"Challenges in Treatment of"Challenges in Treatment of

Elderly AML"Elderly AML"

Pr. Mohamad MOHTYHead, Clinical Hematology and

Cellular Therapy Dpt.Université Pierre & Marie Curie

Hôpital Saint-AntoineParis, France

AML: Change in overall survival with time

(A) Age 15 to 59 years

(B) 60 or more years

Simplified Classification of AML

• AML sensitive to conventional chemotherapy• CBF leukemias (without c-KIT mutation)• Diploid AML with NPM1 and CEBP mutation (without FLT3 mutation)• Dose intensification of chemotherapy may be helpful

• Chemo-resistant and high risk AML• AML with adverse cytogenetics• AML with FLT3-ITD• Others (older patients, younger patients with t-AML and/or AHD)• New agents are needed• Allo-SCT in the mainstay of therapy

Therapy for AML (non-APL): Decision checkpoints Therapy for AML (non-APL): Decision checkpoints and Factors influencing therapeutic decisions and Factors influencing therapeutic decisions

Diagnosis

Intensive CT

Postremission therapy

Rescue treatment

Relapse

Performancestatus

Age

Comorbidities

Cytogenetics

Molecular profile

MRD persistencePharmacogenetics

Early death seems to be increased if palliative-low dose treatment is administered

WHO/ECOG PS 0-II WHO/ECOG PS III-IV

Intensive Palliative Intensive Palliative

N.Pts % ED N.Pts % ED N.Pts % ED N.Pts % ED

491 4 12 25 38 26 4 50

344 6 22 27 43 28 19 63

435 8 131 21 62 34 92 54

211 14 397 17 56 36 271 52

Age group

(yrs)

16-55

56-65

66-75

76-89

Juliusson G, et al. Blood 2009;113:4179-87

Although,• Comorbidity scores may be more discriminant• Cytogenetics should be taken into account• Is this true with targeted treatment?

Intensive CT is the first option, regardless of age. Consider alternative agents if poor cytogenetics

Targeting molecular abnormalities

Target Class of Agents

FLT3 FLT3-inhibitors- Non specific

- Specific

KIT (CD117) TKI (imatinib, dasatinib)

Epigenetic changes - Hypomethylating agents

- HDAC inhibitors

RAS FT inhibitors

CD33 Anti-CD33 MoAbs

Me

O

O

NH

S

H

HOO

OCH3

NH O

O

OCH3

N

CH3CH2

O

OHOCH3

HOCH3

OCH3

HNHO

OO

OH

CH3

S

CH3

OCH3

OCH3

I

O

O

O

O

S

O

NHN

Me Me

O

CH3

hP67.6

hP67.6 conjugated to NAc-calicheamicin

Gemtuzumab Ozogamicin (GO)

Arm A Arm B

2nd course if BM blasts >10% at D15DNR 60 mg/m2 D1, D2

AraC 1g/m2/12h D1 to D3

INDUCTION

1st CONSOLIDATION

2nd CONSOLIDATION

Fractionated Doses of Gemtuzumab Ozogamicin Combined to Standard ChemotherapyIn Newly-Diagnosed de novo AML Patients

Aged 50-70 Yrs

Randomization

CR or CRp

DNR 60 mg/m2 D1 to D3AraC 200 mg/m2 D1 to D7

DNR 60 mg/m2 D1 AraC 1g/m2/12h D1 to D4

DNR 60mg/m2 D1,D2 AraC 1g/m2/12h D1 to D4

DNR 60 mg/m2 D1 to D3AraC 200 mg/m2 D1 to D7GO 3 mg/m2 D1, D4, D7

DNR 60 mg/m2 D1 AraC 1g/m2/12h D1 to D4GO 3 mg/m2 D1

DNR 60 mg/m2 D1,D2 AraC 1g/m2/12h D1 to D4GO 3mg/m2 D1

Castaigne et al., Lancet 2012Castaigne et al., Lancet 2012

Event-free survival

EFS A (control)(n=139)

B (GO)(n=139)

Events 104 76

Median 11,9 mo

19.6 mo

2-year 16.5% 41.1%

HR(95% CI)

1 0.57 (0.42-0.77)

P= 0.00018by the log-rank test

GO arm

Control arm

Castaigne et al., Lancet 2012Castaigne et al., Lancet 2012

Overall survival

OS A (control) (n=139)

B (GO)

(n=139)

Deaths 71 59

Median 19.2 mo

34 mo

2-year 43.5% 53.1%

HR(95% CI)

1 0.70(0.50-0.99)

P= 0.046by the log-rank test

GO arm

Control arm

Castaigne et al., Lancet 2012Castaigne et al., Lancet 2012

Epigenetic Therapy

M M M M

DNA Methylation Histone Modification

Phosphorylation

Methylation

Acetylation

5-AzacytidineDecitabine

SAHAValproic acid

Belinostat•

Azacitidine in AML

• 358 pts AZA-001; 113 20% blasts (WHO

AML)

• 55 randomized to AZA, 58 to CCR

• Median age 70 y.; poor cytogen 24%

• Median FU 20 m.; median cycles 8 (1-39)

• Parameter AZA CCR P

- Median OS (m) 24 16 .004

- % 2-yr survival 50 16 .004

- % CR 18 16 NS

• Survival better in int cytogen., not in

unfavourable cytogenetics.

Fenaux et al. J Clin Oncol 2010

Randomized trial of Decitabine vs. treatment of choice in AML ≥ 65 years

Kantarjian H, J Clin Oncol, 2012

CR/CRp Decitabine 17.8%TC 7.8%

P=.001

Decitabine

N

N N

N

OHO

HO

NH2

F

HO

Deoxyadenosine analogues

N

N N

N

OHO

HO

NH2

Cl

N

N N

N

NH2

OHO

HO

Cl

F

Fludarabine Cladribine Clofarabine

Single Agent Clofarabine in AMLSingle Agent Clofarabine in AML

• Phase I 32 pts with acute leukemia: CR 6%; OR 15% MTD: 40 mg/m2/d i.v. x 5d; DLT: hepatotox.• Phase II

N Median age

(yr)

CR (%)

OR (%)

Frontline * Faderl1 16 71 (60-83) 31 31

Burnett2 36 > 70 44 56

Salvage Kantarjian3 31 54 (19-82) 42 55

Foran4 14 54 (20-78) 7 7

* CLO 30 mg/m2/dose

1 Blood 2005; 106: 786a; 2 Haematologica 2006; 91 (s1): 45; 3 Blood 2003; 102: 2379; 4 Blood 2002; 100: 271b

- N=106

- Median age= 71 years (range, 60-84)

- 30% adverse-risk cytogenetics

- 36% WHO PS≥2

- 48% CR (32% CR, 16% CRi)

Clofarabine + cytarabine combination studies

1. Faderl S et al. Blood 2005;105:940 2. Powell B et al. Blood 2008;112:Abstract 19363. Becker PS et al. Blood 2008;112:Abstract 2964

N Age (y) Dose* Response

Faderl2005

29 63 (18–84)CLO 40 x 5

Ara-C 1 x 5CR 24%; OR 41%; IM 3%

Powell 2008

39 53 (18–79)CLO 40 x 5

Ara-C 2 x 5CR 38%; OR 43%; IM 8%

Becker 2008

16 18–70

CLO 15,20,25 x 5

Ara-C 2 x 5

G-CSF

5/8 CR O/E (HDAC, FLAG) 3.2:1

* CLO mg/m2; Ara-C g/m2

The next question: anthracycline combinations with clofarabine and cytarabine (at diagnosis and at relapse)…

Much of the success of allo-SCT in cancer is due to the

Graft-vs.-Tumor effect

Confirming Barnes et al. (Br J Haematol 3: 241, 1957)

Weiden et al., N. Engl. J. Med. 300:1068, 1979 Weiden et al., N. Engl. J. Med. 304:1529, 1981.

Myeloablative HCT (MTX)

Years after Sibling Marrow Grafts

The European Group for Blood and Marrow TransplantationH.B. 3.2011

H.B. 3.2011

EBMT Activity Survey on HSCT 1990-2009:changes in AML

HSCT

Increase of allo-SCT as from 2001 due to:

- Introduction of RIC- Increased use of

alternative donors

Flu-TBI 2 G

y.

d-6 d-5 d-4 d-3 d-2 d-1 d0

Fludarabine 30 mg/m²/d(or Clofarabine)

X X X X X

I.V. Busulfan3.2 mg/Kg/d

(X) (X) (X) X

Thymoglobuline2.5 mg/Kg/d

X X

Cyclosporine 3 mg/Kg/d X X X X

MMF (2 g/d if MUD) X X X X

PBSC X

I.V. BU-based Reduced Toxicity Conditioning (RTC) platform towards a patient-tailored conditioning

RIC allo-SCT for AML: “donor” vs. “no donor” (N=95; Intention-to-treat analysis)

Median FU = 60 months

Ove

rall

surv

ival

(“i

nte

nti

on

to

tre

at”)

“donor” group

“no donor” group

Time (months)

P=0.003

Ove

rall

su

rviv

al

Time (months)

“donor” group

“No donor” group

P=0.003

In the multivariate analysis, only actual performance of RIC-allo-SCT (P=0.0005; RR=4.1; 95%CI, 1.8-9.1), was significantly predictive of an improved long term LFS

Mohty et al., Leukemia, 2005 Leukemia, 2009

Day -6 -5 -4 -3 -2 -1 0Bu 130 mg/m2 qdFlu 30 mg/m2 qdThymoglobuline 2.5 mg/KgPBSC

I.V. Bu-based “submyeloablative" conditioning (FB3): Prospective Multicentre Trial, N=80

I.V. Bu-based “submyeloablative" conditioning (FB3): Prospective Multicentre Trial; N=80

NRM

0 2 4 6 8 10 12 14

0.0

0.2

0.4

0.6

0.8

1.0

10%

Protocol NCT 00841724; Mohty et al. ASH 2012

• AML therapy remains non-specific and challenging for most

patients

• A number of demographic features can predict the outcome of

treatment including cytogenetics and an increasing list of

molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha,

EVI1) multi-agent approach needed

• Emerging therapies are promising, and targeted therapies

started addressing small subgroups, BUT allo-SCT will remain

the recommended treatment for many patients !

• RTC allo-SCT appears increasingly to be a safer procedure in

the “older” AML patients

Conclusions