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Oncology Journal Club
Addressing Imatinib-resistant CML
Frank Giles, MD, FRCPI, FRCPathChief, Division of Hematology and Medical Oncology
Director, Institute for Drug Development
Deputy Director, CTRC at University of Texas
Health Science Center
San Antonio, TX
Historical CML Survival Curve
Targets in CML Signaling PathwaysCEP701, MLN518
PKC412
Ribosomebiogenesis
PI3K
Raptor
mTOR
PDK1
IRS
Perifosine Triciribine
eIF4E
eIF4EeIF3
eIF4GPABP
TSC2TSC1
RHEB
4E-BP1
S6K1
AKT
Cap-dependenttranslation
TranslationRibosomal
proteins
P
P P
P
VEGF PDGF Flt3
Cell membrane
Hif-1a
ERK
RAD001 CCI-779 AP23573
Bcr-Abl
Jak2
MK-0457
DasatinibNilotinibMK-0457SKI606
Dasatinib
SunitinibSurafinibPTK787
Human tyrosine kinases
Human Kinase Dendrogram
Manning. Science; 298: 1912, 2002
ASH 2007, Abstract 25
Hochhaus A. et al
IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation
in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-
CP) Treated with Imatinib
IRIS 6-Year Update: Overall Survival (ITT Principle)
6 year OS is 88% (95% considering only CML-related deaths)
38 (7%) patients lost to follow-up by 5 years
(incl. 3% after BMT, 4% non-CML related)
CML-related deaths
All deaths
Aliv
e, %
0
10
20
30
40
50
60
70
80
90
100
Months Since Randomization0 12 24 36 48 60 72 84
Hochhaus A. et al, Blood. 110, 11. Abstract 25. ASH 2007
IRIS 6-Year Update: Annual Event Rates
3.3
7.5
4.8
1.5
0.80.4
1.5
2.8
1.6
0.90.5
00
1
2
3
4
5
6
7
8
1st 2nd 3rd 4th 5th 6th
% A
nnua
l Rat
es
Year
EventLoss of CHR,Loss of MCyR,AP/BC,Death during treatment
AP/BC
Hochhaus A. et al, Blood. 110, 11. Abstract 25. ASH 2007
Incidence of CML by Age
SEER 2001
*Time on therapy without significant gaps in refills.
Tsang J-P, Rudychev I, Pescatore SL. Poster presented at ASCO 2006.
685
Pat
ient
s
Months
0–1
3500
3000
2500
2000
1500
0
1000
500
1–2 2–3 3–4 4–5 5–6 6–7 7–8 8–9 9–10 10–11 11–12 12–13 13+
2,921Patients taking recommended dose of imatinib
Adherence to Imatinib May Decline Over Time
• In this US study, persistency* was near 100% at month 4
• Persistency declined from 94% at month 5, to 23% at month 14
• Imatinib plasma level testing may help identify patients who become less adherent
Radich. PNAS 103: 2794, 2006
Genes Associated with CML Progression
Dasatinib in Blast Phase CML Overall Survival
0 3 6 9 12 15 18 21
Months
Pro
port
ion
aliv
e
1.0
0.8
0.6
0.4
0.2
0
N No. of deaths Median (mo)
CML-MB 109 49 11.8 CML-LB 48 27 5.3
Martinelli. ASH 2006. Abs 745
Clinical Resistance to Imatinib Mechanisms
• Primary resistance
– Insufficient inhibition of BCR-ABL
• Low plasma levels of imatinib
• Activity of drug pumps
• Secondary resistance
– Imatinib-resistant BCR-ABL kinase-domain mutations
– Overproduction of BCR-ABL
– BCR-ABL-independent mechanisms
• ? Activation of other kinases
• ? Other molecular events
Giles. Hematol Am Soc Hematol Educ Program:2005:183-187;
von Bubnoff. Leukemia. 203;17:829.
After Fabian et al. Nature Biotech. 2005;23:329
Kinase Selectivity Profiles Of Nilotinib And Dasatinib
IC50
< 10 nM
10-50 nM
50-250 nM
250-1000 nM
Dasatinib15 targets
Imatinib4 targets
Nilotinib4 targets
“Targets” of Imatinib, Nilotinib, and Dasatinib
Imatinib Nilotinib Dasatinib
ABL
ARG
BCR-ABL
KIT
PDGFR
DDR1
NQO2
ABL
ARG
BCR-ABL
KIT
PDGFR
DDR1
NQO2
ABL
ARG
BCR-ABL
KIT
PDGFR
SRC
YES
FYN
LYN
HCK
LCK
FGR
BLK
FRK
CSK
BTK
TEC
BMX
TXK
DDR1
DDR2
ACK
ACTR2B
ACVR2
BRAF
EGFR/ERBB1
EPHA2
EPHA3
EPHA4
EPHA5
FAK
GAK
GCK
HH498/TNNI3K
ILK
LIMK1
LIMK2
MYT1
NLK
PTK6/Brk
QIK
QSK
RAF1
RET
RIPK2
SLK
STK36/ULK
SYK
TAO3
TESK2
TYK2
ZAK
Dasatinib: SRC/ABL Kinase Inhibitor
Shah. Science 305: 399, 2004
Dasatinib 70 mg BID in CP-CML
0
25
50
75
100
%
Complete hematologicresponse
Major cytogeneticresponse
CHR
91
59
11
49
80
5
75
52
13
40
CCyR
PCyR
Total Total Imatinibintolerant
Imatinibresistant
Baccarani. Blood. 2006;108: Abstr 164.
Efficacy at 15.2 month Median Follow-up
0 2 4 6 8 10 12 14 16 18 20
Months
Progression-Free Survivalwith Dasatinib 70 mg BID in CP CML
* * 70 mg BID70 mg BID†† Progression defined as confirmed AP / BC, loss of CHR / MCyR, ↑ WBC count, or death
Pro
port
ion
prog
ress
ion-
free
1.0
0.8
0.6
0.4
0.2
0
N No. progressed
Intolerant 99 3
Resistant 287 37
Total 386 40
Baccarani. Blood 2006; 108: Abstract 164.
Dasatinib 70 mg BID in CP-CML Dose Adjustment
ResistantResistant
(N = 288)(N = 288)
IntolerantIntolerant
(N = 99)(N = 99)
TotalTotal
(N = 387)(N = 387)
Reduction (%) 73 75 73
Interruption (%) 86 89 87
Escalation (%) 21 9 18
Median daily dose (mg) (range)
101
(18–171)
104
(11–140)
101
(11–171)
Dasatinib 70 mg BID in CP-CML Fluid Retention/Cardiac AEs
Percentage
Any G3-4
Pleural effusion 27 6
Peripheral edema 18 0
Pericardial effusion 4 <1
Pulmonary edema 1 <1
Congestive heart failure 5 3
Other cardiac dysfunction 2 1
Baccarani. Blood 2006; 108: abst# 164
ASCO 2007, Abstract 7004
Shah NP. et al.
Dasatinib 50 Mg Or 70 Mg BID Compared To 100 Mg Or 140 Mg QD In Patients With
CML In Chronic Phase (CP) Who Are Resistant Or Intolerant To Imatinib:
One-year Results Of CA180034
Dasatinib in CP-CML Study Design
662 treated
100 mg QD (N = 165)
140 mg QD (N = 163)
50 mg BID (N = 167)
70 mg BID (N = 167)
100 mg
140 mg
Imatinib-Imatinib-resistant orresistant or-intolerant -intolerant CP-CMLCP-CML
International, 139-center, Randomized, Open-label, Phase III
• Accrual period: July 2005–March 2006: Total 662 pts• Minimum follow-up: 6 months• Median treatment duration, months (range): 8 (<1–15)
670 randomized
Shah et al .JCO 25; 2007 Abstract # 7004.
Dasatinib Phase III in CP-CML Failing Imatinib (N = 662)
Parameter (%)
100mg
QD
N = 165
50mg
BID
N = 167
140mg
QD
N = 163
70mg
BID
N = 167
P
value
MCyR 64 58 62 58 NS
CCyR 46 46 47 50 NS
Interruption 58 66 69 71 0.047
Reduction 33 45 54 57 <0.001
Neutropenia 34 46 43 43 0.123
Thrombocytopenia 22 34 40 38 0.003
Pleural effusion 10 16 20 18 0.058+
+ 100 QD vs 70 BID
Shah, JCO. 2007;25: Abstract 7004
Pro
port
ion
prog
ress
ion
free
1.0
0.8
0.6
0.4
0.2
00 2 4 6 8 10 12 14 16 18 20
Months
Dasatinib Phase III in CP-CML Failing ImatinibProgression-free Survival
N No. progressed
100 mg QD 165 16
50 mg BID 167 22
140 mg QD 163 23
70 mg BID 167 30
Kantarjiran. Blood. 2006;108: Abstr 746
Dasatinib: Pleural Effusions in CML
• 138 patients: Phase I (50); Phase II (88)
• Pleural effusion: 48 patients (35%; grade 3/4 in 23 [17%]). 29% in CP, 50% in AP, 33% in BP
• MVA risk factors: History of cardiac disease, hypertension, twice-daily schedule
• Exudative in 78% of assessable cases
• Increased RV systolic pressure documented
• Management included:- Drug interruption - 83%
- Diuretics - 71%
- Corticosteroids - 27%
- Thoracentesis - 19% Quintás-Cardama. JCO 25: 3908, 2007
ABL Binding Surfaces
Weisberg. Ca Cell 7:129, 2005Manley. Biochem Bio Acta 1754:3, 2005
NilotinibNilotinibImatinibImatinib
Nilotinib / Imatinib: Potency and Selectivity
Nilotinib
(cell prolif. IC50)
ABL
(25 nM)
> PDGFR
(53 nM)
> KIT
(158 nM)
Imatinib
(cell prolif IC50)
PDGFR
(39 nM)
> KIT
(98 nM)
> ABL
(649 nM)
Nilotinib has no significant effect on other kinases evaluated, including Src, FLT3, VEGFR, EGFR,
InsR, RET, MET , IGFR at concentrations <3000 nM.
Mestan. Blood 104 546a: Abs 1978, 2004
Weisberg. Cancer Cell 7:129, 2005
• More potent, more selective, inhibitor of Bcr-Abl auto, substrate phosphorylation than imatinib
• Selectively induces apoptosis, inhibits proliferation of Bcr-Abl transfected and primary leukemia cells
• Increases survival in murine Bcr-Abl MPD models including imatinib-resistant models
• Inhibits PDGFRα,ß and KIT ~ Imatinib
• STAT, CRKL inhibitor
Nilotinib: Pre-clinical Activity
Verstovsek et al. Cancer. 2005;104:1230 Golemovic et al. Clin Ca Res. 2005;11:4941 Griffin et al. Blood. 2004;104:160a Abs# 551 Le Coutre et al. Blood. 2004;104:218a Abs# 76Mahon et al. Blood. 2004;104:251b Abs# 4670Martinelli et al. Blood. 2004;104:255b Abs# 4687
Weisberg et al. Br. J. Cancer 2006, 94, 1765 O’Hare et al. Cancer Res. 2005;65(11):4500-5 Manley et al. Biochim Biophys Acta. 2005 1754(1-2) Scuto et al. Blood. 2004;104:546a Abs# 1977 Weisberg et al. Cancer Cell. 2005;7(2):129-41
Nilotinib Phase I Study CML Hematologic Responses
DiagnosisN
EvaluableOR (%) CHR MR RTC
CP 12 11 (92) 11 – –
AP 46 33 (72) 21 3 9
AP clonal evolution only 5 5 (100) 5 – –
Myeloid BP 24 10 (42) 2 2 6
Lymphoid BP 9 3 (33) – 1 2
Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006* Indicates co-first author.
Nilotinib Phase I Study: PK
Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006.*Indicates co-first author.
• Median time to peak concentrations 3 hours post dose• Mean apparent half-life = 15 hours• Steady state by day 8 in both QD and BID regimens• All trough levels > IC50 for cellular Bcr-Abl phosphorylation• PK parameters dose proportional to 400 mg QD• Exposure is greatest in the 600 mg BID group
Dose (mg)
Daily
Twice daily
60,000
20,000
40,000
AU
C (
ng
/ml/
hr)
050 100 200 400 600 400 600800 1200
Clinical Resistance to Imatinib Mechanisms
• Primary resistance– Insufficient inhibition of BCR-ABL
• Low plasma levels of imatinib
• Activity of drug pumps
• Secondary resistance– Imatinib-resistant BCR-ABL kinase-domain mutations
– Overproduction of BCR-ABL
– BCR-ABL-independent mechanisms
• ? Activation of other kinases
• ? Other molecular events
Giles. Hematol Am Soc Hematol Educ Program:2005:183-187; von Bubnoff. Leukemia. 203;17:829.
BCR-ABL Mutations Associated With Imatinib Resistance
F486S F486S E255K/V/V
M244V M351T/L/L
M343T M343T
Y253F/H
E279K E279K
F317L
E355G/D/D
F359V/C/D/I/C/D/I
H396R/P/P
Q252H/R/R
S417YS417Y
E459K/Q E459K/Q
E450G/Q/K E450G/Q/K
M388L M388L G250E/A/F /A/F
D276GD276G
T277A/NT277A/N
L387F/M L387F/M
V379I V379I
A397PA397P
P-loopP-loop Activation loopActivation loop
T315I**F311L/I/VF311L/I/V
V289A/IV289A/I
L248V L248V
F382LF382L
E281A E281A
V299LV299L
L364I L364I
G383DG383D
L298VL298V
E292VE292VE453G/K/A/V E453G/K/A/V
Q447RQ447R
S438CS438C
G236E G236E
D241GD241G
M237IM237I
L324Q L324Q
K357RK357R
K285NK285N
E275KE275K
S348LS348L
A344VA344V
A350VA350VM472IM472I
I418VI418V
Nilotinib Inhibits 32 of 33 Imatinib-resistant BCR-ABL Mutant Phenotypes With IC50 < 1 Um
P-loop
Nilotinib resistant:
>10,000 nM
F317C
G250V
M38
8L
E255D
S348L
F317V
E275K
M23
7I
E355A
M35
1T
L387F
E355G
E281K
E255R
K285N
G250A
Q252H
M24
4V
F486S
D276G
E292K
F317L
L248V
G250E
F311V
F359V
A380S
F359C
E255K
Y253H
E255V
T315I
0
500
1,000
1,500
10,000
IC50
Cel
l Pro
lifer
atio
n (
nM
)
Nilotinib sensitive:
Range 19–791 nM
H396R
T315IT315I
Nilotinib: Phase I StudyGrade 3/4 Possibly Related Laboratory AEs
Overall (N=119)
400 BID (N=32)
600 BID (N=18)
0%
0%
11%
11%
5%
3%
9%
3%
5%
3%
5%
3%
Amylase
ALT/AST
Lipase
Bilirubin
Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006* Indicates co-first author
ASH 2007, Abstract 471 and 735
Le Coutre P. et al. (471)
Kantarjian HM. et al. (735)
Nilotinib Is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia
(CML-CP) Patients with Imatinib-Resistance or Intolerance
CML-CPCML-CP (N = 321)(N = 321)
CML-AP CML-AP (N = 127)(N = 127)
Median age, years58
(21-85)
58
(22-82)
Additional chromosomal abnormalities, % 24.4 31
Median duration of CML, months58
(5-75)
71
(2-298)
Median duration of prior imatinib use, months
33 29
Imatinib-resistant/intolerant, % 71/29 80/20
Nilotinib: Phase II Baseline Demographics and Disease Characteristics
Kantarjian HM et al. ASH abstract 735, Blood 2007: 110 (11).Le Coutre P et al. ASH abstract 471, Blood 2007: 110 (11).
Nilotinib Phase II Studies: Dose Intensity (mg/day)
800 797 787
Planned Delivered
(CP)N = 316
Delivered
(AP)N = 64
le Coutre et al. ASH 2006; Abst #165Kantarjian et al. ASH 2006; Abst #2169
Nilotinib Phase II CML-CP Study Response Rates
5460
40
77
57 5563
4134
5152 55
74
56
76
0
20
40
60
80
100
CHR* MCyR Imatinib Resistant
Imatinib Intolerant
CCyR
% P
ati
en
ts
Hematologic Response
Cytogenetic Response
ASH'06 Patients with ≥ 6 months of follow-up (N = 279)
ASCO'07 Patients with ≥ 6 months of treatment (N = 320)
ASH'07 Patients with ≥ 11 months of treatment (N = 321)
CHR at baseline / *No CHR at baseline, N 115 / 206
Time to first CHR* 1 month
Time to first MCyR (N=178) 2.8 months
Median duration of MCyR has not been reached at the time of data cutoff
Nilotinib Phase II CML-AP Study:Response Rates
23 2429
16
54
2631
19
36
22
59
45
0
20
40
60
80
100
HR CHR MCyR CCyR
% P
atie
nts
Hematologic Response
Cytogenetic Response
ASH'06 Patients with ≥ 8 months of treatment (N = 64)
ASCO'07 Patients with ≥ 6 months of treatment (N = 119)
ASH'07 Patients with ≥ 6 months of treatment (N = 129)
95% 91%
Months Since Start of Treatment
Ali
ve,
%
Total = 321Failed = 25lll = Censored observations
Nilotinib Phase II Study: CML-CP Overall Survival Post Imatinib Failure
Kantarjian et al. ASH 2007 abstract 735
Patients = 129
Number deaths = 27
92% 81%
Ali
ve,
%
Months Since Start of Treatment
Phase II CML-AP StudyOverall Survival Post Imatinib Failure
Le Coutre et al. ASH 2007 abstract 471
N = 321 Grades 3/4 (%)
AST 2
ALT 4
Bilirubin (total) 8
Bilirubin (direct) 5
Creatinine 1
Hypocalcemia 1
Hypomagnesemia <1
Hypophosphatemia 14
Lipase elevation 15
Hyperglycemia 13
Phase II CML-CP StudyGrades 3/4 Biochemical Laboratory Abnormalities
Kantarjian et al. ASH 2007 abstract 735
N = 321 All Grades (%) Grades 3/4 (%)
Rash 30 2
Pruritus 25 <1
Nausea 24 <1
Fatigue 20 1
Headache 18 2
Vomiting 12 <1
Constipation 12 0
Diarrhea 12 2
Phase II CML-CP Study Possibly Related Non-hematologic AEs
(frequency >10%)
Kantarjian et al, ASH 2007 abstract 735
Cross-intolerance Between Imatinib and Nilotinib
CML-CP (N=94) / CML-AP (N=23)
31
23
17
13 10
0 0 1 1 0
Patients enrolled in nilotinib study 2101 with grade 3/4 imatinib intolerance
Patients with cross-intolerance (grade 3/4) after switching to nilotinib
Rash / skin
toxicity
Fluid retention
GI intolerance
Liver toxicity
Myalgias / Arthralgias
Cortes et al. ASH abstract 29, Blood 2007:110 (11)
Nilotinib Cross Intolerance in Patients with Imatinib Intolerance Nonhematologic AEs
Reason for Imatinib
Intolerance
Imatinib Intolerant*
Grade 3/4 AE or
persistent Grade 2 AE on nilotinib**
Gr. 3/4 AE on Nilotinib***
AE that led to dose reduction
of nilotinib
D/C nilotinib due to AE
N N N N
CML-CP N = 95
Non-hematologic
57 4 1 0 0
Rash/Skin 26 0 0 0 0
Fluid Retention 17 0 0 0 0
GI
- diarrhea17 3 1 0 0
Liver Toxicity
- ALT
- AST
12 3 1 0 0
Myalgia/arthralgia 9 1 0 0 0
Nilotinib Phase II Study CML-CP MyelosuppresionAll
GradesGrade
3/4
ASH'06 Patients with ≥ 6 months of follow-up (N = 316)
ASCO'07 Patients with ≥ 6 months of treatment (N = 320)
ASH'07 Patients with ≥ 11 months of treatment (N = 321)
Grade 3/4
Median Duration (days) 9 15 23
Median Onset (days) 61 55 42
50
28
50 5261
9
33
51 5358
10
30 28
5058
9
2931
0
10
20
3040
50
6070
80
90
100
Anemia Neutropenia Thrombocytopenia
% Patients
Most Frequent Newly Occurring or Worsening Hematologic Lab Abnormalities Regardless of Causality
Nilotinib Phase II Study CML-AP MyelosuppresionAll
GradesGrade
3/4
ASH'06 Patients with ≥ 8 months of treatment (N = 64)
ASCO'07 Patients with ≥ 6 months of treatment (N = 127)
ASH'07 Patients with ≥ 11 months of treatment (N = 136)
Grade 3/4
Median Duration (days) 8 15 27
Median Onset (days) 14 21 21
60
45
58 6165
24
39
5863
67
25
39 41
60
4039
0
10
20
3040
50
6070
80
90
100
Anemia Neutropenia Thrombocytopenia
% Patients
Most Frequent Newly Occurring or Worsening Hematologic Lab Abnormalities Regardless of Causality
1. Giles F et al. Presented at: 43rd ASCO Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 7038.2. Giles F et al. Presented at: 12th Congress of the EHA; June 7-10, 2007; Vienna, Austria. Abstract 554.
Nilotinib: CML CP After Dasatinib and Imatinib
Cautions With Dasatinib / Nilotinib
• QTc prolongation: Both – Baseline EKG, Close K
and Mg monitoring
• Past pancreatitis: Nilotinib C/I
• Hypertension, COPD, CCF, Chest wall injury,
Asthma, Pneumonia, GI bleeding, Auto-immune
disorders, aspirin: Dasatinib C/I
Addressing Imatinib-resistant CML
Future Directions
Young. Ca Res 66;1007, 2006
Giles. Blood. 109, 500 2007
MK-0457 Phase I: Patient with T315I CML BP
1
Cycles of therapy
WB
C (
x109
/L)
2 76543 8 9 10
12 mg/m2/hr 20 mg/m2/hr16 mg/m2/hr
0
Decreasing residual
leukemia
Nu
mb
er of leu
kemia cells (lo
g10 )
1
2
3
4
5
6
7
8
9
10
11
12
13
0
6.0
5.0
4.0
3.0
1.0
0
Lo
g r
edu
ctio
n f
rom
bas
elin
e Leukocytosis
Ph-chromosome pos
RQ-PCR <3 log
Cure ?
2.0CCyR
MMR
RQ-PCR negative(undetectable)
RQ-PCR >3 log
Ph Chromosome And BCR-ABL Transcript Numbers As Measures Of ‘Residual’ Leukemia During Treatment
NilotinibNewly Diagnosed CML-CP
Jabbour E. ASCO 2006. Abstract 2172
Nil 400mg BID
0
10
20
30
40
50
60
70
80
90
100
49 48 46202 190 18114 13 11N=
9 mos3 mos 6 mos
% C
CyR
93100 100
61
37
85
54
92
67
IM 400mg/day
IM 800mg/day
Dasatinib in ECP CMLNon-Hematologic Adverse Events
0 5 10 15 20 25 30 35
Hyperglycemia
Pleural effusion
Constipation
Diarrhea
Dyspnea
Anorexia/Nausea
Infection with normal ANC
Dizziness
Skin
Headache
Fatigue
Musculoskeletal pain
G1
G2
G3
Number of patients
PercentagePercentage
G1G1 G2G2 G3G3
34 20
26 29
40 9 3
26 17 3
37 3
14 20
23 9
26 6
23 6
11 17
0 11
9
ASCO 2007, Abstract 7023
Hochhaus A. et al.
Efficacy Of Dasatinib In Chronic Phase Chronic Myelogenous Leukemia Patients
After Imatinib Failure According To Baseline BCR-ABL Mutations
Cellular IC50
Dasatinib Imatinib N nM nM
H396P/R 0.6-1.3 850-4200
7
M351T 1.1 930 8
M244V 1.3 2000 8
G250E 1.8 1350-3900 9
Y253F/H 1.3-10 >10000 5
L387M 2 1000 2
F359V 2.2 1200 2
Q252H 3.4 1300-3900 2
E255K/V 5.6-13 4400-8400 6
F317L 7.4-18 810-1500
3
T315I >1000 >10000 3
Complete CyR
Partial CyR
Complete HR
No response
Dasatinib Response: Cellular IC50 Of Post-imatinib Mutation (CP-CML)
Hochhaus et al. JCO 25; 2007 Abstract # 7023
ASCO 2007, Abstract 7024
Mueller MC. et al.
Response Dynamics To Nilotinib Depend On The Type Of Bcr-abl Mutations In Patients
With Chronic Myelogenous Leukemia (CML) After Imatinib Failure
CML-CP: Best Response Within 6 Months by Cellular IC50 to Nilotinib
Baseline CellularMutation IC50 (nM)
T315I >10,000
Y253H 700
E255K 548
F359C 161
F317L 91
D276G 77
M244V 67
E355G 47
H396R 41
M351T 38
IC50 >10,000 nM:
4 no response
IC50 >100 nM:
2 PCyR2 CHR5 no response
IC50 <100 nM:
8 CCyR
2 PCyR
7 CHR
1 no response
Mueller et al.JCO 25; 2007 Abstract # 7024
CML: Potential Antigen Targets
Junction Peptides
• b3a2-p210Bcr/Abl
• b2a2-p210Bcr/Abl
• e1a2-p190Bcr/Abl
Non-specific
• Hsp70
Tissue-specific Antigens
• Proteinase 3
• Tryptase
• Cathepsin G
• Leukotriene-B4 omega hydroxylase
• C-pim, C-fes
• MRP14
• GM-CSF receptor chain
CML in 2008
• Imatinib (IM) optimal frontline therapy: No role for
frontline AlloSCT in adults
• Dasatinib / nilotinib are effective in IM-failure in
equivalent % patients with approved regimens
• Toxicities should dictate order of use of dasatinib
and Nilotinib. Each will generate new patterns of
resistance
• MK-0457 is active in T315I phenotype patients
• Need to avoid manufactured discontent
• Need to focus on cure
Questions on Patients and/or Studies with/of Hematologic Malignancies or
Refractory Solid Tumors?
frankgiles@aol.com
832-606-0285
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