Imatinib

Article Author:
James Flynn
Article Editor:
Valerie Gerriets
Updated:
6/26/2020 7:11:15 PM
PubMed Link:
Imatinib

Indications

Imatinib mesylate (Imatinib) is an oral tyrosine kinase inhibitor that initially received FDA approval for chronic myelogenous leukemia in 2001.  Subsequently, it has received approval for the treatment of several other oncologic conditions.  Currently, FDA approved indications include:

  • First-line adult and pediatric Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase (Ph+ CML CP):
    • IRIS Trial: treatment with imatinib in adults with newly diagnosed CML resulted in a 10-year overall survival rate of 83.3%.[1]    
  • Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis (Ph+ CML BC):
    • In a single-arm phase 2 study of Ph+ CML BC patients, imatinib induced a major cytogenetic response in 16% of patients and a complete hematologic response in 52% of patients.[2]
  • Philadelphia chromosome-positive chronic myelogenous leukemia in accelerated phase(Ph+ CML AP):
    • In a single-arm phase 2 study of Ph+ CML AP patients, imatinib induced a significant cytogenetic response in 24% of patients and a complete hematologic response in 82% of patients.[3]
  • Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase after failure of interferon-alpha therapy:
    • In a single-arm phase 2 study of Ph+ CML CP treatment failures with interferon-alpha, imatinib induced a significant cytogenetic response in 60% of patients and a complete hematologic response in 95% of patients. [4]
  • Adult relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL):
    • In a single-arm phase 2 study of relapsed/refractory Ph+ ALL patients, imatinib induced a complete cytogenetic response in 17% of patients and a complete hematologic response in 19% of patients.[5]
  • First-line pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy:
    • AALL0031 Trial: treatment with imatinib plus chemotherapy resulted in a 5-year disease-free survival of 70% as compared to a 65% rate in the sibling donor bone-marrow transplant cohort.[6]
  • Adult myelodysplastic(MDS)/myeloproliferative(MPD) diseases associated with platelet-derived growth factor receptor gene re-arrangements:
    • In an open-label phase 2 study, an additional study, and 12 published case reports in adult myelodysplastic(MDS)/myeloproliferative(MPD) disease associated with platelet-derived growth factor receptor gene re-arrangements, imatinib induced a major cytogenetic response in 39% of patients and a complete hematologic response in 45% of patients.
  • Adult aggressive systemic mastocytosis(ASM) without D816V c-Kit mutations (or unknown c-Kit mutational status):
    • In a phase 2 study and ten published case reports, imatinib induced a complete hematologic response in 29% of patients.
  • Adult hypereosinophilic syndrome(HES) or chronic eosinophilic leukemia(CEL) with FIP1L1-PDGFR-alpha fusion kinase and for patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who are FIP1L1-PDGFR-alpha fusion kinase negative or unknown:
    • In a phase 2 study and 35 published case reports, treatment with imatinib induced a complete hematologic response in 61% of patients.
  • Adult unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP):
    • In a phase 2 study and five published case reports, treatment with imatinib induced an 83% response rate, including a 39% complete response rate. 
  • Kit positive unresectable and/or metastatic malignant gastrointestinal stromal tumors(GIST):
    • In two large randomized phase 3 clinical trials of patients with Kit positive unresectable and/or metastatic malignant GIST, treatment with imatinib 400mg/day resulted in a 1.58 year(18.9 months) progression-free survival and a 4.08 year(49.0 months) overall survival.[7]
  • Adult adjuvant treatment following resection of Kit positive GIST:
    • In a randomized, double-blind, placebo-controlled phase 3 trial of adult adjuvant treatment following resection of Kit positive GIST, imatinib therapy resulted in a recurrence-free survival of 98% at one year as compared to placebo at 83%, p<0.0001, hazard ratio = 0.35.[8]

Mechanism of Action

Imatinib mesylate is a 2-phenylamino-pyrimidine derivative protein tyrosine kinase inhibitor initially targeted to the platelet-derived growth factor receptor.[9] Subsequently, it has also been found to inhibit other protein tyrosine kinases such as c-kit (gastrointestinal stromal tumors) and BCR-ABL fusion protein (Philadelphia chromosome chronic myelogenous leukemia).  These protein tyrosine kinases as a whole phosphorylate specific amino acids on substrate proteins, which induce signal transduction resulting in changes to cell biology, including cell growth, differentiation, and death, constitutive activation of which, through mutation or other means, can lead to malignancy.[10] Blocking of this constitutive action has been shown to induce downstream apoptosis without further differentiation.[11] Imatinib, as a therapeutic, blocks constitutive action of protein tyrosine kinase by working as a competitive inhibitor of the ATP binding cleft of ABL inducing apoptosis of leukemic cells.[12]

Administration

Imatinib is FDA-approved to be administered orally and is typically supplied in 100mg and 400mg tablet formulations.  Imatinib was initially available under a branded name; however, after the expiration of several patents, there are no generic versions available. The recommended dosing for imatinib varies by indication:

  • Adult Ph+ CML CP 400 mg/day
  • Adult Ph+ CML AP 600 mg/day
  • Adult Ph+ CML BC 600 mg/day
  • Pediatric Ph+ CML 340 mg/m2/day
  • Adult Ph+ ALL 600 mg/day
  • Adult MDS 400 mg/day
  • Adult MPD 400 mg/day
  • Adult ASM 100 mg/day or 400mg/day
  • Adult HES 100 mg/day or 400mg/day
  • Adult CEL 100 mg/day or 400mg/day
  • Adult DFSP 800 mg/day
  • Adult metastatic/unresectable GIST 400 mg/day
  • Adult adjuvant GIST 400 mg/day
  • Mild to moderate hepatic impairment 400 mg/day
  • Severe hepatic impairment 300 mg/day

800 mg doses should be administered as a 400 mg dose twice daily; all other doses should be given once daily.  Patients should take imatinib with meals and a large glass of water to minimize gastrointestinal upset, and food does not impact bioavailability.[13]

Adverse Effects

Clinically significant warnings and precautions include[14]:

  • Dermatologic: including cases of Stevens-Johnson syndrome (SJS) and erythema multiforme (although the etiology of imatinib causing SJS is unclear)
  • Embryo-fetal toxicity
  • Fluid retention and edema
  • Gastrointestinal disorders and perforations
  • Growth retardation in children
  • Hematologic toxicity (anemia, neutropenia, thrombocytopenia)
  • Hemorrhage (gastrointestinal and intra-tumoral grade 3/4 hemorrhages)
  • Hepatotoxicity
  • Hypereosinophilic cardiac toxicity (cardiogenic shock and left ventricular dysfunction have been reported in HES patients initiating imatinib therapy)
  • Hypothyroidism
  • Long-term use toxicity (cardiac, kidney and liver toxicities suggested by animal studies)
  • Pregnancy (category D – avoid pregnancy while taking imatinib)
  • Renal toxicity
  • Severe congestive heart failure with left ventricular dysfunction
  • Tumor lysis syndrome

Common side effects that occurred in over 10% of clinical trial participants include[6][7][8][5]:

  • Abdominal pain/distention
  • Alanine aminotransferase increase
  • Alopecia
  • Anemia
  • Anorexia
  • Arthralgia
  • Aspartate aminotransferase increase
  • Asthenia
  • Blood creatine increase
  • Blood lactate dehydrogenase increase
  • Bone pain
  • Constipation
  • Cough
  • Depression
  • Diarrhea
  • Dizziness
  • Dyspepsia
  • Dyspnea
  • Fatigue
  • Flatulence
  • Fluid retention
  • Headache
  • Hemoglobin decrease
  • Hemorrhage (non-GI/CNS)
  • Hypoalbuminemia
  • Hypokalemia
  • Hypoproteinemia
  • Infection
  • Influenza
  • Insomnia
  • Joint pain
  • Muscle cramps/spasms
  • Musculoskeletal pain
  • Myalgia
  • Nasopharyngitis
  • Nausea
  • Neutropenia
  • Night sweats
  • Pain
  • Peripheral edema
  • Periorbital edema
  • Pharyngolaryngeal pain
  • Pneumonia
  • Pruritis
  • Pyrexia
  • Rhinitis
  • Rigors
  • Skin rash
  • Sinusitis
  • Thrombocytopenia
  • Upper respiratory tract Infection
  • Vision, blurred
  • Vomiting
  • Weight increase
  • White blood cell decrease

Contraindications

There are no contraindications for imatinib.

Imatinib gets metabolized through the enzyme cytochrome p450 3A4 (CYP3A4).[15] 

  • Administration of imatinib with CYP3A4 inducers may reduce total imatinib exposure
  • Administration of imatinib with CYP3A4 inhibitors may increase total imatinib exposure
  • Avoid grapefruit juice as it has the potential to increase the plasma concentration of imatinib
  • Imatinib will increase plasma concentrations of other CYP3A4 metabolized drugs

Monitoring

  • Monitor patients regularly for the signs and symptoms of fluid retention.
  • Monitor patients for signs and symptoms of cardiac or renal failure, especially in those with a history of cardiac disease or renal failure
  • Monitor liver function (alkaline phosphatase, bilirubin, and transaminases) before starting treatment and then monthly afterward or as indicated going forward
  • Monitor hepatic function
  • Monitor TSH levels in patients after thyroidectomy[16]
  • Monitor growth in children
  • Monitor patients with a high proliferative rate or high tumor burden for tumor lysis syndrome
  • Monitor renal function before starting therapy and on an ongoing basis, especially in those with congestive heart failure, diabetes mellitus or preexisting renal impairment
  • Monitor complete blood counts for evidence of hematologic toxicity (anemia, neutropenia, and thrombocytopenia)

Toxicity

  • Treatment with imatinib is associated with hematologic toxicity (anemia, neutropenia, and thrombocytopenia)
  • Treatment with imatinib is associated with hepatotoxicity.
  • Treatment with imatinib is associated with hypereosinophilic cardiac toxicity in patients with hypereosinophilic syndrome.
  • Treatment with imatinib can cause fetal harm to a pregnant woman (Imatinib has demonstrated teratogenicity in rats at the 800 mg/day equivalent human maximum dose)[17]
  • Treatment with imatinib is associated with renal toxicity.
  • Treatment with imatinib is associated with dermatologic toxicities, including erythema multiforme and Stevens-Johnson syndrome.

Enhancing Healthcare Team Outcomes

Imatinib is a powerful targeted therapeutic drug for several types of cancer. Despite showing a favorable risk/benefit tradeoff in several clinical trials, and being FDA approved for nearly two decades, it does require close monitoring for safety. In addition to the prescribing physician, pharmacists and nurses are responsible for educating the patient on the potential side effects of the drug.  While most side effects occur in the first two years of use, many patients will be on chronic therapy for many years, so it is essential to stay vigilant in monitoring for side effects.[16]  Particularly severe side effects to carefully monitor for include Stevens-Johnson syndrome, gastrointestinal perforations/hemorrhage, fluid retention, organ (cardiac, renal and liver) failure, and hematologic toxicities. Additionally, imatinib does have several interactions with other medications that are also metabolized by CYP3A4. The pharmacist needs to monitor all medications that the patient is currently taking to make sure that there are no interactions. If concurrent medications are necessary, this requires proper dose adjustments due to potential drug-drug interactions. The physicians, nurses, and pharmacists should regularly check liver function, renal function, and complete blood counts to monitor for organ damage or immunosuppression and adjust imatinib dosing as necessary, while continually informing the ordering clinician. Nursing will notably have the optimal chance to see any issues that arise since they will have the first contact with the patient, so they must be familiar with the adverse event and interaction profile. This is where an oncology specialty nurse is invaluable. This collaborative paradigm exemplifies the type of interprofessional teamwork the healthcare team requires to administer imatinib effectively to achieve optimal patient outcomes while minimizing patient risks.    

It was one of the first targeted therapeutics to reach the market and also now is generic. Imatinib presents interesting time-series data on the costs of precision medications.  At approval in 2001, a one-month supply of the 400mg daily dose cost $2200 in the US.[18] In 2010, this cost had ballooned to $5143 per month, and by 2018 it was $10620 per month.[19] A generic form of imatinib was launched in the US in 2015 at a 30% discount to the branded price (which was substantially higher than the 82% discount at which the Canadian generic was launched).[20] Therefore because of dysfunctional market maximizing forces, ironically, the price of imatinib generics was higher than the original branded version, and pricing relief remained elusive for years. However, during 2018, generic imatinib pricing finally dropped below its original launch price, yet it still cost several thousand dollars per annum despite being generic. With expensive therapies such as imatinib, the physicians, pharmacists, and other healthcare professionals (such as social workers or charity assistance programs) need to coordinate care and advocate for coverage to maximize access to life-saving medications.


References

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