Imatinib
Imatinib, sold under the brand names Gleevec and Glivec among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Specifically, it is used for chronic myelogenous leukemia and acute lymphocytic leukemia that are Philadelphia chromosome–positive, certain types of gastrointestinal stromal tumors, hypereosinophilic syndrome, chronic eosinophilic leukemia, systemic mastocytosis, and myelodysplastic syndrome.
Common side effects include vomiting, diarrhea, muscle pain, headache, and rash. Severe side effects may include fluid retention, gastrointestinal bleeding, bone marrow suppression, liver problems, and heart failure. Use during pregnancy may result in harm to the baby. Imatinib works by stopping the Bcr-Abl tyrosine-kinase. This can slow growth or result in programmed cell death of certain types of cancer cells.
Imatinib was approved for medical use in the United States in 2001. It is on the World Health Organization's List of Essential Medicines. A generic version became available in the UK as of 2017.
Medical uses
Imatinib is used to treat chronic myelogenous leukemia, gastrointestinal stromal tumors and a number of other malignancies. In 2006 the FDA expanded approved use to include dermatofibrosarcoma protuberans, myelodysplastic/myeloproliferative diseases, and aggressive systemic mastocytosis.Imatinib is considered to be a very effective treatment for CML, and has been shown to improve outcomes for people with this type of leukemia. It can also be used to treat some types of ALL, but is not considered a standard of care for ALL. In many cases, imatinib can induce a complete cytogenetic response and major molecular response and many patients can have a long-term remission. It is also used to maintain remission in chronic phase CML patients.
While imatinib is a very effective treatment for CML and some types of ALL, it is not a cure for leukemia. Instead, it is a 'chronic therapy' that helps to control the disease and prevent it from progressing. Some patients may need to continue taking imatinib for an extended period of time to maintain remission, and some patients may eventually require additional treatment options.
Chronic myelogenous leukemia
The U.S. Food and Drug Administration has approved imatinib as first-line treatment for Philadelphia chromosome-positive CML, both in adults and children. The drug is approved in multiple contexts of Philadelphia chromosome-positive CML, including after stem cell transplant, in blast crisis, newly diagnosed, and accelerated phase.Due in part to the development of imatinib and related drugs, the five-year survival rate for people with chronic myeloid leukemia increased from 31% in 1993, to 59% in 2009, to 70% in 2016. By 2023, the five year survival rate for people with chronic myeloid leukemia had risen to 90%. Starting from 2011, it became clear that CML patients who continue to respond to imatinib have the same or almost the same life expectancy as the general population.
Gastrointestinal stromal tumors
The FDA first granted approval for advanced GIST patients in 2002. On 1 February 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence. The drug is also approved in unresectable KIT-positive GISTs.Dermatofibrosarcoma protuberans (DFSP)
The FDA granted approval for the treatment of dermatofibrosarcoma protuberans patients in 2006. Specifically adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. Prior to approval DFSP was considered unresponsive to chemotherapy treatments.Other
The FDA has approved imatinib for use in adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia, myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, aggressive systemic mastocytosis without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-KIT tyrosine kinase blocking properties of imatinib. There have been several phase 2 trials of imatinib for aggressive fibromatosis.
Contraindications and cautions
The only known contraindication to imatinib is hypersensitivity to imatinib. Cautions include:- Hepatic impairment
- Risk of severe CHF or left ventricular dysfunction, especially in patients with comorbidities
- Pregnancy, risk of embryo-fetal toxicity
- Risk of fluid retention
- Risk of growth stunting in children or adolescents
Side effects
Cardiotoxicity
In some individuals, imatinib use was reported to be associated with left ventricular dysfunction which sometimes progressed to congestive cardiac failure despite an absence of prior heart disease. Clinical trials of imatinib did not report cardiac adverse effects, but had reported a notably high incidence of peripheral oedema, with some cases classified as severe.Patient biopsies as well as mice treated with large doses of imatinib exhibited cellular signs of cardiotoxicity. Studies determined a potential pathway that led to cardiotoxicity, stemming from a stress response within the endoplasmic reticulum and the effects of c-ABL inhibition. Cardiotoxic effects appeared to mediated by inhibition of cytoplasmic ABL1 tyrosine kinase.
Childhood growth inhibition
Multiple human and animal studies suggest that if imatinib is used in prepubescent children, it may delay normal growth, although some may experience at least partial catch-up growth during puberty.The reason for this side effect is unclear; interference with a growth hormone -related pathway may be involved.
Pigmentation changes
Imatinib use may cause lightening/depigmentation or darkening/repigmentation of hair and/or skin as well as hyperpigmentation of the gingiva. The median onset of hair color change is 4 weeks after initiation of therapy, is dose-dependent, and is reversible upon treatment discontinuation or dose reduction.C-kit receptors - one of the biological target of imatinib - are expressed by melanocytes.
Hepatotoxicity
Both mild and severe hepatotoxicity can occur. 5% of patients developed mild hepatotoxicity within the first 2 years of beginning treatment. However, severe hepatotoxicity is rare. Both severe and mild hepatotoxicity can be reversed by either stopping treatment or reducing the dosage of imatinib.Overdose
Medical experience with imatinib overdose is limited. Treatment is supportive. Imatinib is highly plasma protein-bound: dialysis is unlikely to be helpful removing imatinib.Interactions
Its use is advised against in people on strong CYP3A4 inhibitors such as clarithromycin, chloramphenicol, ketoconazole, ritonavir and nefazodone due to its reliance on CYP3A4 for metabolism. Likewise it is a CYP3A4, CYP2D6 and CYP2C9 inhibitor and hence concurrent treatment with substrates of any of these enzymes may increase plasma concentrations of said drugs. Since imatinib is mainly metabolised via the liver enzyme CYP3A4, substances influencing the activity of this enzyme change the plasma concentration of the drug. An example of a drug that increases imatinib activity and therefore side effects by blocking CYP3A4 is ketoconazole. The same could be true of itraconazole, clarithromycin, grapefruit juice, among others. Conversely, CYP3A4 inductors like rifampicin and St John's Wort reduce the drug's activity, risking therapy failure. Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of a number of other drugs like simvastatin, ciclosporin, pimozide, warfarin, metoprolol, and possibly paracetamol. The drug also reduces plasma levels of levothyroxin via an unknown mechanism.As with other immunosuppressants, application of live vaccines is contraindicated because the microorganisms in the vaccine could multiply and infect the patient. Inactivated and toxoid vaccines do not hold this risk, but may not be effective under imatinib therapy.
Eating grapefruit and drinking grapefruit juice are strongly discouraged as it increases the concentration of imatinib in the blood.
Pharmacology
Mechanism of action
Imatinib is a 2-phenyl amino pyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain in abl, c-kit and PDGF-R.
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr, termed bcr-abl. As this is now a constitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.
The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosine phosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively. This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.
Imatinib is quite selective for bcr-abl, though it does also inhibit other targets mentioned above, as well as ABL2 and DDR1 tyrosine kinases and NQO2 – an oxidoreductase. Imatinib also inhibits the abl protein of non-cancer cells, but these cells normally have additional redundant tyrosine kinases, which allows them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl. Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions, leading to tumor cell death.