Imatinib (Gleevec) Basics
Imatinib (Gleevec in the USA and Glilvec elsewhere) is a relatively non-toxic, well-tolerated, targeted therapy for GIST cancer. This page answers the following common questions about Gleevec (click the question to skip to that section).
How does imatinib work?
What are the side effects of imatinib?
What drug interactions occur with imatinib?
How should I take my imatinib?
Can I take imatinib pre-surgery to shrink my GIST?
What about pregnancy and imatinib?
Where can I see detailed information about imatinib effectiveness?
What materials about imatinib are available from Novartis?
Is financial assistance available for imatinib (Gleevec)?
How does imatinib work?
Focusing on GIST, the effect of imatinib (Gleevec) is to stop the cell-proliferation actions of the KIT and PDGFRA tyrosine kinases. These are growth factor receptors that initiate a signaling pathway causing the cell to proliferate (reproduce through cell division). When GIST cells divide, the tumor gets larger. This signaling normally occurs only when KIT or PDGFRA receptors are triggered by molecules called ligands. The ligand for KIT is stem cell factor, and the ligand for PDGFRA is platelet-derived growth factor (PDGF). However, when the genes for these receptors are mutated, then the proteins are abnormally constructed, and they activate signaling without being stimulated by their ligands (constitutive activation). This abnormal growth signaling causes the GI stromal tumor to develop and keep enlarging. You can refer to our website page Mutation Analysis: KIT and PDGFRA for a more detailed discussion. Imatinib binds the intracellular activation pocket of the receptor in the inactive position, blocking binding by ATP, and thereby preventing the growth signals from being sent.
You can read a discussion of the effects of imatinib on GIST cells by Dr. Jonathan Trent in the Ask the Professional section of our website.
What are the side effects of imatinib?
It is difficult to compare imatinib (Gleevec) side effects between different trials because the researchers have reported data in different ways. Results from the EORTC/ISG/AGITG Phase III trial (Verweij et al, 2004) are shown in the following table. The percent of subjects showing less severe side effects (grades 1 and 2) versus more severe side effects (grades 3 and 4) are shown separately for the groups assigned to take 400 mg imatinib per day versus 800 mg imatinib per day.
|
Percent of subjects showing side effects by severity grade and dose group in EORTC/ISG/AGITG Phase III trial, from Verweij et al (2004) |
||||
|
400 mg |
800 mg | |||
| GRADE 1-2 | GRADE 3-4 | GRADE 1-2 | GRADE 3-4 | |
| Any side effect |
67% |
32% |
49% |
50% |
| anemia |
82% |
7% |
81% |
17% |
| leukopenia/neutropenia |
40% |
3% |
46% |
3% |
| granulocytopenia |
34% |
7% |
36% |
7% |
| thrombocytopenia |
4% |
1% |
5% |
1% |
| edema |
69% |
3% |
78% |
9% |
| fatigue |
62% |
6% |
68% |
11% |
| fever |
47% |
4% |
48% |
7% |
| myalgia |
46% |
3% |
57% |
3% |
| anorexia |
46% |
2% |
51% |
5% |
| diarrhea |
24% |
2% |
41% |
5% |
| infection |
24% |
3% |
35% |
3% |
| rash |
24% |
2% |
39% |
2% |
| cough |
24% |
0% |
27% |
1% |
| headache |
14% |
3% |
16% |
5% |
| nausea |
15% |
1% |
22% |
1% |
| arthralgia |
16% |
0% |
13% |
1% |
| vomiting |
15% |
1% |
17% |
1% |
| bleeding |
13% |
1% |
15% |
3% |
| renal / genitourinary |
13% |
0% |
15% |
1% |
| dyspnea |
13% |
0% |
14% |
0% |
| pleuritic pain |
11% |
1% |
16% |
1% |
| dizziness |
8% |
3% |
13% |
4% |
| constipation |
11% |
0% |
13% |
0% |
| pruritis (itching) |
8% |
3% |
14% |
8% |
Grade 1-2 side effects (less severe) are much more common than grade 3-4 problems. The most commonly occurring side effects reported in this study include anemia, edema, fatigue, fever, myalgia (muscle aches/cramps), anorexia, diarrhea, infection, and skin rash. The rates of side effects are higher for the 800-mg dose than for the 400-mg dose. The U
S Intergroup S0033 Phase III trial has not yet reported detailed side effect information for comparison.
Additional side-effect data are available from the earlier US-Finland Phase II study (Demetri et al, 2002) and from the Z9000 trial. For comparison, a separate table summarizing data from these studies is shown below.
|
US-Finland (N=147) |
Z9000 (N=106) |
|||
| GRADE 1-2 | GRADE 3-4 | GRADE 1-2 | GRADE 3-4 | |
| any adverse effect |
77% |
21% |
NR* |
NR |
| edema |
73% |
1% |
55% |
0% |
| nausea, vomiting |
63% |
2% |
43% |
1% |
| diarrhea |
43% |
2% |
41% |
2% |
| myalgia |
39% |
0% |
15% |
0% |
| fatigue |
35% |
0% |
46% |
1% |
| dermatitis, rash, itching |
32% |
3% |
45% |
3% |
| headache |
26% |
0% |
20% |
1% |
| abdominal pain |
25% |
1% |
NR |
NR |
| flatulence |
22% |
0% |
NR |
NR |
| hemorrhage |
7% |
5% |
NR |
NR |
| dyspepsia |
11% |
0% |
15% |
0% |
| increased lacrimation |
10% |
0% |
NR |
NR |
| anemia |
7% |
2% |
25% |
0% |
| loose stools |
8% |
0% |
NR |
NR |
| taste disturbance |
8% |
0% |
NR |
NR |
| neutropenia, leukopenia |
5% |
6% |
19% |
3% |
| abdominal distention |
5% |
0% |
NR |
NR |
| elevated liver function tests |
3% |
3% |
10% |
3% |
| arthralgia |
4% |
0% |
NR |
NR |
| paresthesia |
4% |
0% |
NR |
NR |
| esophageal reflux |
4% |
0% |
NR |
NR |
| pain (extremities) |
3% |
0% |
NR |
NR |
| blurred vision |
3% |
0% |
NR |
NR |
| photosensitivity |
3% |
0% |
NR |
NR |
|
* NR = not reported |
||||
The finding for increased side effects at higher doses has held true across all the available imatinib trials. Most side effects appear within the first few months of imatinib therapy. There is general agreement that side effects diminish with time. Additional information about side effects can be found in the complete prescribing information.
Elevated Liver Enzymes
Some patients develop elevations in liver enzymes as a reaction to imatinib (Gleevec). This will be detected in the regular bloodwork tests performed by your oncologist if it occurs. A temporary dose reduction may solve the problem. Your concologist may also prescribe corticosteroid medication (such as prednisolone) for a brief period of time to solve the liver reaction. There is at least one published report (Ikuta et al, 2005) and several anecdotal reports on the GIST Support International mailing list that the oral steroid drug prednisolone is effective in reducing elevated liver enzymes.
Thin Skin, Bruising
At least one problem commonly discussed by patients on the GSI mailing list – thinning skin and easy bruising and skin tears — was not mentioned in the trials, perhaps because this effect emerges only after a longer duration of therapy.
Bone Metabolism:
One potential side effect recently brought to light involves changes in bone metabolism. This is a topic of current investigation following a paper by Berman et al (2006). One of the authors, Dr. Robert Maki, has written a Q&A piece for GSI; view this now on our Ask the Professional page. Dr. Maki recommends some routine monitoring tests for patients on imatinib.
Heart Function:
Another uncommon but potentially serious side effect involves cardiotoxicity in the form of reduced heart function involving the left ventricle of the heart. A new paper by Kerkela et al (2006) suggests that a small percent of patients taking imatinib may experience reduced heart funct
ion. Dr. Thomas Force, the corresponding author of the paper, discussed this possibility on National Public Radio on July 28, 2006. Dr. Force also spoke by phone to GSI. He stated that his research group plans to collaborate with several other institutions to collect baseline and post-treatment data to determine what percent of patients may be affected. They anticipate that the percentage will be small. Standard drug treatments such as ACE inhibitors may be helpful. Dr. Force urged oncologists to be aware of this possible side effect and to monitor their patients who take imatinib, so that those who experience this side effect can be treated for it. You can read a summary story at the EurekAlert website. You may also want to read a Medscape summary news story “Cardiotoxicity of imatinib is a surprise” including quotes from additional oncologists with experience with imatinib (Gleevec), who state that the benefits far outweigh the (apparently small) risk of heart problems. [Access to Medscape is free but requires a simple registration.] In early 2007 Verweij et al published a paper analyzing data from one large imatinib trial fo potential heart problems; they “could not identify an excess of cardiac events” and concluded that heart-related effects, if any, are rare.
Depression
A letter to the editor of the Journal of Clinical Oncology by physicians at Dana-Farber describes 7 patients who experienced depression apparently related to taking either Gleevec or dasatinib. The free-access citation is:
Quek et al (2009) Small Molecule Tyrosine Kinase Inhibitor and Depression.
Five of the seven patients described are GIST patients who experienced depression on imatinib; one is a GIST patient who became depressed on dasatinib, and one patient had a different sarcoma and experienced depression on dasatinib. The authors believe the depressions to be drug-induced because in all cases the symptoms were relieved when drugs were reduced in dose or changed to a different drug. When you consider how many patients are seen at Dana-Farber taking these drugs, this is a very small percentage of affected patients, but it is important to know about this.
Coping with Side Effects:
Not many medical papers have addressed methods of coping with patients’ side effects, but two relevant papers are by Guilhot (2004) and by Griffin, St. Amand, and Demetri (2005). Your physician can also access case descriptions of imatinib side effects and potential solutions at the http://www.gleevec.com/ website. If you join GIST Support International, you can search our archives for tips on how other patients have coped with side effects. Please also see the page Managing Side Effects under the For New GIST Patients section of our site.
Approaches to reducing or eliminating muscle cramps from Gleevec include supplementing calcium and magnesium. Some patients drink tonic water to obtain small doses of quinine, but the FDA has ruled against prescription of quinine tablets for muscle cramps. In one report, 10 mg at bedtime of chlordiazepoxide (which has sedative, anxiety-reducing, and muscle relaxant properties) helped one patient according to Medeiros and Lipton, 2006).
Patients newly prescribed imatinib receive blood tests (more frequent early in therapy) to identify any liver function or blood count abnormalities.
Patients can usually proceed with imatinib therapy in spite of side effects, although temporary dosage decreases may be necessary, as advised by their physicians.
What drug interactions occur with imatinib?
Imatinib (Gleevec) is metabolized primarily by liver enzyme CYP3A4. Therefore, drugs also metabolized by this same enzyme may interact with imatinib, as well as drugs or other substances that increase (induce) or decrease (inhibit) the amount of this enzyme in the body. Information about drug interactions is available in the prescribing information for imatinib at the website http://www.gleevec.com/ and in Griffin, St. Amand and Demetri (2005). Patients already taking other medications can consult their pharmacists for an analysis of any potential interactions.
Inhibitors of CYP3A4 would increase blood levels of Gleevec, thereby effectively increasing the dose and exacerbating side effects. These include: grapefruit or grapefruit juice, clarithromycin, erythromycin, itraconazole, ketoconazole, voriconazole, and aprepitant.
Inducers of CYP3A4 would decrease blood levels of Gleevec, thereby effectively reducing the dose and possibly reducing effectiveness. These include: St. John’s wort (hypericum perforatum), carbamazepine, dexamethesone, phenobarbitol, phenytoin, rifabutin, and rifampin.
Imatinib itself, by competing for CYP3A4 (keeping CYP3A4 busy), may increase blood levels of other drugs also processed by this same enzyme [see O’Brien et al (2003) and Jennissen (2006)]. Drugs in this category include cyclosporine, dihydropyridine calcium channel blockers, eletriptan, pimozide, simvastatin and similar hydroxymethyl-glutaryl coenzyme A reductase inhibitors, triazolobenzodiazepines, and warfarin.
The common pain reliever acetaminophen (Tylenol) should not be used with imatinib to avoid stressing the liver. For the same reason, alcohol should be avoided.
For a free-access medical paper with tables detailing many different drug interactions with imatinib and sunitinib, see the following (click title to link to the free paper):
Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA.
Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib.
Blood. 2011 Feb 24;117(8):e75-87. PubMed PMID: 20810928.
How should I take my imatinib?
The Novartis prescribing information advises taking imatinib with food and a large glass of water. Because the half-life is about 18 hours, it is possible to take the entire daily dose at once for doses up to 600 mg, but Novartis advises splitting higher doses. Many patients prefer to split lower doses because this may minimize side effects, and it is acceptable to split any daily dose, as confirmed by Novartis in an opinion shown on our page Novartis Answers ABout Gleevec.
The archives of the GSI mailing list include many strategies patients use to take their imatinib with the least problems, and some of these are included in Managing Side Effects and in our GIST Support Wiki. The bottom line is that each individual should find a method that he/she prefers: as long as you take your entire daily dose it does not matter.
Can I take imatinib pre-surgery to shrink my GIST?
As discussed in the Surgery section, pre-shrinking GIST with neo-adjuvant imatinib (Gleevec) is a good strategy for larger tumors and initially inoperable tumors. At least one clinical trial (RTOG S0132) is currently studying the success of this approach.
Should I take imatinib post-surgery to prevent recurrence or metastasis?
Several clinical trials are ongoing to evaluate this question. Therefore, the answer is not yet known. The trials include ACOSOG Z9000, ACOSOG Z9001, SSG VIII, NCT00171977, and EORTC 62024. When the results of these studies begin to appear, patients and physicians will have a better idea whether a defined course (for example, 1 or 2 years) of adjuvant imatinib can prevent recurrence or metastasis in intermediate-risk or high-risk patients. For a summary of what is currently known, see our page Post-Surgery Preventive Imatinib (Adjuvant Gleevec).
What about pregnancy and imatinib?
Patients and their partners are advised to use birth control while either the man or the woman is taking imatinib (Gleevec) and for 3 months after stopping imatinib. For data on pregnancy outcomes of patients on Gleevec, see Pregnancy and Gleevec.
Where can I see detailed information about imatinib effectiveness?
You can view webcasts from the American Society of Clinical Oncology and other medical association meetings to hear presentations and see the slides used by presenters in discussing the research done on imatinib (Gleevec) used against GIST. Direct links to most of the available presentations are provided for you on our page Webcasts and Slide Shows. You can also obtain the medical papers and presentations identified with links earlier in this page.
What materials about imatinib are available from Novartis?
Many materials are available at the website www.gleevec.com
One pamphlet you can download is: TARGETING KIT+ GIST: YOUR GUIDE TO THERAPY WITH GLIVEC
Is financial assistance available for imatinib (Gleevec)?
The Max Foundation
The Max Foundation (TMF) is a US-based non-profit cancer organization with international focus. TMF is dedicated to helping patients with blood-related cancers and other rare cancers worldwide by facilitating access to treatment and providing care and support for those who have limited access to resources.
The Glivec International Patient Assistance Program (GIPAP) is a program of Novartis Pharma AG. The Max Foundation is a partner in the administration of GIPAP. As part of our Patient Services, patients who are screened, approved, and referred by TMF for a donation of Glivec through GIPAP may also benefit from access to the following TMF services:
locally-based, culturally competent care and support specialist
patient support groups
informational, emotional, and practical support
help navigating their health care system