la leucemia mieloide acuta nel paziente anziano lam · la leucemia mieloide acuta nel paziente...

LaleucemiamieloideacutanelpazienteanzianoLAM

F.Ferrara

DivisionediEmatologiaeTMO,

OspedaleCardarelli,Napoli

Medianage:65yrs.

Which is the age limit for considering anAML patient as 'elderly' ?

• the age limit according to which aggressiveinduction and post-induction therapy isspecifically designed by age (?).

• not in USA (3-7 for all, at least in induction)

• the age limit which discriminates betweenaggressive therapy aiming at CR achievement andattenuated treatment or supportive care only

Hematology and SCT, Cardarelli

Juliusson et al, Leukemia, 2006

Accrual into aggressive regimens aimed at CRachievement in different age subgroups

Ferrara F, Clin Leuk, 2008

Elderly AML patient: > 70 yrs.

p:0.24

Juliusson et al., Clin lymph myel and leuk, 2011

AMLOUTCOMEinOlderPa9ents(n=>6000)

ECOGECOGtrials

MD Anderson data

Survivalof211pa9entstreatedwithBSCand/orHUMedianage76yrs(69‐89)

Mediansurvival:60days

FerraraF,unpublished

FerraraF,TheLancet,2010

OlderAdultAML:30dayMortality

• 30daymortalityisadverselyaffectedbyageandperformancestatus

Modified from Appelbaum et al. Blood 2006;107:3481Modified from Appelbaum et al. Blood 2006;107:3481

AML:Earlydeath(<8wks.survivalaccordingtoini9altreatment)

Juliusson et al., Clin Lymph Myel and Leuk, 2011

AML:CRrateaccordingtoage

Juliusson et al., Clin Lymph Myel and Leuk, 2011

FerraraF,ClinLeuk,2009

Juliusson et al., Clin Lymph Myel and Leuk, 2011

FerraraF,ClinLeuk,2009

Therapeutic options in AML of older patients

Conventional chemotherapy followed,whenever possible, by SC transplantation: FIT

Attenuated therapy however aiming at CRachievement or disease control: UNFIT

Supportive care +/- HU: FRAIL

Investigational: FIT or UNFIT

Hematology Cardarelli 10/2011

Chemotherapy-based trials inolder adults with AML*

Stone NEJM 1995; Godwin Blood 1998; Lowenberg J Clin Oncol 1998; Baer Blood 2002;Anderson Blood 2002; Rowe Blood 2004

* Deemed chemotherapy candidates, all aged > 55 years

Study Median age(years)

CR Toxicdeath

Survival(months)

CALGB 8923 69 52% 25% 9.6SWOG 9031 68 45% 16% 8.5

HOVON AML 9 68 42% 18% 9.5CALGB 9720 70 46% 20% 10ECOG 3351 68 42% 17% 7.5SWOG 9333 68 43% 18% 9

• Remarkably similar induction rate, toxic death rate, and poor overallsurvival across studies

Blood, 2009

How to improve CR rate and quality ?

• Adding hematopoietic growth factor:shorten neutropenia and hospitalization

• Using alternative anthracycline or GO instead of DNR:no results

• Increasing dose of DNR

• Adding new drug to 3+7

FerraraF,Drugs&Aging,inpress

Lowenberg et al, NEJM, 2009

Median age: 68 yrs.

DNR 45 mg/mq vs 90 mg/mq

Lowenberg et al, NEJM, 2009

Lowenberg et al, NEJM, 2009

Lowenberg et al, NEJM, 2009

Total CBF patients: 33/562 (5.8 %)

Lowenberg et al, NEJM, 2009

Most older AML patients do not benefit from intensified 3 + 7 regimens

Median age: 71 yrs.

Blood, 2010

AML16 Intensive: Outline

D + Ara-C

D+Clofarabine

D + Ara-C

D+Clofarabine

Demethylation(Azacytidine)

No Treatment

R2

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

CR/PR vs

Course 1 Course 2

+ Mylotarg

+ Mylotarg

D+ Ara-C

No Rx

Demethylation(Azacytidine)

No Treatment

CALGB, NEJM, 1994

% of patients receiving 4 courses of therapy

all patients

< 60 yrs.

> 60 yrs.

CALGB, NEJM, 1994

I don’t know, may be, no definitive data, no HD-ARA-C

ID-ARA-C may be a reasonable option

Canstemcelltransplanta9oncureAMLinolderpa9ents?

Yes,manypaperssuggestit

PAPERSonALLOGENEICSCTINOLDERAMLPATIENTS:

PUBMEDRESULTSINTHELASTTHREEYEARS

14/259:5.4%

Registration n=7841st randomization n=7822nd randomization n=215Not eligible n=9

Cycle 1N=570 (100%)

Cycle 2N=401(70%)

CR

On protocol n=88Off protocol form n=108No treat n=9

Off protocol n=169 (30%)- Death n=78- Toxicity n=26- No compliance n =17- No CR/relapse n=14- Other n=34Off protocol

n=106 (19%)no

R2N=170 (30%)

yes Off protocol n=96 (17%)- Death n=30- Toxicity n=10- No compliance n =17- relapse n=15- Other n=24

Mini-SCTN=29 (5%)

Hovon/SAKK trialBlood, 2010

ASCT for elderly patients with AML

Ferrara F et al, Hemat Oncol, 2009

Feasibility of AuSCT in elderly patients with AML

47#patients

CR obtained

Furtherconsolidation

CD34+mobilisatio

nActually

transplanted

Montillo et al.

(BJH 2000)Ferrara et al,

Hematologica, 2005

24 (51%)

63

13 (28%)

5 (11%)

3 (6%)

13 (28%)Evaluated formobilisation

42 (67%)

23 (37%)

29 (46%)

35 (55%)

17 (22%)

135

82 (61%)

75 (56%)

41 (30%)

16 (12%)

51 (38%)

Oriol et al.

(Haematologica 2004)

Ferrara F et al, Hemat Oncol, 2009

% of older AML patient cured with SCT

Ferrara F, submitted

Ferrara et al, Hematologica, 2004

Relapse in AML of the elderly

Ferrara et al, Hematologica, 2004

FerraraF,ClinLympMyelandLeuk,2011

Survivalof211pa9entstreatedwithBSCand/orHUMedianage76yrs(69‐89)

Mediansurvival:60days

FerraraF,ClinLympMyelandLeuk,2011

Burne`etal,Cancer,2007

Low Dose Ara-C vs Best Support Care:Survival in Elderly AML Patients with

Adverse Cytogenetics

No CR with LDARA-C in adv. cytog.

Burne`etal,Cancer,2007

AML16 non-intensive

‘Pick a winner’ 3-month survival (randomised phase 2)

LD-Ara-C

LD Ara-C+ATO

LD Ara-C+ Mylotarg

LD Ara-C +Zarnestra

LDClofarabine 20

vs vs

vs vs

Phase 3

Winner DFS/OS

Drug X

vs

Main Challenges in AML of the elderly

• Relapsed patients

•Unfavorable cytogenetics

• Unfit patients

• New drugs are needed !!!!Hematology and SCT, Cardarelli

• Theprocessofleukemogenesisdependsonmul9plemolecularaberra9onsthatcooperateinpermiangtheexpansionofahighlydysregulatedcellcohort

• ThepresenceofPgPindependentmechanismsofresistanceshouldbetakenintoaccount.

• Inthiscontext,itisnotsurprisingthatmodula9onofasinglemechanismwillfailtoreversethecomplexinterplayoffactorsopera9veintheleukemicgrowth.

Therapeutic failures with most new agents:why ?

FerraraF,Drugs&Agng,inpress

Schiffer CA, ASH 2009

The AML paradigm:Whatevertheage,CRisanessen9al

prerequisiteforachievinglong‐termsurvivalorcure

Ferrara et al, Clinical Geriatrics, 2000

Patients aged75 yrs or older

Fenaux et al, JCO, 2010

Fenaux et al, JCO, 2010

Prognostic factors:

ECOG > 1

BM blast % at diagnosis

Cashen et a, JCO, 2010

Are HMA changing the paradigmin older patients with AML ?

I don’t know ! May be ……

Ferrara & Musto, Cancer, 2011

Hypoproliferative AML(20-30% BM blast, low WBC count andadverse karyotype; Unfit patients withintermediate or favorable karyotype )

CR+CRi/CRpRatesbyRiskFactors

EU USNumber of patients 66 113

Age < 70Age > 70

10/25 (40%)22/41 (54%)

24/43 (56%)28/70 (40%)

ECOG PS 2+ECOG PS 0-1

10/26 (38%)42/87 (48%)

Prior AHDNo prior AHDUnknown AHD

21/42 (50%)29/66 (44%)2/5 (40%)

Secondary AMLDe Novo AML

5/16 (31%)24/50 (48%)

Cytogenetics - Intermediate - Unfavorable - Not available

20/43 (47%)9/19 (47%)

24/46 (52%)24/56 (43%)4/11 (36%)

CLO243

BIO121

FerraraF,ClinLympMyelandLeuk,2011