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Response Rate & Related Exon Mutations
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Gleevec Blood Levels
At the 2008 GI ASCO (American Society of Clinical Oncologists), Dr. George Demetri presented new information about Gleevec blood levels in GIST patients.
Correlation of imatinib plasma levels in GIST patients
A higher concentration
of
Gleevec in the
blood correlates
with better clinical
outcome according
to
George Demetri,
M.D., of the
Dana-Farber
Cancer Institute.
In an interview
with Peggy Peck on the medpageTODAY
website, Dr. Demetri said that the
imatinib plasma level was not associated
with age, gender, disease bulk, or body
weight. “You really need to do pharmacokinetic
testing to determine the level
of imatinib because there are no clues,”
Demetri reported at the Symposium. The
findings suggest that “we may have been
under-dosing some people,” he said.
This report is based on analysis of the pharmacokinetic data from the original phase II Gleevec trial for GIST (B2222), which started in July of 2000. Plasma levels (plasma is one component of blood) taken after 29 days of Gleevec, were available for 73 of the 147 patients enrolled in the trial. These plasma levels were grouped into quartiles according to imatinib trough plasma concentrations (the level of drug in the blood at its lowest point during the day, just before taking the daily Gleevec capsule).The plasma levels and response rates of these groups are listed in the table below.
Plasma levels and response rates
| Objective response | Median Time to Progression |
Objective Response Exon 11 patients |
|
|---|---|---|---|
Quartile 1 <1,110 ng/ml |
44% |
11.3 months |
55.6% |
Quartile 2+3 |
67% |
30.6 months |
94.1% |
Quartile 4 |
74% |
33.1 months |
92.3% |
The authors concluded that, “Exposure to adequate drug levels of imatinib appears to correlate with clinical benefit; patients with the lowest imatinib levels show lowest objective response and shortest time to progression. These results suggest that monitoring pharmacokinetic/ pharmacodynamic relationships may provide novel predictive markers and that exposure to adequate IM trough plasma concentrations (>1,110 ng/mL) is important for optimal clinical response.”
A video report is available on the medpageTODAY website. In the interview, Dr. Demetri explained that “when you give Gleevec or any other kinase inhibitor to a group of patients, they will handle it very differently, some people will have high levels and some people will have low levels… The important part about that is whether we for years might be underdosing people, and whether we perhaps should develop a blood test to check the levels of this drug in people’s blood and have more certainty that there’s actually therapeutic levels in the blood.” Demetri went on to explain that “it’s possible that we could have done this analysis and found nothing at all, but in fact, we saw something that is a bit worrisome for the patients with the lowest levels of the drug.” The next step according to Demetri will be to “… talk with our colleagues, decide exactly how much this is worth pursuing, (and) decide how to mount a large trial.”
Blood Level Testing
Patients can request testing of imatinib blood levels. Determining an optimum imatinib blood level will probably require a well designed clinical trial that examines multiple factors. For now, the best information (Demetri et al. 2008 GI ASCO) we have is preliminary and suggests that trough imatinib plasma levels should be above 1,100 ng/ml (see above). Testing imatinib blood levels is currently available for GIST patients. See www.gleevecmonitor.com (check the FAQs area under the Overview menu for information about GIST for details about this program).
References
Is there a role for testing Gleevec drug levels?
1. Correlation of imatinib plasma levels with clinical benefit in patients (Pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST)
G. D. Demetri, Y. Wang, E. Wehrle, C. Blanke, H. Joensuu, M. von Mehren
References
1. Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+)
M. C. Heinrich, J. S. Shoemaker, C. L. Corless, D. Hollis, G. D. Demetri, M. M. Bertagnolli, J. A. Fletcher
2. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors
Maria Debiec-Rychtera, Raf Sciotb, Axel Le Cesned, Marcus Schlemmere, Peter Hohenbergerf, Allan T. van Oosteromc, Jean-Yves Blayg, Serge Leyvrazh, Michel Stula, Paolo G. Casalii, John Zalcbergj, Jaap Verweijk, Martine Van Glabbekel, Anne Hagemeijera, Ian Judsonm and On behalf of the EORTC Soft Tissue and Bone Sarcoma Group, The Italian Sarcoma Group and the Australasian GastroIntestinal Trials Group
3. Safety
and efficacy of imatinib (STI571) in
metastatic gastrointestinal stromal
tumors: a phase I study.
van Oosterom AT, Judson I, Verweij
J, Stroobants S, Donato di Paola E,
Dimitrijevic S, Martens M, Webb A,
Sciot R, Van Glabbeke M, Silberman
S, Nielsen OS; European Organisation
for Research and Treatment of Cancer
Soft Tissue and Bone Sarcoma Group
4. Efficacy and Safety of Imatinib
Mesylate in Advanced
Gastrointestinal Stromal Tumors
George D. Demetri, M.D.,
Margaret von Mehren, M.D.,
Charles D. Blanke, M.D., Annick
D. Van den Abbeele, M.D., Burton
Eisenberg, M.D., Peter J.
Roberts, M.D., Michael C.
Heinrich, M.D., David A. Tuveson,
M.D., Ph.D., Samuel Singer,
M.D., Milos Janicek, M.D.,
Ph.D., Jonathan A. Fletcher,
M.D., Stuart G. Silverman, M.D.,
Sandra L. Silberman, M.D.,
Ph.D., Renaud Capdeville, M.D.,
Beate Kiese, M.Sc., Bin Peng,
M.D., Ph.D., Sasa Dimitrijevic,
Ph.D., Brian J. Druker, M.D.,
Christopher Corless, M.D.,
Christopher D.M. Fletcher, M.D.,
and Heikki Joensuu, M.D
5. Progression-free
survival in gastrointestinal
stromal tumors with high-dose
imatinib: randomised trial*
ProfJaap Verweij MDa, , , Paolo
G Casali MDb, ProfJohn Zalcberg
MDc, Axel LeCesne MDd, Peter
Reichardt MDe, ProfJean-Yves
Blay MDf, ProfRolf Issels MDg,
ProfAllan van Oosterom MDh,
ProfPancras CW Hogendoorn MDi,
Martine Van Glabbeke MScj,
Rossella Bertulli MDb, ProfIan
Judson MDk, for the EORTC Soft
Tissue and Bone Sarcoma Group,
the Italian Sarcoma Group and
the Australasian
Gastrointestinal Trials Group
6. Phase III dose-randomized study
of imatinib mesylate (STI571)
for GIST: Intergroup S0033 early
results. (ASCO abstract)
R. S. Benjamin, C. Rankin, C.
Fletcher, C. Blanke, M. Von
Mehren, R. Maki, V. Bramwell, L.
Baker, E. Borden, G. D. Demetri,
for the Sarcoma Intergroup; UT
MD Anderson Cancer Ctr, Houston,
TX; SWOG, San Antonio, TX;
Dana-Farber Cancer Institute,
Boston, MA; ECOG, Philadelphia,
PA; CALGB, New York, NY; NCIC,
Calgary, Canada; SWOG, Ann
Arbor, MI; DFCI, CALGB, and
Sarcoma Intergroup, San Antonio,
TX
