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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FerraraF,unpublished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