Before the molecular era, the outlook for patients with CML was bleak. Diagnosis was poor and tended to occur at later disease stages². Prognosis was poor. Available treatment options promised only limited efficacy and were often associated with difficult side effects.

Glivec is the first protein-tyrosine kinase inhibitor to reach the clinic and is thus the most established molecularly targeted agent of its class. It differs from interferon alfa (IFN-α) and chemotherapeutic agents in having a well-characterised mechanism of action and in exerting its effects on a particular abnormal protein within the leukaemic cell. In clinical trials, Glivec demonstrated efficacy in CML superior to that achieved with previous systemic therapies, and it has been well tolerated by patients in all studies.

Efficacy of Glivec

Glivec is the standard of care in Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) with proven efficacy and longevity. With more than 5 years of follow-up data in the IRIS study, Glivec has consistently achieved and maintained exceptional rates of response. No other drug for CML has established as proven and durable a track record of efficacy and safety as Glivec.

Few drugs have succeeded to the extent that Glivec has in fundamentally changing the natural history of a disease.

Glivec is confirmed as the standard first-line therapy for all CML patients by clinical studies with 5-year follow-up ^4-7.

• An 89% overall survival rate at 5 years with Glivec exceeds that of all other CML therapies, with <5% of deaths related to CML.
• An estimated 98% of patients in chronic-phase CML have had a best response of CHR, and an estimated 92% of patients have had a best response of major cytogenetic response with Glivec
• Late responses to Glivec occur and responses are durable.
• Annual risk of progression is decreasing with time.
• The annual rate of progression to advanced phases of CML (accelerated phase/blast crisis) at year 5 declined to 0.6% (from 1.5% in year 1).
• Increasing the daily dose of Glivec to 600 or 800 mg may be considered for patients in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropaenia or thrombocytopaenia in certain circumstances, including disease progression, failure to achieve response within prespecified time points, or loss of response (refer to SmPC for further details)⁴.
• Overall risk of progression to advanced phase is low and is associated with the degree of response, regardless of when achieved.

Treatment with Glivec in newly diagnosed and untreated paediatric patients with chronic-phase CML is tolerated well and produces cytogenetic response rates comparable to the results observed in adults^{4, 75}.

Dosage

Glivec Dosage Information

Glivec is supplied as 100-mg and 400-mg film-coated tablets. The recommended starting doses for adult patients in whom Glivec therapy is indicated are 400 mg/d for chronic-phase CML and 600 mg/d for accelerated-phase or blast-crisis disease. The recommended starting dosages for children with CML in whom Glivec therapy is indicated is 340 mg/m²/d for chronic-phase CML and advanced-phase CML (not to exceed the total dose of 800 mg)⁴.

Dose increases from 400 mg to 600 mg or 800 mg in adult patients with chronic-phase disease, or from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients in accelerated phase or blast crisis, may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropaenia or thrombocytopaenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response⁴.

Please refer to local prescribing information for specific indications.

Glivec Safety Information

While its efficacy has been outstanding, Glivec has also been well tolerated in patients with CML. Most patients experience undesirable adverse events that are generally of mild to moderate severity, including gastrointestinal side effects that may be minimised when the medication is taken with a meal and a large glass of water. The most frequently reported drug-related adverse events were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps, and rash-which were easily manageable; superficial oedemas were also a common finding⁴. Fewer than 5% of patients have experienced serious adverse effects (such as skin rashes, liver toxicity, fluid retention syndrome, and haemorrhages) that led to discontinuation of treatment. Cardiac disorders including cardiac tamponade and skin disorders including acute febrile neutrophilic dermatosis (Sweet's syndrome) have rarely been reported (≤ 1/1000)⁴. Data from a larger patient cohort followed for 8 years have demonstrated that congestive heart failure is a rare event with Glivec therapy, primarily observed in elderly patients with preexisting cardiac conditions (1.8%, 22/1276 patients). The study authors recommend close monitoring of patients with a history of cardiac conditions⁷⁶. Analysis of patients with CML who developed phosphataemia during treatment with Glivec indicate that it may be related to digestive side effects, the symptoms of which may be alleviated by management of diarrhoea⁷⁷.

Long-term follow-up in the IRIS trial confirmed that Glivec is well tolerated; moreover, the frequency of adverse events decreased substantially over time with continued Glivec therapy⁷⁸.

Glivec represents a significant medical advance in the treatment of neoplastic disease. As the first and most established molecularly targeted, rationally designed drug therapy for CML, Glivec establishes a new paradigm for future drug development. The clinical trial data have provided proof of its clinical and survival benefits, and with its specific mechanism of action, Glivec offers an effective and well-tolerated therapeutic option for patients with Ph+ CML.

Read about emerging recommendations for Ongoing Management of CML.