CCO Hematology 2010 CML

Chronic Myeloid Leukemia
CCO Independent Conference Coverage

of the 2010 Annual Meeting of the American Society of Hematology*
December 4-7, 2010 Orlando, Florida
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This program is supported by educational grants from

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Faculty
Jerald Radich, MD
Member and Professor Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, 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

Stratified by Hasford risk score
Patients with previously untreated CP-CML (N = 519)
Dasatinib 100 mg/day (n = 259)

5-yr follow-up
Imatinib 400 mg/day (n = 260)
Primary analysis at 14-mo median follow-up: dasatinib efficacy superior to imatinib[1] Current report includes 18-mo median follow-up data[2]
1. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270. 2. Shah N, et al. ASH 2010. Abstract 206.

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
P = .0086
P = .0366
Confirmed CCyR (%)
77 67
78 70
Dasatinib 100 mg QD Imatinib 400 mg QD
60
40 20
0 By 12 Mos
By 18 Mos

DASISION: CCyR Rates Over Time (ITT)

100 Dasatinib 100 mg QD Imatinib 400 mg QD 78 67 CCyR (%) 60 54 59 83 72 85 80
80
73
40
31
20
Mo 3
Mo 6
Mo 9
Mo 12
Any time
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)

DASISION: MMR Rates Over Time (ITT)

100 Dasatinib 100 mg QD Imatinib 400 mg QD P = .0002 80
P < .0001
MMR (%)
60
57
46
40 39
41 28
27
20 8 0 0.4 8 18
Mo 3
Mo 6
Mo 9
Mo 12
Any Time
By analysis of time to MMR, likelihood of achieving MMR 1.8-fold higher with dasatinib vs imatinib

DASISION: Nonhematologic Drug-Related Adverse Events

Nonhematologic DrugRelated Adverse Events,* % Dasatinib 100 mg/day (n = 258) All Grades Grade 3/4 Imatinib 400 mg/day (n = 258) All Grades Grade 3/4
Fluid retention
Superficial edema Pleural effusion Myalgia Nausea
23
10 12 22 9
1
0 <1 0 0
43
36 0 38 21
1
<1 0 1 0
Vomiting
Diarrhea Fatigue Headache Rash
*Occurring in 10% of patients. Shah N, et al. ASH 2010. Abstract 206.
5
18 8 12 11
0
<1 <1 0 0
10
19 11 10 17
0
1 0 0 1

DASISION: Grade 3/4 Myelosuppression

Grade 3/4 Hematologic Event, % Neutropenia Thrombocytopenia Anemia Dasatinib (n = 258) 22 19 11 Imatinib (n = 258) 20 10 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

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

Stratified by Sokal risk score
Nilotinib 300 mg BID (n = 282) Patients newly diagnosed with Ph-positive CP-CML within 6 mos (N = 846) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283)
5-yr follow-up
Primary analysis: nilotinib efficacy superior to imatinib[1] Current report includes minimum 24-mo follow-up data[2]
1. Saglio G, et al. N Engl J Med. 2010;362:2251-2259. 2. Hughes TP, et al. ASH 2010. Abstract 207.

ENESTnd: MMR Rates at 12 and 24 Mos

100 80 P < .0001 MMR (%) 60 44 40 22 20 P < .0001 43 37 62 Nilotinib 300 mg BID Nilotinib 400 mg BID
Imatinib 400 mg QD
P < .0001 P < .0001 59
0 At 12 Mos
Hughes TP, et al. ASH 2010. Abstract 207.
At 24 Mos

ENESTnd: Cumulative MMR Incidence

100 90 Patients With MMR (%) 80 Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) By 12 Mos 55%; P < .0001 67%; P < .0001 51%; P < .0001
By 24 Mos 71%; P < .0001
70
60 50
40 30
20 10 27%
44%
0
0 3 6 9 12 15 18 Mos 21 24 27 30 33

ENESTnd: CCyR Rates by 24 Mos and OS

P = .0018 P = .016 100 87 85 77 Estimated 24-Mo OS, % Nilotinib 300 mg BID CCyR (%) 60 Nilotinib 400 mg BID Imatinib 400 mg QD 97.4
80
97.8
96.3
40
20
0
n = 282 n = 281 n = 283

ENESTnd: Nonhematologic Drug-Related Adverse Events

Nonhematologic Drug-Related Adverse Events, % Nilotinib 300 mg BID (n = 279) All Grades Grade 3/4 Nilotinib 400 mg BID (n = 277) All Grades Grade 3/4 Imatinib 400 mg QD (n = 280) All Grades Grade 3/4
Nausea
Diarrhea Vomiting Peripheral edema Facial edema
14
8 5 5 <1
<1
<1 0 0 0
21
7 9 6 2
1
0 1 0 0
34
26 18 15 11
0
1 0 0 <1
Eyelid edema
Periorbital edema Muscle spasms Rash Headache
<1
<1 8 32 14
0
0 0 <1 1
2
1 7 37 22
<1
0 <1 3 1
16
14 27 13 9
<1
0 <1 2 <1

ENESTnd: Grade 3/4 Myelosuppression

Grade 3/4 Hematologic Event, % Neutropenia Nilotinib 300 mg BID (n = 279) 12 Nilotinib 400 mg BID (n = 277) 11 Imatinib 400 mg QD (n = 280) 21
Thrombocytopenia
Anemia
10
4
12
4
9
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 Phpositive CP-CML

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

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

S0325: Response and Survival Outcomes

Outcome Dasatinib 100 mg QD (n = 123) 3.3 59 27 21 86 Imatinib 400 mg QD (n = 123) 2.8 43 20 14 90 P Value
MMR at 12 mos Median log reduction > 3 log reduction, % > 4 log reduction, % > 4.5 log reduction, % CHR within 12 mos, % .048 .042 .31 .26 .25
CCyR within 12 mos, %

OS at 12 mos, % PFS at 12 mos, %
82
100 99
69
99 96
.097
.65 .20

S0325: Adverse Events

Adverse Events, n Fluid retention Edema (any) Pleural effusion Diarrhea Nausea Vomiting Muscle pain Dasatinib 100 mg QD (n = 122) All Grades 24 14 41 32 19 12 Grade 3/4 1 2 6 0 1 0 Imatinib 400 mg QD (n = 123) All Grades 59 2 49 59 23 44 Grade 3/4 3 1 2 0 0 1
Rash
Headache Fatigue Prolonged QTc Thrombocytopenia
40
34 61 2 70
0
3 1 1 22
34
19 63 1 40
2
2 1 0 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 Mos

OR (95% CrI)* Imatinib 400 mg QD Dasatinib 100 mg QD Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD -2.06 (1.31-3.06) 2.22 (1.49-3.21) 1.94 (1.31-2.78) Dasatinib 100 mg QD 0.51 (0.33-0.76) -1.13 (0.61-1.93) 0.99 (0.54-1.67) Nilotinib 300 mg BID 0.47 (0.31-0.67) 0.96 (0.52-1.63) -0.89 (0.58-1.31) Nilotinib 400 mg BID 0.53 (0.36-0.76) 1.10 (0.60-1.85) 1.17 (0.76-1.71) --
*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

Stratified by Sokal risk score and geographic region
Bosutinib 500 mg/day (n = 250)

5-yr follow-up
Primary endpoint: CCyR rate at 12 months

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

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

100
80 Response (%) 60 40 20 0 CCyR
P = .601 70
Bosutinib 500 mg QD Imatinib 400 mg QD
68 P = .002 39 26
MMR

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

100 90 80 70 60 50 40 30 20 10
0 0 12 24 36 Time to Response (Wks) 48 Cumulative Probability of Response (%)
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
Probability of OS (%) 95 90
85
80 0 0 12
Median OS (95% CI) Bosutinib: NA Imatinib: NA
P = .117
24 36 Time to Death (Wks)
48

Bosutinib vs Imatinib: Nonhematologic Adverse Events

Nonhematologic Adverse Events,% Diarrhea Vomiting Bosutinib 500 mg QD (n = 248) All Grades 68 32 Grade 3/4 10 3 Imatinib 400 mg QD (n = 251) All Grades 21 13 Grade 3/4 1 0 Overall P Value < .001 < .001
Nausea
Rash Pyrexia Upper abdominal pain Abdominal pain Fatigue Headache Upper respir. infection Bone pain
31
20 16 12 12 11 10 10 4
1
1 1 0 1 1 1 0 0
35
15 9 5 5 12 8 6 10
0
1 1 0 0 1 0 0 1
NS
NS .022 .007 .005 NS NS NS .004

Bosutinib vs Imatinib: Grade 3 Myelosuppression

Grade 3 Hematologic Event, % Thrombocytopenia Bosutinib 500 mg QD (n = 248) 12.5 Imatinib 400 mg QD (n = 251) 13.1
Neutropenia
Anemia
8.9
6.0
22.7
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 Nilotinib 300 mg: n = 2 Bosutinib 500 mg: n = 2
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.

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

Leukocyte Count 16 12 109/L 8 4 0
0 4 8 1216 20 0 4 8 12 16 2024hours
Lymphocyte count Dasatinib concentration 10 8 6 4 2 0 0.1 M 0.01 0.001 0 6 12 18 0 6 12 18 0 Hrs After Dasatinib Intake
Dasatinib 100 mg Dasatinib 100 mg
No marked changes in blood leukocytes after imatinib, nilotinib, or bosutinib intake
109/L

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


5-yr follow-up
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.

Response Rates Similar With vs Without Baseline CV Condition in DASISION

Dasatinib (n = 259) Outcome No CV Condition (n = 216) Any CV Condition (n = 43) Imatinib (n = 260) No CV Condition (n = 218) 71 28 Any CV Condition (n = 42) 76 26
CCyR at Mo 12, %
MMR at Mo 12, % Median time to response, wks CCyR MMR
83
43
86
63
13 27
13 25
24 39
25 39

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

Adverse Event, % Dasatinib No CV Any CV Condition Condition (n = 215) (n = 43) 16 7 7 11 18 11 11 8 5 24 21 35 16 23 12 14 12 9 7 7 5 9 Imatinib No CV Condition (n = 216) 39 33 0 22 16 16 18 9 2 21 11 Any CV Condition (n = 42) 57 48 0 31 26 21 14 12 10 17 10
Nonhematologic events, all grades Fluid retention Superficial edema Pleural effusion* Nausea/vomiting Diarrhea Rash Myalgia/arthralgia Fatigue Cardiac Hematologic events, grade 3/4 Neutropenia Thrombocytopenia
*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) Nilotinib therapy Detected Only by Mass Spec at BL T315I (n = 12) 100 (3/3) Nilotinib Resistant (n = 28) 89 (8/9) Dasatinib Resistant (n = 10) 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

CCyR According to Baseline Mutations
Mutations Dasatinib/nilotinib resistant Dasatinib/nilotinib resistant Other None n 26 19 95 82 Sequencing Direct Mass spec only Direct and/or mass spec Direct and/or mass spec CCyR, % 0 16 41 43 < .0001 P Value
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

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% P = .0002
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 = .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 CPCML 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-ABLspecific RT-PCR amplification
Analysis excluded BCR-ABL polymorphisms
1. Quints-Cardama A, et al. ASH 2010. Abstract 2297. 2. Hochhaus A, et al. Leukemia. 2008;22:12001206. 3. Kantarjian H, et al. Cancer. 2009;115:4136-4147. 4. Shah NP, et al. J Clin Oncol. 2008;26:32043212. 6. Shah NP, et al. Haematologica. 2010;95:232-240.

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

Outcome at 2 Yrs, % Best response* No Baseline Mutations (n = 641) Any Baseline Mutation (n = 402) 1 Baseline Mutation (n = 332) 2 Baseline Mutations (n = 70)
MCyR
CCyR
65
56
56
43
56
45
52
36
*Ph-negative patients from study 034 excluded.
Quints-Cardama A, et al. ASH 2010. Abstract 2297.

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

PFS
100 Not Progressed (%) 80 100 80 Alive (%)
OS*
60
40 20 0 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)
60
40 20 0 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)
*Survival data from START-R unavailable and not included in analysis.

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

Response at 1 Yr No Baseline Mutations (n = 420) 97 94 75 2-Yr PFS,* % Any Baseline 1 Baseline Mutation Mutation (n = 239) (n = 199) 93 92 87 88 73 80 2 Baseline Mutations (n = 40) 100 75 42
CCyR PCyR Other
*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.
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Chronic Myeloid Leukemia

CCO Independent Conference Coverage

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Chronic Myeloid Leukemia

About These Slides

Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

Newly Diagnosed Chronic-Phase CML

Chronic Myeloid Leukemia

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

Patients with previously untreated CP-CML (N = 519)

Dasatinib 100 mg/day (n = 259)

Imatinib 400 mg/day (n = 260)

Chronic Myeloid Leukemia

DASISION: Response Definitions

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

Chronic Myeloid Leukemia

DASISION: Confirmed CCyR Rate (ITT)

Confirmed CCyR (%)

Dasatinib 100 mg QD Imatinib 400 mg QD

Chronic Myeloid Leukemia

DASISION: CCyR Rates Over Time (ITT)

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

Chronic Myeloid Leukemia

DASISION: MMR Rates Over Time (ITT)

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

Chronic Myeloid Leukemia

DASISION: Nonhematologic Drug-Related Adverse Events

Chronic Myeloid Leukemia

DASISION: Grade 3/4 Myelosuppression

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

Chronic Myeloid Leukemia

Dasatinib generally well tolerated

Chronic Myeloid Leukemia

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

Chronic Myeloid Leukemia

ENESTnd: MMR Rates at 12 and 24 Mos

P < .0001 P < .0001 59

Chronic Myeloid Leukemia

ENESTnd: Cumulative MMR Incidence

By 24 Mos 71%; P < .0001

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

Chronic Myeloid Leukemia

ENESTnd: CCyR Rates by 24 Mos and OS

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

Chronic Myeloid Leukemia

ENESTnd: Nonhematologic Drug-Related Adverse Events

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

Chronic Myeloid Leukemia

ENESTnd: Grade 3/4 Myelosuppression

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

Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

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

Patients with previously untreated CP-CML (N = 246)

Dasatinib 100 mg/day (n = 123)

Imatinib 400 mg/day (n = 123)

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

Chronic Myeloid Leukemia

S0325: Response and Survival Outcomes

CCyR within 12 mos, %

Chronic Myeloid Leukemia