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

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Page 1: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

LeucemiaLeucemia MieloideMieloide AcutaAcutaTerapieTerapie Innovative Innovative

Adriano Venditti

Ematologia Universita’ Tor Vergata, Roma

Page 2: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

LeucemiaLeucemia MieloideMieloide AcutaAcutaTerapieTerapie Innovative Innovative

Adriano Venditti

Ematologia Universita’ Tor Vergata, Roma

Page 3: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

AML.Current outcome of therapy

10 (10 mo) 25 20 50 >60

35 (24 mo) 10 45 75 <60

OS % (med) ED% DFS %CR %Age, y

Page 4: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

New strategies in AML

• 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)

• Nucleoside analogues− Clofarabine− Troxacitabine− Ester of ARAc

• Alkylating agents− Cloretazine

• Inhibitors of Ribonucleotidereductase− Triapine

Novel cytotoxic drugs Targeted therapy

Page 5: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Fludarabine Cladribine Clofarabine

ClofarabineResistant to Deamination & Phosphorolysis

Page 6: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Metabolism and mechanism of action

Clofarabine

Clofarabine

Clofarabine

Clofarabine

P

P P

P P PRNR

DNAPolymerases

dCyd kinase

dNTP pool

DNA incorporation

Inhibition of DNA synthesis

CELL DEATH

Apoptosome

Page 7: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Clofarabine in AML

657Untreated37Clo + D + GO

616Rel/Untreated23Clo + Hd-AC

635Untreated42Clo + Ld-AC

604Untreated60Clo + Id-AC

413Rel/Ref29Clo + Id-AC

442Untreated66Clo (Biov-121)

321Rel/Ref31Clo

CR+CRi%PopulationNRegimen

1Kantarjian et al, Blood 2003; 2Burnett et al, ASH 2006; 3Faderl et al, Blood 2005; 4Faderl et al,Blood 2006; 5Faderl et al, ASH 2005; 6Agura et al, ASH 2006; 7Burnett et al, ASH 2006

Page 8: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

AML16 intensive: Outline

*Randomise 2 vs 3 courses if at least PR after course 1 Mini-allo after course 2

D + Ara-C

D+Clofarabine

D + Ara-C

D+Clofarabine

Demethylation(Azacytidine)

No Treatment

R2CR/PR vs

Course 1 Course 2

+ Mylotarg

+ Mylotarg

D + Ara-C

No Rx

Demethylation(Azacytidine)

No Treatment

Page 9: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Cloretazine

• Novel sulfonylhydrazine alkylating agent

• Phase I dose-finding study in advanced AML(MDACC)

− 38 pts (28 AML, 5 MDS)

− 600 mg/m2 single iv infusion recommended dosefor 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/m2 single iv infusion

− 2 CR (4%)

Page 10: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Cloretazine

Phase II multicenter study in elderly untreated poor risk patientswith de novo AML or High Risk MDS

♣N=104♣600 mg/m2 single iv infusion♣Risk factors included ≥60 yrs, ECOG PS , secondary AML,

unfavorable cytogenetics, and organ dysfunction

Results:

• Currently being evaluated in a multicenter phase III trial incombination with Ara-C in 1st relapse AML

22%941Age+2

34%1029Age+ ≥3

32%722Age+1

58%712Age+0

CR/CRp(%)

CR/CRp(N=33)

# ofpatients

Risk Factors

Giles et al, JCO 2007

Page 11: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Burnett AK et al. ASH 2006. Abstract 13

MRC AML 15 Schema

DA 3+10

± GO

FLAG-Ida± GO

DA 3+8

FLAG-Ida

MACE

± GOMidAc

AraC 3g/m2

± GO

Ara-C

3g/m2

AraC1.0g/m2

ADE

8+3+5

Ara-C1.5g/m2

± GO

Ara-C1.5g/m2

Stoptherapy

Course 1 Course 2 Course 3 Course 4

R

Course 5

ADE

10+3+5

± GO

RISK

ASSESSMENT

R

Page 12: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

CR

MRC AML 15 trial: study design

*Consolidation arms included gemtuzumab + chemotherapy.

Patients withuntreated AML

< 60 years of age

(N = 1115)

ADE ± GO(n = 160)

DA ± GO(n = 474)

FLAG-Ida ± GO(n = 479)

Induction:Course 1

ADE

DA

FLAG-Ida

Induction:Course 2

Risk assessment

Secondrandomization,thenconsolidation*

Burnett AK, et al. ASH 2006. Abstract 13.

To compare threeinduction schedules(namely ADE, DA and

FLAG-Ida)

To assess the value of GOduring induction when usedin combination with ADE or

DA or FLAG-Ida

Page 13: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

MRC AML 15 trial: relapse and DFS

60

50

40

30

20

10

03 Years From CR

Rel

apse

(%

)

P = .027

54

39

Relapse

60

50

40

30

20

10

03 Years From CR

Dis

ease

Fre

e (%

)

P = .007

38

49

DFS

No gemtuzumab Gemtuzumab

Burnett AK, et al. ASH 2006. Abstract 13.

Page 14: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma
Page 15: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma
Page 16: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

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 favorableor intermediate cytogenetics (P < .02) withoutimprovement in overall survival

• Treatment generally tolerable with similar rates ofadverse events in each arm

• Addition of gemtuzumab to induction chemotherapymay benefit those with favorable/intermediatecytogenetics

Burnett AK, et al. ASH 2006. Abstract 13.

Page 17: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Studies of MDR modulation in AML

No benefitDA ± PSC-833PSC-833HOVON*

No benefitMEC ± PSC-833PSC-833ECOG

No benefitADE ± PSC-833PSC-833GALGB*

No benefitME ± CSPCSPHOVON

No benefitADE ± CSPCSPMRC

RFS/OS ImprD/HiDAC ± CSPCSPSWOG

OUTCOMEREGIMENMODULATORGROUP

*De novo > 60 yrs

Page 18: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Inhibition of MDR: zosuquidar

• Selective P-gp inhibitor1

• Binds to P-gp with high affinity1

• In vitro concentrations of 50-100nM circumvent P-gp-mediatedresistance 2,3

• Does not alter pharmacokinetics ofco-administered drugs2

• Phase II trial in poor-risk AMLCR/CRi 61%4

• Can be combined with inductionchemo5

1Sato Cancer Res, 1991; 2Dantzig Cancer Res, 1996; 3Green Biochem Pharmacol, 2001;4Cripe ASH, 2002 (abstr); 5Gerrard Haematologica, 2004

Page 19: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

ECOG protocol E3999: daunorubicin + cytarabine+/- zosuquidar in older adults

Induction Consolidation I

CRorMR

Cytarabine

Consolidation II

EVALUATE

Cripe L et al. ASH 2006

Daunorubicin

Cytarabine

Zosuquidar

Daunorubicin

Cytarabine

Placebo Daunorubicin

Cytarabine

Zosuquidar

Daunorubicin

Cytarabine

Placebo

Page 20: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Median OS (months)MDR status and treatment arm

11.4 (n=31)

11.7 (n=32)

11.4 (n=63)

MDR -

0.08

0.5

0.08

P value

7.8 (n=318)All Patients

9.2 (n=158)Placebo

7.0 (n=160)Zosuquidar

MDR +

P = .523

Cripe L et al. ASH 2006

•Schedule modified to eliminate neurologic toxicity•No difference in OS or CR was seen overall between treatmentgroups

Page 21: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

FLT3 inhibition in AML

• FLT3 is expressed at high levels in 70% to100% 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 tyrosinekinase

− Stimulate proliferation and inhibit apoptosis of AMLcells

• Important negative prognostic factor

Gilliland DG, et al. Blood. 2002;100:1532.

Page 22: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

FLT3 inhibitors currently in clinical trials in AML

• MLN-518 (Tandutinib, quinazoline)

• PKC412 (Staurosporine)

• SU11248 (Indolinone)

• CEP701 (Lestaurtinib, indolocarbazole)

Page 23: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Studies of FLT3 inhibitors in AML

Antileukemicactivity in 5/8

mutated

50-700 mg

twice daily

Adult unfit

Mutated/Wild

MLN5182

Phase I

PR in 4/4 mut

PR in 2/15 wild

50-70 mgdaily

Adult refractory

Mutated/Wild

SU112481

Phase I

HI in 3/5 Mut

HI in 5/22 Wild

60(80) mgtwice daily

Elderly unfit

Mutated/Wild

CEP7014

Phase II

HI in 14/2075 mg 3times daily

Refractory/Relapsed

Mutated

PKC4123

Phase II

OUTCOMEREGIMENPOPULATIONSTUDY

1Fiedler et al, BLOOD 2005; 2De Angelo et al, BLOOD 2006; 3Stone et al, BLOOD 2005;4Knapper et al, BLOOD 2006;

COMBINATION

THERAPY

CEP701 is synergistic withstandard therapy only if usedsimultaneously or immediatelyfollowing chemo

Levis et al, BLOOD 2004

PKC412 can be given safely insimultaneous and sequentialcombination with DHARAc

Stone et al, ASH 2005

Page 24: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Why Target Ftase?

• Ftase is an enzyme that modifies proteins forlocalization to cell membrane

• Many proteins are farnesylated, some of whichare important in cancer development

• Transforming activity of RAS proteins depends onfarnesylation

• Activating mutations of RAS in 15-30% of AMLs

• Blocking farnesylation may have therapeuticpotentialTipifarnib, lonafarnib

Targeting signaling pathways

Page 25: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

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%

• PR or HI 9%

• 7,3 mos median duration of CR

• 18 mos median duration of OS in responders

Lancet, et al. Blood. 2007

ORR = 23%

Page 26: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

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%

• HI in 7%

• 12 mos median duration of OS in responders

Harousseau, et al. Blood. 2007

ORR = 11%

Page 27: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

♣ Alteration of the heritable state of gene expressioncausing 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

Targeting epigenetic events

Epigenetics

Page 28: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Decitabine

Incorporates into RNAPro-drug for decitabine

5-Azacytidine

Incorporates into DNA

HO O

N

N

NH2

O

HO

N

OH

O

N

N

NH2

OHO

HO OH

Page 29: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Complete response

Partial responseHematologic improvement

Response

Non responders

0

10

20

30

40

50

60

70

SubcutaneousAzacytidine

(n = 55)

IntravenousAzacytidine

(n = 25)

% o

f p

atie

nts

Azacytidine effective in AML

Silverman LR, et al. ASH 2005. Abstract 1848.

• Azacytidine evaluated inpatients meeting WHO IWGcriteria for AML

♣ Phase II/III studies

− CALGB 8421(IV administration)

− CALGB 8921 (S.C.administration)

− CALGB 9221 (S.C.administration)

− Dose schedule for alltrials: 75 mg/m2/day for7 days, every 28 days

• Median response: 279 days

Page 30: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Phase II decitabine in frontline AML

• Decitabine 20 mg/m2 given as IV infusion once dailyfor 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

Page 31: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Phase I-II study of 5-AZA, VPA and ATRAin 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%

• BM response in 13%

• 26 weeks median duration of responseSoriano, et al. Blood. 2007

ORR = 42%

Page 32: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Phase I study of DAC and VPA in AML

• 25 untreated/relapsed AML

• Age range: 37-83 years (median: 70)

• 14 pts treated with DAC alone (d 1-10)

− 8, 15 mg/m2/d

− 6, 20 mg/m2/d

• 11 pts treated with DAC at OBD + VPA (d 5-21)

− 3, 15 mg/kg

− 6, 20 mg/kg

− 2, 25 mg/kg

♣ ORR 52% (11 pts, 4 CR, 4 CRi, 3 PR)

Blum et al. JCO. 2007

OBD

To determine the OBD of DAC alone and MTD of VPA + DAC

encephalopathy

Page 33: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Critical pathways that may be targeted in leukemiastem cells

Differentiation

Quiescence

Self-renewal

Apoptosis

LSC

•PIK3/PTEN•JunB/AP-1 pathway•Wint/β-Catenin•HOX genes•Notch•BMI-1•Shh

Page 34: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

UpstreamUpstream activatorsactivators

DownstreamDownstream effectorseffectors

Rapamycin/Analogs

Page 35: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

A Phase I dose escalation study of the mTORinhibitor sirolimus and MEC chemotherapy in AML

Sirolimus combinations in AML Salvage: A Dose Finding Phase IStudy of Sirolimus + mitoxantrone/etoposide/ara-C

•sirolimus MTD (12 mg loading dose and then 4 mg daily)•MEC (M at 8 mg/m2 X 5d, E at1 00 mg/m2 X 5d, ara-C at1000 mg/m2 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) isthe predominant toxicity•Phase II study will be required to test efficacy

Luger S, et al Blood 2006

Page 36: Leucemia Mieloide Acuta Terapie Innovative - Siematologia · Leucemia Mieloide Acuta Terapie Innovative Adriano Venditti Ematologia Universita’ Tor Vergata, Roma

Conclusive remarks

• AML still a challenge, particularly in elderly

• A wide range of novel agents available for phaseIII clinical trials (“multitargeted therapy”)

• New strategies should consider combinationtherapies

• LSC targeted therapy