Transcript Targeted therapy in CML

Chronic Myeloid Leukemia (CML)
and Targeted Therapy
 CML
– Proliferative disorder of hematopoietic stem cells
– Well-characterized clinical course
 Philadelphia (Ph) chromosome
– Unique chromosomal abnormality
 Bcr-Abl tyrosine kinase
– A single molecular abnormality that causes
transformation of a hematopoietic progenitor
into a malignant clone
Incidence of Hematologic Malignancies
Type of Leukemia
Overall
CML
CLL
AML
ALL
Incidence per 100,000*
6–10
1–2
2–3
2–3
1–2
*1990, Western hemisphere.
CLL = chronic lymphoid leukemia; AML = acute myeloid leukemia; ALL = acute lymphoid leukemia.
Black RJ et al. Eur J Cancer. 1997;33:1075-1107.
Epidemiology of CML
 Median age range at presentation: 45 to 55 years
 Incidence increases with age
– 12%–30% of patients are >60 years old
 Male-to-female ratio–1.3:1
 At presentation
– 50% diagnosed by routine laboratory tests
– 85% diagnosed during chronic phase
Clinical Presentation of CML
 Common Symptoms
– Fatigue
– Weight loss/anorexia
– Abdominal fullness
 Common Signs
– Palpable splenomegaly
 Common Laboratory Findings
– Abnormal differential
– Leukocytosis
– Thrombocytosis
– Anemia
– Basophilia
CML: Peripheral Blood Smear
Courtesy of John K. Choi, MD, PhD, University of Pennsylvania.
Clinical Course: Phases of CML
Advanced phases
Chronic phase
Median 5–6 years
stabilization
Accelerated phase
Blast crisis
Median duration
6–9 months
Median survival
3–6 months
Typical Laboratory Parameters
by Phase of CML
Phase of CML
Parameter
Chronic
WBC count
20 x 109/L
Blasts
Accelerated
Blast Crisis
—
—
1%–15%
15%
30%

20%
—
 or 

Basophils
Platelets
 or normal
Bone marrow
Myeloid hyperplasia
Cytogenetics
Ph+
Bcr-Abl
+
WBC = white blood cell; Ph+ = Ph chromosome–positive.
+
+
Definition of Accelerated Phase
M.D. Anderson Cancer Center
(Kantarjian 1988)
PB blasts 15%
PB blasts + promyelocytes 30%
PB basophils 20%
Platelet count 100 x 109/L
unrelated to therapy
Sokal
(Sokal 1988)
IBMTR
(Speck 1984)
PB or BM blasts 5%
–
PB basophils 20%
Thrombopenia unrelated to therapy
PB or BM blasts 10%
PB or BM blasts+promyelocytes 20%
Cytogenetic karyotypic evolution
Thrombopenia unresponsive to BU or
HU therapy
Cytogenetic karyotypic evolution
Persistent thrombocytosis
Myelofibrosis
Anemia unresponsive to BU or HU
therapy
Progressive splenomegaly
Rapid doubling time of leukocytes <5d
Platelet 1000 x 109/L despite
adequate therapy
Marrow collagen fibrosis
Anemia unrelated to therapy
Progressive splenomegaly
Leukocyte doubling time <5d
PB basophils + eosinophils 20%
Frequent Pelger-Huët–like
neutrophils; nucleated erythrocytes;
megakaryocyte nuclear fragments
Leukocyte count difficult to control with
BU or HU therapy
Fever not otherwise explained
Development of chloromas
PB = peripheral blood; BM = bone marrow; HU = hydroxyurea; BU = busulfan.
Kantarjian HM et al. Cancer. 1988;61:1441-1446.
Sokal JE et al. Semin Hematol. 1988;25:49-61.
Speck B et al. Semin Hematol. 1984;21:48-52.
Therapies for Advanced Stages of CML
Usual Therapy
Accelerated phase
Blast crisis
IFN- = interferon-alpha.
Various single-agent or
combination
chemotherapy, IFN-
Acute leukemia type
multiagent
chemotherapy
Hematologic
Response
(complete)
<50%
Cytogenetic
Response
Survival
anecdotal
<18 months
20%–40%
(5%–30%)
anecdotal
3–6 months
Ph Chromosome
Cytogenetic Abnormality of CML:
The Ph Chromosome
1
6
2
7
3
8
13
14
19
20
4
9
15
21
5
10
16
22
11
17
x
12
18
Y
Prevalence of the Ph Chromosome
in Hematologic Malignancies
Leukemia
% of Ph+ Patients
CML
95
ALL (Adult)
15–30
ALL (Pediatric)
5
AML
2
Faderl S et al. Oncology. 1999;13:169-180.
The Ph Chromosome: t(9;22) Translocation
9
9 q+
22
Ph ( or 22q-)
bcr
bcr-abl
abl
FUSION PROTEIN
WITH TYROSINE
KINASE ACTIVITY
bcr-abl Gene and Fusion Protein Tyrosine Kinases
Chromosome 22
Chromosome 9
c-bcr
1
2-11
2-11
Exons
Introns
CML Breakpoints
ALL Breakpoints
2-11
p210Bcr-Abl
p185Bcr-Abl
c-abl
p210Bcr-Abl Fusion Protein Tyrosine Kinase
Extracellular
space
Cytoplasm
Y177
BAP-1
SH3
SH2
SH1
GRB2
CBL SHC CRKL
Faderl S et al. N Engl J Med. 1999;341:164-172.
Molecular Methods for Detecting bcr-abl
at the Ph Chromosome
 Fluorescence in situ hybridization (FISH)
Interphase
Courtesy of Charles Sawyers, UCLA.
Metaphase
Therapeutic Options
Goals of Therapy for CML: Response Criteria
 Hematologic Response
 Cytogenetic Response
– Complete:
Normal peripheral blood count
WBC <10 x 109/L
Platelets <450 x 109/L
No immature cells
– Major:
Complete:
Partial:
– Minor:
 Disappearance of splenomegaly
 Normal physical examination
0% Ph+ cells
1%–35% Ph+ cells
36%–95% Ph+ cells
Therapeutic Options for CML
 Allogeneic stem cell transplantation (SCT)
 IFN-–based treatments
 Chemotherapy with hydroxyurea, busulfan
 Imatinib mesylate (formerly STI571)
100%
Chronic Myelogenous Leukemia
Survival by Disease Stage
90%
S
u
r
v
i
v
a
l
100%
90%
80%
80%
P=0.0001
70%
60%
70%
60%
First Chronic Phase (n=1903)
50%
50%
40%
40%
Accelerated and 2nd CP (n=744)
30%
30%
20%
20%
Blast Phase (n=159)
10%
10%
0%
0%
0
1
2
3
Years After Transplant
June 2001, based on transplants 1987 - Feb 2001
4
5
S
u
r
v
i
v
a
l
PROBABILITY OF SURVIVAL AFTER
ALLOGENEIC TRANSPLANTS FOR CML IN CHRONIC
PHASE
BY DONOR TYPE AND DISEASE DURATION, 1994-1999
100
PROBABILITY, %
80
HLA-identical sibling, <1y (N = 2,876)
HLA-identical sibling, 1y (N = 1,391)
60
Unrelated, <1y (N = 613)
40
Unrelated, 1y (N = 936)
20
P = 0.0001
0
0
1
2
3
4
5
6
YEARS
SUM02_3.ppt
Advances in SCT
 Donor lymphocyte infusion (DLI) after SCT
– Used to prevent or treat relapse after SCT
– Can induce a graft-versus-leukemia effect
– High rate of graft-versus-host disease (GVHD)
 Non-myeloablative SCT
– Low-dose, less toxic preparative regimens
– Provides immunosuppression to allow donor cells to engraft,
while graft-versus-leukemia effect eradicates tumor
– Permits SCT use in patients not eligible for conventional SCT
– Is still investigational
IFN-: Chronic Phase CML
 IFN- has multiple biologic effects
– Inhibition of proliferation
– Regulation of cytokine expression
– Modulation of immune system
 Higher doses correlate with better response and
greater toxicity
 Cytogenetic response may take 12 to 18 months
 Survival advantage in low-risk patients with early chronic
phase CML
 IFN- in combination with cytarabine (ara-C) may be superior
to IFN- alone
IFN-: Clinical Results in CML
IFN-
IFN- + ara-C
(results from 7
clinical trials)1-7
(results from 4
clinical trials)8-11
CHR (%)
31–80
64–92
Cytogenetic responses (%)
Any
Major
18–58
6–38
41–74
10–50
3-year survival rates (%)10
79
86
Response
CHR = complete hematologic response.
1. Kantarjian HM et al. Ann Intern Med. 1995;122:254-261. 2. Ozer H et al. Blood. 1993;82:2975-2984. 3. Mahon F et al. Blood. 1994;84:3592. 4. Hehlmann
R et al. Blood. 1994;84:4064-4077. 5. Italian Cooperative Study Group on CML. N Engl J Med. 1994;330:820. 6. Allan NC et al. Lancet. 1995;345:13921397. 7. Ohnishi K et al. Blood. 1995;86:906-916. 8. Silver RT et al. Blood. 1996;88 (suppl 1)638a. 9. Tura S et al. Blood. 1998;92(suppl 1) 317a. 10. Guilhot
F et al. N Engl J Med. 1997;337:223-229. 11. Kantarjian HM et al. J Clin Oncol. 1999;17:284-292.
Achieving a Cytogenetic Response Correlates
with Increased Survival
Major response
1.0
0.9
Proportion Surviving
0.8
0.7
P <.001
0.6
0.5
0.4
Minor or no response
0.3
0.2
0.1
0.0
0.0
12
24
36
Months After Treatment
Guilhot F et al. N Engl J Med. 1997;337:223-229.
48
60
IFN-: Safety and Tolerability
in Patients With CML
 Chronic adverse events include fatigue, depression,
insomnia, and weight loss as well as gastrointestinal
disorders, neurologic symptoms, psychiatric disorders,
dermatologic effects, renal dysfunction, and hematologic
cytopenias
 >90% of patients experience constitutional symptoms
 >50% of patients require IFN- dose reduction
 >25% of patients discontinue treatment due to severe
drug-induced toxicity
Chemotherapy: Chronic Phase CML
 Oral cytotoxic agents
– Hydroxyurea
– Busulfan
 Hematologic response in up to 90% of patients
 Rare MCR (0.9%–5%)
 Palliative care—no effect on disease progression
MCR = major cytogenetic response.
Pegylated IFN-
 IFN- coupled to polyethylene glycol (PEG)
 Has a longer half-life than IFN- and is administered
once a week
 Phase III trials do not find an efficacy advantage
over interferon
Imatinib Mesylate
Gleevec
Imatinib Mesylate (Formerly STI571)
Tyrosine Kinase Inhibitor
for CML
The Ideal Target for Molecular Therapy
 An abnormality present in the majority of patients with
a specific disease
 Determined to be the causative abnormality
 Has unique activity that is
– Required for disease induction
– Dispensable for normal cellular function
Bcr-Abl as a Therapeutic Target for CML
 Bcr-Abl is detected in 95% of patients with CML
 Bcr-Abl is the causative abnormality of CML
 Bcr-Abl tyrosine kinase is constitutively
activated intracellularly
– Tyrosine kinase activity is required for CML cell function
 Abl null mice are viable
 Imatinib mesylate: targets the cause of CML
Structure of Imatinib Mesylate
• CH3SO3H
C29H31N7O•CH4SO3
Class: Phenylaminopyrimidines, 589.7 mw
Mechanism of Action of Imatinib Mesylate
Goldman JM, Melo JV. N Engl J Med. 2001;344:1084-1086.
Rationale for Use of Imatinib Mesylate in CML
 CML is characterized by a 9;22 translocation known as
the Ph chromosome
 The product of this fusion gene is Bcr-Abl tyrosine
kinase, which is leukemogenic
 Imatinib mesylate is a selective inhibitor of Bcr-Abl
kinase
 Inhibition of Bcr-Abl kinase should be an effective
therapy for CML
 Imatinib mesylate has shown antileukemic activity in
in vitro and in vivo studies
Cellular Selectivity of Imatinib Mesylate: IC50 M
Kinases Inhibited
Kinases Not Inhibited
v-Abl
p210Bcr-Abl
p185Bcr-Abl
TEL-Abl
PDGF-R
TEL-PDGF-R
c-Kit
Flt-3
c-Fms, v-Fms
EGF receptor
c-erbB2
Insulin receptor
IGF-I receptor
v-Src
JAK-2
0.1–0.3
0.25
0.25
0.35
0.1
0.15
0.1
>10
>10
>100
>100
>100
>100
>10
>100
PDGF-R = platelet-derived growth factor receptor; EGF = epidermal growth factor; IGF-I = insulin-like growth factor-I.
Druker BJ et al. Nat Med. 1996;2:561-566.
Imatinib Mesylate Inhibits the Growth of
Bcr-Abl–Positive Cells
U937*
KG1*
SU DHL1*
KCL22†
K562†
KU812†
Imatinib Mesylate Concentration (M)
*Bcr-Abl–negative cell lines.
Gambacorti-Passerini C et al. Blood Cells Mol Dis. 1997;23:380-394.
†Bcr-Abl–positive
cell lines.
Imatinib Mesylate: Achieving Steady-State
Pharmacokinetics at 400mg and 600mg Doses
 Rapidly and completely absorbed after oral administration
 Absolute bioavailability 98%
 Terminal half-life (t1/2)  18–22 h; volume of distribution
 435 L; and clearance  14 L/h
 Linear and dose-proportional increase in AUC with doses
25mg to 1000mg
 Imatinib mesylate is metabolized in the liver by the P450
enzyme system
 Imatinib mesylate can alter the metabolism of drugs that are
substrates of CYP3A4 and may alter CYP2D6 substrates
AUC = area under the concentration time curve.
Phase I Studies with Imatinib Mesylate
 Study design
– Open-label, dose escalation
 Study objectives
– Safety
– Tolerability
– Evidence of antileukemic activity
 Eligibility
Chronic Phase CML
– Ph+ CML
– WBC >20,000, <15% blasts
– IFN- failure
Acute Leukemia
CML in Blast Crisis
Ph+ ALL
Ph+ AML
Phase I Studies With Imatinib Mesylate: Results
Hematologic and Cytogenetic Responses
IFN-–Resistant
Chronic Phase CML
300mg–1000mg/day
(n=55)
Blast Crisis
Myeloid
Phenotype
(n=39)
Blast Crisis
Lymphoid
Phenotype
(n=20)
Hematologic response
Complete
98%
98%
54%
13%
70%
20%
Cytogenetic response
Major
Complete
49%
31%
14%
4%
40%
20%
Most adverse events were mild to moderate in severity (grades 1–2)
A maximal tolerated dose (MTD) was not reached
Higher frequency and severity of adverse events with doses 800mg
Imatinib Mesylate: Rapid Responses
Hematologic Response
100
Cytogenetic Response
100
% Ph+
10
60
40
20
1
0
WBC x 103
80
0
Days on Imatinib Mesylate
Days on Imatinib Mesylate
Imatinib Mesylate: Phase I Conclusions
 Generally well tolerated with a mild side-effects profile
 In all phases of CML, imatinib mesylate achieved
– Hematologic responses
– Cytogenetic responses
 Time to response was rapid
Phase II Studies With Imatinib Mesylate
 3 large international trials have been conducted
– 0110: Patients with CML in chronic phase
after failure of IFN- therapy
– 0109: Patients with CML in accelerated phase
– 0102: Patients with CML in myeloid blast crisis
 Study design and objectives
– Open-label, multicenter, noncontrolled
– Imatinib mesylate dose: 400mg to 600mg
– Assess safety, efficacy, and survival rate
Imatinib Mesylate: Phase II Study 0110—Patients
With CML in Chronic Phase After IFN- Failure
 Treatment schedule: 400mg daily
 Accrual time: December 1999 to May 2000
 Patients with CML in chronic phase:
– Hematologic failure
• Lack of complete cytogenetic response (CHR) after
6 months IFN-
• Loss of CHR
– Cytogenetic failure
• No cytogenetic response after 12 months of IFN-
• Loss of a cytogenetic response
– IFN- intolerant
 Primary endpoint: cytogenetic response
Patient Demographics
 Enrolled patients: N=532, confirmed chronic phase CML n=454 (85%)
 Median age [yrs] (range)
57 (18–90)
 IFN- failure





– Hematologic failure
– Cytogenetic failure
– IFN- intolerance
Months from diagnosis (range)
Months of prior IFN-* (range)
WBC (x109/L) (range)
Platelets (x109/L) (range)
Additional chromosomal abnormalities
*IFN- at doses >25 MIU/week.
152 (29%)
188 (35%)
192 (36%)
32 (3–218)
14 (>1–135)
14 (1.8–260)
296 (75–2081)
87 (16%)
Response Criteria in Chronic Phase CML Patients
(Study 0110)
 CHR
– WBC <10 x 109/L
– Platelets <450 x 109/L
– No blasts, basophils <20%
– No extramedullary disease
 Cytogenetic responses
– Complete cytogenetic response (CCR)
– Partial cytogenetic response (PCR)
– Major cytogenetic response (MCR)
0% Ph+
1% to 35% Ph+
CCR + PCR
Results in Chronic Phase CML Patients
(Study 0110)
Total
Hematologic
Failures
Resistant
Cytogenetic
Failures
Relapsed
IFN-
Intolerant
Resistant
Relapsed
Cytogenetic Response
Major
60
41
57
55
83
66
Complete
41
25
41
31
76
47
Partial
19
16
16
24
7
19
5
8
1
8
2
2
11
16
16
9
2
11
95
89
99
97
98
93
Minor
Minimal
Hematologic Response
Complete
Kantarjian H et al. N Engl J Med. 2002;346:645-653.
2002 Massachusetts Medical Society. All rights reserved.
Proportion of Patients Who Responded
Time to MCR and CCR in Chronic Phase CML
(Study 0110)
MCR
CCR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10
11 12
Months Since Start of Treatment
13
14
15
Durable Response in Chronic Phase Patients
(Study 0110)
n 100
o
is 90
s
e
rg 80
o
rp 70
tu 60
o
h
t 50
iw
s 40
tn
e 30
it
a 20
p
fo 10
%
0
0
= Censored
observations
2
4
6
8
10
12
14
16
18
Months since start of
Months
Since
Start of Treatment
treatment
tttreatment
Kantarjian H et al. N Engl J Med. 2002;346:645-653.
2002 Massachusetts Medical Society. All rights reserved.
20
22
First-Line Use of Imatinib Mesylate in Early
Chronic Phase CML
 Front-line use of imatinib mesylate in early chronic
phase is supported by the results of a single institution
study recently presented at ASH 2001
– Median time from diagnosis: 1 month
– Dose: 400mg daily
– MCR rate: 77% at 3 month follow-up
– CCR rate: 36%
– Severe adverse events in 5% of patients
 A large multinational multicenter phase III clinical trial
comparing imatinib mesylate vs IFN- plus ara-C as
first-line therapy is ongoing (Study 106)
International Multicenter Clinical Trial: Imatinib
as First-Line Therapy in CML (IRIS Study)
 Study design and objectives:
– Imatinib mesylate versus IFN- + ara-C in newly diagnosed
previously untreated, chronic phase CML patients
– Phase III, multicenter, randomized, open-label
– Primary objectives: time-to-treatment failure which includes
• Failure to achieve a CHR at 6 months
• Failure to achieve an MCR at 6 months
• Loss of CHR
• Progression, intolerance of treatment, or death
 Secondary objectives include:
– Quality of life (QoL)
– Rate and duration of CHR
– Rate and duration of CCR
Imatinib Mesylate as First-Line Therapy
(IRIS Study)
 1,106 adult patients were randomized to either
– Imatinib mesylate 400mg/day
– IFN- with a target dose of 5MU/m2/day and ara-C
20mg/m2/day for 10 days every months
 Treatment with each drug will be continued until:
– Crossover
– Progression
– Death
– Intolerance to treatment
Study Design for Phase III Trial
Imatinib mesylate
S
R
If:
• Progression
• Intolerance of treatment
• Failure to achieve MCR
at 24 months
Crossover
IFN- + ara-C
S = screening
R = randomization
Progression:
• Death
• Accelerated phase or blast crisis
• Loss of MCR or CHR
• Increasing WBC count
Multicenter Clinical Trial with Accelerated
Phase CML Patients (Study 0109)
 Treatment schedule: 400mg (n=77) or 600mg (n=158)
daily
 Patient selection:
– Blood or bone marrow blasts 15% but <30%
– Blasts + promyelocytes in peripheral blood or bone
marrow 30%
– Peripheral basophils 20%
– Thrombocytopenia <100 x 109/L unrelated to therapy
 Primary endpoint: hematologic response
Response Criteria (Study 0109)
 CHR
– Marrow blasts <5%, no peripheral blood blasts
– ANC 1.5 x 109/L and platelet count 100 x 109/L
– No extramedullary disease
• No evidence of leukemia: as for CHR except for
(ANC >1.0 x 109/L) and platelets (>20 x 109/L)
• Return to chronic phase (RTC)
 Cytogenetic responses
– Complete cytogenetic response (CCR)
0% Ph+
– Partial cytogenetic response (PCR) 1% to 35% Ph+
– Major cytogenetic response (MCR)
CCR + PCR
Clinical Results in Patients With Accelerated CML
(Study 0109)
Results
400mg
600mg
Overall
Hematologic response
Complete
65%
27%
71%
37%
69%
34%
No evidence of leukemia
10%
13%
12%
Return to chronic phase
27%
21%
23%
Major cytogenetic response
Complete
Partial
16%
11%
5%
28%
19%
8%
24%
17%
7%
Higher Doses of Imatinib Delays the Time to
Disease Progression (Study 0109)
400mg
600mg
1.0
Proportion of Patients
Without Progression
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18
Months Since Start of Treatment
Increased Survival: Achieved with a cytogenetic
response at 3 Months (Study 0109)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Hematologic Response at 3 Months
Yes
No
0.2
0.1
0.0
0 1
2
3 4
5
6
7 8
9 10 11 12 13 14 15 16 17 18
Months Since Start of Treatment
Cytogenetic Response
Proportion of Patients Alive
Proportion of Patients Alive
Hematologic Response
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Cytogenetic Response at 3 Months
0.2
Yes
No
0.1
0.0
0 1
2
3 4
5
6
7 8
9 10 11 12 13 14 15 16 17 18
Months Since Start of Treatment
Multicenter Clinical Trial In Blast Crisis CML
Patients (Study 0102)
 Treatment schedule: 400mg (n=37) or 600mg
(n=223) daily
 Patient selection:
– Blast crisis: blood or bone marrow blasts 30%;
extramedullary involvement other than spleen or liver
– Prior treatment: previously treated/no prior treatment
except hydroxyurea, IFN-, busulfan, low-dose ara-C
 Primary endpoint: hematologic response
Response Criteria (Study 0102)
 CHR
– Marrow blasts <5%, no peripheral blood blasts
– ANC 1.5 x 109/L and platelet count 100 x 109/L
– No extramedullary disease
• No evidence of leukemia: as for CHR except for
(ANC >1.0 x 109/L) and platelets (>20 x 109/L)
• Return to chronic phase (RTC)
 Cytogenetic responses
– Complete cytogenetic response (CCR)
0% Ph+
– Partial cytogenetic response (PCR) 1% to 35% Ph+
– Major cytogenetic response (MCR)
CCR + PCR
Clinical Results in Blast Crisis CML Patients
(Study 0102)
Results by Subgroup
Previously
Untreated
Previously
Treated
Overall
34%
8%
20%
4%
29%
6.5%
4%
1%
3%
Return to chronic phase (RTC)
22%
15%
20%
Major cytogenetic response (MCR)
Complete
Partial
14.5%
7%
8%
16%
6%
9.5%
15%
6.5%
8.5%
Hematologic response
Complete
No evidence of leukemia
Achieving a Hematologic Response in Blast Crisis
Correlates with Survival (Study 0102)
1.0
0.9
Yes
No
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1
2
3 4
5
6
7 8
9 10 11 12 13 14 15 16 17 18
Months Since Start of Treatment
Overall Survival
Proportion of Patients Alive
Proportion of Patients Alive
Hematologic Response at 3 Months
1.0
0.9
Untreated
Pretreated
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1
2
3 4
5
6
7 8
9 10 11 12 13 14 15 16 17 18
Months Since Start of Treatment
Overview of Clinical Results with Imatinib
% of Patients (CI95%)
Hematologic response
Complete response
No evidence of leukemia
Return to chronic phase
(RTC)
Major cytogenetic
response (MCR)
Complete
Partial
Study 0110
Chronic Phase
IFN- Failure
(n=454)
Study 0109
Accelerated
Phase
(n=235)
Study 0102
Blast Crisis
(n=260)
95%
_
95%
–
–
71%
(61.8–75.7)
34%
12%
23%
29%
(23.4–34.8)
7%
3%
20%
60%
–
41%
19%
26%
(17.8–30.6)
17%
7%
15%
(10.9–19.9)
7%
8%
Improved Hematologic Responses Occurs in All
Phases of CML with Imatinib Mesylate
Percentage of Patients Responding
Hematologic response, original report
100
90
80
70
60
50
40
30
20
10
0
95
Hematologic response, latest report
71
88
63
29
26
Chronic Phase
Accelerated Phase
Blast Crisis
Percentage of Patients Responding
Improved Cytogenetic Responses Occurs in
All Phases of CML With Imatinib
Major cytogenetic response, original report
70
60
60
Major cytogenetic response, latest report
50
40
49
26
30
15
20
21
10
13.5
0
Chronic Phase
Accelerated Phase
Blast Crisis
Resistance to Imatinib Mesylate Predominately
Occurs During Advanced Phase CML
 Advanced stage cancers are characterized by multiple
genetic changes
 Patients in advance phase often relapse with the
development of chemotherapy resistance
 Some patients in blast crisis CML initially respond to
imatinib mesylate but then tend to relapse
Resistance to Imatinib Mesylate
 Studies of patients resistant to imatinib mesylate (most of them
in blast crisis) indicated that for some patients, point mutations
in the ATP-binding domain of the kinase were involved in the
resistance to imatinib mesylate
Study
No. of patients with
a mutation
Mutations (number of
patients)
Gorre et al 1
Kreil et al2
No. of patients
resistant to imatinib
mesylate
11
40
6
6
Branford et al3
12
9
Shah et al4
31
26
van Bubnoff et al 5
8
7
T315I (6)
T315I(2); Y253F (1);
E255K(2); E255V (1)
T315I (1); G250E (2);
Y253H (1); E255k (3);
F317L (1); M351T (1)
T315I (9); Q252H (6);
E255K (5); M351T (4)
G250E (2)
T315I (1); others
1. Gorre ME et al. Science. 2001;293:876. 2. Kreil S et al. Blood. 2001;98:435a. 3. Branford S et al. Blood.
2001;98:769a. 4. Shah N et al. Blood. 2001;98:770a. 5. van Bubnoff N et al. Blood. 2001;98:771a.
Evolution of Resistance to Imatinib Mesylate in CML
Chronic Phase
Ph-negative
Ph-positive
Ph+ blasts
Ph+ imatinibresistant blasts
Courtesy of Charles L. Sawyers, MD.
Relapse
Bone marrow to peripheral blood
Hematopoietic
differentiation
Blast Crisis
Resistance to Imatinib Mesylate
 Other mechanisms of resistance are predicted to exist:
– Amplification of the bcr-abl gene
– Unknown
 Results obtained so far indicate that, in blast crisis CML,
where the cancer is more complex than in earlier phases,
it still remains dependent on activation of Bcr-Abl
Other Possible Mechanisms of
Resistance to Imatinib Mesylate
Mechanisms of resistance
 Ph+ cell lines
– Bcr-Abl overexpression
– Gene amplification
– Drug reflux mediated by P-glycoprotein
– Other
 In vivo murine model
– Binding in the plasma of alpha 1-acid
glycoprotein to imatinib mesylate
Avoiding and Managing Resistance to
Imatinib Therapy
 The earlier CML is treated, the more likely resistance
can be avoided
 A major benefit of regular cytogenetic monitoring is early
detection of impending resistance/relapse
 To manage resistance occurring during therapy
• Dose escalate, use intermittent dosing
• Add additional drugs, switch to non-cross–resistant
drugs
Drug-Relevant Adverse Events in Phase II Trials
Most Common Adverse Experiences Reported in Clinical Trials
(10% of all patients in any trial)(1)
Preferred term
Nausea
Fluid retention
Superficial edemas
Other fluid retention events (2)
Muscle cramps
Diarrhea
Vomiting
Hemorrhage
CNS hemorrhage
Gastrointestinal hemorrhage
Musculoskeletal pain
Skin rash
Headache
Fatigue
Arthralgia
Dyspepsia
Myalgia
Weight increased
Myeloid Blast Crisis
N=260
(%)
All
Grade
grades
3/4
69
3
69
10
65
5
16
6
26
0.4
41
3
52
4
48
17
5
3
5
3
42
9
34
4
26
4
28
3
24
4
10
0
8
0
5
0.8
Accelerated Phase
N=235
(%)
All
Grade 3/4
grades
71
5
71
6
69
3
9
3
37
0.4
53
4
55
3
39
8
1
0.4
3
1
43
9
43
5
29
2
36
3
29
6
20
0
20
2
11
2
Chronic Phase
IFN- Failure
N=532 (%)
All grades
Grade 3/4
58
56
55
3
50
37
30
16
0.6
0.4
32
39
30
31
30
21
21
24
(1) All adverse events occurring in 10% of patients are listed regardless of suspected relationship to treatment.
(2) Other fluid retention events include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated,
and fluid retention not otherwise specified.
2
2
1
0.6
1
1
0.9
0.8
0.6
0
1
3
0.2
0.6
0.6
0
0.2
4
Lab Abnormalities in Phase II Trials
Myeloid Blast Crisis
N=260
(%)
Accelerated Phase
N=235
(%)
Chronic Phase, IFN-
Failure
N=532
(%)
Grade 3
Grade 4
Grade 3
Grade 4
Grade 3
Grade 4
Neutropenia
16
47
23
35
26
8
Thrombocytopenia
27
33
31
12
17
<1
Anemia
40
11
33
6
5
<1
Hematology parameters
Myelosuppression: Sometimes a Good Thing
 More common in advanced phases of CML
 Identified risk factors are those associated with advanced
phase CML
 Onset within 4 weeks in blast crisis; later in
earlier phases
 Myelosuppression is a therapeutic effect of imatinib
mesylate
– Normal hematopoiesis is not suppressed
– Imatinib targets only Ph+ cells, which leads to a
cytogenetic response
Managing Myelosuppression: Chronic Phase
ANC <1000/mm3 or
PLTs <50,000/mm3
Withhold imatinib mesylate and allow recovery to ANC
>1500/mm3 and PLTs >100,000/mm3
Normal Recovery
(2-4 weeks)
Resume imatinib at 400mg
ANC = absolute neutrophil count; PLTs = platelets.
Slow Recovery
(>4 weeks)
Resume imatinib at 300mg
Escalate imatinib to 400mg,
as long as recovery continues
Managing Myelosuppression: Advanced Phases
PLTs <10,000/mm3 or
<50,000/mm3 with bleeding
Withhold until
bleeding stops
Continue at 600mg
and transfuse PLTs
Hypercellular BM
or blasts >30%
Continue at 600mg
Continue at 600mg and monitor
BM if ANC <500/mm3
Hypocellular BM and
ANC <500/mm3 for >2-4 weeks
Dose
interrupt
Reduce
dose
Continue at 600mg and
administer myeloid growth
factors
Practical Considerations for Nonhematologic
Side Effects
 GI upset, nausea, vomiting, diarrhea
– Take dose with a meal and large glass of water
– Take at least 2 hours before bedtime
– Take 800mg dose as 400mg bid
– Use antiemetic and antidiarrheal medications for severe
effects
Practical Considerations for Nonhematologic
Side Effects (cont.)
 Edema/fluid retention
– Mild (generally periorbital)
• Limit salt intake
• Use diuretics and topical steroids
– Severe (pulmonary edema, pleural/pericardial
effusion, ascites):
• Use diuretics
• Dose reduction/interruption/continuation
• Weigh patient regularly
Practical Considerations for Nonhematologic
Side Effects (cont.)
 Muscle cramps/bone pain/arthralgia
– Ca++ supplements
– Nonsteroidal anti-inflammatory drugs (NSAIDs)
• +/- proton pump inhibitors
• +/- histamine H-2 inhibitors
– Mild narcotics
Management of Hepatotoxicity
 Liver function tests (LFTs) including AST, ALT, bilirubin
– Grade 2
• Dose adjustment not necessary
• Minimize alcohol
• Substitute other nonhepatotoxic drugs
• Avoid acetaminophen
– Grades 3/4
• Dose interrupt
• Resume at reduced dose when LFTs normalize
• Resume initial dose after 6-12 weeks of normal LFTs
 For persistently elevated LFTs, perform hepatic evaluation
AST = aspartate transaminase; ALT = alanine transaminase.
Management of Dermatologic Side Effects
 Skin rash is generally mild
– Maculopapular rash
– Occurs most often on the arms and trunk
– Treat with antihistamines, topical or oral steroids
 Severe, desquamative rash is much rarer
– Treat with systemic steroids
Optimal Dosing of Imatinib Mesylate
 Starting dose in chronic phase: 400mg once daily
 Starting dose in advanced phases: 600mg once daily
 Consider dose escalation (400mg to 600mg, 600mg to
800mg) for:
– Disease progression
– Failure to achieve a hematologic response after at least
3 months
– Loss of a previously achieved hematologic response
Optimal Dosing of Imatinib Mesylate (cont.)
 Dose interruption or discontinuation is only
recommended for the management of severe
adverse events
 Preliminary results from ASH 2001 support the use of
higher doses in nonresponding patients in chronic
phase
– 67% of patients achieved or regained a CHR
– 30% achieved or improved their cytogenetic
response
Maximizing the Potential of Imatinib
Mesylate Therapy
WBC >20,000/mm3
WBC elevated,
on HU
Start
imatinib mesylate
Continue allopurinol
until WBC normal;
Maintain hydration
to avoid TLS
Start
imatinib mesylate
Continue HU for
up to 3 weeks
Monitor CBC
Weeks 1-4:
weekly (CP),
at least weekly
(AP, BC)
Weeks 8-12:
every 2 weeks
WBC normal,
on HU
WBC <1500/mm3
and/or PLTs
<100,000/mm3,
on IFN-
PLTs elevated,
on anagrelide
Start
imatinib mesylate
Discontinue
IFN-; allow
WBC to normalize
Taper HU
during week 1
More frequently
if ANC
<1500/mm3
and/or
PLTs
<100,000/mm3
Start
imatinib mesylate
Start
imatinib mesylate
After week 12:
monthly
Continue anagrelide
up to 5 weeks
Adapted from Druker BJ. In preparation.
WBC = white blood cell; TLS = tumor lysis syndrome; CBC = complete blood count; HU = hydroxyurea;
CP = chronic phase; AP = accelerated phase; BC = blast crisis; PLTs = platelets; ANC = absolute neutrophil count;
IFN- = interferon-alpha.
Hematologic Response: Monitoring to
Maximize Patient Outcome
 Hematologic monitoring, consisting of CBC and differential,
should begin immediately
– Weeks 1–4: monitor CBC weekly
– Weeks 5–12: monitor CBC every 2 weeks
– After week 12: monitor CBC monthly
 Perform more frequently
– If ANC <1500/mm3
– And/or PLTs <100,000/mm3
ANC = absolute neutrophil count; PLTs = platelets.
Cytogenetic Response: Monitoring to Maximize
Patient Outcome
“A systematic plan must be established for
evaluating the degree and duration of
cytogenetic and molecular response”1
 Recommended cytogenetic monitoring schedule
based on imatinib mesylate clinical trials
– Cytogenetic analysis for the Ph chromosome
should be performed every 3 months
1. Silver RT et al. Blood. 1999;94:1517-1536.
Molecular Monitoring for a Response is Critical for
the Optimal Treatment of CML
 Molecular analyses may be performed
– FISH to assess the presence and copy number of the
bcr-abl fusion gene
– RT-PCR to quantify bcr-abl mRNA transcript levels
 Frequent cytogenetic or molecular monitoring has
prognostic value for predicting clinical responses and
disease status
Imatinib Metabolism and Elimination
 Cytochrome P450 3A4 isoenzyme(CYP3A4)
– Major metabolic enzyme responsible for metabolizing
imatinib and many other agents
– A cause of many drug interactions
 Other cytochrome P450 enzymes play a minor role in
metabolism (CYP1A2, CYP2D6, CYP2C9, CYP2C19)
 81% of imatinib eliminated within 7 days
– 68% in feces
– 13% in urine
Drug–Drug Interactions
 CYP3A4 inhibitors
– Increase imatinib concentrations
– Ketoconazole (antifungal), erythromycin (antibiotic),
diltiazem (cardiovascular), verapamil (CV), nifedipine
(CV), grapefruit juice, cyclosporine (transplant),
cimetidine (H-2 blocker)
 CYP3A4 inducers
– Decrease imatinib concentrations
– Phenytoin (anti-seizure), carbamazepine (anti-seizure),
dexamethasone (steroid), St. John’s Wort, rifampin
Drug–Drug Interactions (cont.)
 Imatinib mesylate may affect levels of other CYP3A4,
CYP2C9, or CYP2D6 substrates
 Use caution when coadministering these substrates that
have a narrow therapeutic window
– Substitute low-molecular weight or standard heparin for
warfarin (CYP3A4 and CYP2C9 substrate)
Imatinib Mesylate has Revolutionized the
Treatment of CML
 Therapy specifically designed to target the molecular
cause of CML
– Potent and selective inhibitor of Bcr-Abl
 Outstanding rates of rapid hematologic and cytogenetic
responses in all stages of disease
 Significant Improvement in survival and delay in the time of
disease progression in all phases of CML
 Excellent side-effect profile
– Most adverse events were mild to moderate in severity
 Convenient once-daily oral dosing
Possible Concepts for the Future:
Individualizing Therapy
Biologically Early
Biologically Late
Bcr-Abl: unique molecular abnormality
Additional molecular abnormality
Molecular remission with imatinib mesylate
Lack of molecular remission
Imatinib mesylate as single-agent therapy
Imatinib mesylate + other therapies
Concepts for the Future: Optimizing Therapy
 Define the molecular signature of specific response
Dx expression analysis
Responsive
genotype
“Conservative”
therapy
Unresponsive
genotype
MRD monitoring
“Hi-risk”
MRD = minimal residual disease.
Courtesy of Jerry Radich, Fred Hutchinson Cancer Research Center.
“Aggressive”
therapy
Imatinib Mesylate: Solid Tumors
 Additional molecular targets
– Kit
– PDGF-R
 Relationship to prognosis and malignant transformation
is unknown
 Tumors associated with these targets
– Sarcomas
– Lung cancer
– Prostate cancer
– Gliomas and neuroblastomas
– Breast cancer
– Seminomas and germ-cell tumors
 Evidence for mutations leading to constitutive activation
Imatinib Mesylate: Kit Targets
 GISTs
– Study 2222
• Immunohistochemically Kit+, unresectable or
metastatic disease
 SCLC
– Study 0202
• Newly diagnosed, extensive stage disease
• Sensitive relapse (any stage)
– Study 0205
• Newly diagnosed, extensive stage disease in
combination with cisplatin/etoposide
GISTs = gastrointestinal stromal tumors;
SCLC = small-cell lung cancer.
Imatinib Mesylate: PDGF-R Targets
 Prostate cancer
– Study 0201
• Single-agent therapy in hormone-refractory
prostate cancer (HRPC)
– Study 0210
• Neoadjuvant therapy in prostate cancer
 Glioma
– Study 0204
• Imatinib mesylate in adult glioma
– Study of recurrent pediatric glioma planned
 Breast cancer
– Study 0206
• Imatinib mesylate in combination with standard
chemotherapy in advanced breast cancer