AML IN OLDER PATIENTS Whenever possible, intensive induction therapy should be considered

Charles A. Schiffer, M.D. Karmanos Cancer Institute Wayne State University School of Medicine Detroit, MI

WHY ARE MOST SUBTYPES OF AML SO DRUG RESISTANT?

•

Hematopoietic precursors are “designed”

to survive repeated exposure to multiple types of natural toxins

•

Most resistance mechanisms have been shown to be amplified in undifferentiated precursors

•

They can survive exposure to huge doses of chemotherapeutic agents in vitro (marrow “purging”)Therefore,It is not surprising that leukemias which derive from hematopoietic stem cells are particularly resistant (eg - Ph chromosome pos diseases, MDS, MPD, FAB M0)

HOW TO DEFINE AML

and

WHO IS BEING TREATED ON THESE TRIALS?

OLDER ELDERLY

“REAL” AML WHO – MDS/AML

Burnett et al, Cancer 109:1114, 2007

MRC – LOW DOSE ARA-C vs.SUPPORTIVE CARE – MEDICALLY“UNFIT” PATIENTS

~ 15% CR

S0432: Overall Survival by Tipifarnib Regimen

Erba et al Blood 2007; 110: 136a (abstract 440)

THE ISSUE OF “UNFIT” FOR “INTENSIVE” THERAPY

•

Very subjective and difficult to definePS, “comorbidities”, karyotype

•

Implications for clinical trials •

Critical in making recommendations for individual patients

•

Implications for new drug assessment/approval

Control arm?

Azacitidine Treatment Prolongs Overall Survival in Higher-Risk MDS Patients

Compared with Conventional Care Regimens: Results of the AZA-001 Phase III Study

Azacitidine Treatment Prolongs Overall Azacitidine Treatment Prolongs Overall Survival in HigherSurvival in Higher--Risk MDS Patients Risk MDS Patients

Compared with Conventional Care Compared with Conventional Care Regimens: Results of the Regimens: Results of the AZAAZA--001 Phase III Study001 Phase III Study

P Fenaux, MD, GJ Mufti, MD, V Santini, MD, C Finelli, MD, P Fenaux, MD, GJ Mufti, MD, V Santini, MD, C Finelli, MD, A Giagounidis, MD, R Schoch, MD,A List, MD, S Gore, MD, A Giagounidis, MD, R Schoch, MD,A List, MD, S Gore, MD, J Seymour, MD, E HellstromJ Seymour, MD, E Hellstrom--Lindberg, MD, J Bennett, MD, Lindberg, MD, J Bennett, MD,

J Byrd, MD, J Backstrom, MD, L Zimmerman, BSN, J Byrd, MD, J Backstrom, MD, L Zimmerman, BSN, D McKenzie, MS, CL Beach, PharmD and L Silverman, MD D McKenzie, MS, CL Beach, PharmD and L Silverman, MD

on behalf of the International Vidaza Highon behalf of the International Vidaza High--Risk MDS Risk MDS Survival Study GroupSurvival Study Group

Azacitidine Survival StudyAzacitidine Survival StudyAzacitidine Survival Study

AZAAZA 75 mg/m75 mg/m22/d x 7 d q28 d/d x 7 d q28 d

CCRCCRRandomizationRandomization

BSC was included with each armTx continued until unacceptable toxicity or AML transformation or disease progression

•

Best Supportive Care (BSC) only•

Low Dose Ara-C (LDAC, 20 mg/m20 mg/m22/d x 14 d q28/d x 14 d q28--42 d42 d))

•

Std Chemo (7 + 3)

Screening/CentralPathology Review

Investigator CCRTx Selection

Baseline Clinical Characteristics N = 358

Baseline Clinical Baseline Clinical CharacteristicsCharacteristics N = 358N = 358

ParameterParameterAZA AZA

N=179N=179CCRCCR

N=179N=179

CCR RegimensCCR RegimensBSC BSC Only Only

N=105N=105LDAC LDAC N=49N=49

Std Std Chemo Chemo N=25N=25

Age (yrs) Age (yrs) MedianMedianPts Pts ≥≥

65 (%)65 (%)

69696868

70707676

70707777

71718686

65655252

FAB FAB (%)(%)

RAEBRAEBRAEBRAEB--TTCMMLCMML

5858343433

5858353533

6565292944

5151393922

4040525200

IPSS IPSS (%)(%)

INTINT--11INTINT--22HighHigh

3343434646

7739394848

9944444444

4443434343

8812127272

Overall Survival: Azacitidine vs CCR ITT Population

Overall Survival: Azacitidine vs CCR Overall Survival: Azacitidine vs CCR ITT PopulationITT Population

LogLog--Rank p=0.0001Rank p=0.0001HR = 0.58 [95% CI: 0.43, 0.77]HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113Deaths: AZA = 82, CCR = 113

0 5 10 15 20 25 30 35 40

Time (months) from RandomizationTime (months) from Randomization

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prop

ortio

n Su

rviv

ing

Prop

ortio

n Su

rviv

ing

CCRCCRAZAAZA

Difference: 9.4 monthsDifference: 9.4 months

24.4 months24.4 months

15 months15 months

50.8%50.8%

26.2%26.2%

And some do OK without treatment

SHOULD OLDER/ELDERLY PATIENTS BE TREATED?

SHOULD OLDER/ELDERLY SHOULD OLDER/ELDERLY PATIENTS BE TREATED?PATIENTS BE TREATED?

•

Not at all - supportive care

•

With standard anthracycline/cytarabine

•

With experimental therapy since it is hard to do “worse” – focus on noncytotoxics

Age, Performance Status and Early Death in AML

N = 437

Age, Performance Status and Age, Performance Status and Early Death in AMLEarly Death in AML

N = 437N = 437Performance

StatusDeath within 30 days

56-60 61-70

71+

0 0% 13% 9%

1 0% 14% 21%2 38% 19% 42%

3 17% 24% 62%

SWOG -

Appelbaum

Age, Performance Status and Complete Response Rate in AML

Age, Performance Status and Age, Performance Status and Complete Response Rate in AMLComplete Response Rate in AMLPerformance Complete Response

Status 56-60 61-70 +70

0 70% 40% 50%

1 60% 49% 38%

2 25% 38% 27%

3 50% 41% 29%

SWOG -

AppelbaumN = 437

THE MAJOR ADVANCE IN AML THERAPY IN THE

PAST 10-15 YEARS:

ZOFRANAZOLES FOR PREVENTION/TREATMENT OF INFECTIONS WITH MOLDS

LEUCOCYTE DEPLETION TO PREVENT ALLOIMMUNIZATION

CALGB 8923AGE > 60 YEARS

CONVENTIONAL DOSE ARA-C X 4 vsHIDAC/MITOXANTRONE X 2

RELAPSE FREE SURVIVAL

THE DECISION FROM HELL: MDS PATIENT WITH WORSENING

CYTOPENIAS AND INCREASING BLASTS

•

AML induction therapy – “7 & 3”

•

Decitabine or azacytidine`•

Azacytidine + GO

•

GO•

Clofarabine

•

Low dose Ara-C•

Clinical trials

•

Supportive care

WHAT TO DO TOMORROW FOR POST REMISSION THERAPY FOR PATIENTS

NOT ON A CLINICAL TRIAL•

Assess patient’s goals

•

Individualize•

Conventional dose Ara-C

•

HIDAC for the occasional patient with favorable cytogenetics or NPM1 mutated

•

No maintenance•

Don’t rush into reinduction treatment

•

Consider clinical trials of non- myeloablative allogeneic transplantation

A CRITICAL CHALLENGE: THE DEVELOPMENT OF METHODOLOGY

TO EFFICIENTLY EVALUATE NEW NONCYTOTOXIC THERAPIES

•

Angiogenesis inhibitors•

Tyrosine kinase

inhibitors -

FLT3

•

Farnesyl

transferase

inhibitors•

Modulators of apoptosis

•

Other signal transduction inhibitors•

Immunologic manipulations

•

Histone

deacetylase

inhibitors•

Et al

WHAT TO DO NEXT?

•

1200 -

1500 patients = 1-2 monster phase III studies or….

•

30 phase II exploratory trials-

dose/schedule

-

biologic correlates whenever possiblefocus on responders