Risk-adapted therapy of AMLin younger adults

Sergio AmadoriTor Vergata University HospitalRome

Pescara 11/2010

AML: treatment outcome

Better treatment strategies needed

<10<202550>60

40451075<60

6060585<15

OS %DFS %ED %CR %Age

Molecular-cytogenetic heterogeneity

Otheradverse14%

MLL‐PTD5%

inv(3)/t(3;3)/EVI‐13%

FLT3‐ITD/NPM1wt12%

21%

CEBPAmut(biallelic)/FLT3‐ITDneg3%NPM1mut/FLT3‐ITDneg/WT1wt18%

inv(16)/t(16;16)/CBFB‐MYH115%

t(8;21)/RUNX1‐RUNX1‐T18%

t(15;17)/PML‐RARA11%

INTERMEDIATE

ADVERSE

FAVORABLE

Grimwade & Hills, ASH 2009

Factor CommentAge Major impact at diagnosis

WBC Continuous variable

Prior therapy or MDS? Karyotype may be more important

Extramedullary disease Variable

Day 14 blast count Higher percentage worse

# cycles of induction One better than two

Cytogenetic/molecular profile Major impact at diagnosis

Gene expression profile Can further subdivide patients

MicroRNA expression Needs validation by other groups

Gene sequencing Future application

MRD detection at CR Independent predictor of outcome

AML: prognostic factors

How do we treat younger patients withAML in 2010?

ν Treatment stratification based on age andgenotypeCytogeneticsMolecular diagnostics

AML therapy: current standard

ν Remission induction chemotherapyAnthracycline + Ara-C (3+7 or variants)

ν Post-remission therapyID/HD-Ara-C based consolidation (1 or more courses)Auto-SCTAllo-SCT

Decision based on risk and doctor/patient preference

Strategies to improve current standard

ν Add and/or intensify cytotoxic drugsν Add new agentsν Add immunotherapy (IL-2) as

maintenance

Add and/or intensify cytotoxic drugs

ν Addition of VP-16 or 6-TG or HD-Ara-Cproduced no survival advantage

ν Which anthracycline?ν Anthracycline doseν How much treatment?

Which anthracycline?

Mandelli et al, JCO 2009

DNR 50x3MXR 12x3IDA 10x3

EORTC-GIMEMA AML-10

Anthracycline dose

Is DNR “90” better than “45/50”?

ECOG 1900

ECOG 1900: Outline

Daunorubicin45 mg/m2 x 3

+SDAC

AllogeneicSCT

CRDaunorubicin90 mg/m2 x 3

+SDAC

HighRisk

HiDAC x 2PBSCH after2nd course

GO 6 mg/m2

(1 mo pre-SCT)

AutologousSCT

A

B

ECOG 1900: Results

ν Phase 3ν 657 pts (median age 48y, range 17-60)ν CR%: 57.3 (SD) vs 70.6 (HD), (P = 0.001)ν ID%: 4.5 (SD) vs 5.5 (HD)ν OS (median/mos): 15.7 (SD) vs 23.7 (HD), (P=0.003)

Age >50: no survival benefit (HD)Adverse cytogenetics: no survival benefit (HD)

Fernandez et al, NEJM 2009

But…

ECOG 1900 vs MRC AML15

ν ECOG 1900Overall CR rate 63.9%HD 70.6%SD 57.3%

ν Median survivalHD 23.7 mosSD 15.7 mos

ν MRC AML15DNR 50x3Overall CR rate 79.8%

ν Median survivalWhole cohort 29.9 mos

SWOG 0106 vs ECOG 1900

Appelbaum F, EHA 2010

How much treatment?(MRC: 4 vs 5 courses)

Burnett A, 2010

How much treatment?(MRC: 3 vs 4 courses)

Overall Good Risk

Poor RiskInt Risk

Burnett A, 2010

Add new agents

ν New cytotoxicsNucleoside analogs

ν Targeted agentsGemtuzumab (GO)FLT3 inhibitorsATRA

ν 673 pts age 18 to 60 yrs randomized to DA + ara-C (DAA n=223), DA +fluda (DAF; n=219), DA + cladribine (DAC; n=210)

ν Median follow up 34 m:

ν Early death rates: 9-11% (NS)

Holowiecki et al, ASH 2009

Outcome DAC DAF DAA p (vs DAA) p (vs DAF)

CR (%) 68 59 56 .013 .08

CR post 1 (%) 62 55 51 .017 .016

3-yr OS (%) 46 30 31 .02 .02

2-yr LFS (%) 47 40 39 NS NS

Adding Cladribine

Clofarabine in combination with a standardremission induction regimen in patients 18-60years old with previously untreatedintermediate and poor risk acute myelogenousleukemia (AML) or high risk myelodysplasia(MDS): a phase 1-2 study

Adding ClofarabineEORTC-GIMEMA AML-14A

Study design (2)

ν Remission inductionIdarubicin: 10 mg/m2/d, on d1, d3, d5

Ara-C: 100 mg/m2/d ci on d1-d10 Clofarabine (1 hrs inf./push injection): test dose on d2, d4, d6, d8, d10 if PR after 1st induction: 2nd induction if CR: start consolidation

ν ConsolidationAra-C (c.i.): 500 mg/m2/12h (2-hr infusion) on d1-6Idarubicin (i.v): 10 mg/m2/d on d4-6

Step TDClofarabine

(mg/m2)

Arm A: Arm B:

dose/day(mg/m2)

Nrof pts

dose/day (mg/m2)

Nrof pts

-2 25 5 3 5 3

-1 37.5 7.5 3 7.5 3

0 50 10 3 10 3

1 75 15 6 15 3

2 100 20 3 20 3

3 125 25 3 25 3

4 150 30 3 30 3

EORTC-GIMEMA AML-14A (phase 1)

No furtherTreatment

DA 3+10

+/- GO

FLAG-Ida

+/- GO

DA

3+8

FLAG

-Ida

MACE

+/- GO MidAc

AC 3g/m2

+/- GO AC 3g/m2

AC 1g/m2

ADE10+3+5

+/- GOADE

8+3+5

AC 1.5g/m2

+/- GO AC 1.5g/m2 R

Course 1 Course 2 Course 3 Course 4

R

Course 5

RISK

ASSESSMENT

R

Adding GO: MRC AML15

GO: MRC AML15

Burnett A, 2010

GO: MRC AML15

GO: SWOG 0106

RANDOMIZATION

DNR+Ara-C+GO (6 mg/m2)

HiDAC

3 courses

RANDOMIZATION

GO x 3(5 mg/m2 monthly)

No therapyDNR+Ara-C

GO: SWOG 0106

ν No improvement in CR rate, RFS or OSν Higher fatal AE rate during induction in GO armν No improvement in DFS on GO maintenanceν GO may improve RFS and OS in pts with favorable

cytogenetics

Petersdorf et al, ASH 2009

Adding FLT3 inhibitors

Stone et al, ASH 2009

PKC412

PKC412

Schlenk et al, Leukemia 2004

Adding ATRAAge 61+

Schlenk et al, Haematologica 2009

Adding ATRA

Age 61+

Adding ATRA: MRC AML12

MRC AML12

Burnett et al, Blood 2010

MRC AML12

Burnett et al, Blood 2010

ν IL-2 activates T and NK cellsν Rationale for efficacy in preventing relapse

based on preclinical dataν No benefit in any of 6 large randomized trials

using IL-2 monotherapyν Histamine (HDC) protects T and NK cells from

inactivation by myeloid cells (induced by ROSproduction)

Add IL-2 immunotherapy as maintenance

Reference: Hellstrand et al., J. Immunol. 153: 4940-7 (1994)

How HDC may improve IL-2 efficacy

Romero et al, Scand. J. Immunol. 2009

IL-2/HDC maintenance in AML

Brune et al, Blood 2006

Strategies to improve current standard

ν Refine pre-therapy risk stratificationthrough incorporation of MRD data

Buccisano et al, Blood 2010

alloSCT > autoSCT for High-risk AML

792356Total

471730H-risk

32626L-risk

TotalalloSCTauSCT

Adverse KFLT3+Good K / MRD+Int K / MRD+

Good K / MRD-Int K / MRD-

High-RiskLow-Risk

Buccisano et al, Blood 2010

GIMEMA AML1310: a study of risk-adapted and MRD-directed therapy foradult AML

Low-risk: CBF/Kitwt; NPM1+/FLT3-Int-risk: all othersHigh-risk: Adverse K; FLT3+

Diagnosis

Low-risk

Int-risk

High-risk

MRD-

MRD+

MRD marker

LAIP

Risk stratif

CG, molecular

MRD assess

LAIP

FLA-I salvageNo CR CR

CRIn

duct

ion

(1 o

r 2 c

ours

es)

Con

solid

atio

n 1

autoSCT

alloSCT

alloSCT:MRD, MUD,UCB, HRD

AML: personalized therapy