Optimal Management

Management of
of CML
CML in
in 2015
2015
Optimal
Neil Shah,
Shah, MD
MD PhD
PhD
Neil
Edward S.
S. Ageno
Ageno Distinguished
Distinguished Professor
Professor
Edward
in Hematology/Oncology
Hematology/Oncology
in
Leader, Hematopoietic
Hematopoietic Malignancies
Malignancies
Leader,
Program
Program
Helen Diller
Diller Family
Family Comprehensive
Comprehensive Cancer
Cancer
Helen
Center at
at UCSF
UCSF
Center
San Francisco,
Francisco, California
California
San

The importance
importance of
of CML
CML to
to molecular
molecular oncology
oncology
The
CML was the first malignancy shown to be
associated with a particular genetic mutation
CML was the first disease to be treated with
small molecule tyrosine kinase inhibitors (TKI)
Lessons learned from TKI treatment have
informed multiple other oncologic areas
In 2015, the diagnosis, treatment, and
monitoring of malignancies is increasingly
molecular and personalized, and to a large
extent CML has paved the way

CML -- clinical
clinical features
features
CML

Approximately 6000 new US cases per year

median age at presentation: 53 years
men comprise approximately 60 percent of cases
disease is clinically divided into two phases
chronic phase
advanced phase
Accelerated phase
Blast crisis phase
Myeloid blast phase
Lymphoid blast phase

CML -- chronic
chronic phase
phase
CML

Approximately 40 percent of patients are without symptoms

(fatigue)
85 percent of newly diagnosed CML cases present in the
chronic phase
Median duration of chronic phase (prior to 2000)
approximately 4-6 years
After 2000 - unknown, greater than 10 years
Interventions can lead to durable responses in chronic
phase
Medical therapy (interferon, TKIs)
Stem cell transplantation

CML -- blast
blast crisis
crisis phase
phase
CML

Failure of normal development of blood cells

Responds poorly to medical intervention
bleeding, infections, anemia common
Median survival approximately 6 months

First hint
hint at
at the
the cause
cause of
of CML:
CML:
First
46,XX,t(9;22)(q34;q11.2)

Forrest et al, 2008; Bakshi et al, 2008; Image courtesy of Larry Beauregard, Jr., PhD.

ThePhiladelphia
Philadelphia(Ph)
(Ph)Chromosome
ChromosomeLeads
Leadsto
toCML
CML
The
BCR

ABL

Ph chromosome
BCR-ABL
(activated
tyrosine kinase)

CML

FDA
Approval,
May 2001

IMATINIB AS FRONTLINE THERAPY

FOR CML

IMATINIB AS FRONTLINE THERAPY

FOR CML
7-8 year update of newly-diagnosed
Chronic Phase CML patients treated
with 400 mg daily imatinib

OBrien et al. ASH 2008, Abstract 186

Annual Event Rates: Imatinib Arm

KM estimated EFS at 8 years = 81%

KM estimated rate without AP/BC at 8 years = 92%
7.5

% With Event

Event
Loss of CHR,
Loss of MCR,
AP/BC,
Death during treatment

4.8

AP/BC
3.3

2.8
1.5

2.0

1.6 1.7

0.9

0.8

1.2
0.5 0.3

0.4

0.4

Year

*Total events (n=3) including two CML-unrelated deaths (n=2), and one patient with progression to AP/BC

11
Deininger et al. ASH 2009, Abstract 1126

Overall Survival (ITT Principle): Imatinib Arm

% Without Event

100
90
80
70
60
50
40
30
20
10
0

Estimated overall survival

at 8 years is 85%
(93% considering only
CML-related deaths)
Survival: deaths associated with CML
Overall Survival
0

12

24
36
48
60
72
Months Since Randomization

84

96
12

A Healthcare Team Approach to Optimal Care

Imatinib Has Revolutionized the Therapeutic

Landscape for Patients With CML

clinicaloptions.com/oncology

Best Available Therapy

Survival Probability
(All Ph+ CML Disease Phases)

1.0
0.9

2002-2008, imatinib

0.8
0.7

Imatinib*
IFN- or SCT plus
2nd-line imatinib
IFN- or SCT 63
IFN-
53
Hydroxyurea
Busulfan

5-Yr OS, %

93

2010

71

2000

46
38

1997-2008, IFN- or SCT

plus 2nd-line imatinib

0.6
0.5

1990

1995-2008, IFN- or SCT

0.4

1980

0.3
1986-2003, IFN-

0.2

1983-1994, hydroxyurea

0.1

1983-1994, busulfan

0
0

*CML IV. CML IIIA. CML III.

1970

8
10
12
14
Yrs After Diagnosis

Leitner AA, et al. Internist (Berl). 2011;52:209-217.

16

18

20

22

1960

A Healthcare Team Approach to Optimal Care

Estimate of Rapidly Increasing CML

Prevalence

clinicaloptions.com/oncology

200,000
180,000
160,000
Cases (n)

140,000
120,000
100,000
80,000
60,000
40,000

Incidence 4700/yr
Age-matched mortality ratio vs normal population = 1.53
Accounts for increased US population to 392 million in 2050

20,000
2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
Yr
Huang X, et al. Cancer. 2012;118:3123-3127.

Imatinib -- Conclusions
Conclusions
Imatinib
Imatinib (400 mg daily) remains the standard dose for
chronic phase CML patients
85% overall survival with imatinib exceeds that of all other
CML therapies, with 7% patients dying from CML after eight
years
82% of patients treated with imatinib achieved a CCyR
55% of all imatinib randomized patients are still on study

treatment, and nearly all of these are in CCyR

Responses are typically durable, and the annual risk of

progression appears to decrease after 2-3 years
No new safety findings seen with long term follow-up
Many patients experience chronic lower grade toxicities

Chronic Phase CML Treatment Landscape Evolution

Imatinib
approved by FDA

2000

2002

2004

2006

2008

2010

2012

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16

MONITORING DISEASE IN PATIENTS

WITH CML

Treatment Response
Level of Response

Definition

Complete hematologic response (CHR)

Normal CBC and differential, no

extramedullary disease

Minor cytogenetic response

36%90% Ph-positive metaphases*

Partial cytogenetic response (PCyR)

1%35% Ph-positive metaphases*

Complete cytogenetic response (CCyR)

0% Ph-positive metaphases*

Major molecular response (MMR)

3-log reduction of BCR-ABL

Complete molecular response

Negativity by RT-PCR (4.5 log

reduction of BCR-ABL)

*Cytogenetic response is based on analysis of at least 20 metaphases.

PCyR + CCyR = major cytogenetic response (MCyR).

Adapted from NCCN Clinical Practice Guidelines in Oncology: chronic myelogenous leukemia.
V.3.2008. http://www.nccn.org. Accessed 02/04/2008; Deininger MW. Hematology Am Soc Hematol
Educ Program. 2005;174-182.

CML MONITORING

A Primer

Monitoring Disease Burden in CML

Bone marrow metaphase karyotype The historical gold standard.
Requires growing and dividing cells, hence marrow biopsy generally
necessary in chronic phase CML patients. Advantage: well-validated as a
surrogate marker of survival. Disadvantages: invasive procedure, operatordependent interpretation. Ph chromosome not always distinguishable
despite its presence. Poor sensitivity (~5%).

CellCycle
Centromere

Chromosomes
aremaximally
condensedin
metaphaseof
mitosis

Sister
Chromatids

The Philadelphia Chromosome

46,XX,t(9;22)(q34;q11.2) a.k.a. the Philadelphia chromosome

Forrest et al, 2008; Bakshi et al, 2008; Image courtesy of Larry Beauregard, Jr., PhD.

Monitoring Disease Burden in CML

Bone marrow metaphase karyotype The historical gold standard.
Requires growing and dividing cells, hence marrow biopsy generally
necessary in chronic phase CML patients. Advantage: well-validated as a
surrogate marker of survival. Disadvantages: invasive procedure, operatordependent interpretation. Ph chromosome not always distinguishable
despite its presence. Poor sensitivity (~5%).
Fluorescence in situ hybridization Performed on non-dividing (interphase)
cells. Advantage: can be performed on peripheral blood. Disadvantages:
Not validated with outcome, does not always correlate with metaphase
karyotype. Relatively poor sensitivity (~2%).

Detecting Mutations: FISH

Example of FISH detecting a reciprocal

chromosome translocation

Monitoring Disease Burden in CML

Bone marrow metaphase karyotype The historical gold standard.
Requires growing and dividing cells, hence marrow biopsy generally
necessary in chronic phase CML patients. Advantage: well-validated as a
surrogate marker of survival. Disadvantages: invasive procedure, operatordependent interpretation. Ph chromosome not always distinguishable
despite its presence. Poor sensitivity (~5%).
Fluorescence in situ hybridization Performed on non-dividing (interphase)
cells. Advantage: can be performed on peripheral blood. Disadvantages:
Not validated with outcome, does not always correlate with metaphase
karyotype. Relatively poor sensitivity (~2%).
BCR-ABL quantitative PCR Quantifies the BCR-ABL transcript level to the
level of a housekeeping gene detected. Advantages: can be performed on
peripheral blood. Highly sensitive (0.001%). Disadvantages: Not wellstandardized. Results obtained from one laboratory cannot be compared
with results from a different laboratory. May not detect abnormal fusions.

Monitoring Disease Burden in CML

Cytogenetics

CML (log10)

1-2 log reduction

MMR = 3 log
~ 5-6 log reduction

Dx

Treatment

Time

FISH
RT-PCR

PCR: Polymerase Chain Reaction

IMATINIB-RESISTANT DISEASE

How is it defined?

Imatinib Resistance
Resistance in
in Chronic
Chronic Phase
Phase CML
CML
Imatinib
Definitions
Definitions

Primary resistance: lack of an acceptable initial response

Primary hematologic resistance rare
Primary cytogenetic resistance ~35% of patients
lack of PCyR (35% Ph) by 3 months
lack of CCyR (0% Ph) by 12 - 18 months

Imatinib Resistance
Resistance in
in Chronic
Chronic Phase
Phase CML
CML
Imatinib
Definitions
Definitions

Primary resistance: lack of an acceptable initial response

Primary hematologic resistance rare
Primary cytogenetic resistance ~35% of patients
lack of PCyR (35% Ph) by 3 months
lack of CCyR (0% Ph) by 12 - 18 months

Secondary resistance: loss of an established initial response (relapse despite tx)

Hematologic Relapse WBC >nl and increasing)
Cytogenetic Relapse 30% increase in Ph+ metaphases
Molecular Relapse confirmed 1-log increase in BCR-ABL transcript level with
lack/loss of MMR

Imatinib Resistance
Resistance in
in Chronic
Chronic Phase
Phase CML
CML
Imatinib
Definitions
Definitions

Primary resistance: lack of an acceptable initial response

Primary hematologic resistance rare
Primary cytogenetic resistance ~35% of patients
lack of PCyR (35% Ph) by 3 months
lack of CCyR (0% Ph) by 12 - 18 months

Secondary resistance: loss of an established initial response (relapse despite tx)

Hematologic Relapse WBC >nl and increasing)
Cytogenetic Relapse 30% increase in Ph+ metaphases
Molecular Relapse confirmed 1-log increase in BCR-ABL transcript level with
lack/loss of MMR

Primary resistance is a risk factor for the development of secondary resistance

Patients without AP/BC (%)

ImatinibSurvival
Survival Without
WithoutAccelerated
Accelerated Phase/Blast
Phase/Blast Crisis
Crisis
Imatinib
byMolecular
Molecular Response:
Response: IRIS
IRISStudy
Study
by
100
90
80
70
60
50
Estimated rate at 60 months

40 Response at 18 months
30
20
10
0

CCyR with 3 log reduction

n=139 100%

CCyR with <3 log reduction

n=54

98%

No CCyR

n=88

87%

12

18

24

30

36

42

48

54

Time (months since randomization)

Druker B et al. N Engl J Med. 2006;355:2408-2417.

P<.001

60

66

P=.11

IMATINIB-RESISTANT DISEASE
Can it be identified early, and ideally
by less invasive methods than bone
marrow aspiration?

Chronic Myeloid Leukemia: Translating State-of-the-Art Practice to Patient Care

clinicaloptions.com/oncology

BCR-ABL/ABL after 3 Months of Imatinib

Predicts OS Outcomes

Probability of Survival

1.0
BCR-ABL/ABL< 9.84%
8-yr OS: 93.3%

0.8
BCR-ABL/ABL > 9.84%
8-yr OS: 56.9%

0.6

P < .001

0.4
0.2
0
0

Time From Onset of Imatinib Therapy (Yrs)

Marin D, et al. J Clin Oncol. 2012;30:232-238.

Individual 3-month decline

of BCR-ABL transcript levels as an
optimized predictor of survival in CML
B. Hanfstein, V. Shlyakhto, R. Hehlmann, M. Lauseker,
S. Saussele, P. Erben, A. Fabarius, U. Proetel,
S. Schnittger, H.J. Kolb, S.W. Krause, J.E.A. Schubert,
H. Einsele, M. Hnel, J. Dengler, C. Falge, L. Kanz, A. Neubauer,
M. Kneba, F. Stegelmann, M. Pfreundschuh, C.F. Waller,
K. Spiekermann, G.M. Baerlocher, M. Pfirrmann, J. Hasford,
W.-K. Hofmann, A. Hochhaus and M.C. Mller
for the SAKK and the German CML Study Group

Absolute 3-month transcript levels

give an estimate of BCR-ABL slope
diagnosis

3 months

BCR-ABLIS (%)

100%

10%
Time since imatinib onset

BCR-ABL slope is defined by

3-month reduction ratio of
transcripts

BCR-ABLIS (%)

diagnosis

3 months

reduction ratio =
BCR-ABL at 3 months
BCR-ABL at diagnosis

Time since imatinib onset

Overall survival (OS) according to

BCR-ABL reduction to 0.35-fold at 3
months

BCR-ABL reduction to

5Y-OS

0.35-fold

253

98%

> 0.35-fold

48

83%

p-value

0.001

Overall survival (OS) according to

10% BCR-ABLIS at 3 months

BCR-ABLIS at 3 months
10%
> 10%

234
67

5Y-OS

p-value

97%
90%

n.s.

Wide variability in BCR-ABL

transcript levels in untreated
patients
250

200

BCR-ABLIS (%)

Median 33%
Range 1-230

150

using GUS
(CF=2.18)

100

50

Patient #

Imatinib: IRIS 8-Yr Update Shows 37% Have

Unacceptable Outcome

Deininger M, et al. ASH 2009. Abstract 1126.

*Unacceptable outcome.

CML monitoring
monitoring simplified
simplified
CML
Quantitative BCR-ABL PCR at diagnosis and every three
months thereafter
Achievement of 10% BCR-ABL (IS) or PCyR after 3
months of imatinib is associated with superior survival in
multiple studies
The value of a 0.5 log reduction compared with the
patients own baseline requires confirmation in other
studies
Bone marrow cytogenetics should be performed at
diagnosis in all patients, and at three and/or 12 months in
select cases thereafter
Achievement of a complete cytogenetic response remains
the minimum acceptable level of response on TKI therapy
Ideally achieved within 12-18 months of TKI initiation

Long-Term Adherence
Adherence to
to Imatinib
Imatinib Is
Is
Long-Term
Critical for
for Achieving
Achieving Molecular
Molecular
Critical
Response
Response
Adherence to imatinib tracked for 3 mos in 87 consecutive
CML patients with CCyR using microelectronic monitoring
devices
MMR

0.8

Adherence > 90% (n = 64)

Adherence 90% (n = 23)
P < .001

0.6
0.4
0.2
0

1.0
Probability of CMR

Probability of MMR

1.0

CMR

0.8

Adherence > 90% (n = 64)

Adherence 90% (n = 23)
P = .002

0.6
0.4
0.2
0

0 6 12 18 24 30 36 42 48 54 60 66 72
Mos Since Start of Imatinib Therapy
Marin D, et al. J Clin Oncol. 2010;28:2381-2388.

0 6 12 18 24 30 36 42 48 54 60 66 72
Mos Since Start of Imatinib Therapy

IMATINIB-RESISTANT DISEASE

What are its causes?

Clinical Resistance
Resistance to
to Imatinib
Imatinib is
isMost
Most Often
OftenAssociated
Associated
Clinical
withRestoration
Restorationof
ofBCR-ABL
BCR-ABLKinase
KinaseActivity
Activity
with

ATP-binding pocket of T315I mutant BCR-ABL

cannot accommodate imatinib
WILD-TYPE

T315I MUTANT (MODEL)

structural data provided by B. Nagar and

J. Kuriyan UC Berkeley (Gorre et al, Science, 293:876, 2001)

(Incomplete) map of BCR-ABL kinase domain

mutations associated with clinical resistance
to imatinib
L248V
L298V F311L/I
G250E/A/F
E292V
T315I/N
Q252H/R

Y253H/F
E255K/V

F317L
L364I

D276G

M351T

A397P

M388L
H396R/P

E453G/K
E450G/Q

E459K/Q
F486S

S417Y
A

M244V

G383D
L387F/M

V379I

E355G/D
E279K V289A F359C/V/D/I
E281A

T277A

Gorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; RocheLEstienne et al, 2002; Shah et al, 2002; Hochhaus et al, 2002; Al-Ali et al, 2004

Courtesy Tim Hughes

BCR-ABL gene amplification

associated with clinical imatinib resistance
MB13

imatinib

MB14

imatinib

chemotherapy

Gorre et al, Science, 293:876, 2001

Role of Kinase Conformation in

Imatinib Resistance
Point mutations in BCR-ABL kinase domain
can destabilize the inactive conformation

Mutations that
directly affect
imatinib binding
Mutations that affect the
conformation required
to bind imatinib

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

Molecular Mechanisms
Mechanisms of
of Resistance
Resistance
Molecular
to Imatinib
Imatinib
Implications
Implications
to

BCR-ABL kinase inhibitors that are:

(1) more potent than imatinib and
(2) have activity against imatinib-resistant kinase
domain mutations
may be of significant therapeutic benefit to imatinib-resistant and
-intolerant patients

Normalized cell number after 48

hours of drug exposure

DasatinibInhibits
InhibitsGrowth
Growthofof14/15
14/15Imatinib-Resistant
Imatinib-ResistantBCR-ABL-Expressing
BCR-ABL-ExpressingBa/F3
Ba/F3
Dasatinib
CellLines
Linesininvitro
vitro
Cell
1.2

Parental Ba/F3 cells

T315I
0.8

Ba/F3
Bcr-Abl
E255K
T315I
M351T
M244V
G250E
Q252H

0.6

Q252R
Y253F

0.4

Y253H
E255V
F317L

0.2

E355G
F359V

0.5

2.5

25

Concentration of dasatinib (nM)*

Shah et al, Science, 2004

50

H396R
F486S

*Dasatinib is 300-400 more potent than imatinib in vitro