Chronic%20Myeloid%20Leukemia%20(CML)%20and%20Targeted%20Therapy

1
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

2
Incidence of Hematologic Malignancies

• Type of Leukemia Incidence per 100,000
• Overall 610
• CML 12
• CLL 23
• AML 23
• ALL 12

1990, Western hemisphere. CLL chronic
lymphoid leukemia AML acute myeloid leukemia
ALL acute lymphoid leukemia. Black RJ et al.
Eur J Cancer. 1997331075-1107.
3
Epidemiology of CML

• Median age range at presentation 45 to 55 years
• Incidence increases with age
• 1230 of patients are gt60 years old
• Male-to-female ratio1.31
• At presentation
• 50 diagnosed by routine laboratory tests
• 85 diagnosed during chronic phase

4
Clinical Presentation of CML

• Common Symptoms ? Common Signs
• Fatigue Palpable splenomegaly
• Weight loss/anorexia
• Abdominal fullness
• Common Laboratory Findings
• Abnormal differential Anemia
• Leukocytosis Basophilia
• Thrombocytosis

5
CML Peripheral Blood Smear
Courtesy of John K. Choi, MD, PhD, University of
Pennsylvania.
6
Clinical Course Phases of CML
Advanced phases
Chronic phase Median 56 yearsstabilization
Accelerated phase Median duration69 months
Blast crisis Median survival36 months
7
Typical Laboratory Parameters by Phase of CML
Phase of CML

• Parameter Chronic Accelerated Blast Crisis
• WBC count ?20 x 109/L
• Blasts 115 ?15 ?30
• Basophils ? ?20
• Platelets ? or normal ? or ? ?
• Bone marrow Myeloid hyperplasia
• Cytogenetics Ph
• Bcr-Abl

WBC white blood cell Ph Ph
chromosomepositive.
8
Definition of Accelerated Phase
PB peripheral blood BM bone marrow HU
hydroxyurea BU busulfan. Kantarjian HM et al.
Cancer. 1988611441-1446. Sokal JE et al.
Semin Hematol. 19882549-61. Speck B et al.
Semin Hematol. 19842148-52.
9
Therapies for Advanced Stages of CML
IFN-? interferon-alpha.
10
Ph Chromosome
11
Cytogenetic Abnormality of CMLThe Ph Chromosome
1
2
3
4
5
6
7
8
10
11
9
12
13
14
15
16
17
18
19
20
21
22
x
Y
12
Prevalence of the Ph Chromosome in Hematologic
Malignancies

• Leukemia of Ph Patients
• CML 95
• ALL (Adult) 1530
• ALL (Pediatric) 5
• AML 2

Faderl S et al. Oncology. 199913169-180.
13
The Ph Chromosome t(922) Translocation

9
9 q
22
Ph ( or 22q-)
bcr
bcr-abl
abl
FUSION PROTEINWITH TYROSINEKINASE ACTIVITY
14
bcr-abl Gene and Fusion Protein Tyrosine Kinases
Chromosome 9
Chromosome 22
2-11
c-bcr
c-abl
1
2-11
p210Bcr-Abl
2-11
p185Bcr-Abl
Exons Introns CML Breakpoints ALL Breakpoints
15
p210Bcr-Abl Fusion Protein Tyrosine Kinase
Extracellular space
Cytoplasm
Y177
SH2
SH3
SH1
GRB2
BAP-1
CBL
SHC
CRKL
Faderl S et al. N Engl J Med. 1999341164-172.
16
Molecular Methods for Detecting bcr-abl at the
Ph Chromosome

• Fluorescence in situ hybridization (FISH)

Interphase
Metaphase
Courtesy of Charles Sawyers, UCLA.
17
Therapeutic Options
18
Goals of Therapy for CML Response Criteria

• ? Hematologic Response ? Cytogenetic Response
• Complete Major
• Normal peripheral blood count Complete 0
  Ph cells
• WBC lt10 x 109/L Partial 135 Ph
  cells
• Platelets lt450 x 109/L Minor 3695 Ph
  cells
• No immature cells
• Disappearance of splenomegaly
• Normal physical examination

19
Therapeutic Options for CML

• Allogeneic stem cell transplantation (SCT)
• IFN-?based treatments
• Chemotherapy with hydroxyurea, busulfan
• Imatinib mesylate (formerly STI571)

20
(No Transcript)
21
PROBABILITY OF SURVIVAL AFTER ALLOGENEIC
TRANSPLANTS FOR CML IN CHRONIC PHASE BY DONOR
TYPE AND DISEASE DURATION, 1994-1999
100
80
HLA-identical sibling, lt1y (N 2,876)
60
HLA-identical sibling, ³1y (N 1,391)
PROBABILITY,
Unrelated, lt1y (N 613)
40
Unrelated, ³1y (N 936)
20
P 0.0001
0
0
1
2
3
4
6
5
YEARS
SUM02_3.ppt
22
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

23
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
  andgreater 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

24
IFN-? Clinical Results in CML
a
a
IFN-
IFN-

ara-C
Response
(results from 7
(results from 4
1-7
8-11
clinical trials)
clinical trials)
CHR ()
3180
6492
Cytogenetic responses ()
Any
1858
4174
Major
638
1050
3-year survival rates ()10
79
86
CHR complete hematologic response. 1.
Kantarjian HM et al. Ann Intern Med.
1995122254-261. 2. Ozer H et al. Blood.
1993822975-2984. 3. Mahon F et al. Blood.
1994843592. 4. Hehlmann R et al. Blood.
1994844064-4077. 5. Italian Cooperative Study
Group on CML. N Engl J Med. 1994330820. 6.
Allan NC et al. Lancet. 19953451392-1397. 7.
Ohnishi K et al. Blood. 199586906-916. 8.
Silver RT et al. Blood. 199688 (suppl 1)638a.
9. Tura S et al. Blood. 199892(suppl 1) 317a.
10. Guilhot F et al. N Engl J Med.
1997337223-229. 11. Kantarjian HM et al. J Clin
Oncol. 199917284-292.
25
Achieving a Cytogenetic Response Correlates with
Increased Survival
Major response
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
P lt.001
Proportion Surviving
Minor or no response
0.0 12 24 36 48 60
Months After Treatment
Guilhot F et al. N Engl J Med. 1997337223-229.
26
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
• gt90 of patients experience constitutional
  symptoms
• gt50 of patients require IFN-? dose reduction
• gt25 of patients discontinue treatment due to
  severe drug-induced toxicity

27
Chemotherapy Chronic Phase CML

• Oral cytotoxic agents
• Hydroxyurea
• Busulfan
• Hematologic response in up to 90 of patients
• Rare MCR (0.95)
• Palliative careno effect on disease progression

MCR major cytogenetic response.
28
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

29
Imatinib MesylateGleevec
30
Imatinib Mesylate (Formerly STI571)

• Tyrosine Kinase Inhibitor
• for CML

31
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

32
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

33
Structure of Imatinib Mesylate
CH3SO3H
C29H31N7OCH4SO3

• Class Phenylaminopyrimidines, 589.7 mw

34
Mechanism of Action of Imatinib Mesylate
Goldman JM, Melo JV. N Engl J Med.
20013441084-1086.
35
Rationale for Use of Imatinib Mesylate in CML

• CML is characterized by a 922 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

36
Cellular Selectivity of Imatinib Mesylate IC50
?M

• Kinases Inhibited Kinases Not Inhibited
• v-Abl 0.10.3 Flt-3 gt10
• p210Bcr-Abl 0.25 c-Fms, v-Fms gt10
• p185Bcr-Abl 0.25 EGF receptor gt100
• TEL-Abl 0.35 c-erbB2 gt100
• PDGF-R 0.1 Insulin receptor gt100
• TEL-PDGF-R 0.15 IGF-I receptor gt100
• c-Kit 0.1 v-Src gt10
• JAK-2 gt100

PDGF-R platelet-derived growth factor receptor
EGF epidermal growth factor IGF-I
insulin-like growth factor-I. Druker BJ et al.
Nat Med. 19962561-566.
37
Imatinib Mesylate Inhibits the Growth
ofBcr-AblPositive Cells
U937 KG1 SU DHL1
KCL22 K562 KU812
Imatinib Mesylate Concentration (?M)
Bcr-Ablnegative cell lines. Bcr-Ablpositive
cell lines.
Gambacorti-Passerini C et al. Blood Cells Mol
Dis. 199723380-394.
38
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) ? 1822 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.
39
Phase I Studies with Imatinib Mesylate

• Study design
• Open-label, dose escalation
• Study objectives
• Safety
• Tolerability
• Evidence of antileukemic activity
• Eligibility
• Chronic Phase CML Acute Leukemia
• Ph CML CML in Blast Crisis
• WBC gt20,000, lt15 blasts Ph ALL
• IFN-? failure Ph AML

40
Phase I Studies With Imatinib Mesylate Results
Hematologic and Cytogenetic Responses
Blast CrisisMyeloidPhenotype (n39) 54
13
Blast CrisisLymphoidPhenotype (n20) 70
20
IFN-?ResistantChronic Phase CML300mg1000mg/day
(n55) 98 98
49 31
Hematologic response Complete
14 4
40 20
Cytogenetic response Major
Complete

• Most adverse events were mild to moderate in
  severity (grades 12)
• A maximal tolerated dose (MTD) was not reached
• Higher frequency and severity of adverse events
  with doses ?800mg

41
Imatinib Mesylate Rapid Responses
Hematologic Response
Cytogenetic Response
100
100
80
10
WBC x 103
60
Ph
40
20
1
0
200
300
400
30
60
90
120
150
100
0
Days on Imatinib Mesylate
Days on Imatinib Mesylate
42
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

43
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

44
Imatinib Mesylate Phase II Study 0110Patients
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

45
Patient Demographics

• Enrolled patients N532, confirmed chronic phase
  CML n454 (85)
• Median age yrs (range) 57 (1890)
• IFN-? failure
• Hematologic failure 152 (29)
• Cytogenetic failure 188 (35)
• IFN-? intolerance 192 (36)
• Months from diagnosis (range) 32 (3218)
• Months of prior IFN-? (range) 14 (gt1135)
• WBC (x109/L) (range) 14 (1.8260)
• Platelets (x109/L) (range) 296
  (752081)
• Additional chromosomal abnormalities 87 (16)

IFN-? at doses gt25 MIU/week.
46
Response Criteria in Chronic Phase CML Patients
(Study 0110)

• CHR
• WBC lt10 x 109/L
• Platelets lt450 x 109/L
• No blasts, basophils lt20
• No extramedullary disease
• Cytogenetic responses
• Complete cytogenetic response (CCR) 0 Ph
• Partial cytogenetic response (PCR) 1 to 35 Ph
• Major cytogenetic response (MCR) CCR PCR

47
Results in Chronic Phase CML Patients (Study
0110)
Total
Hematologic
Cytogenetic
IFN-?
Failures
Failures
Intolerant
Resistant
Relapsed
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
Minor
5
8
1
8
2
2
Minimal
11
16
16
9
2
11
Hematologic Response
Complete
95
89
99
97
98
93
Kantarjian H et al. N Engl J Med.
2002346645-653.
?2002 Massachusetts Medical Society. All rights
reserved.
48
Time to MCR and CCR in Chronic Phase CML (Study
0110)
49
Durable Response in Chronic Phase Patients (Study
0110)
Patients Without Progression ()
Months Since Start of Treatment
Kantarjian H et al. N Engl J Med.
2002346645-653.
?2002 Massachusetts Medical Society. All rights
reserved.
50
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-a plus ara-C as first-line therapy is ongoing
  (Study 106)

51
International Multicenter Clinical Trial
Imatinib as First-Line Therapy in CML (IRIS Study)

• Study design and objectives
• Imatinib mesylate versus IFN-a 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

52
Imatinib Mesylate as First-Line Therapy (IRIS
Study)

• 1,106 adult patients were randomized to either
• Imatinib mesylate 400mg/day
• IFN-a 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

53
Study Design for Phase III Trial
Imatinib mesylate

• If
• Progression
• Intolerance of treatment
• Failure to achieve MCRat 24 months

S
R
Crossover
IFN-? ara-C

• Progression
• Death
• Accelerated phase or blast crisis
• Loss of MCR or CHR
• Increasing WBC count

S screening R randomization
54
Multicenter Clinical Trial with Accelerated Phase
CML Patients (Study 0109)

• Treatment schedule 400mg (n77) or 600mg
  (n158) daily
• Patient selection
• Blood or bone marrow blasts ?15 but lt30
• Blasts promyelocytes in peripheral blood or
  bone marrow ?30
• Peripheral basophils ?20
• Thrombocytopenia lt100 x 109/L unrelated to
  therapy
• Primary endpoint hematologic response

55
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 gt1.0 x 109/L) and platelets (gt20 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

56
Clinical Results in Patients With Accelerated CML
(Study 0109)
Results
400mg 65 27 10 27 16
11 5
600mg 71 37 13 21
28 19 8
Overall 69 34 12 23
24 17 7
Hematologic response Complete No evidence
of leukemia Return to chronic phase Major
cytogenetic response Complete Partial
57
Higher Doses of Imatinib Delays the Time to
Disease Progression (Study 0109)
58
Increased Survival Achieved with a cytogenetic
response at 3 Months (Study 0109)
59
Multicenter Clinical Trial In Blast Crisis CML
Patients (Study 0102)

• Treatment schedule 400mg (n37) or 600mg
  (n223) 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

60
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 gt1.0 x 109/L) and platelets (gt20 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

61
Clinical Results in Blast Crisis CML Patients
(Study 0102)
Results by Subgroup
PreviouslyUntreated 34 8 4
22 14.5 7 8
PreviouslyTreated 20 4 1
15 16 6 9.5
Overall 29 6.5 3 20
15 6.5 8.5
Hematologic response Complete No evidence
of leukemia Return to chronic phase (RTC) Major
cytogenetic response (MCR) Complete
Partial
62
Achieving a Hematologic Response in Blast Crisis
Correlates with Survival (Study 0102)
63
Overview of Clinical Results with Imatinib
64
Improved Hematologic Responses Occurs in All
Phases of CML with Imatinib Mesylate
Hematologic response, original report Hematologic
response, latest report
95
100
90
71
80
88
70
60
63
Percentage of Patients Responding
50
40
29
30
20
26
10
0
Chronic Phase
Accelerated Phase
Blast Crisis
65
Improved Cytogenetic Responses Occurs in All
Phases of CML With Imatinib
Major cytogenetic response, original
report Major cytogenetic response, latest report
70
60
60
50
49
40
Percentage of Patients Responding
26
30
15
20
21
10
13.5
0
Chronic Phase
Accelerated Phase
Blast Crisis
66
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

67
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
No. of patients with
Mutations (number of
resistant to
imatinib
a mutation
patients)
mesylate
1
Gorre et al
11
6
T315I (6)
2
Kreil et al
40
6
T315I(2) Y253F (1)
E255K(2) E255V (1)
3
Branford et al
12
9
T315I (1) G250E (2)
Y253H (1) E255k (3)
F317L (1) M351T (1)
4
Shah et al
31
26
T315I (9) Q252H (6)
E255K (5) M351T (4)
G250E (2)
5
van
Bubnoff et al
8
7
T315I (1) others
1. Gorre ME et al. Science. 2001293876. 2.
Kreil S et al. Blood. 200198435a. 3. Branford
S et al. Blood. 200198769a. 4. Shah N et al.
Blood. 200198770a. 5. van Bubnoff N et al.
Blood. 200198771a.
68
Evolution of Resistance to Imatinib Mesylate in
CML
Chronic Phase
Blast Crisis
Relapse
Hematopoietic differentiation
Bone marrow to peripheral blood
Ph-negative
Ph-positive
Ph blasts
Ph imatinib- resistant blasts
Courtesy of Charles L. Sawyers, MD.
69
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

70
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

71
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-crossresistant drugs

72
Drug-Relevant Adverse Events in Phase II Trials
Most Common Adverse Experiences Reported in
Clinical Trials(?10 of all patients in any
trial)(1)
(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.
73
Lab Abnormalities in Phase II Trials
74
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

75
Managing Myelosuppression Chronic Phase
ANC lt1000/mm3 orPLTs lt50,000/mm3
Withhold imatinib mesylate and allow recovery to
ANC gt1500/mm3 and PLTs gt100,000/mm3
Slow Recovery(gt4 weeks)
Normal Recovery(2-4 weeks)
Resume imatinib at 400mg
Resume imatinib at 300mgEscalate imatinib to
400mg, as long as recovery continues
ANC absolute neutrophil count PLTs platelets.
76
Managing Myelosuppression Advanced Phases
PLTs lt10,000/mm3 orlt50,000/mm3 with bleeding
Withhold until bleeding stops
Continue at 600mg and transfuse PLTs
Continue at 600mg and monitor BM if ANC lt500/mm3
Hypocellular BM andANC lt500/mm3 for gt2-4 weeks
Hypercellular BMor blasts gt30
Reduce dose
Dose interrupt
Continue at 600mg and administer myeloid growth
factors
Continue at 600mg
77
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

78
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

79
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

80
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.

81
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

82
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

83
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

84
Maximizing the Potential of Imatinib Mesylate
Therapy
Continue allopurinoluntil WBC normalMaintain
hydration to avoid TLS
Monitor CBC Weeks 1-4 weekly (CP), at least
weekly (AP, BC) Weeks 8-12 every 2
weeks After week 12 monthly More frequently
if ANC lt1500/mm3 and/or PLTs lt100,000/mm3
Start imatinib mesylate
WBC gt20,000/mm3
WBC elevated, on HU
Start imatinib mesylate
Continue HU forup to 3 weeks
WBC normal, on HU
Start imatinib mesylate
Taper HU during week 1
WBC lt1500/mm3 and/or PLTs lt100,000/mm3, on IFN-?
Discontinue IFN-? allow WBC to normalize
Start imatinib mesylate
PLTs elevated, on anagrelide
Start imatinib mesylate
Continue anagrelideup to 5 weeks
Adapted from Druker BJ. In preparation. WBC
white blood cell TLS tumor lysis syndrome CBC
complete blood count HU hydroxyureaCP
chronic phase AP accelerated phase BC blast
crisis PLTs platelets ANC absolute
neutrophil count IFN-? interferon-alpha.
85
Hematologic Response Monitoring to Maximize
Patient Outcome

• Hematologic monitoring, consisting of CBC and
  differential, should begin immediately
• Weeks 14 monitor CBC weekly
• Weeks 512 monitor CBC every 2 weeks
• After week 12 monitor CBC monthly
• Perform more frequently
• If ANC lt1500/mm3
• And/or PLTs lt100,000/mm3

ANC absolute neutrophil count PLTs platelets.
86
Cytogenetic Response Monitoring to Maximize
Patient Outcome

• A systematic plan must be established for
  evaluating the degree and duration of cytogenetic
  and molecular response1
• 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. 1999941517-1536.
87
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

88
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

89
DrugDrug 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.
  Johns Wort, rifampin

90
DrugDrug 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)

91
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

92
Possible Concepts for the Future
Individualizing Therapy

• Biologically Early
• Bcr-Abl unique molecular abnormality
• Molecular remission with imatinib mesylate
• Imatinib mesylate as single-agent therapy

• Biologically Late
• Additional molecular abnormality
• Lack of molecular remission
• Imatinib mesylate other therapies

93
Concepts for the Future Optimizing Therapy

• Define the molecular signature of specific
  response

Dx expression analysis
Responsive genotype
Unresponsive genotype
MRD monitoring
Conservative therapy
Aggressive therapy
Hi-risk
MRD minimal residual disease.Courtesy of Jerry
Radich, Fred Hutchinson Cancer Research Center.
94
Imatinib Mesylate Solid Tumors

• Additional molecular targets
• Kit
• PDGF-R
• Relationship to prognosis and malignant
  transformationis 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

95
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 tumorsSCLC
small-cell lung cancer.
96
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