CML- Imatinib Mesylate (Gleevec™) Philadelphia Chromosome • Short chromosome 22 • Bcr region of chromosome 22 with Abl proto- oncogene of chromosome 9
Apr 02, 2015
CML- Imatinib Mesylate (Gleevec™)
Philadelphia Chromosome
• Short chromosome 22
• Bcr region of chromosome 22 with Abl proto-oncogene of chromosome 9
CML- Imatinib Mesylate (Gleevec™)
Normal Abl gene product is a tightly regulated tyrosine kinase involved in cell division and apoptosis
Bcr-Abl gene product is a constitutively active tyrosine kinase
• induces a CML-like illness in mice
• induces CML in man
CML- Imatinib Mesylate (Gleevec™)
Blocks proliferation and induces apoptosis of Bcr-Abl expressing cell lines and fresh leukemic cells.
CML- Imatinib Mesylate (Gleevec™)
•Potent inhibitor of the receptor tyrosine kinases for PDGF, stem cell factor and c-Kit (CD 117)
•Active in c-kit expressing GIST
CML- Imatinib Mesylate (Gleevec™)
Toxicology
•13-week dog
• 6-month rat
• 9-month monkey
Toxicity: Hematopoietic, renal, hepatic, gastrointestinal, testis and ovary
CML- Imatinib Mesylate (Gleevec™)
Clinical Pharmacology
• Bioavailability 98%
• 95% protein bound
• CGP74588 is major active metabolite. Its plasma AUC is 16% of Imatinib AUC
• Metabolized by CYP3A4
CML - Submitted Studies
• Phase I
• Phase II
-Blast crisis (BC) CML
-Accelerated Phase (AP) CML
-Chronic phase (CP) CML - IFN Refractory, Resistant, Intolerant
Study Patient Characteristics
BC AP CP
Characteristic N=260) N=235 N=532
Age Median 56 56 57
Sex - Male/Female % 52/48 50/50 58/42
Race - Caucasian % 85 89 87
PS - 0-1 % 58 77 91
Ph + & other % 64 54 16
Extramedullary disease 68 68 24
STI-571 - % 400mg/d 14 33 86
BC CML - Definition
• > 30% blasts in PB or BM or
• Extramedullary involvement other than spleen or liver
PB=peripheral blood; BM=bone marrow
BC CML - Hematologic Remission
Characteristic N=260
Hematologic Response 68 (26%)
-Complete 11 (4%)
-No evidence of leukemia 7 (3%)
-Return to chronic phase 50 (19%)
Time to HR- median (d) 29 (26-64)
Censored for response duration 57 (84%)
BC CML - Cytogenetic Remission
Characteristic n=260
Major response 35 (13.5%)
Complete 9 (3%)
Confirmed 3 (1%)
Accelerated phase (AP) definition
• > 15% <30% blasts in PB or BM
• > 30% blasts+promyelocytes in PB or BM but <30% blasts in PB or BM
• > 20% basophils in PB
• <100 x 109/L platelets
at least one of the 4 criteria must be fulfilled
AP CML - Hematologic Response
Characteristic N=235
Hematologic Response 148 (63%) -Complete 60 (26%)
-No evidence of leukemia 27 (11%)
-Return to chronic phase 61 (26%)
Time to HR- median (d) 29 (26-334)
Censored for response duration 133 (90%)
AP CML - Cytogenetic Response
Characteristic n=235
Major response 50 (21%)
Complete 17 (7%)
Confirmed 10 (4%)
Chronic Phase (CP) CML Definition
• < 15% blasts in PB & BM
• < 30% blasts+promyelocytes in PB & BM
• < 20% basophils in PB
• > 100 x 109/L platelets
• No extramedullary involvement other than spleen or liver
All 5 criteria must be fulfilled
CP CML - Patient Characteristics
Characteristic n=532IFN Hematologic resistant/refractory 152 (29)
IFN Cytogenetic resistant/refractory 186 (35)
IFN intolerant 194 (36)
Median Duration of prior IFN (mo)
IFN hematologic failure 12.1 (1-83)
IFN cytogenetic failure 22.0 (4-135) IFN intolerant 7.1 (3-15)
CP CML - Cytogenetic Response
Characteristic n=532
Major response 265 (49.8%)
Complete 107 (20%)
Confirmed 84 (16%)
Time to MCyR (d) 91 (77-315)
CP CML - Hematologic Remission
Characteristic N=532
Complete Hematologic Response 468 (88%)
Days to CHR- median (range) 22 (5-267)
Censored for response duration 438 (93.6%)
Common SAE’s
BC CML AP CML CP CML
n= 260 (%) n=235 (%) n=532 (%)
All grades 3/4 All grades 3/4 All grades 3/4
Nausea 68 3 68 5 55 2
Fluid retent 67 10 68 6 52 2
Vomiting 49 3 54 3 28 1
Muscle cramps 25 .4 34 .4 46 .9
Diarrhea 39 3 49 4 33 .9
Dermatitis 32 4 39 4 36 3 Hemorrhage 48 16 35 8 13 .4
Grade 4 Hematology Abnormalities (%)
BC AP CP
Hgb 10 5 <1
WBC 46 34 8
ANC 61 34 8
Platelets 31 12 <1
Grade 3/4 Biochemistry Abnormalities (%)
BC AP CP
Hepatic 1.9-3.5 1.3-3.0 0.4-1.7
Renal 1.2 1.3 0
Imatinib mesylate-FDA Action
5/10/01
Accelerated Approval, Subpart H, CFR§314.510, for CML BC, AP, and CP after interferon- failure
Phase IV Commitments
• Interval F/U of Phase II BC, AP, CP trials
• Interval F/U of Phase III CP trial
• Pediatric trials
• Hepatotoxic drug interaction study
• Concomitant medication-Gleevec interaction
• Pathogenesis and Rx of fluid retention