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Profiles in CML: Overview of Practice Challenges PowerPoint PPT Presentation


Profiles in CML: Overview of Practice Challenges. Moshe Talpaz, MD Professor Department of Internal Medicine, Hematology-Oncology University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan. Chronic Myelogenous Leukemia (CML).

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Profiles in cml overview of practice challenges l.jpg

Profiles in CML: Overview of Practice Challenges

Moshe Talpaz, MDProfessor

Department of Internal Medicine, Hematology-OncologyUniversity of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan


Chronic myelogenous leukemia cml l.jpg

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 l.jpg

CML—A Myeloproliferative Disorder

Normal

CML Chronic-Phase

Courtesy of John K. Choi, MD, PhD.


Cml is linked to a single cytogenetic abnormality the philadelphia chromosome l.jpg

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

X

Y

19

20

21

22

CML Is Linked to a Single Cytogenetic 
Abnormality—The Philadelphia Chromosome

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


The philadelphia chromosome and bcr abl l.jpg

The Philadelphia Chromosome and BCR-ABL

Chromosome 22

Chromosome 9

9 q+

9

2-11

c-BCR

1

c-ABL

Ph (or 22q-)

22

2-11

p210BCR-ABL

2-11

BCR

p190BCR-ABL

BCR-ABL

Exons

Introns

CML breakpoints

ALL breakpoints

ABL

FUSION PROTEINWITH TYROSINEKINASE ACTIVITY

BCR-ABL gene structure

t(9;22) translocation

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

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


Slide7 l.jpg

q34

Chromosome 22

(q34;q11)

Chromosome 9

t(9;22)

BCR

wwwww

BCR-ABL

q11

wwwwwwwww

wwwwwww

wwwwwwww

ABL

BCR

ABL

210 KD protein

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

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


The clinical course of untreated cml l.jpg

The Clinical Course of Untreated CML

Advanced Phases

Chronic Phase

Accelerated Phase

Blast Crisis

Median duration5–6 years

Median duration6–9 months

Median survival3–6 months

Faderl S, et al. Ann Intern Med. 1999;131:207-219.

Pasternak, G et al. J Cancer Res Clin Oncol. 1998;124:643-660.


Incidence and mortality of cml l.jpg

Incidence and Mortality Of CML

Based on current data,

median survival is expected to exceed 15–20 years.

Parker SL, et al. CA Cancer J Clin. 1997;47:5-27.

Jemal A, et al. CA Cancer J Clin. 2007;57:43-66..


Survival in early chronic phase cml l.jpg

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 l.jpg

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 l.jpg

IRIS Overall Survival (ITT Principle)Imatinib Arm

Estimated overall survival

at 7 years is 86%

(94% considering only

CML-related deaths)

Probability of Survival

Survival: deaths associated with CML

Overall survival

Months Since Randomization

Abbreviation: ITT, intent to treat.

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


Annual event rates imatinib arm l.jpg

Annual Event Rates—Imatinib Arm

  • KM estimated EFS at 7 years = 81%

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

Event

Loss of CHR,

Loss of MCR,

AP/BC,

Death during treatment

AP/BC

% with Event

a

Year

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 patientin 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.


Iris 7 year update key findings l.jpg

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 l.jpg

Imatinib Resistance

  • BCR-ABL specific

    • Mutations

      • >50 described with variable degrees of impact

      • ~50% of patients

    • Amplification or overexpression

      • ~7-10 %

50%–60%

  • BCR-ABL independent

    • Cellular pharmacology

      • Drug import/export

    • Other pathways

      • Wnt, notch

      • Autocrine factors

      • Lyn (other Src-family kinases)

40%–50%

Courtesy of M. Talpaz, MD.


24 mutations in 19 amino acids l.jpg

C

C

A

A

A‘

A‘

M

M

M

M

M

CC

A

A

A

A

A‘

M

M

C

C

C

A

A

A

L

C

C

C

C

M

M

M

C

C

C

C

A

A‘

CC

C‘

A

A‘

M

C

C

A

A

B

C

C

C

C

A

A

M‘

C

A‘

A

C

C‘

A

AA‘

C

A

A

M‘

A

C

M

P-Loop

KD

A-Loop

M244V

L248V

D267G

T315I

M351T

L387F/M

G250E/R

T277A

F317L

E355G

H396R

Q252H

F311L

L324Q

F359C/V

A397P

Y253F/H

V379I

E255K/V

24 Mutations in 19 Amino Acids

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 l.jpg

Role of Kinase Conformation in Imatinib Resistance

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

Mutations thatdirectly affect imatinib binding

Mutations that affect the conformation requiredto bind imatinib

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.


Slide18 l.jpg

Ba/F3

Bcr-Abl

E255K

T315I

M351T

M244V

G250E

Q252H

Q252R

Y253F

Y253H

E255V

F317L

E355G

F359V

H396R

F486S

Dasatinib Inhibits the Growth of Most
Imatinib Mesylate—Resistant BCR-ABL—Expressing Ba/F3 Cell Lines In Vitro

1.2

Parental Ba/F3 cells

1.0

T315I

0.8

Relative Growth After48 h of Drug Exposure

0.6

E255K

0.4

Wild-typeBCR-ABL

0.2

M351T

0

0

0.5

2.5

5

25

50

Concentration of Dasatinib (nM)

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


Slide19 l.jpg

Imatinib

20

Dasatinib

Nilotinib

15

% BCR-ABL Mutation

10

5

0

F3111

F317L

V299L

T315I

E255K

G250E

M351T

E355G/A

F359C/V

H396R/P

Y253H/F

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.

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


Case 1 ak l.jpg

Case 1: AK

Neil P. Shah, MD, PhDAssistant Professor

Division of Hematology/OncologyUCSF School of MedicineSan Francisco, California


Ak 33 year old male l.jpg

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 l.jpg

Decision Point 1

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

  • Hematopoietic stem cell transplantation

  • Imatinib

  • Dasatinib

  • Nilotinib

  • Interferon alpha


Slide23 l.jpg

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 l.jpg

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


Slide25 l.jpg

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 l.jpg

L248V

G383D

L298V

F311L/I

L387F/M

G250E/A/F

A397P

E453G/K

E292V

T315I/N

M388L

Q252H/R

E459K/Q

E450G/Q

H396R/P

Y253H/F

F317L

F486S

S417Y

L364I

E255K/V

x

A

C

P

V379I

D276G

M351T

M244V

E355G/D

T277A

V289A

E279K

F359C/V/D/I

E281A

(Incomplete) Map of BCR-ABL Kinase Domain Mutations Associated with Clinical Resistance to Imatinib

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

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.

Courtesy of Tim Hughes, MD.


Role of kinase conformation in imatinib binding l.jpg

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

Helix C

Imatinib

P-loop

Activation

loop

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


Differential binding of dasatinib and imatinib to abl kinase l.jpg

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.


How resistant is the e255k mutation to imatinib in vitro l.jpg

How Resistant is the E255K Mutation to Imatinib in Vitro?


Resistance to imatinib of cells bearing bcr abl mutations l.jpg

Resistance to Imatinib of CellsBearing BCR-ABL Mutations

Measured by determining concentration dependence of normalized viable cell counts.

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


Decision point 3 l.jpg

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 l.jpg

How Resistant is the E255K Mutation to Dasatinib in Vitro?


Efficacy of dasatinib against imatinib resistant kinase domain mutations in vitro l.jpg

Ba/F3

Bcr-Abl

E255K

T315I

M351T

M244V

G250E

Q252H

Q252R

Y253F

Y253H

E255V

F317L

E355G

F359V

H396R

F486S

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

1.2

Parental Ba/F3 cells

1.0

T315I

0.8

Relative Growth After48 h of Drug Exposure

0.6

E255K

0.4

unmutatedBCR-ABL

0.2

0

0

0.5

2.5

5

25

50

Concentration of Dasatinib (nM)

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


How responsive is the e255k mutation to dasatinib in patients l.jpg

How Responsive is the E255K Mutation to Dasatinib in Patients?


Dasatinib 70 mg twice daily in cml cp response by individual baseline bcr abl mutation l.jpg

Complete CyRPartial CyR

Complete HR

No response

Dasatinib 70 mg Twice Daily in CML-CPResponse by Individual Baseline BCR-ABL Mutation

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

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


How is longer term survival impacted by dasatinib in chronic phase cml patients l.jpg

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


Slide37 l.jpg

Dasatinib 100 mg in Imatinib-Resistantand -Intolerant CML-CPOverall Survival

100

80

60

0

% Alive

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

036912151821242730

Months

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

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


Slide38 l.jpg

Survival of Patients Who Discontinued Imatinib Study Therapy

100

Survival 85% at 5 years after discontinuing study

90

80

70

60

% Survival (all deaths)

50

40

Survival approximately 50% at 5 years after stopping imatinib study drug

30

Safety (n = 30)

Efficacy (n = 82)

Bone marrow transplant (n = 16)

Other reason (n = 80)

20

10

0

0

12

24

36

60

72

84

96

48

Months After Stopping Imatinib Study Therapy

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 l.jpg

How Resistant is the E255K Mutation to Nilotinib in Vitro?


Activity of nilotinib on imatinib resistant bcr abl mutants in vitro l.jpg

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

Ba/F3 cell proliferation

3000

Imatinib

Nilotinib

2500

2000

IC50 (nM) on Proliferation

1500

1000

500

0

F359V

E255V

T315I

+ IL3

M237I

F317L

L387F

L248V

F311V

F317V

S348L

F468S

F317C

F359C

Y253H

E255D

E255K

E255R

E275K

E281K

E292K

E355A

A380S

G250E

G250V

E276G

K285N

D325N

M351T

E355G

M388L

M244V

G250A

Q252H

Maternal

BCR-ABL wt

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.


How responsive is the e255k mutation to nilotinib in patients l.jpg

How Responsive is the E255K Mutationto Nilotinib in Patients?


Phase ii nilotinib in cml cp response and progression based on mutation ic 50 l.jpg

Phase II Nilotinib in CML-CPResponse and ProgressionBased on Mutation IC50

  • 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

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

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


Slide43 l.jpg

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 l.jpg

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 l.jpg

Case 2: WL

Michael J. Mauro, MD

Associate Professor

Center for Hematologic Malignancies, Knight Cancer Institute

Oregon Health & Science University

Portland, Oregon


Wl 45 year old female l.jpg

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 147 l.jpg

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 l.jpg

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


Wl follow up at month 3 l.jpg

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 250 l.jpg

Decision Point 2

  • Response to 3-month results?

    • Decrease imatinib dose to 300 mg/day dueto 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


Slide51 l.jpg

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


3 month qpcr predictive of ability to achieve subsequent mmr iris trial l.jpg

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

100%

100

>2 log reduction

90

1–2 log reduction

80

0–1 log reduction

69%

70

P <.001

60

50

% Achieving MMR

40

30

20

13%

10

0

3

6

9

12

15

18

21

24

27

30

Months on Imatinib

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

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


Wl follow up at month 6 l.jpg

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 354 l.jpg

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


Slide55 l.jpg

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

ABL kinase domain mutation testing should be considered


Failure suboptimal response european leukemianet consensus l.jpg

Failure, Suboptimal Response—European LeukemiaNet Consensus

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.

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


Probability of ccyr efs by cytogenetic response at 6 months iris trial l.jpg

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

(n = 81)

(n = 19)

% of Patients with Subsequent CCyR

(n = 16)

(n = 16)

1%–35%

36%–65%

CyR at 6 months (Ph+):

66%–95%

>95%

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.


Slide58 l.jpg

ENDPOINTS:

Primary: MCyR and CCyR at 3 months

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

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

Cytogenetics at 12 weeks

Randomization 2:1

Dasatinib 70 mg BID(n = 101)

Continue therapyor crossover for:

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

Imatinib 800 mg (n = 49)

  • Progression

  • Lack of MCyR

  • Intolerance

Abbreviations: CCyR, complete cytogenetic response; IM, imatinib; MCyR, major cytogenetic response.

Kantarjian H, et al. Blood. 2007;110: abstract 736.


Dasatinib vs high dose im in cml cp best response prior to cross over l.jpg

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

P = .017

Dasatinib

60

Imatinib

53

P = .0025

50

44

P = .028

40

33

29

30

Percent

18

20

12

10

0

MCyR

CCyR

MMR

Abbreviations: CCyR, complete cytogenetic response; IM, imatinib; MCyR, major cytogenetic response; MMR, major molecular response.

Kantarjian H, et al. Blood. 2007;110: abstract 735.


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100

80

60

40

20

0

P = .0562

P = .0033

% PFS

Imatinib 400 mg Dasatinib

Imatinib 400 mg Imatinib 800 mg

Imatinib 600 mg Dasatinib

Imatinib 600 mg Imatinib 800 mg

03691215182124273033

Months

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

Abbreviation: PFS, progression-free survival.

With permission from Kantarjian H, et al. Blood. 2007;110: abstract 736.


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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.


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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.


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WL1-Year Mark

  • At 6 months, imatinib was increased
to 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?


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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


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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)


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Patients Without Progression (%)

Patients Without Progression (%)

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

A

B

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


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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.


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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.


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

aBlack box warning regarding QT prolongation and sudden death.


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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


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

100

76%

80

65%

59%

56%

60

51%

% of Patients

44%

41%

40

20

0

CHRa

Overall

Imatinib

Resistant

Imatinib

Intolerant

Overall

Imatinib

Resistant

Imatinib

Intolerant

321

226

95

321

226

# of Pts =

95

207

MCyR

CCyR

Median time to CHR 1 month; MCyR 2.8 months

aPatients without CHR at baseline.

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


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

Y253H

T315I

4%

3%

E255K/V

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

4%

F359C/V

5%

45%

Othersa

15%

No Mutation

24%

IC50≤ 150 nM

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.


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Decision Point 5

  • What is your response to 15-month results?

    • Failure, change therapy

    • Failure, proceed to matched unrelated donor stem cell transplantation


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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


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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


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Conclusions

Moshe Talpaz, MDProfessor

Department of Internal Medicine, Hematology-OncologyUniversity of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan


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Conclusions

  • The development of imatinib has revolutionized the treatment of CML

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


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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


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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


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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


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Conclusions

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


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