =.007 Relapse (%) 60 50 40 30 20 10 54 39 Disease Free (%) 60 50 40 30 20 10 38 49 0 3 Years From CR 0 3 Years From CR Burnett AK, et al. ASH 2006. Abstract 13.

MRC AML 15 trial: preliminary results Similar rates of postinduction CR with gemtuzumab + induction vs induction chemotherapy alone 84% vs 86% Similar mortality, resistant disease rate in both groups 8% to 7% Gemtuzumab increased DFS in patients with favorable or intermediate cytogenetics (P <.02) without improvement in overall survival Treatment generally tolerable with similar rates of adverse events in each arm Addition of gemtuzumab to induction chemotherapy may benefit those with favorable/intermediate cytogenetics Burnett AK, et al. ASH 2006. Abstract 13.

Studies of MDR modulation in AML GROUP MODULATOR REGIMEN OUTCOME SWOG CSP D/HiDAC ± CSP RFS/OS Impr MRC CSP ADE ± CSP No benefit HOVON CSP ME ± CSP No benefit GALGB* PSC-833 ADE ± PSC-833 No benefit ECOG PSC-833 MEC ± PSC-833 No benefit HOVON* PSC-833 DA ± PSC-833 No benefit *De novo > 60 yrs

Inhibition of MDR: zosuquidar Selective P-gp inhibitor1 Binds to P-gp with high affinity1 In vitro concentrations of 50100nM circumvent P-gp-mediated resistance 2,3 Does not alter pharmacokinetics of co-administered drugs2 Phase II trial in poor-risk AML CR/CRi 61%4 Can be combined with induction chemo5 1Sato Cancer Res, 1991; 2Dantzig Cancer Res, 1996; 3Green Biochem Pharmacol, 2001; 4Cripe ASH, 2002 (abstr); 5Gerrard Haematologica, 2004

ECOG protocol E3999: daunorubicin + cytarabine +/- zosuquidar in older adults Induction Consolidation I Daunorubicin Cytarabine Zosuquidar Daunorubicin Cytarabine Placebo E V A L U A T E CR or MR Cytarabine Consolidation II Daunorubicin Daunorubicin Cytarabine Cytarabine Zosuquidar Placebo Cripe L et al. ASH 2006

Median OS (months) MDR status and treatment arm MDR + MDR - P value All Patients 7.8 (n=318) 11.4 (n=63) 0.08 Zosuquidar 7.0 (n=160) 11.7 (n=32) 0.5 P =.523 Placebo 9.2 (n=158) 11.4 (n=31) 0.08 Schedule modified to eliminate neurologic toxicity No difference in OS or CR was seen overall between treatment groups Cripe L et al. ASH 2006

FLT3 inhibition in AML FLT3 is expressed at high levels in 70% to 100% of cases of AML FLT3-activating mutations Internal tandem duplication (ITD) and point mutations occur in ~30% of patients with AML Lead to constitutive activation of the tyrosine kinase Stimulate proliferation and inhibit apoptosis of AML cells Important negative prognostic factor Gilliland DG, et al. Blood. 2002;100:1532.

FLT3 inhibitors currently in clinical trials in AML MLN-518 (Tandutinib, quinazoline) PKC412 (Staurosporine) SU11248 (Indolinone) CEP701 (Lestaurtinib, indolocarbazole)

Studies of FLT3 inhibitors in AML STUDY POPULATION REGIMEN OUTCOME PKC412 can be given SU11248 1 safely in simultaneous and sequential combination with DHARAc Phase I MLN518 2 Stone et al, ASH 2005 Phase I PKC412 3 Phase II CEP701 4 Phase II Adult refractory Mutated/Wild Adult unfit Mutated/Wild Refractory/Relapsed Mutated Elderly unfit Mutated/Wild 50-70 mg daily COMBINATION 50-700 mg twice daily THERAPY CEP701 is synergistic with standard therapy PR in only 4/4 if mut used simultaneously PR in or 2/15 immediately wild following chemo 75 mg 3 times daily 60(80) mg twice daily Antileukemic activity in 5/8 mutated Levis et al, BLOOD 2004 HI in 14/20 HI in 3/5 Mut HI in 5/22 Wild 1 Fiedler et al, BLOOD 2005; 2 De Angelo et al, BLOOD 2006; 3 Stone et al, BLOOD 2005; 4 Knapper et al, BLOOD 2006;

Targeting signaling pathways Why Target Ftase? Ftase is an enzyme that modifies proteins for localization to cell membrane Many proteins are farnesylated, some of which are important in cancer development Transforming activity of RAS proteins depends on farnesylation Activating mutations of RAS in 15-30% of AMLs Blocking farnesylation may have therapeutic potential apple Tipifarnib, lonafarnib

Phase II study of tipifarnib in AML Poor risk and elderly with untreated AML 158 patients enrolled Age range: 34-85 years (median: 74) 600 mg twice a day for 21 days CR in 14% ORR = 23% PR or HI 9% 7,3 mos median duration of CR 18 mos median duration of OS in responders Lancet, et al. Blood. 2007

Phase II study of tipifarnib in AML Refractory/relapsed AML 252 patients enrolled Age range: 34-85 years (median: 62) 600 mg twice a day for 21 days CR/CRi in 4% ORR = 11% HI in 7% 12 mos median duration of OS in responders Harousseau, et al. Blood. 2007

Epigenetics Targeting epigenetic events Alteration of the heritable state of gene expression causing loss of function (gene silencing) Gene silencing mediated by: DNA methylation (DNA Methyltransferase) Histone de-acetylation (Histone deacetylase) RNA interference (post-transcriptional) MicroRNA Epigenetic events reversible Hypomethylating agents and HDACi in clinical use Azacytidine, Decitabine Valproic acid, SAHA, Depsipeptide

Decitabine 5-Azacytidine NH 2 NH 2 N N N HO O N O HO O N O HO OH HO OH Incorporates into DNA Incorporates into RNA Pro-drug for decitabine

Azacytidine effective in AML Azacytidine evaluated in patients meeting WHO IWG criteria for AML Phase II/III studies CALGB 8421 (IV administration) CALGB 8921 (S.C. administration) CALGB 9221 (S.C. administration) Dose schedule for all trials: 75 mg/m2/day for 7 days, every 28 days Median response: 279 days % of patients 70 60 50 40 30 20 10 0 Response Intravenous Azacytidine (n = 25) Subcutaneous Azacytidine (n = 55) Non responders Complete response Partial response Hematologic improvement Silverman LR, et al. ASH 2005. Abstract 1848.

Phase II decitabine in frontline AML Decitabine 20 mg/m 2 given as IV infusion once daily for 5 days every 4 weeks 42 patients enrolled Median age=73.5 years 28 patients evaluable for response, 25 for safety Overall response: 29%; CR=2, CRc=2, CRi=4 Grade 3/4 Adverse events: febrile neutropenia (32%), dyspnea (20%), hypokalemia (12%), pneumonia (28%), vomiting (8%) Cashen A, et al. ASH 2006

Phase I-II study of 5-AZA, VPA and ATRA in AML/HRMDS Untreated/refractory/relapsed AML 53 patients enrolled (4 HRMDS), 19 in the phase I Age range: 5-84 years (median: 69) Schedule: 5-AZA 75 mg/m2 days 1-7, subcutaneously VPA 50, 62.5 and 70 mg/kg days 1-7, orally ATRA 45 mg/m2, days 3-5 CR/CRi in 29% ORR = 42% BM response in 13% 26 weeks median duration of response Soriano, et al. Blood. 2007

Phase I study of DAC and VPA in AML To determine the OBD of DAC alone and MTD of VPA + DAC 25 untreated/relapsed AML Age range: 37-83 years (median: 70) 14 pts treated with DAC alone (d 1-10) 8, 15 mg/m 2 /d 6, 20 mg/m 2 /d OBD 11 pts treated with DAC at OBD + VPA (d 5-21) 3, 15 mg/kg 6, 20 mg/kg encephalopathy 2, 25 mg/kg ORR 52% (11 pts, 4 CR, 4 CRi, 3 PR) Blum et al. JCO. 2007

Critical pathways that may be targeted in leukemia stem cells Self-renewal Differentiation PIK3/PTEN JunB/AP-1 pathway Wint/β-Catenin HOX genes Notch BMI-1 Shh LSC Quiescence Apoptosis

Upstream activators Rapamycin/Analogs Downstream effectors

A Phase I dose escalation study of the mtor inhibitor sirolimus and MEC chemotherapy in AML Sirolimus combinations in AML Salvage: A Dose Finding Phase I Study of Sirolimus + mitoxantrone/etoposide/ara-c sirolimus MTD (12 mg loading dose and then 4 mg daily) MEC (M at 8 mg/m 2 X 5d, E at1 00 mg/m 2 X 5d, ara-c at 1000 mg/m 2 X 5d) N=23 Preliminary Results: CR = 4 (17%) Therapeutic sirolimus levels safely achieved Conclusions: Sirolimus can be combined with chemotherapy Myelosuppression and hepatoxicity (hyperbilirubinemia) is the predominant toxicity Phase II study will be required to test efficacy Luger S, et al Blood 2006

Conclusive remarks AML still a challenge, particularly in elderly A wide range of novel agents available for phase III clinical trials ( multitargeted therapy ) New strategies should consider combination therapies LSC targeted therapy