Best of ASH 2007Best of ASH 2007Acute LeukemiasAcute LeukemiasCharles Linker MDCharles Linker MD

#439#439 Tipifarnib for elderly AMLTipifarnib for elderly AML

#593#593 Combination arsenic & ATRA for APLCombination arsenic & ATRA for APL

#297#297 NPM predicts ATRA response in AMLNPM predicts ATRA response in AML

#7#7 Dasatinib + Prednisone for Ph+ ALLDasatinib + Prednisone for Ph+ ALL

#296#296 Poor outcome of elderly AMLPoor outcome of elderly AML

Tipifarnib (Zarnestra®)Induction for elderly AML

• Farnesyltransferase inhibitorFarnesyltransferase inhibitor

• Oral and well-toleratedOral and well-tolerated

• Conflicting results of prior trialsConflicting results of prior trials

French Tipifarnib Randomized TrialFrench Tipifarnib Randomized TrialFor elderly AMLFor elderly AML

• n = 457n = 457• Eligibility Eligibility

Age > 70, not wishing aggressive chemoAge > 70, not wishing aggressive chemo• StratificationStratification

Age < > 75, PS 0-1 vs 2Age < > 75, PS 0-1 vs 2• TreatmentTreatment

Tipifarnib 600 mg BID for 21 of 28 daysTipifarnib 600 mg BID for 21 of 28 days• ResultsResults

OS 3.6 vs 3.6 moOS 3.6 vs 3.6 moTipifarnib CR 8%, MDCR 8 moTipifarnib CR 8%, MDCR 8 mo

Harousseau, ASH 2007 #439Harousseau, ASH 2007 #439

SWOG Tipifarnib Dose TrialFor elderly AML

• n = 388n = 388• Eligibility Eligibility

Age > 70, not wishing aggressive chemoAge > 70, not wishing aggressive chemoWBC < 30,000WBC < 30,000

• TreatmentTreatmentTipifarnib 4 different dose schedulesTipifarnib 4 different dose schedules

• ResultsResultsNo difference between dosesNo difference between dosesCR 6%CR 6%1-year OS 20%1-year OS 20%

Erba, ASH 2007 #440Erba, ASH 2007 #440

CALGB 9710 SchemaCALGB 9710 Schema

• InductionInductionDaunorubicin, Ara-C, ATRADaunorubicin, Ara-C, ATRA

• Experimental randomized armsExperimental randomized armsArm AArm A - observation - observation

Arm BArm B - Arsenic trioxide 0.15 mg/kg IV x 50 doses - Arsenic trioxide 0.15 mg/kg IV x 50 doses

5 days/week x 5 weeks repeated twice with 2-week 5 days/week x 5 weeks repeated twice with 2-week restrest

• Consolidation x 2Consolidation x 2Daunorubicin, ATRADaunorubicin, ATRA

• MaintenanceMaintenance

Powell, ASCO 2007Powell, ASCO 2007

CALGB 9710 ResultsCALGB 9710 Results

• InductionInductionCR 427/480 (89%)CR 427/480 (89%)

• Effect of arsenicEffect of arsenic3-year EFS 81% vs. 66% (p = 0.0007)3-year EFS 81% vs. 66% (p = 0.0007)

3-year OS 86% vs. 79% (p = 0.035)3-year OS 86% vs. 79% (p = 0.035)

CALGB 9710 ResultsCALGB 9710 Results

LowLow Int Int HiHi _p__p_

Complete Complete RemissionRemission

94%94% 93%93% 75%75% <0.0001<0.0001

Death during Death during InductionInduction

3%3% 3%3% 19%19% < 0.0001< 0.0001

Relapse < 1 yearRelapse < 1 year 2%2% 3%3% 9%9% 0.010.01

Low Low WBC WBC ≤ 10,000 and platelets > 40,000≤ 10,000 and platelets > 40,000

Intermediate Intermediate WBC WBC ≤ 10,000 and platelets ≤ 40,000≤ 10,000 and platelets ≤ 40,000

High High WBC > 10,000WBC > 10,000

EFS in Arsenic Arm EFS in Arsenic Arm Risk Groups Risk Groups

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

EF

S

0 10 20 30 40 50 60 70 80 90

MONTHS

Low

Inter

High

p < 0.0001

ATRA alone,

WBC >10K

Su

rviv

al

DFS Time DFS Time

No Arsenic

WBC <10K

Arsenic

WBC <10K

Arsenic

WBC >10K

p = 0.0016, HR 2.24

No Arsenic

WBC >10K

DFS by Treatment Arm and RiskDFS by Treatment Arm and Risk

Combination ATRA & ArsenicCombination ATRA & ArsenicShanghai, ASH 2006Shanghai, ASH 2006

• InductionInductionATRA + Arsenic to CRATRA + Arsenic to CR

• Consolidation Chemo x 3Consolidation Chemo x 3

• Consolidation biologics x 5 coursesConsolidation biologics x 5 coursesATRA + ArsenicATRA + Arsenic

• ResultsResultsCR 93% (56/60)CR 93% (56/60)

EFS 94% [FU 48mo (25-60)]EFS 94% [FU 48mo (25-60)]

OS 98%OS 98%

Liu, ASH 2006 #565Liu, ASH 2006 #565

Oral Arsenic & ATRAOral Arsenic & ATRAShanghaiShanghai

• Arsenic tetra-sulfide is orally absorbedArsenic tetra-sulfide is orally absorbed

AsAs44SS44

• InductionInductionArsenic tetra-sulfideArsenic tetra-sulfide

ATRA (if no leucocytosis)ATRA (if no leucocytosis)

Chemotherapy if WBC > 4000/uLChemotherapy if WBC > 4000/uL

• Consolidation chemo x 4-6 cyclesConsolidation chemo x 4-6 cycles

• MaintenanceMaintenanceArsenic tetra-sulfide & ATRA x 4 yearsArsenic tetra-sulfide & ATRA x 4 years

Wu, ASH 2007 #591Wu, ASH 2007 #591

Oral Arsenic & ATRAOral Arsenic & ATRA

• Induction ResultsInduction Results68/68 CR68/68 CR

• Post-remission resultsPost-remission results68 new CR + 46 previous CR = 114 patients68 new CR + 46 previous CR = 114 patients

median age 33 (10 - 73)median age 33 (10 - 73)

median FU 36 mo (3 - 76)median FU 36 mo (3 - 76)

4-year DFS 94%4-year DFS 94%

RING B B Coiled-Coil DNA HORMONE

SUMOK160 D522 AF2

11S recruitment 19S association

NLS

As2O3 RA

DEGRADATION DEGRADATION

(SUG-1)K490

Degradation of PML/RARA Degradation of PML/RARA

Zhu PNAS 1997 & 1999, Lallemand JEM 2001Zhu PNAS 1997 & 1999, Lallemand JEM 2001

Lallemand JEM 1999, Rego PNAS 2000Lallemand JEM 1999, Rego PNAS 2000

5

AS

4

3

1

2

40 80 120 160 200 240 280 Days

RA

RA/AS

PCR-

SurvivalTreatment

Mouse Model of APLMouse Model of APLSynergy of ATRA and ArsenicSynergy of ATRA and Arsenic

Prognostic factors in AMLPrognostic factors in AML

• Treatment of AML CR1, age < 60 is risk-Treatment of AML CR1, age < 60 is risk-adapted, by cytogeneticsadapted, by cytogenetics

FavorableFavorable 10%10%

Intermediate risk Intermediate risk 75%75% (50-60% normal cyto)(50-60% normal cyto)

High riskHigh risk 15%15%

• Molecular mutation analysis can better define Molecular mutation analysis can better define prognostic subgroups within the large group prognostic subgroups within the large group of normal cytogeneticsof normal cytogenetics

German AML TrialsGerman AML TrialsRole of NPM and FLT3Role of NPM and FLT3

872 AML normal cyto872 AML normal cyto

NPM1 mut NPM1 mut 53%53%

FLT3-ITD mutFLT3-ITD mut 31%31%

FLT3-TKDFLT3-TKD 11%11%

CEBPACEBPA 14%14%

666 CR1 (76%)666 CR1 (76%)

NPM1+/ITD- prognostic for CR (p < 0.0001)NPM1+/ITD- prognostic for CR (p < 0.0001)

Schlenk, ASH 2006 #4Schlenk, ASH 2006 #4

German AML TrialsGerman AML Trials

666 CR1666 CR1

171 sib donor171 sib donor 495 no donor495 no donor

143 Allo SCT (84%)143 Allo SCT (84%) chemo vs ASCTchemo vs ASCT

German AML TrialsGerman AML TrialsRole of NPM and FLT3Role of NPM and FLT3

ITT analysis of donor vs no donorITT analysis of donor vs no donor

4-year DFS and OS, Median FU 4.1 yrs4-year DFS and OS, Median FU 4.1 yrs

NPM+/FLT3 ITD-NPM+/FLT3 ITD-

DFS 61% (donor) vs 57%, p = NSDFS 61% (donor) vs 57%, p = NS

HR for DFS 0.89, for OS .93HR for DFS 0.89, for OS .93

OthersOthers

DFS 47% (donor) vs 23% ***DFS 47% (donor) vs 23% ***

HR .56 (.39 - .81) for DFS; .69 (.48 - .98) for OSHR .56 (.39 - .81) for DFS; .69 (.48 - .98) for OS

ATRA TrialATRA TrialAML Age > 60AML Age > 60

• German Study Group TrialGerman Study Group Trial

• AML age > 60AML age > 60

• Explore role of ATRA in addition to chemoExplore role of ATRA in addition to chemo

• InductionInduction

Ida, cytarabine, etoposideIda, cytarabine, etoposide

• Consolidation x 1Consolidation x 1

Intermediate dose cytarabineIntermediate dose cytarabine

Schlenk ASH 2007 # 297Schlenk ASH 2007 # 297

ATRA Trial - 2ATRA Trial - 2

• 372 enrolled372 enrolled

Age 67 (61 - 83)Age 67 (61 - 83)

67% de-novo, 33% secondary67% de-novo, 33% secondary

• Standard Risk groupsStandard Risk groups

LowLow 7% 7% APL and inv16qAPL and inv16q

StandardStandard 58%58% normal, non-complexnormal, non-complex

HighHigh 35%35% complex **complex **

ATRA Trial - 3ATRA Trial - 3

• 242 randomized to ATRA vs none242 randomized to ATRA vs none

Randomization stopped for no differenceRandomization stopped for no difference

• 130 others allocated to non-ATRA arm130 others allocated to non-ATRA arm

ATRA Trial ResultsATRA Trial Results

• NPM1+/ITD- is prognostic for CR NPM1+/ITD- is prognostic for CR

HR 2.6 (1.2 - 5.5)HR 2.6 (1.2 - 5.5)

• ITT analysis of randomized patientsITT analysis of randomized patients

Median FU 5.7 yrsMedian FU 5.7 yrs

• 5-year OS5-year OS

NPM1+/ITD-NPM1+/ITD- 57% (ATRA) vs 6%, p= 0.002 ***57% (ATRA) vs 6%, p= 0.002 ***

OthersOthers 2% (ATRA) vs 2% 2% (ATRA) vs 2%

Molecular Subgroups of Molecular Subgroups of AML with normal cytoAML with normal cyto

• NPM1+/ITD- group is less frequent in older AMLNPM1+/ITD- group is less frequent in older AML

• NPM1+/ITD- group is more favorableNPM1+/ITD- group is more favorable

• NPM1+/ITD- group benefits from ATRANPM1+/ITD- group benefits from ATRA

Prednisone + Dasatinib for Ph+ ALLPrednisone + Dasatinib for Ph+ ALLGIMEMA StudyGIMEMA Study

• 1 week pre-phase with prednisone 60 mg/m21 week pre-phase with prednisone 60 mg/m2Continue for 1 monthContinue for 1 month

• Dasatinib 70 mg bid x 12 weeksDasatinib 70 mg bid x 12 weeks

• Patient FeaturesPatient FeaturesMedian age 56 (30 - 73)Median age 56 (30 - 73)

• ResultsResults27/27 CR27/27 CR

With FU of 7 mo, 7/22 completing therapy relapsedWith FU of 7 mo, 7/22 completing therapy relapsed

Foa, ASH 2007 #7Foa, ASH 2007 #7

Post-remission therapyAML CR1, age > 60

Background

• CALGB AML age > 60 with cytogeneticsCALGB AML age > 60 with cytogeneticsn = 600n = 600

CR 50%CR 50%5-year OS 7%5-year OS 7%Cytogenetics predictive of outcomeCytogenetics predictive of outcome

• No signs of progress in chemotherapyNo signs of progress in chemotherapy• New approaches are warrantedNew approaches are warranted

Baer, ASH 2007 #296Baer, ASH 2007 #296

OS by Cytogenetics

OS by Age

AML CR1 age > 60Background - 2

• Results in best group are still poor (n = 276)Results in best group are still poor (n = 276)Age 60-75Age 60-75

Receive first consolidation on randomized trialReceive first consolidation on randomized trial

• 2-year DFS 24%2-year DFS 24%

• 3-year DFS 17%3-year DFS 17%

CALGB 100103CALGB 100103mini-allo for AML CR1, age > 60mini-allo for AML CR1, age > 60

• AML CR1AML CR1

Prior MDS, t-AML allowedPrior MDS, t-AML allowed

• Age 60-74Age 60-74

• Sibling or unrelated donorSibling or unrelated donor

• ObjectiveObjective2-year DFS > 35%2-year DFS > 35%