Gleevec

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Gleevec

• MOLECULAR TARGETED THERAPY IN CML

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BACKGROUND LEUKEMIAS
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Incidence of Hematologic Malignacies
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Epidemiology of CML

• Median age range at presentation 45-55 yrs
• Male-to-female ratio1.3 / 1
• At presentation
• 50 diagnosed by routine lab tests
• 85 diagnosed during the chronic phase

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Clinical Presentation of CML
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CML Blood Smear Marrow Specimen

• Sawyers CL. NEJM. 1999 340(17)1331

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Clinical Course Phases of CML
Advanced phases
Chronic phase Median 46 yearsstabilization
Accelerated phase Median durationup to 1 year
Blastic phase (blast crisis) Median survival36
monthsTerminal phase
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Therapeutic Options for CML

• Chemotherapy?Hydroxyurea, Busulfan
• Interferon-alpha
• Allogenic Stem Cell Transplantion
• Gleevec (Imatinib Mesylate)

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Cytogenetic Abnormality of CMLThe Philadelphia
Chromosome
Chronic Myelogenous Leukemia (CML). The Leukemia
Lymphoma Society. P-32 20M. Rev 10/99.
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Prevalence of the Philadelphia Chromosome in
Hematologic Malignancies
Leukemia of Ph Patients CML 95 ALL
(Adult) 1530 ALL (Pediatric) 5 AML 2
Faderl S et al. Oncology (Huntingt).
199913169-184.
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The Philadelphia Chromosome t(922)
Translocation

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9
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Ph
bcr
bcr-abl
abl
FUSION PROTEINWITH TYROSINEKINASE ACTIVITY
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Structure of BCR-ABL Fusion Proteins

• Sawyers CL. NEJM. 1999 340(17)1332

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p210Bcr-Abl Fusion Protein Tyrosine Kinase

Extracellular space
Cytoplasm
Y177
SH2
SH1
SH3
GRB2
BAP-1
CBL
SHC
CRKL
Faderl S. N Engl J Med. 1999341169.
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Tyrosine Kinase

• Biochemistry 2nd Ed 19951185

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Bcr-Abl Signal Transduction Pathways

• Sawyers CL. NEJM. 1999 340(17)1331

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Gleevec-Tyrosine Kinase Inhibitor
Bcr-Abl
Bcr-Abl
Substrate
Substrate
STI571
P
ATP
P
P
Y Tyrosine P Phosphate
P
Goldman JM. Lancet. 20003551031-1032.
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Structure of Gleevec (Imatinib Mesylate)
O
CH3SO3H
Class Phenylaminopyrimidines, 589.7 mw
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Clinical Trials

• Phase I Trials- Published Data
• 1. Druker, et al (2001).
• Dose-escalating study of Gleevec (n83)
• Dose range from 25 mg-1000 mg/ day po
• Primary Endpoint?Safety, Tolerability of Gleevec
• Secondary Endpoints?Antileukemic Activity
• Hematologic Response gt50 ? in WBC count X2 wks
• Complete Hem Response ? WBC to lt10,000 Plt
  gt450,000
• Cytogenic Response of Ph cells (conversion to
  normal)

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Clinical Trials

• Phase I Trials- RESULTS
• Hematologic Response
• 98 of pts receiving gt300 mg/day had a complete
  hematologic response
• Cytogenic Response
• 54 of pts receiving gt300 mg/day had some
  cytogenic response
• 31 had major cytogenic responses
• 13 had complete cytogenic remissions

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Gleevec Phase I Study Time to Normalizationof
WBCs (500 mg/day)
100
WBC x 103
10
1
0
60
120
150
30
90
Days on STI571
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Clinical Trials

• Phase I
• Drucker et al (2001)
• Antileukemic activity and safety of Gleevec in
  Ph CML in blast crisis and Ph ALL (n58)
• Doses 300 mg-1000mg po qd
• Outcomes
• -Hematologic Responses
• -Marrow Responses
• -Cytogenic Responses

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Clinical Trials

• Phase I- RESULTS
• Drucker et al
• Myeloid Blast Crisis
• Overall response 21/38 (55)
• 4 (11)had complete hematologic response
• 7 remain in remission from 101-349 days after
  starting treatment
• Ph Chromosome ALL
• Overall response 14/20 (70)
• All but 1 patient relapsed

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Clinical TrialsPhase II- Unpublished
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Adverse EffectsGenerally Well Tolerated!
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Gleevec

• Drug Interactions
• Primarily CYP 3A4 (Competitive Inhibitor)
• also CYP 1A2, 2D6, 2C9, 2C19
• Dosage
• 400 mg/day in Chronic Phase CML
• 600 mg/day in Accelerated/Blast Crisis
• Cost
• 2400/ month (400 mg/day)

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Conclusions

• CML is a result of a single genetic mutation
  termed the Philadelphia Chromosome
• Gleevec is a Tyrosine Kinase Inhibitor that
  targets the protein product of the mutation
• Ongoing trials show Gleevec to be effective in
  Chronic Phase CMLgtAcceleratedgtBlast Crisis
• Response to therapy is generally seen in 1 month
• Duration of response is unknown and trials are
  still ongoing
• Gleevec is generally well-tolerated