oncology journal club addressing imatinib-resistant cml frank giles, md, frcpi, frcpath chief,...

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




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)



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




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


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


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?

[email protected]

832-606-0285

oncology journal club addressing imatinib-resistant cml frank giles, md, frcpi, frcpath chief,...

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