Treating older patients with AML

Sergio Amadori Tor Vergata University Hospital

Rome

Istanbul 2012

Meet-the-Expert: AML

Poor prognosis Minority treated with intensive

Cx Treatment less

successful

Outcome has not changed

over the last 40 years

AML in older patients

Burnett et al, JCO 2011 Kantarjian, ASCO 2011

Reasons for lack of progress

Poor tolerance for intensive Cx •  Poor PS and

comorbidities

Inherent drug resistance •  Adverse

biology

Therapeutic nihilism •  Lack of

accrual to clinical trials

Available options

Intensive

Rx

Investigational Rx

Low-Int Rx Supp care

EORTC AML-7 (age 65+) (Lowenberg et al, JCO 1989)

Target: CR Prerequisite for better OS

and QOL

Lesser responses:

limited benefit

ECOG SWOG MDACC 6,283 pts

Walters et al, JCO 2010

Intensive Rx: treatment of choice

Older adults are not all the same

FIT Poor risk

FIT Low risk

UNFIT

Candidate for intensive Cx?

YES What is best strategy?

NO What are alternatives?

Candidates for intensive Rx? Prognostic Risk Models

Intensive Rx

•  DNR + Ara-C (3+7 regimen) for induction •  Ara-C-based consolidation (1-2 courses)

–  CR, DFS and OS rates inferior to younger pts

Better therapies needed

Standard approach:

Age, y CR% ED % RR% Cure %

<60 75 <10 50 45

>60 50 ~20 85 <15

New strategies

Treatment Intensification

Induction

DNR dose

Add new agents

Postremiss RIC-SCT

Focus on

R

Induction cycle I

DNR 45 mg/m2 x3

Ara-C 200 mg/m2 x7

R

Ara-C 1 g/m2 q12 hrs

Induction cycle II

DNR 90 mg/m2 x3

Ara-C 200 mg/m2 x7

Ara-C 1 g/m2 q12 hrs

x 6 days

RIC-SCT (optional)

Post induction

none

GO 6 mg/m2

q 4 weeks x 3

x 6 days

HOVON/SAKK AML-43

Lowenberg et al, NEJM 2009

Induction outcome

DNR 45 DNR 90 P value

% CR 54 64 0.002

% CR @course1 35 52 < 0.001

% CR age 60-65y 51 73 0.02

% CR CBF 74 93

% 30-d mortality 12 11 NS

N=813, age 60-83y

Survival

3  RCT  

ALFA  0701  

NCRI    AML  16  

E/G  AML  17  

Addi5on  of  gemtuzumab  (GO)  

Patients aged 50-70 yrs with de novo AML

(N = 278)

GO 3 mg/m2/day on Days 1, 4, and 7 + Daunorubicin 60 mg/m2 on Days 1-3 +

Cytarabine 200 mg/m2 on Days 1-7 (n = 139)

CR

/CR

p

Daunorubicin 60 mg/m2 on Days 1-3 + Cytarabine 200 mg/m2 on Days 1-7

(n = 139)

GO 3 mg/m2/day on Day 1 + Daunorubicin 60 mg/m2 on Day 1

(first course) or Day 1-2 (2nd course) + Cytarabine 1 g/m2/12 hrs on Days 1-4

Daunorubicin 60 mg/m2 on Day 1 (first course) or Day 1-2 (2nd course) + Cytarabine 1 g/m2/12 hrs on Days 1-4

Induction Consolidation (2 courses)

Day 15 additional treatment* for persistent marrow blasts

*Patients with persistent marrow blasts > 10% at Day 15 received additional daunorubicin 35 mg/m2 on Days 1-2 + cytarabine 1 g/m2/12 hrs on Days 1-3.

ALFA 0701 study

Castaigne et al, ASH 2011

Outcomes

OS by cytogenetics

Benefit only in patients with fav/interm CG

Fav/Int K Unfav K

Treatment Schedules  DA 3+10   Dauno 50 mg/m2 d1,3,5; Cytarabine 100 mg/m2 d1-10 every 12h  DA 3+8   Dauno 50 mg/m2 d1,3,5; Cytarabine 100 mg/m2 d1-8 every 12h  DA 2+5   Dauno 50 mg/m2 d1,3; Cytarabine 100 mg/m2 d1-5 every 12h  DClo   Dauno 50 mg/m2 d1,3,5; Clofarabine 20 mg/m2 d1-5  Mylotarg   Mylotarg 3mg/m2 d1 of course 1.  

Azacytidine  

Azacytidine 75mg/m2 daily for 5 days repeated every 6 weeks for 9 courses  

NCRI AML16 study

Burnett et al, ASH 2011

Age >60

Outcomes CIR

OS Surv from CR

OS by baseline features

Patients with adverse CG or other poor-risk features unlikely to benefit

Treatment  Schedules  

MICE    Mito  7  mg/m2  d1,3,5;  Ara-­‐C  100  mg/m2  d1-­‐7;  Eto  100  mg/m2  d1-­‐3  

GO  induc5on    6  mg/m2  d  1,  15  

GO  consolid    3  mg/m2  d  0  

ICE    Ida  8  mg/m2  d1,3,5;  Ara-­‐C  100  mg/m2  d1-­‐5;  Eto  100  mg/m2  d1-­‐3  

GOx2 MICE CR/CRp GO+ ICEx2

MICE CR/CRp ICEx2 R

Amadori et al, EHA 2012

EORTC/GIMEMA AML-17 study

No  GO   GO   No  GO   GO  CR+CRp  (%)   47,4   52,3   52,4   32,5  No  resp  (%)   40,8   29,4   29,8   31,3  Ind  death  (%)   9,9   11,8   15,5   26,5  Inev/unkn  (%)   2   6,6   2,4   9,6  

0  

10  

20  

30  

40  

50  

60  

Pa5e

nts  %

 

Age  61-­‐69   Age  70-­‐75  

P=0.01  

Induction results by age

(years)0 1 2 3 4 5 6

0102030405060708090

100

O N Number of patients at risk : Treatment 204 236 102 61 42 30 13210 236 78 41 32 27 17

No GOGO

Logrank test: p=0.07

(years)0 1 2 3 4 5 6

0102030405060708090

100

O N Number of patients at risk : Treatment 76 84 35 21 15 9 277 83 16 5 5 4 2

No GOGO

Logrank test: p=0.002

(years)0 1 2 3 4 5 6

0102030405060708090

100

O N Number of patients at risk : Treatment 33 34 12 4 1 1 036 44 21 14 10 8 7

No GOGO

Logrank test: p=0.02

OS  (all  pts)   OS  (age  70-­‐75y)  

OS    

sAML  61-­‐69y  

Survival

Postremission therapy

Group   Study   PRT   Outcome  

MRC   AML-11   1 vs 4 cycles  

No diff  

HOVON   AML-43   GO vs obs  

No diff  

ALFA   9803   6 non-int vs 1 int cycle  

Better DFS and OS at 2y  

•  No proven value •  All large studies

included PRT –  Poor compliance –  <50% of pts in CR

proceeded to PRT –  No clear benefit

•  Survival benefit restricted to pts with favorable CG (GOELAMS, retrosp study)*

•  Focus on AlloSCT

*Prebet et al, JCO 2009

Goldstone et al, Blood 2001 Lowenberg et al, Blood 2010 Gardin et al, Blood 2007

RIC-AlloSCT in elderly AML

• Viable option for patients up to age 75-80 years • TRM comparable to pts age 40-60

• Prospective studies needed

McClune et al, JCO 2010

CIBMTR (1080 pts age 40-79) N=545 AML in CR1

Not candidates for intensive Rx

Frail PS>2, comorbid

Toxicity

Low intensity Rx Supportive care

Poor risk Multiple risk factors

Chemo resistance

Investigational Rx

Poor CG

LDAC (N=103)

HU (N=99)

Early death 26% 26%

CR 18% 1%

Fav/Int CG

Burnett et al, Cancer 2007

Frail: LDAC > HU (NCRI AML 14)

Poor risk: Novel agents to watch…

CPX-351

CR/CRi 67%

ED 3%

Laromustine

CR/CRp 32%

ED 14%

Clofarabine

CR/CRp 46%

ED 10%

Decitabine

CR/CRi 64%

ED 2%

HD-LEN

CR/CRi 30%

ED 24%

Lancet et al, ASH 2010; Schiller et al, JCO 2010; Kantarjian et al, JCO 2010; Blum et al, PNAS 2010; Fehninger et al, Blood 2010

Myelosuppressive  regimens  

Responses  in  all  poor  risk  groups  

Randomized  trials  (vs  3+7)      

•  Intensive Rx (even at high age) •  Define optimal therapy, consider RIC-SCT

Fit (Low Risk)

Treating elderly AML in 2012

•  Investigational Rx •  Consider RIC-SCT

Fit (Poor Risk)

•  Less intensive Rx (LDAC) •  Supportive care (HU) Unfit/Frail

Define who should have intensive or

non-intensive treatment

Novel treatments

New approach to trial design

Avoid therapeutic

nihilism

The road to progress