Profiles in CML: Overview of Practice Challenges

Moshe Talpaz, MDProfessor

Department of Internal Medicine, Hematology-OncologyUniversity of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan

Chronic Myelogenous Leukemia (CML)

• Abnormal clonal hematopoietic stem cell disorder, increased proliferation, decreased apoptosis and adhesion

• Chronic, accelerated, and blastic phases

• Ph t(9;22) (q34;q11) cytogenetic and BCR-ABL molecular abnormalities

CML—A Myeloproliferative Disorder

Courtesy of John K. Choi, MD, PhD.

Normal CML Chronic-Phase

CML Is Linked to a Single Cytogenetic Abnormality—The Philadelphia

Chromosome

1 2 3 4 5

6 7 8 10 119 12

13 14 15 16 17 18

19 20 21 22

X Y

Stoll C, et al. Blood. 1978;52:828-838.

The Philadelphia Chromosome and BCR-ABL

BCR-ABL

ABLFUSION

PROTEINWITH

TYROSINEKINASE

ACTIVITY

22

BCR

Ph (or 22q-)

99 q+

1

p210BCR-ABL

p190BCR-ABL2-11

2-11

Chromosome 9

c-BCR

Chromosome 22

c-ABL

2-11

Exons

Introns

CML breakpoints

ALL breakpoints

t(9;22) translocation BCR-ABL gene structure

Faderl S, et al. N Engl J Med. 1999;341:164-172.

Melo JV. Blood. 1996;88:2375-2384.

ABL

Chromosome 9Chromosome 22

wwwwwww

BCRwwwww

BCR-ABL

wwwwwwwwq34

wwwwwwwwwq11

t(9;22)(q34;q11)

BCR ABL

210 KD protein

Faderl S, et al. N Engl J Med. 1999;341:164-172.

Melo JV. Blood. 1996;88:2375-2384.

Chronic PhaseAccelerated

PhaseBlast Crisis

Advanced Phases

The Clinical Course of Untreated CML

Faderl S, et al. Ann Intern Med. 1999;131:207-219.Pasternak, G et al. J Cancer Res Clin Oncol. 1998;124:643-660.

Median duration5–6 years

Median duration6–9 months

Median survival3–6 months

Incidence and Mortality Of CML

Based on current data, median survival is expected to exceed 15–20 years.

Year Number of Cases Number of Deaths

19971 4300 2400

20072 4570 490   

1.Parker SL, et al. CA Cancer J Clin. 1997;47:5-27.2.Jemal A, et al. CA Cancer J Clin. 2007;57:43-66..

Survival in Early Chronic Phase CML

With permission from Quintas-Cardama A, et al. Mayo Clin Proc. 2006;81:973-988.

IRIS Study in Chronic Phase CML—7-Year Update

• 1106 patients originally enrolled, 553 per arm

• Estimated overall survival at 7 years: 86%

• Late-progression events– Kaplan-Meier estimate of event-free survival at 7 years: 81%

– Kaplan-Meier estimated rate without accelerated phase/blast crisis at 7 years: 93%

• Safety– Grade 3/4 events decreased in incidence after years 1–2

– No unique, previously unreported adverse events emerged

O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.

IRIS Overall Survival (ITT Principle)Imatinib Arm

With permission from O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.

Abbreviation: ITT, intent to treat.

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72 84 96

Months Since Randomization

Pro

babi

lity

of S

urvi

val

Survival: deaths associated with CML

Overall survival

Estimated overall survivalat 7 years is 86%

(94% considering onlyCML-related deaths)

Annual Event Rates—Imatinib Arm• KM estimated EFS at 7 years = 81%

• KM estimated rate without AP/BC at 7 years = 93%

7.5

4.8

1.7

0.80.3

1.5

2.8

1.6

0.90.5

00.4

2.0

3.3

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7Year

% w

ith E

vent

Event

Loss of CHR,

Loss of MCR,

AP/BC,

Death during treatment

AP/BC

aTotal events (n = 5), including loss of MCR (n = 3) and deaths (n = 2, one of which was coded a progression to AP/BC in a patient in CHR 6 months prior to death).Abbreviations: AP/BC, accelerated phase/blast crisis; CHR, complete hematologic response; EFS, event-free survival; MCR, major cytogenic response; KM, Kaplan-Meier.

With permission from O’Brien SG, et al. 50th Annual ASH Meeting; December 6-9, 2008. Abstract 186.

a

IRIS 7-Year Update—Key Findings

• Overall survival: 86%

• Event-free survival: 81%

– 7% progression to accelerated phase/blast crisis (AP/BC)

• Complete cytogenetic response (CCR) achieved by 456/553 (82%) patients

– 17% subsequently lost CCR

– 3% progressed to AP/BC

– 2% died from CML

– Time to CCR did not correlate with the rate of progression to AP/BC

• Major molecular response rates and depth of molecular response increased over time

• While imatinib is efficacious, it does not work for all patients

O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.

Imatinib Resistance

• BCR-ABL specific– Mutations

>50 described with variable degrees of impact

~50% of patients

– Amplification or overexpression ~7-10 %

• BCR-ABL independent– Cellular pharmacology

Drug import/export

– Other pathways Wnt, notch

Autocrine factors

Lyn (other Src-family kinases)

50%–60%

40%–50%

Courtesy of M. Talpaz, MD.

24 Mutations in 19 Amino Acids

P-Loop KD A-Loop

M244V

Q252H

Y253F/H

E255K/V

T315I M351T

E355G

L387F/M

H396R

CCAA

BCCC

CCAAA‘A‘MMMMM

CCCCMMM

CCCAAAL

CCAAAAA‘MM

AA‘

CAAM‘

CCC‘AA‘M

L248V

CA‘

C‘A

F317L

AC

F311L

A

F359C/V

CCCCAA‘

CA

A397P

T277A

M‘

D267G

A M

V379I

G250E/R

L324Q

C

5 patients had 2 or more mutations (‘).

Gorre ME, et al. Science. 2001;293:876-880. von Bubnoff N, et al. Lancet. 2002;359:487-491. Branford S, et al. Blood. 2002;99:3472-3475. Hofmann W-K, et al. Blood. 2002;99:1860-1862. Roche-Lestienne C, et al. Blood. 2002;100:1014-1018. Shah NP, et al. Cancer Cell. 2002;117-125. Hochhaus A, et al. Leukemia. 2002;16:2190-2196. Al-Ali HK, et al. Hematol J. 2004;5:55-60.

Role of Kinase Conformation in Imatinib Resistance

Point mutations in BCR-ABL kinase domain restricts its ability to adopt an inactive conformation

With permission from Schindler T, et al. Science. 2000;289:1938-1942. With permission from Lombardo LJ, et al. J Med Chem. 2004;47:6658-6661.

Mutations thatdirectly affect imatinib binding

Mutations that affect the conformation requiredto bind imatinib

Dasatinib Inhibits the Growth of MostImatinib Mesylate—Resistant BCR-ABL—

Expressing Ba/F3 Cell Lines In Vitro

With permission from Shah NP, et al. Science. 2004;305:399-401.

Ba/F3Bcr-AblE255K

M351TM244VG250EQ252HQ252RY253FY253HE255VF317LE355GF359VH396RF486S

T315I

Parental Ba/F3 cells

M351T

0

0.2

0.4

0.6

0.8

1.0

1.2

0 2.5 5 25 50

Rel

ativ

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row

th A

fter

48

h o

f D

rug

Exp

osu

re

Concentration of Dasatinib (nM)

Wild-typeBCR-ABL

E255K

T315I

0.5

With permission from Cortes J, et al. Blood. 2007; 110:4005-4011.

Spectrum and Frequency of BCR-ABL Kinase Domain Mutations Developing

During Treatment with Imatinib, Dasatinib, and Nilotinib

The solid color corresponds to the 1st amino acid change; the broken color corresponds to the 2nd amino acid change if applicable.

0

5

10

15

20 ImatinibDasatinibNilotinib

G25

0E

Y25

3H/F

E25

5K

V29

9L

F311

1

T315

I

F317

L

M35

1T

E35

5G/A

F359

C/V

H39

6R/P

% B

CR

-AB

L M

uta

tio

n

Case 1: AK

Neil P. Shah, MD, PhDAssistant Professor

Division of Hematology/OncologyUCSF School of MedicineSan Francisco, California

AK33-Year-Old Male

• Referred for recently discovered leukocytosis of 253K noted in blood work performed after he presented to his primary care physician with left shoulder pain and ongoing night sweats

• Palpable splenomegaly

• Differential: 3% basophils, immature granulocytes, and 2% blasts

• Bone marrow biopsy revealed: hypercellular marrow with 4% blasts and an M:E ratio of 10:1, consistent with a myeloproliferative disorder

• Cytogenetics: t(9;22) in all 20 metaphases analyzed

• AK has 2 siblings and no other significant medical history

Decision Point 1

What is the appropriate first-line treatment for this patient?

•Hematopoietic stem cell transplantation

• Imatinib

•Dasatinib

•Nilotinib

• Interferon alpha

AK

• Imatinib 400 mg daily is initiated

• AK tolerates therapy well, with the exception of peripheral edema, mild nausea, and muscle cramps

• 1 month later, CBC reveals a complete hematologic response (CHR)

• 6 months after initiating therapy, AK continues to have a CHR. Bone marrow aspiration is performed, and the t(9;22) translocation is detected in 5/20 metaphases

• 12 months after initiating therapy, only 2/20 bone marrow metaphases contain the t(9;22) translocation

• 6 months later, despite continuing to have a CHR, marrow metaphase analysis reveals the t(9;22) translocation in 18/20 metaphases

Decision Point 2

What is your next step?

• Assess patient compliance

•Do a mutational analysis

• Increase imatinib dosage

• Switch to dasatinib or nilotinib

•Refer for allogeneic stem cell transplantation

• All of the above

AK

• AK states that he has been very compliant with therapy

• BCR-ABL kinase domain mutation test is ordered; the imatinib dose is increased to 800 mg daily

• AK experiences increased fatigue, nausea, and edema on this dose

• 3 months after imatinib dose escalation– CBC: WBC of 18K with immature forms and 3% basophils

– Mutation analysis: E255K mutation in a large proportion of cells

(Incomplete) Map of BCR-ABL Kinase Domain Mutations Associated with

Clinical Resistance to Imatinib

Gorre ME, et al. Science. 2001;293:876-880. von Bubnoff N, et al. Lancet. 2002;359:487-491. Branford S, et al. Blood. 2002;99:3472-3475. Hofmann W-K, et al. Blood. 2002;99:1860-1862. Roche-Lestienne C, et al. Blood. 2002;100:1014-1018. Shah NP, et al. Cancer Cell. 2002;117-125. Hochhaus A, et al. Leukemia. 2002;16:2190-2196. Al-Ali HK, et al. Hematol J. 2004;5:55-60.

E255K/V

M244V M351T

Y253H/F

E279K

F317L

E355G/D

F359C/V/D/I

H396R/PQ252H/R

S417Y

E459K/Q

F486S

E450G/Q M388L

G250E/A/F

D276G

T277A

L387F/M

V379I

A397P E453G/KT315I/N

F311L/I

V289A

L298VL248V

E281A

L364I

G383D

E292V

xP C A

Abbreviations: P, P-loop; C, catalytic domain; A, activation loop.Abbreviations: P, P-loop; C, catalytic domain; A, activation loop.

Courtesy of Tim Hughes, MD.Courtesy of Tim Hughes, MD.

Role of Kinase Conformation in Imatinib Binding

Imatinib binds to an inactive conformation of BCR-ABL, and is stabilized by a H-bond with Thr315

Imatinib

With permission from O’Hare T, et al. Cancer Res. 2005;652:4500-4505.

Helix C

Activationloop

P-loop

Differential Binding of Dasatinib and Imatinib to ABL Kinase

With permission from Schindler T, et al. Science. 2000;289:1938-1942. With permission from Lombardo LJ, et al. J Med Chem. 2004;47:6658-6661.

QuickTime™ and aCinepak decompressor

are needed to see this picture.

How Resistant is the E255K Mutation to Imatinib in Vitro?

Resistance to Imatinib of CellsBearing BCR-ABL Mutations

Mutation Biologic IC50 (µM)

E355G 2.38

M351T 4.38

F317L 7.50

Y253F 8.94

Q252H 3.12

G250E >10

T315I >10

E255K >10

WT P210 0.60

Measured by determining concentration dependence of normalized viable cell counts.

Shah NP, et al. Cancer Cell. 2002;2:117-125.

Decision Point 3

How would you treat this imatinib-resistantpatient with a E255K mutation?

•Hematopoietic stem cell transplantation

• Switch to dasatinib

• Switch to nilotinib

How Resistant is the E255K Mutation to Dasatinib in Vitro?

Efficacy of Dasatinib Against Imatinib-Resistant Kinase Domain Mutations in Vitro

With permission from Shah NP, et al. Science. 2004;305:399-401.

Ba/F3Bcr-AblE255K

M351TM244VG250EQ252HQ252RY253FY253HE255VF317LE355GF359VH396RF486S

T315I

Parental Ba/F3 cells

0

0.2

0.4

0.6

0.8

1.0

1.2

0 2.5 5 25 50

Rel

ativ

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row

th A

fter

48

h o

f D

rug

Exp

osu

re

Concentration of Dasatinib (nM)

unmutatedBCR-ABL

E255K

T315I

0.5

How Responsive is the E255K Mutation to Dasatinib in Patients?

With permission from Stone R, et al. 49th ASH; December 8-11, 2007. Abstract 734.

Dasatinib 70 mg Twice Daily in CML-CP Response by Individual Baseline BCR-ABL

MutationCellular IC50 (nM)

Dasatinib Imatinib n

M244V 1.3 2000 17

L248V 1500 9

G250E/V 1.8 1350–3900 23

Y253F/H/K 1.3–10 >10,000 14

E255K/V 5.6–13 4400–8400 10

D276G 1500 3

T315I >1000 >10000 3

F317L 7.4 1050 4

M351T 1.1 930 15

E355G 400 6

F359C/I/V 2.2 1200 8

L387M 2.0 1000 2

H396P/R 0.6–1.13 850–4200 17

Other 30

Complete CyRPartial CyRComplete HRNo response

Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; CyR, cytogenetic response; HR, hematologic response.Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; CyR, cytogenetic response; HR, hematologic response.

How Is Longer-Term Survival Impacted by Dasatinib in Chronic Phase CML Patients?

Dasatinib 100 mg in Imatinib-Resistantand -Intolerant CML-CP

Overall Survival

Months

% A

live

100

80

60

0

100 mg once daily 24-month overall survival = 91%

0 3 6 9 12 15 18 21 24 27 30

Overall survival

n 12 Months 24 Months

100 mg once daily 167 96% 91%

70 mg BID 168 94% 88%

140 mg once daily 167 96% 94%

50 mg BID 168 96% 90%

With permission from Shah NP, et al. 50th ASH; December 6-9, 2008. Abstract 3225.

Abbreviation: CML-CP, chronic myeloid leukemia-chronic phase.Abbreviation: CML-CP, chronic myeloid leukemia-chronic phase.

Survival of Patients Who Discontinued Imatinib Study Therapy%

Su

rviv

al (

all

dea

ths)

0

10

20

30

40

50

60

70

80

90

100

Months After Stopping Imatinib Study Therapy

0 12 24 36 48 60 72 84 96

Safety (n = 30)Efficacy (n = 82)Bone marrow transplant (n = 16)Other reason (n = 80)

Survival 85% at 5 years after discontinuing study

Survival approximately 50% at 5 years after stopping

imatinib study drug

With permission from O’Brien SG, et al. 50th ASH; December 6-9, 2008. Abstract 186.

How Resistant is the E255K Mutation to Nilotinib in Vitro?

Activity of Nilotinib on Imatinib-Resistant BCR-ABL Mutants in Vitro

Ba/F3 cell proliferation

72-hour proliferation assay with BCR-ABL–expressing Ba/F3 cells

Weisberg E, et al. Br J Cancer. 2006;94:1765-1769. O’Hare T, et al. Cancer Res. 2005;65:4500-4505. Weisberg E, et al. Cancer Cell. 2005;7:129-141.

Ma

tern

al

+ I

L3

BC

R-A

BL

wt

M2

37

I

M2

44

V

L2

48V

G25

0A

G25

0E

G25

0V

Q25

2H

Y25

3H

E25

5D

E25

5K

E25

5V

E25

5R

E27

5K

E27

6G

E28

1K

K28

5N

E29

2K

F3

11V

T3

15I

F3

17C

F3

17L

F3

17V

D32

5N

S34

8L

M3

51

T

E35

5A

E35

5G

F3

59C

F3

59V

A38

0S

L3

87F

M3

88

L

F4

68S

0

500

1000

1500

2000

2500

3000

IC5

0 (

nM

) o

n P

roli

fera

tio

n

Imatinib

Nilotinib

How Responsive is the E255K Mutationto Nilotinib in Patients?

Phase II Nilotinib in CML-CPResponse and Progression

Based on Mutation IC50

Patients, n/N (%)

Mutation CCyR Progressed

No mutation 35/83 (42) 19/83 (23)

IC50 ≤150 nM 18/45 (40) 14/45 (31)

IC50 >150 nM

Y253H 0/8 (0) 3/8 (38)

E255K/V 0/8 (0) 6/8 (75)

F359C/V 0/10 (0) 9/10 (90)

Others 14/33 (42) 13/33 (39)

• Response rates and progression rates were similar in patients without baseline mutations and in patients with mutations with IC50 ≤150 nM for nilotinib

• Less favorable responses seen in patients with Y253H, E255K/V, and F359C/V

– 8 of 26 patients were dose escalated to 600 mg BID

– Highest rates of progression for E255K/V and F359C/V

With permission from Hughes TP, et al. Blood. 2007;110(11). Abstract 320. Blood. 2007;110(11). Abstract 320.

Abbreviations: CCyR, complete cytogenetic response; CML-CP, chronic myeloid leukemia-chronic phase. Abbreviations: CCyR, complete cytogenetic response; CML-CP, chronic myeloid leukemia-chronic phase.

AK

• Dasatinib 100 mg daily is initiated

• Therapy is tolerated well except for an occasional mild headache

• 2 weeks later, AK once again has a normal CBC

• After 6 months, bone marrow aspiration reveals no karyotypically abnormal cells

• 12 months later, AK continues to have a complete cytogenetic response on dasatinib

Conclusions

• Loss of response to imatinib is frequently associated with the evolution of resistance-conferring BCR-ABL kinase domain mutations

• Mutations confer varying degrees of resistance to imatinib, and many are not likely to respond to imatinib dose escalation

• Dasatinib and nilotinib are effective against most imatinib-resistant BCR-ABL kinase domain mutants in vitro and in patients– Survival data with dasatinib compare favorably with transplant after 2

years

• Patients with select imatinib-resistant BCR-ABL kinase domain mutations should be preferentially treated with either dasatinib or nilotinib– Consultation with a chronic myeloid leukemia expert is indicated when

treating patients with imatinib resistance

Case 2: WL

Michael J. Mauro, MDAssociate Professor

Center for Hematologic Malignancies, Knight Cancer InstituteOregon Health & Science University

Portland, Oregon

WL45-Year-Old Female

• Diagnosed with chronic myeloid leukemia (CML)

• WBC 150k– Left shift, 3% blasts, 3% basophils, platelets 700k

• Splenomegaly 8 cm below left costal margin

• Bone marrow shows typical CML chronic phase (CML-CP)– 95% cellular, myeloid hyperplasia, 5% blasts

– Karyotype: 100% classic t(9:22)

• Matched unrelated donor option identified; no sibling donor

Patient asks about initial treatment options

Decision Point 1

• What should be the initial therapy for this patient?– Imatinib 400 mg/day

– Imatinib 600 mg/day

– Imatinib 800 mg/day

– Immediate matched unrelated donor stem cell transplantation

Imatinib 400 mg/day is the Indicated Dose for Initial Therapy in This Patient

• Imatinib 400 mg/day

• Imatinib 600 mg/day

• Imatinib 800 mg/day

• Immediate matched unrelated donor stem cell transplantation

WLFollow-Up at Month 3

• Imatinib 400 mg/day was advised

• At month 3– Complete hematologic response with mild leukopenia (WBC

2.5–4k, ANC >1500)

– Periorbital edema and myalgias present

• Peripheral blood qPCR is performed– Results: 1.0 log reduction from baseline

How is she doing?

Any recommendations, changes?

Decision Point 2

• Response to 3-month results?– Decrease imatinib dose to 300 mg/day due

to reduced WBC

– Continue imatinib at 400 mg/day

– Increase imatinib dose due to failure

– Change to nilotinib or dasatinib due to failure

– Move to matched unrelated donor stem cell transplantation

CHR at 3 Months is an Adequate Response, Although the Transcript Reduction is Marginal; the Toxicity (Including Myelosuppression) Does

Not Warrant Dose Interruption or Reduction

• Decrease imatinib dose to 300 mg/day due to reduced WBC

• Continue at 400 mg/day imatinib

• Increase imatinib dose due to failure

• Change to nilotinib or dasatinib due to failure

• Move to matched unrelated donor stem cell transplantation

% A

chie

vin

g M

MR

50

60

70

80

90

100

20

30

40

10

0

P <.00169%

100%

3 6 9 12 15 18 24 3021 27

Months on Imatinib

13%

>2 log reduction

1–2 log reduction

0–1 log reduction

Hughes T, Branford S. Blood Rev. 2006;20:29-41.

Abbreviations: MMR, major molecular response; qPCR, quantitative polymerase chain reaction.

3-Month qPCR Predictive of Ability to Achieve Subsequent MMR—IRIS Trial

WLFollow-Up at Month 6

• Bone marrow at 6 months shows 80% Ph+ by karyotype

• She feels well; edema and myalgias manageable

• CBCs have shown fairly consistent minimal leukopenia (total WBC 3–4k) with ANCs >1500

How is she doing now?

Would you change anything at this point?

What do you tell her about her response?

Decision Point 3

• Response to 6-month results?– Continue imatinib at 400 mg/day

– Increase imatinib based on failure

– Change to dasatinib or nilotinib trial because of failure

– Move to matched unrelated donor stem cell transplantation

ABL kinase domain mutation testing should be considered

Imatinib 800 mg/day Could be Considered Given that the Cytogenetic Response is Adequate (<95% Ph+) but Considered

“Suboptimal” (36%–95% Ph+) at 6 Months

• Continue imatinib at 400 mg/day

• Increase imatinib to 800 mg/day based on suboptimal response

• Change to dasatinib or nilotinib trial because of failure

• Move to matched unrelated donor stem cell transplantation

With permission from Baccarani M, et al. Blood. 2006;108:1809-1820.

Kinase mutations: high degree = IM resistance, failure; low degree = suboptimal response. Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematological response; CyR, cytogenetic response; HR, hematologic response; MMR, major molecular response; PCyR, partial cytogenetic response;qPCR, quantitative polymerase chain reaction.

Failure, Suboptimal Response—European LeukemiaNet Consensus

Time Failure Suboptimal Response Warnings

Diagnosis — — Sokal High; del9q+; clonal evolution

3 mo No HR Less than CHR —

6 mo No CyR(Ph+ >95%)

Less than PCyR(Ph+ >35%)

—

12 mo Less than PCyR(Ph+ >35%)

Less than CCyR(0% Ph+)

Less than MMR

18 mo Less than CCyR Less than MMR —

Anytime Loss of CHR;loss of CCyR

Confirmed loss of MMR;evidence of clonal evolution

Change in qPCR;Ph (-) clonal

cytogenetic abnormalities

CyR at 6 months (Ph+): 1%–35% 36%–65%66%–95% >95%

(n = 81)

(n = 16)

(n = 16)

(n = 19)

Graph: with permission from Druker B, et al. Blood. 2003.102;182a. Abstract 634.

Table: with permission from Baccarani M, et al. Blood. 2006;108:1809-1820.

Probability of CCyR, EFS by Cytogenetic Response at 6 Months—IRIS Trial

% Ph+at 6 mo

CCyRat 12 mo

EFSat 42 mo

0%

1%–35%

N/A

80%95%

36%–90%

>95%

50%

15%75%%

of

Pa

tien

ts w

ith S

ub

seq

ue

nt

CC

yR

Dasatinib 70 mg BID(n = 101)

Imatinib 800 mg (n = 49)

CML-CP resistant to imatinib 400–600 mg/day

Randomization 2:1 Cytogenetics at 12 weeks

Continue therapyor

crossover for:ProgressionLack of MCyRIntolerance

ENDPOINTS:• Primary: MCyR and CCyR at 3 months

• Secondary: rates of MCyR, CCyR, major molecular response; time to treatment failure; progression-free survival

Abbreviations: CCyR, complete cytogenetic response; IM, imatinib; MCyR, major cytogenetic response.Kantarjian H, et al. Blood. 2007;110: abstract 736.

What If This Was Imatinib Failure?Dasatinib vs Higher Dose IM in CML-CP

for Imatinib Failure—Study Schema

53

44

2933

18

12

0

10

20

30

40

50

60

MCyR CCyR MMR

Dasatinib

Imatinib

Pe

rce

nt

P = .017

P = .0025

P = .028

Abbreviations: CCyR, complete cytogenetic response; IM, imatinib; MCyR, major cytogenetic response; MMR, major molecular response.Kantarjian H, et al. Blood. 2007;110: abstract 735.

Dasatinib vs High-Dose IM in CML-CPBest Response (Prior to Cross-Over)

P = .0033

P = .0562

% P

FS

100

80

60

40

20

0

Imatinib 400 mg Dasatinib

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

Imatinib 400 mg Imatinib 800 mgImatinib 600 mg Dasatinib

Imatinib 600 mg Imatinib 800 mg

Abbreviation: PFS, progression-free survival.With permission from Kantarjian H, et al. Blood. 2007;110: abstract 736.

Start-R—PFS by Prior Imatinib Dose (400 & 600 mg) and Intervention (High-Dose Imatinib or Switch to Dasatinib)

Suboptimal Response and Failure Early in the Course of Imatinib (6–12 Months)

Have Similar Outcomes• At 6 months: failure = no cytogenetic response (>95%

Ph+)• At 6 months: suboptimal response = minor/minimal

reduction (35%–95% Ph+)• Suboptimal and failure category patients both have

significantly inferior likelihood of gaining remission and remaining progression free– Likelihood of complete cytogenetic response

Failure at 6 months (Y/N): 19% vs 92% Suboptimal at 6 months (Y/N): 64% vs 97%

– Progression-free survival: Failure at 6 months (Y/N): 73% vs 87% Suboptimal at 6 months (Y/N): 62% vs 91%

Marin D, et al. Blood. 2008;112:4437-4444.

Suboptimal Response and Failure Early in the Course of Imatinib (6–12 months)

Have Similar Outcomes• Combine failure and suboptimal into “nonresponder”

group– Likelihood of complete cytogenetic response:

39% “nonresponders” vs 96% “responders”

– Overall survival: 87% vs 98%

– Progression-free survival: 70% vs 92%

• Similar data for “lumping” suboptimal and failure together at 12 months

• At 18 months, no statistical difference in overall and progression-free survival: failure vs suboptimal– Note: 18-month response based on molecular findings (MMR or

no MMR)

Marin D, et al. Blood. 2008;112:4437-4444.

WL1-Year Mark

• At 6 months, imatinib was increasedto 800 mg/d– Bone marrow studies performed at 1 year

Karyotype: 60% Ph+, 40% normal XX Fish: 55% of cells with fusion signal c/w Ph+

– Blood counts and side effects remain similar

How is she doing at this time?

Would you change anything at this point?

How do you counsel her regarding the results?

Decision Point 4

• What is your reaction to 12-month results?– Optimal response; no change in therapy

– Suboptimal but adequate, no change in therapy

– Suboptimal, change therapy

– Failure, change to alternate therapy

Lack of Major Cytogenetic Response (ie, >35% Ph+) at 12 Months is Considered “Failure” and

Therapy Change is Warranted

• Optimal response; no change in therapy

• Suboptimal but adequate, no change in therapy

• Suboptimal, change therapy

• Failure, change to alternate therapy

ABL kinase domain mutation testing should be performed(if not done previously and repeated, if done previously)

Rate of Progression to the Accelerated Phase or Blast Crisis on the Basis of Cytogenetic

Response After 12 Months or Molecular Response After 18 Months of Imatinib Therapy

With permission from Druker BJ, et al. N Engl J Med. 2006;355:2408-2417.

B

Pat

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%)

A

Pat

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%)

Mechanisms of Resistance to Imatinib

• BCR-ABL kinase domain mutations1

– Most common cause for clinical resistance to imatinib (≥50%)

– ~100 identified, occur at various regions and convey variable degrees (activation loop <phosphorylation loop <<kinase-binding pocket) of imatinib insensitivity

– Mutation at position 315 conveys resistance to imatinib as well as dasatinib and nilotinib

• BCR-ABL amplification/increased expression

• Ph+ clonal evolution

1. O’Hare T, et al. Blood. 2007;110:2242-2249.

Mechanisms of Resistance to Imatinib

• Decreased drug exposure– Decreased amount/activity of influx protein OCT-1

– Increased P-glycoprotein (ABCB1/MDR1) efflux 1 acid glycoprotein sequestration

• Other mechanisms– Src-related (Lyn) kinase overexpression?1

– Others: HSP70 overexpression; p53 mutations; PI3K/Akt/mTor activation; autocrine GM-CSF based JAK-2/STAT-5 activation

1. Donato NJ, et al. Blood. 2003;101:690-698.

Suggested Common and Differentiating Factors in Choosing Salvage Therapy (Dasatinib or Nilotinib) After Imatinib

Factor Potential Issue for Dasatinib Potential Issue for Nilotinib

Clinical

Myelosuppression (for both dasatinib and nilotinib)

? Select cardiac diseases(hypertension, hypercholesterolemia)

? Pre-existing pleural/pericardial disease

? Autoimmune disease

? Rash on prior imatinib or after starting dasatinib

Ongoing need for anticoagulation, antiplatelet therapy

Pre-existing bleeding disorders

? Prior pancreatic disease and liver disease

? Poorly controlled diabetes

Known QTc prolongationa

Required concomitant therapy with risk of prolonging the QTc

Molecular

ABL mutation T315I (for both dasatinib and nilotinib)

ABL mutation at positions 317 and 299 ABL mutation at positions 253, 255, 359

aBlack box warning regarding QT prolongation and sudden death.

WL: Month 18

• ABL kinase mutation analysis done: NO MUTATION

• Based on imatinib failure, prior myelosuppression issues, etc, nilotinib chosen, 400 mg BID

• Marrow at 15 months still shows rising burden of Ph+ cells– Now 80% Ph+ by karyotype, FISH concurs at 80%

• Repeat ABL kinase domain mutation now shows a T315I mutation, dominant over wild-type

Patient asks how she is doing and ifany change is needed

Nilotinib Phase II CML-CP—Efficacy(19 Month Follow-Up)

With permission from Kantarjian H, et al. Blood. 2008;112(11): abstract 3238.

# of Pts =

Median time to CHR 1 month; MCyR 2.8 monthsaPatients without CHR at baseline.

207

CHRa

76%

95

ImatinibIntolerant

65%

321

Overall

44%

ImatinibResistan

t

41%

0

100

80

60

40

20

321

Overall

59%

226

ImatinibResistan

t

56%

MCyR

ImatinibIntolerant

226 95

51%

CCyR

% o

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Nilotinib Efficacy According to Baseline BCR-ABL Mutations in CML-CP

3%4%

4%

5%

15%

24%

45%No Mutation

IC50 ≤ 150 nM

Y253H

E255K/V

F359C/V

T315I

Othersa

IC50-based groupingb

IC50 ≤150 nM M244V, L248V, G250E,

Q252H, E275K, D276G, F317L, M351T, E355A, E355G, L387F, F486S

IC50 >150 nM Y253H, E255K/V, F359C/V

IC50 >10,000 nM T315I

aMutations without available IC50 data.bNilotinib IC50 data cited were established in Ba/F3 in vitro proliferation assay (Weisberg E. Br J Cancer. 2006;94:1765-1769.).

With permission from Hochhaus A, et al. Blood. 2008;112(11): abstract 3216.

Decision Point 5

• What is your response to 15-month results?– Failure, change therapy

– Failure, proceed to matched unrelated donor stem cell transplantation

Identification of Resistant Disease Harboring a Dominant T315I Mutation Is

Grounds for Proceeding to Stem Cell Transplantation and/or a Clinical Trial to

Stabilize Disease/Gain Response

• Failure, change therapy

• Failure, proceed to matched unrelated donor stem cell transplantation

Other Novel Alternative ABL Inhibitors

• Bosutinib– Spectrum similar to dasatinib, different toxicity profile

– Less myelosuppression, pleural effusions; GI toxicity, rash

– Activity looks quite promising; being studied in other tyrosine kinase inhibitor resistance and front-line studies

• INNO-406– ABL/Lyn inhibitor, expected to have CNS penetration

– Spectrum and toxicity appear similar to nilotinib

• MK0457– First “t315i” inhibitor; in phase II studies

• PHA 739358, AP 24534, XL 228, SGX 393– The next wave of “T315i” inhibitors; in preclinical or phase I

Conclusions

Moshe Talpaz, MDProfessor

Department of Internal Medicine, Hematology-OncologyUniversity of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan

Conclusions

• The development of imatinib has revolutionized the treatment of CML

• Imatinib is a specific inhibitor of the BCR-ABL tyrosine kinase

Conclusions

• Some patients may be resistant to or intolerant of imatinib or develop resistance during treatment

• In many of these patients, resistance is due to mutations in the BCR-ABL gene

Conclusions

• Early monitoring, by cytogenetic and molecular methods, may help define treatment

• BCR-ABL mutational analysis should be focused on imatinib-resistant patients

• Determination of BCR-ABL mutation may help define specific treatment

Conclusions

• Nilotinib and dasatinib are second-lineBCR-ABL TKIs that have been shown effective in most patients resistant to imatinib

• TKIs that inhibit BCR-ABL with mutations conferring resistance to all 3 agents arein development

Conclusions

• Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for patients resistant to TKIs