AML in elderly

D.Selleslag

AZ Sint-Jan

Brugge, Belgium

BHS GAM 2016

AML is predominantly a disease of the elderly

SEER Cancer Statistics, National Cancer Institute, USA 2002–2006

Available at http://seer.cancer.gov/statfacts/html/amyl.html

incidence2-3/100.000

Projected relative 5-year survival in AML according to age and time period

Gunnar Juliusson et al. Blood 2012;119:3890-3899Swedish Acute Leukemia Registry

Age-related

HOST factors

- Decreased PS

- More Comorbidities

Age-related DISEASE Factors

- More underlying MDS

- More unfavourable cytogenetics

Poorprognosis

Why are treatment results poor in elderly AML ?

Poor treatment

tolerance

Resistant

disease

Elderly population is heterogeneousin terms of fitness

At time of diagnosis we want to identify the patients who are fit to tolerate intensive therapy

In clinical practice

we use performance score

to define fitness

Performance score is more importantthan chronological age for prediction of

day 30 induction mortality r

age < 56 yr 56-65 yr 66-75 yr > 75 yr

PS 0 2 % 11 % 12 % 14 %

PS 1 3 % 5 % 16 % 18 %

PS 2 2 % 18 % 31 % 50 %

PS 3 0 % 29 % 47 % 82 %

% PS 2-3 15 % 24 % 26 % 32 %

Appelbaum et al, Blood, 2006

Performance score has limitations

• Performance score is

– Subjective

– not sensitive to identify vulnerable

patients with limited physiological reserve

capacity

• More objective parameters that define fitness

are derived from retrospective studies

– comorbidity scores

– geriatric assessment scales

• Need prospective validation

Giles F. et al, BJHaem 2007 , 136, 624

HCT-CI Proportion

of pts

Induction

death by

day 28

Overall

survival

(median)

0 22% 3 % 45 weeks

1-2 30% 11 % 31 weeks

3 or more 48% 29 % 19 weeks

N =177, > 60 yrs , treated by intensive AML induction

• N = 74, > 60 yrs, intensive chemotherapy

• ECOG PS 0 or 1 in 78%

• Results of Geriatric Assesment:

– Physical function measured by “Short Physical Performance

Battery” (includes walking speed, chair stands, balance

testing)

– Cognitive function measured by Modified Mini-Mental State

Exam (3MS)

– predict survival independently of tumor and clinical

characteristics, PS and HCT-CI

Blood, 2013, 121:4287

Assesment of elderly AML patient

at diagnosis (H.Klepin)

Diseasebiology

Cytogenetics

Molecularmarkers

Performance score

Comorbidities

HCT-CI

Geriatricassesment

Physical function

Cognitive function

FitNo risk factors

VulnerableImpaired cognitive or

physical function

No major comorbidity

FrailMajor comorbidities

Treatment of elderly AML

Treatment choice and treatment goals are not the same for all elderly AML

Disease biology POOR GOOD

(Karyotype)

Host factors UNFIT FIT

Improve QoL

Prolong survival

Cure

Tre

atm

en

t

inte

ns

ity

Low intensity

treatment

High intensity

treatment

Before 2012: Treatment strategies and

outcome in elderly AML > 65 yrs

Best

supportive

care

LD araC Intensive

chemo

CR (%) 0 15-20 40-65

Median

Overall

Survival

(months)

2 4-6 10

5 yr OS (%) 0 0 15

Effect in

adverse

karyotype

NA No Limited

Induction

• DNR+ Ara C (3+7)

• or variants

Consolidation

• AraC-based (1-2 cycles))

Maintenance

• ??? role

Age, y CR % ED % Cure %

< 60 70-80 < 10 40-50

> 60 40-65 15-20 < 15

Intensive approach

Intensive chemotherapy: induction

• What do we know from randomized studies ?

•Standard: 3 + 7 with

–Dauno 45-60 mg/m2 x 3

–AraC 100 -200 mg/m2 CI x 7

•60-65 yrs: Dauno 90 mg/m2 x 3 : better OS

•No improvement of OS with

–addition of 6TG, etoposide

–new anthracyclins

Intensive therapy: post remission

• What do we know from randomized studies ?

1. Consolidation :

• High vs conventional dose AraC : no advantage

• Multiple (4 vs 1, 4 vs 3) consolidations : no advantage

2. Maintenance:

• LD AraC improves remission duration, but notsurvival

Farag et al, BBMT 2011

CIBMTR/CALGB: 190 AML pts (age 60-70) in CR1

Prospective studies needed

relapseNon relapse mortality

LFS Overall Survival

RIC allo vs chemotherapy in elderly AML

Chemo

Transplant Chemo

ChemoChemo

Transplant

TransplantTransplant

P = 0.08P = 0.001

P < 0.001 P = 0.001

Hypomethylating agents in AML

Hypomethylating Cytosine Analogs

N O

NH2

N

N O

NH2

N

CH3

N O

NH2

NN

Ribose

N O

NH2

NN

Deoxyribose

5-aza-cytidine 5-aza-2’-deoxycytidine5-methyl-cytosineCytosine

(azacitidine) (decitabine)

Vidaza Dacogen(Celgene) (J&J)

CH3 CH3

21

DACO-016: randomized Phase III

Newly diagnosed AML

de novo or sAML

> 65 yrs

Unfit for ICT

BM blast count > 20 %

WBC count < 40 x 109/L

Decitabine 20 mg/m2 IV x 5 days , monthly

Treatment of choice

BSC or

LD AraC 20 mg /m2 SC

for 10 days

N = 485

Primary endpoint: overall survival

Kantarjian et al. J Clin Oncol. 2012; 30(21): 2670-2677

22

OS Ad hoc mature (2010) analysis (446 deaths)

Significant Survival Benefit for decitabine

Kantarjian et al. J Clin Oncol. 2012; 30(21): 2670-2677

23

DACOGEN (decitabine) : EU label

• Adult patients ≥ 65 years

• Newly diagnosed de novo or secondary AML

according to WHO classification (> 20% blasts)

• Not candidate for standard induction chemotherapy

• EU registration since September 2012

• No FDA approval for AML

• Belgian reimbursement since 1 December 2013

23

24

AZA-AML-001 :Randomized Phase III

Newly

Diagnosed

AML*

> = 65 yrs

N = 480

Vidaza

75 mg/m2 SC x 7 days,

repeat q28 days

N = 240

Investigator’s selection

IC (7 +3), LDAC, or BSC

N = 240

A

B

RIn

vesti

ga

tor

Sele

cti

on

IC,

LD

AC

, o

r B

SC

- De novo AML or sAML after MDS

- > 30 % bone marrow blasts and WBC < 15 x 109/l (w/o hydroxyurea)

- ECOG 0-2

- Poor or intermediate cytogenetics

Min 6 cycles

Until PD

Primary endpoint: overall survival

Dombret et al, Blood, 2015,126:291

Overall Survival (ITT)

Pre-planned OS Sensitivity Analysis

Censored for Subsequent AML Therapy*

Censored

Median OS:AZA = 6.4 months (95% CI: 4.2, 8.1), CCR = 3.2 months (2.2, 4.7)HR = 0.68 [95%CI: 0.50, 0.94]; Log-rank P = 0.0185

OS in patients with Poor-risk Cytogenetics

Median OS for AZA vs CCR was calculated using Kaplan-Meier methods, hazard ratios (HR) and 95% confidence intervals (CI) were determined by unstratified Cox proportional hazards model, and P values by log-rank test

AZA

CCR

1-Year Survival: 30.9% vs 14.0% (Δ 16.9%; 95%CI: 4.4%, 29.5%)

3.2 mos

6.4 mos

14.0%

30.1%

28

Comparable overall survival with azacitidine and intensive chemotherapy

September 2015:

Expanded European label

AML > 30 % blasts

65 yrs or older

not eligible for HSCT

Belgian reimbursement under

evaluation

SGI-110 = Guadecitabine (Astex)

2nd generation hypomethylating agent

Other advantages:

- Low injection volume

- Prolonged stability (1 month) after reconstitution

Efficacy of SGI-110 in treatment-naive AML

H. Kantarjian, ASH 2015

ASTRAL 1: Phase III study (first line AML unfit for IC)

SGI-110 vs physician’s choice (LD-AraC,AZA,DAC)

N = 103 5 days 10 days

CR + CRi + CRp 57 % 48%

Overall survival 10.5 mths 8.7 mths

Since 2012: Treatment strategies and

outcome in elderly AML > 65 yrs

Best

supportive

care

LD araC Intensive

chemo

Hypomethylating

agent

Decitabine 5d

Azacitidine 7d

CR (%) 0 15-20 50-55 15-20

Median

Overall

Survival

(months)

2 4-6 10 7-10

5 yr OS (%) 0 0 15 Not curative

unless followed by

allo SCT

Effect in

adverse

karyotype

NA No Limited Moderate

Non M3 AML

Age > 80

Hypomethylatingagent

Age 65-80

Fit and

Good/intermediatekaryotype

Induction 3 + 7

Consolidation x 1/2

Conventional dose AraC

Consider RIC transplant

Unfit or

Poor karyotype

Clinical trial for allpts preferable

Example of treatment algorithm for elderly AML

New targeted therapies for

elderly (and young) adults

with AML

hP67.6

• Humanized mAb to CD33 epitope present on 90% of AML blasts

Covalentlinker

• Cleaved in lysosome

Calicheamicin

• Highly potent cytotoxin

• Binds to dsDNAcausing breaks

• 2-3 bound to each mAb

Human

Mouse

Gemtuzumab Ozogamicin

(Mylotarg) (Pfizer)

Addition of GO to intensive induction chemotherapy improves

survival and relapse in AML with favorable and intermediate

karyotype independent of age :

a meta analysis of 5 randomized trials

R.Hills et al, Lancet Oncology 2014, 15,986-996

Overall survival

Favourable karyotypeOverall survival

intermediate karyotype

AML19 (EORTC-GIMEMA):

GO versus BSC in unfit elderly AML

CR median OS 1 yr OS

GO 27 % 4.9 mths 24.3 %

BSC 0 % 3.6 mths 9.7 %

Amadori et al, ASH 2014

Immunotherapy in development for AML

• Antibody – drug conjugates

– SGN-CD33A (anti CD33 + pyrrolobenzodiazepine

dimer)

CASCADE: newly diagnosed AML unfit for IC

AZA/DAC + SGN-CD33A or placebo

• Bispecific antibodies (BiTE)

– AMG 330 (anti CD33 and CD3)

– MGD 006 (anti CD123 and CD3)

• Stem cell targeting : CD123 = IL3 receptor alfa

– Anti CD123 (CSL362)

– CAR T-123

Flt3 mutations

•30 % of normal karyotype AML are Flt3 receptor mutated•Flt3 ITD or Flt3 D835•Flt3 ITD mutations in AML have a negative prognostic impact •Flt3 mutations are target for inhibitors

RATIFY study : first line , < 60 jr

RATIFY study : first line , < 60 jr

R. Stone et al, ASH 2015, plenary session Midostaurin in combination with IC and 1 yr maintenance improves OS and EFS in FLT3 mutated AML < 60 yrs oldAlso in subgroups with Flt3-ITD low and high and Flt3 TKD

5 yrs OS : 7.7 % difference

Flt3 inhibitors in clinical development

• Quizartinib (Ambit, Daiichi Sankyo)

• Crenolanib (Arog)

• Gilteritinib (ASP-2215) (Astellas)

– CR 30-50% in RR Flt3 ITD + AML

– Frequent incomplete haematological recovery

– Duration of CR 3 months

– Crenolanib, gilteritinib:

• Active against resistance mutations

– Future: - As bridge to allo SCT

- Combination trials with HMA and IC

IDH mutations as a new therapeutic target

• IDH1 mutations: 5-10% of AML, IDH2 mutations: 10-15% of AML

• Negative or no impact on prognosis of AML

• Mutated IDH produces the oncometabolite 2-hydroxyglutarate

• Mutated IDH is a target for IDH inhibitors

First results of IDH inhibition in AML

• AG-120 and AG-221 (Agios)

– first-in-class, oral

– selective inhibitors of the IDH1 and IDH2 mutant enzymes

– inhibit 2-HG accumulation

– promote cell differentiation (> rising neutrophil count with

persisting clone)

N = 121

IDH2 + AML

Relapsed/refractory

Phase I/II dose escalation

ORR = 41%, CR 18%

Response duration 6 mths

Well tolerated

AG 221,

ASH 2015, Stein

AG 120,

ASH 2015, DiNardo

N= 61

IDH1 + AML,MDS

Relapsed/refractory

Phase I Dose escalation

ORR = 36 %, CR 18%

Response duration 5.6 mths

Well tolerated

Flt3/IDH inhibition are

examples of precision medicine

New cytotoxic drugs

O

HNN N N

H3C

CO2H

H3CO

NS

Vosaroxin: A First-in-Class

Anticancer Quinolone Derivative

Key Characteristics

• Targeted topoisomerase II inhibitor

• Active in anthracycline-resistant settings

• Escapes common drug resistance pathways (P-gp)

• Low potential for drug-drug interactions

• Lower potential for off-target damage (cardiotoxicity)

Evanchi. Drug Metab Disp 2009; Hoch. Cancer Chemother Pharmacol 2009; Scaten. ibid 2010; Advani Clin Cancer Res 2010;

Hawtin. PLoS One 2010; Hawtin. Oncotarget 2010; Haematologica 2011; Lancet Leukemia 2011.

Vosaroxin

Quinolone

Core

Vosaroxin intercalates DNA and

inhibits topoisomerase II, causing

DNA breaks and cell death by

apoptosis.

50

VALOR : Phase 3 Randomized Double-blinded, Placebo-controlled

F.Ravandi et al, Lancet Oncology, 2015

*After cycle 1, all subsequent cycles at 70 mg/m2 vosaroxin on days 1 and 4

Study Arm

Control Arm

VOSAROXIN90* mg/m2

days 1, 4

+

Cytarabine (IDAC)1 g/m2

days 1- 5

PLACEBOdays 1, 4

+

Cytarabine (IDAC)1 g/m2

days 1- 5

CR or CRp

CRi, PR or Treatment Failure

Consolidation(1-2 cycles)

Survival Follow Up

Primary Endpoint: Overall Survival (OS)

1:1 Randomization

First Relapsed or Refractory

AML

Stratifications:• Age• Disease

Status• Geography

Induction(1-2 cycles)

51

Intent To Treat Population (N = 451)

median (95% Cl)

5.0 (3.8, 6.4)

7.1 (5.8, 8.1) p = 0.006Vos/Cyt

Pla/Cyt Censored

Censored

VALOR - OS for Patients ≥60 Years of Age(Preplanned Analysis)

CPX-351 (Celator Pharm.)

100-nm bilamellar liposomes

5:1 molar ratio of cytarabine todaunorubicin (maximallysynergistic ratio in cell lines)

Accumulates in BM withpreferential uptake by leukemiccells

Feldman et al, JCO 2011

N.D./AML Age 60-75

PS 0-2

CPX 100 u/m2

d 1, 3, 51-2 Cons

“3+7” regimen 1-2 Cons

OS (sAML)

OS

CPX-351 vs 3+7 (phase 2b)Lancet J, Blood 2014,123: 3239

P=0.61 P=0.01

Cross-over

6.1 vs 12.1 mths