cco hematology 2010 cml

December 4-7, 2010Orlando, Florida

Chronic Myeloid Leukemia CCO Independent Conference Coverageof the 2010 Annual Meeting of the American Society of Hematology*

This program is supported by educational grants from

*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.

clinicaloptions.com/oncologyChronic Myeloid Leukemia

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Faculty

Jerald Radich, MD Member and ProfessorClinical Research DivisionFred Hutchinson Cancer Research CenterSeattle, Washington


Faculty Disclosures

Jerald Radich, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Novartis, and Pfizer and contracted research support from Novartis.


Overview

Newly Diagnosed Chronic-Phase CML

CV Conditions and Dasatinib or Imatinib in CP-CML

Resistance Mutations and Treatment Response

Novel Therapies

Newly Diagnosed Chronic-Phase CML


DASISION: Randomized Phase III Trial of Dasatinib vs Imatinib in CP-CML

1. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270. 2. Shah N, et al. ASH 2010. Abstract 206.

Patients withpreviously untreatedCP-CML

(N = 519)

Dasatinib 100 mg/day(n = 259)

Imatinib 400 mg/day(n = 260)

5-yr follow-up

Stratified by Hasford risk score

Primary analysis at 14-mo median follow-up: dasatinib efficacy superior to imatinib[1]

Current report includes 18-mo median follow-up data[2]


DASISION: Response Definitions

Confirmed CCyR

– CCyR detected in 2 consecutive assessments

CCyR

– No Ph-positive metaphases in bone marrow

MMR

– BCR-ABL ≤ 0.1%

Shah N, et al. ASH 2010. Abstract 206.


DASISION: Confirmed CCyR Rate (ITT)

100

80

60

40

20

0

Co

nfi

rmed

CC

yR (

%)

By 12 Mos By 18 Mos

P = .0086 P = .0366

77

67

7870

Dasatinib100 mg QD

Imatinib400 mg QD



DASISION: CCyR Rates Over Time (ITT)

By analysis of time to CCyR, likelihood of achieving CCyR 1.5-fold higher with dasatinib vs imatinib (stratified log-rank P < .0001; HR: 1.5)

100

80

40

20

0

CC

yR (

%) 60 54

73

59

78

31

67

83

72

Mo 3 Mo 6 Mo 9 Mo 12

Dasatinib 100 mg QD Imatinib 400 mg QD


Any time

8580


DASISION: MMR Rates Over Time (ITT)

By analysis of time to MMR, likelihood of achieving MMR 1.8-fold higher with dasatinib vs imatinib


P < .0001P = .0002

100

80

40

20

0

MM

R (

%) 60

80.4

39

18

46

28

Mo 3 Mo 6 Mo 9 Mo 12 Any Time

27

8

57

41

Dasatinib 100 mg QD Imatinib 400 mg QD


DASISION: Nonhematologic Drug-Related Adverse EventsNonhematologic Drug-Related Adverse Events,* %



All Grades Grade 3/4 All Grades Grade 3/4

Fluid retention 23 1 43 1

Superficial edema 10 0 36 < 1

Pleural effusion 12 < 1 0 0

Myalgia 22 0 38 1

Nausea 9 0 21 0

Vomiting 5 0 10 0

Diarrhea 18 < 1 19 1

Fatigue 8 < 1 11 0

Headache 12 0 10 0

Rash 11 0 17 1*Occurring in ≥ 10% of patients.



DASISION: Grade 3/4 Myelosuppression

Grade 3/4 Hematologic Event, % Dasatinib(n = 258)

Imatinib(n = 258)

Neutropenia 22 20

Thrombocytopenia 19 10

Anemia 11 7



DASISION: Conclusions

Dasatinib continues to demonstrate superior efficacy compared with imatinib for first-line treatment of CP-CML with 18 mos of follow-up

– More rapid development of response and higher response rates, including CCyR, confirmed CCyR, and MMR

Dasatinib generally well tolerated

– Low rates of grade 3/4 hematologic toxicity

On October 28, 2010, the FDA granted accelerated approval to dasatinib for the treatment of adult patients with newly diagnosed Ph-positive CP-CML



Patients newly diagnosed with

Ph-positive CP-CMLwithin 6 mos

(N = 846)

Nilotinib 300 mg BID(n = 282)


Imatinib 400 mg QD(n = 283)

5-yr follow-up

Stratified by Sokal risk score

1. Saglio G, et al. N Engl J Med. 2010;362:2251-2259. 2. Hughes TP, et al. ASH 2010. Abstract 207.

ENESTnd: Randomized Phase III Trial of Imatinib vs Nilotinib in Ph-Positive CP-CML

Primary analysis: nilotinib efficacy superior to imatinib[1]

Current report includes minimum 24-mo follow-up data[2]


100

80

60

40

20

0

MM

R (

%)

At 12 Mos At 24 Mos

ENESTnd: MMR Rates at 12 and 24 Mos

44 43

22

P < .0001

P < .0001

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

P < .0001

P < .0001

62 59

37

Hughes TP, et al. ASH 2010. Abstract 207.


ENESTnd: Cumulative MMR Incidence

Nilotinib 300 mg BID (n = 282)


100

80

60

40

20

0

Pat

ien

ts W

ith

MM

R (

%)

0

90

70

50

30

10

Nilotinib 400 mg BID (n = 281)Imatinib 400 mg QD (n = 283)

3 6 9 12 15 18 21 24 27 30 33

27%

44%51%; P < .0001

67%; P < .0001

71%; P < .0001

55%; P < .0001

By 12 Mos

By 24 Mos

Mos


ENESTnd: CCyR Rates by 24 Mos and OS

Nilotinib 300 mg BID


Imatinib 400 mg QD

n = 282 n = 281 n = 283

100

80

60

40

20

0


P = .0018

P = .016

87 85

77

CC

yR (

%)

Estimated 24-Mo OS, %

97.4

97.8

96.3


ENESTnd: Nonhematologic Drug-Related Adverse EventsNonhematologic Drug-Related Adverse Events, %



Imatinib 400 mg QD(n = 280)

All Grades

Grade 3/4

All Grades

Grade 3/4

All Grades

Grade 3/4

Nausea 14 < 1 21 1 34 0

Diarrhea 8 < 1 7 0 26 1

Vomiting 5 0 9 1 18 0

Peripheral edema 5 0 6 0 15 0

Facial edema < 1 0 2 0 11 < 1

Eyelid edema < 1 0 2 < 1 16 < 1

Periorbital edema < 1 0 1 0 14 0

Muscle spasms 8 0 7 < 1 27 < 1

Rash 32 < 1 37 3 13 2

Headache 14 1 22 1 9 < 1Hughes TP, et al. ASH 2010. Abstract 207.


ENESTnd: Grade 3/4 Myelosuppression

Grade 3/4 Hematologic Event, %


(n = 279)


(n = 277)

Imatinib 400 mg QD

(n = 280)

Neutropenia 12 11 21

Thrombocytopenia 10 12 9

Anemia 4 4 5



ENESTnd: Conclusions

Longer follow-up of ENESTnd trial continues to show superior rates of MMR, CCyR, and CMR with nilotinib 300 mg BID or 400 mg BID vs imatinib 400 mg QD in newly diagnosed Ph-positive CP-CML

– Lower suboptimal response and treatment failure rates with nilotinib vs imatinib

– Nilotinib generally well tolerated at both doses, grade 3/4 adverse events similar to imatinib

On June 17, 2010, the FDA approved nilotinib for the treatment of adult patients with newly diagnosed Ph-positive CP-CML



S0325: Phase II Study of Frontline Dasatinib vs Imatinib in CP-CML

Radich JP, et al. ASH 2010. Abstract LBA-6.


(N = 246)





S0325: Response and Survival Outcomes

Outcome Dasatinib 100 mg QD

(n = 123)

Imatinib 400 mg QD

(n = 123)

P Value

MMR at 12 mos

Median log reduction 3.3 2.8 .048

> 3 log reduction, % 59 43 .042

> 4 log reduction, % 27 20 .31

> 4.5 log reduction, % 21 14 .26

CHR within 12 mos, % 86 90 .25

CCyR within 12 mos, % 82 69 .097

OS at 12 mos, % 100 99 .65

PFS at 12 mos, % 99 96 .20



S0325: Adverse Events


Adverse Events, n Dasatinib 100 mg QD (n = 122) Imatinib 400 mg QD (n = 123)

All Grades Grade 3/4 All Grades Grade 3/4

Fluid retention Edema (any) Pleural effusion

2414

12

59 2

31

Diarrhea 41 6 49 2

Nausea 32 0 59 0

Vomiting 19 1 23 0

Muscle pain 12 0 44 1

Rash 40 0 34 2

Headache 34 3 19 2

Fatigue 61 1 63 1

Prolonged QTc 2 1 1 0

Thrombocytopenia 70 22 40 10


S0325: Phase II Frontline Dasatinib vs Imatinib in CP-CML: Conclusions Dasatinib associated with deeper molecular response vs

imatinib at 12 mos

– Greater median log reduction in BCR-ABL

– Similar rates of > 4 and > 4.5 log reduction

No significant differences in CHR, CCyR, OS, or PFS between treatment groups

Some adverse events more common with dasatinib

– Higher rate of thrombocytopenia, including grade 3/4

– Higher rate of pleural effusion



Meta-analysis: Frontline Imatinib vs Dasatinib vs Nilotinib for CML Bayesian mixed comparison meta-analysis to assess relative

efficacy of BCR-ABL inhibitors across randomized clinical trials of patients with previously untreated CP-CML[1]

– Imatinib 400 mg QD

– Dasatinib 100 mg QD

– Nilotinib 300 mg BID

– Nilotinib 400 mg BID

After systemic review, data from 3 published studies used to construct evidence network for CCyR at 6 mos, CCyR at 12 mos, and MMR at 12 mos[2-4]

1. Mealing S, et al. ASH 2010. Abstract 3436. 2. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270. 3. Saglio G, et al. N Engl J Med. 2010;362:2251-2259. 4. Baccarani M, et al. Blood. 2009;113:4497-4504.


Meta-Analysis: Frontline Imatinib vs Dasatinib vs Nilotinib for CML CCyR at 6 and 12 mos and MMR at 12 mos

– Superior with dasatinib 100 mg QD vs imatinib 400 mg QD (P < .05)

– Superior with nilotinib 300 mg BID vs imatinib 400 mg QD (P < .05)

– Dasatinib similar to nilotinib by indirect comparison

Mealing S, et al. ASH 2010. Abstract 3436.


Meta-Analysis of Imatinib vs Dasatinib vs Nilotinib: Relative CCyR at 12 MosOR (95% CrI)*

Imatinib 400 mg QD

Dasatinib 100 mg QD



Imatinib 400 mg QD

-- 0.51 (0.33-0.76) 0.47 (0.31-0.67) 0.53 (0.36-0.76)

Dasatinib 100 mg QD

2.06 (1.31-3.06) -- 0.96 (0.52-1.63) 1.10 (0.60-1.85)


2.22 (1.49-3.21) 1.13 (0.61-1.93) -- 1.17 (0.76-1.71)


1.94 (1.31-2.78) 0.99 (0.54-1.67) 0.89 (0.58-1.31) --


*Results describe the posterior distributions arising from the meta-analysis of all individual trials; thus, the point estimates should not be interpreted alone but in combination with the CrIs. Pooled information for the baseline intervention (imatinib) was used in analysis, hence derived mean values will be slightly different to results from individual trials. Higher response rates observed among imatinib-treated patients in the DASISION study may have biased the ORs towards the null for the dasatinib 100 mg QD analysis.


Meta-analysis of Frontline Imatinib vs Dasatinib vs Nilotinib for CML: Summary Data suggest CCyR and MMR rates significantly higher

with dasatinib or nilotinib vs imatinib for frontline CP-CML treatment

Relative efficacy of dasatinib and nilotinib similar

– Insufficient data at present to distinguish between these agents by indirect comparison

Analysis limited by few published studies involving newer agents in frontline setting

Available data not sufficient for meta-analysis of PFS, OS, response rates at additional time points, and other outcomes (safety and efficacy)



Randomized Phase III Trial of Bosutinib vs Imatinib in CP-CML

Gambacorti-Passerini C, et al. ASH 2010. Abstract 208.


(N = 502)

Bosutinib 500 mg/day(n = 250)


5-yr follow-up

Stratified by Sokal risk score and geographic region

Primary endpoint: CCyR rate at 12 months


Bosutinib vs Imatinib: CCyR (Primary Endpoint) and MMR at 12 Mos (ITT)


100

80

60

40

20

0

Res

po

nse

(%

)

CCyR MMR

P = .601

P = .002

70 68

39

26

Bosutinib 500 mg QD

Imatinib 400 mg QD


Bosutinib vs Imatinib: Time to CCyR Up to 48 Wks (ITT)


100

80

60

40

20

0

Cu

mu

lati

ve P

rob

abil

ity

of

Res

po

nse

(%

)

Time to Response (Wks)

10

30

50

70

90

0 12 24 36 48

Median Time to CCyR (95% CI)Bosutinib: 12.9 wks (12.6-13.4)Imatinib: 24.6 wks (24.3-25.6)

P < .0001


Bosutinib vs Imatinib: OS Up to 48 Wks (ITT)


100

95

0

Pro

bab

ilit

y o

f O

S (

%)

Time to Death (Wks)

80

85

90

0 12 24 36

Median OS (95% CI)Bosutinib: NAImatinib: NA

P = .117

48


Bosutinib vs Imatinib: Nonhematologic Adverse EventsNonhematologic Adverse Events,%

Bosutinib 500 mg QD (n = 248) Imatinib 400 mg QD (n = 251) Overall P ValueAll Grades Grade 3/4 All Grades Grade 3/4

Diarrhea 68 10 21 1 < .001

Vomiting 32 3 13 0 < .001

Nausea 31 1 35 0 NS

Rash 20 1 15 1 NS

Pyrexia 16 1 9 1 .022

Upper abdominal pain 12 0 5 0 .007

Abdominal pain 12 1 5 0 .005

Fatigue 11 1 12 1 NS

Headache 10 1 8 0 NS

Upper respir. infection 10 0 6 0 NS

Bone pain 4 0 10 1 .004



Bosutinib vs Imatinib: Grade ≥ 3 MyelosuppressionGrade ≥ 3 Hematologic Event, %

Bosutinib 500 mg QD

(n = 248)

Imatinib 400 mg QD

(n = 251)

Thrombocytopenia 12.5 13.1

Neutropenia 8.9 22.7

Anemia 6.0 6.4



Bosutinib vs Imatinib: Conclusions

Higher MMR rate but similar CCyR rate at 12 mos with bosutinib vs imatinib in ITT analysis

Incidence of adverse events, particularly GI events, higher with bosutinib vs imatinib

– Rates of discontinuation caused by adverse events:

– Bosutinib : 19%

– Imatinib: 5%



Dasatinib-Induced Lymphocytosis

In patients with advanced leukemia, increased number of blood lymphocytes associated with

– Very good therapeutic responses

– Autoimmune-related adverse effects

Lymphocytosis following dasatinib dosing recently observed in CML[1-3]

– Result of clonal expansion of preexisting, diagnostic-phase cytotoxic memory cells[4]

1. Mustjoki S, et al. Leukemia. 2009;23:1398-1405. 2. Kim DH, et al. Haematologica. 2009;94:135-139. 3. Valent JN, et al. Leuk Res. 2010;[Epub ahead of print]. 4. Kreutzman A, et al. Blood. 2010;116:772-782.


PK, Cellular, and Molecular Study of Dasatinib-Induced Lymphocytosis Patients with Ph-positive leukemia (N = 23), including CML and acute

lymphoblastic leukemia

Drug treatments (as first-line or second-line therapy)

– Dasatinib 50-100 mg/day: n = 17

– Imatinib 400 mg: n = 2

Blood samples before and 1, 2, 4, and 6-12 hrs after single oral dose

– Plasma dasatinib concentrations by LC/tandem MS

– Lymphocyte immunophenotyping and TCR V-beta expression by FC

– Differential gene expression by oligonucleotide microarray

– Plasma cytokine levels by multiplex bead assay

Mustjoki S, et al. ASH 2010. Abstract 1204.

– Nilotinib 300 mg: n = 2

– Bosutinib 500 mg: n = 2


Rapid Mobilization of Blood Leukocytes After Oral Dasatinib Intake Greatest mobilization in lymphocytes and monocytes with median fold changes from baseline to 1 hr

– Lymphocytes: 2.15 (range: 1.05-5.12; P < .0001)

– Monocytes: 1.64 (range: 0.95-3.25; P = .0026)

Close correlation between lymphocyte count and plasma dasatinib level


No marked changes in blood leukocytes after imatinib, nilotinib, or bosutinib intake

16

Leukocyte Count

109/L

12

8

4

0

Dasatinib 100 mg Dasatinib 100 mg

0 4 8 1216 20 0 4 8 12162024hours

1010

9/L

864

02

0.001

0.01

0.1

µM

Hrs After Dasatinib Intake0 6 1218 0 6 12 18 0

Lymphocyte countDasatinib concentration


Dasatinib-Induced Lymphocytosis: Summary Rapid mobilization of cytotoxic lymphocytes after oral

dasatinib intake detected in patients with Ph-positive leukemia

– Lymphocyte kinetics correlated with plasma dasatinib concentration

– Similar lymphocyte responses not observed after treatment with other tyrosine kinase inhibitors

Dasatinib-induced lymphocytosis a possible mechanism driving potent therapeutic responses and autoimmune adverse effects such as colitis and pleural effusions


CV Conditions and Dasatinib or Imatinib in CP-CML


Impact of Baseline CV Conditions on Dasatinib or Imatinib Therapy in DASISION

Retrospective analysis of 12-mo data: patients in each arm assessed based on presence/absence of baseline CV conditions

CV conditions permitted: HTN, MI > 6 mos before tx, uncontrolled angina and/or CHF > 3 mos before tx, unstable angina, left ventricular dysfunction, CAD, PAD, TIA, stroke, QTc interval ≤ 450 msec

Saglio G, et al. ASH 2010. Abstract 2286.

Patients withpreviously untreated

CP-CML

(N = 519)



5-yr follow-up



Response Rates Similar With vs Without Baseline CV Condition in DASISION


Outcome

Dasatinib (n = 259) Imatinib (n = 260)

No CVCondition(n = 216)

Any CVCondition

(n = 43)


Any CVCondition

(n = 42)

CCyR at Mo 12, % 83 86 71 76

MMR at Mo 12, % 43 63 28 26

Median time to response, wks

CCyR 13 13 24 25

MMR 27 25 39 39


Differences in AE Rates With vs Without Baseline CV Condition in DASISION


Adverse Event, % Dasatinib Imatinib


Any CVCondition

(n = 43)


Any CVCondition

(n = 42)

Nonhematologic events, all grades

Fluid retention 16 35 39 57

• Superficial edema 7 16 33 48

• Pleural effusion* 7 23 0 0 Nausea/vomiting 11 12 22 31 Diarrhea 18 14 16 26 Rash 11 12 16 21 Myalgia/arthralgia 11 9 18 14 Fatigue 8 7 9 12 Cardiac 5 7 2 10

Hematologic events, grade 3/4

Neutropenia 24 5 21 17 Thrombocytopenia 21 9 11 10*No grade 3/4 events.


Impact of Baseline CV Conditions on Dasatinib or Imatinib Therapy: Summary Retrospective analysis of DASISION study suggests that

in patients with CP-CML, baseline CV conditions appear to have no substantial impact on

– Incidence of adverse events

– CCyR rates

– MMR rates


Resistance Mutations and Treatment Response


Low-Level Dasatinib or Nilotinib Resistance After Imatinib Failure Direct sequencing may not detect low-level dasatinib or nilotinib

resistance mutations after imatinib failure

High-throughput, chip-based, mass spec assay used to investigate prevalence and impact of low-level resistance after imatinib failure

– N = 222 (CP: n = 102; AP: n = 64; BC: n = 56)

– Subsequent therapy: nilotinib (n = 91) or dasatinib (n = 131)

– Retrospective assessment of BCR-ABL sequence before dasatinib or nilotinib therapy (baseline)

– Patients with dasatinib/nilotinib resistance mutations: 23% by direct sequencing vs 32% by mass spec

Parker WT, et al. ASH 2010. Abstract 891.


Low-Level Dasatinib/Nilotinib Resistance Detection Predicts Expansion During Tx Mass spec method identified 50 low-level dasatinib/nilotinib resistance mutations not observed by direct

sequencing

– Expansion of 84% of resistant mutations vs 12% of sensitive mutations during subsequent therapy ( P < .0001)


Emerged by Direct Sequencing During Therapy, % (n/N)

Detected Only by Mass Spec at BL

T315I(n = 12)

Nilotinib Resistant(n = 28)

Dasatinib Resistant(n = 10)

Nilotinib therapy 100 (3/3) 89 (8/9) 17 (1/6)

Dasatinib therapy 89 (8/9) 11 (2/19) 50 (2/4) T315I detected by direct sequencing during dasatinib/nilotinib

therapy in 25 additional patients without baseline evidence by either method


Impact of Baseline Dasatinib/Nilotinib Resistance on CCyR

Identification of multiple mutations (n = 60) at baseline by mass spec associated with significantly lower CCyR probability by 18 mos vs ≤ 1 baseline mutation (n = 162) (P < .0001)

– ~ 50% of patients harbored resistant mutations


CCyR According to Baseline Mutations

Mutations n Sequencing CCyR, % P Value

Dasatinib/nilotinib resistant 26 Direct 0

< .0001Dasatinib/nilotinib resistant 19 Mass spec only 16

Other 95 Direct and/or mass spec 41

None 82 Direct and/or mass spec 43


Impact of Nonresistant Mutations at Baseline on CCyR CCyR by 18 mos of dasatinib/nilotinib treatment according

to nonresistant mutations at baseline by mass spec

– ≤ 1 mutation (n = 143): 67%

– Multiple mutations (n = 34): 14%

Incidence of new resistant mutations by Mo 24 of dasatinib/nilotinib therapy according to nonresistant mutations at baseline by mass spec

– ≤ 1 mutation (n = 143): 34%

– Multiple mutations (n = 34): 67%


P = .0002

P = .0006


Low-Level Dasatinib/Nilotinib Resistance After Imatinib Failure: Summary Low-level dasatinib or nilotinib resistance detection

predicts expansion of resistant populations during subsequent dasatinib or nilotinib treatment, respectively

CCyR rates to subsequent dasatinib or nilotinib therapy lower in patients with low-level resistance vs no resistant mutations

Presence of multiple nonresistant mutations associated with lower CCyR rate to subsequent dasatinib or nilotinib therapy vs ≤ 1 nonresistant mutation



Efficacy of Second-line Dasatinib in CP-CML With ≥ 2 BCR-ABL Mutations Retrospective analysis of 3 trials of second-line dasatinib [1]

– Phase II START-C conducted in patients with resistance/ intolerance to imatinib[2]

– Phase II START-R conducted in patients with imatinib resistance[3]

– Phase III CA180-034 dose-optimization trial conducted in patients with resistance, suboptimal response, or intolerance to imatinib[4,5]

Standard sequencing used to detect BCR-ABL mutations (sensitivity: 10% to 20%) after BCR-ABL–specific RT-PCR amplification

– Analysis excluded BCR-ABL polymorphisms

1. Quintás-Cardama A, et al. ASH 2010. Abstract 2297. 2. Hochhaus A, et al. Leukemia. 2008;22:1200-1206. 3. Kantarjian H, et al. Cancer. 2009;115:4136-4147. 4. Shah NP, et al. J Clin Oncol. 2008;26:3204-3212. 6. Shah NP, et al. Haematologica. 2010;95:232-240.


Response to Second-line Dasatinib According to Baseline BCR-ABL Mutations

Quintás-Cardama A, et al. ASH 2010. Abstract 2297.

Outcome at 2 Yrs, %

No Baseline Mutations(n = 641)

Any Baseline Mutation(n = 402)

1 Baseline Mutation(n = 332)

≥ 2 Baseline Mutations

(n = 70)

Best response*

MCyR 65 56 56 52

CCyR 56 43 45 36*Ph-negative patients from study 034 excluded.


Survival Following Second-line Dasatinib According to Baseline BCR-ABL Mutations


*Survival data from START-R unavailable and not included in analysis.

PFS OS*

100

No

t P

rog

ress

ed (

%)

40

0

20

60

80

0 3 6 9 12 15 18 21 24 27 30 33

Mos

Without baseline mutation (n = 641)With baseline mutation (n = 402)With 1 baseline mutation (n = 332)With > 1 baseline mutation (n = 70)

100

Ali

ve (

%)

40

0

20

60

80

0 3 6 9 12 15 18 21 24 27 30 33

Mos

Without baseline mutation (n = 589)With baseline mutation (n = 361)With 1 baseline mutation (n = 299)With > 1 baseline mutation (n = 62)


2-Yr PFS With Second-line Dasatinib by Baseline Mutations and Response at 1 Yr


Response at 1 Yr

2-Yr PFS,* %

No Baseline Mutations(n = 420)

Any Baseline Mutation(n = 239)

1 Baseline Mutation(n = 199)

≥ 2 Baseline Mutations

(n = 40)

CCyR 97 93 92 100

PCyR 94 87 88 75

Other 75 73 80 42

*Only patients with cytogenetic response assessment available at 12 mos included in analysis.


Second-line Dasatinib in CP-CML With ≥ 2 BCR-ABL Mutations: Summary Second-line dasatinib demonstrated efficacy in patients with CP-CML

with or without baseline BCR-ABL kinase domain mutations

However, lower 2-yr response and PFS rates observed among patients with ≥ 2 vs 0-1 baseline mutations

Reduced 2-yr PFS rates in the presence of ≥ 2 vs 0-1 baseline mutations among patients with PR or worse at 1 yr

– Similar 2-yr PFS rates across all mutation groups among patients with CCyR at 1 yr

Preliminary data suggest that outcomes may vary depending on specific mutation clusters observed in patients with ≥ 2 mutations

– Larger population needed to better explore this possibility



Summary

Dasatinib and nilotinib continue to demonstrate superior efficacy vs imatinib for first-line CP-CML in DASISION, ENESTnd trials and in meta-analysis; no major impact of baseline CV conditions on outcomes in DASISION

Higher 12-mos MMR rate but similar CCyR rate with bosutinib vs imatinib in first-line CP-CML treatment; AE incidence higher with bosutinib vs imatinib

Low-level dasatinib or nilotinib resistance detected by MS after imatinib failure predicts expansion of resistant populations during subsequent dasatinib or nilotinib treatment and is associated with lower likelihood of response

Rapid mobilization of cytotoxic lymphocytes after oral dasatinib intake, but not other TKIs, detected in patients with Ph+ leukemia

Second-line dasatinib effective in CP-CML with or without baseline BCR-ABL kinase domain mutations; however, efficacy lower among patients with ≥ 2 vs 0-1 mutations

Phase II S0325 study demonstrates frontline dasatinib associated with deeper molecular response vs imatinib at 12 mos in CP-CML

Novel Therapies


Enhancement of CML Stem Cell Elimination With Nilotinib + Hh Inhibitor Hh pathway activated, SMO upregulated in BCR-ABL+ leukemia SCs

– May play role in progenitor cell maintenance

LDE225

– Small molecule antagonist of SMO that inhibits Hh activity

LDE225 + nilotinib inhibited self-renewing CML SCs in mice

– In vitro tx of human CML cells reduced engraftment in NSG mice

– In vivo tx of mice transplanted with BM from BCR-ABL transgenic mice

– Reduced leukemic cell numbers in spleen and blood but not BM

– Reduced long-term HSC, and granulocyte-macrophage and common myeloid progenitor cells in spleen but not BM

– Was associated with increased survival after tx discontinuation

Zhang B, et al. ASH 2010. Abstract 514.

Go Online for More CCO Coverage of Hematology Data

From Orlando!Capsule Summaries of all the key data

Expert Analysis panel discussions exploring the clinical implications of new data

Downloadable PowerPoint slides

clinicaloptions.com/oncology

http://www.clinicaloptions.com/oncology

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