Glivec

New Therapeutic Approaches to Treating CML

The most exciting new therapeutic approach to the treatment of CML is the introduction of signal transduction inhibitors. The development of Imatinib (Glivec®) provides a dramatic example of how the understanding of disease biology can lead to successful molecularly targeted treatments.

 

Several other approaches to the treatment of CML are also under investigation. These include new transplant strategies and novel agents. Many of these are entering clinical trials, and some have shown encouraging activity.

 

These new strategies include:

 

  • New Tyrosine Kinase Inhibitors [i.e. Dasatinib (Sprycel®) and Nilotinib], which exert cytotoxic activity in Imatinib-resistant CML patients. Up to now, only a few mutations have been described, which also confer a intermediate to high degree of resistance against these novel compounds, namley the T315I, T315A, E255V, E255K, Q252H. Especially when the T315I mutation occurs, other treatment options (i.e. stem cell transplantation or investigational compounds tested in clinical trials) have to be considered, unless novel T315I-targeting compounds will be approved (such as MK0457).
  • Inhibition of gene expression: Antisense oligodeoxynucleotides (ODNs) are short DNA sequences that bind to complimentary mRNA sequences and prevent the translation of the mRNA message into functional proteins. Antisense ODNs directed against the Bcr-Abl mRNA have been somewhat disappointing, possibly due to technical issues.
  • Immunomodulation: Cytotoxic T lymphocytes can suppress Ph+ cells. It is likely that these cells play a role in successful SCT. Recent research has focused on identifying T-cells that can eliminate leukaemic progenitor cells and which might be inducible by vaccination strategies (i.e. peptide vaccination).
  • Novel chemotherapeutic agents: Several agents are under active investigation for the treatment of CML:
    • Polyethylene glycol IFN-α (PEG interferon) has a longer half-life and reduced antigenicity compared with standard IFN-α. It is also administered parenterally. Due to the longer half-life, once-weekly injections are feasible.
    • Decitabine is a cytidine analogue that inhibits DNA methylation. As noted, it has produced promising results in early trials of patients in blast crisis.
    • Homoharringtonine (HHT) is a plant alkaloid that inhibits CML progenitor cells in vitro, but has less effect on normal progenitor cells. Early results suggest that this agent may have activity in chronic phase CML.
    • Histone Deacetylase Inhibitors (HADAC) reciprocally catalyze acetylation and deacetylation of lysine residues, respectively, in the amino terminal tails of the core nucleosomal histones in the chromatin and in several transcription factors. This modulates the expression of genes involved in cell-cycle regulation, differentiation, and apoptosis. Hence, treatment with HDAC inhibitors (HDIs) induces hyperacetylation of the nucleosomal histones and several transcription factors [regulating p21WAF1 and pro-death molecules (eg, Bak, Bax and Bim)] resulting in cell-cycle arrest and apoptosis. Early results suggest that HDAC may have activity in CML especially when combined with TK-inhibitors.

 

New transplantation approaches:

  • Reduced intensity conditioning SCT, sometimes known by the misleading term mini-transplant, uses a non-marrow ablative conditioning regimen. This procedure creates a chimeric immune system in the patient, composed of T-cells from both the donor and the patient. The likelihood of acute GVHD is reduced while the anti-leukaemic effect is preserved. Moreover acute toxicity is less extensive by the milder, pre-transplant conditioning thus making this therapeutical stretegy applicable to patients with higher age. Preliminary results from phase I and II trials suggest that this procedure can lead to molecular remissions in a number of malignancies.
  • Autologous stem cell transplant has been attempted for many years, with limited success, for the treatment of CML. This is due to the persistence of the genetic defect in cells that otherwise appear normal. The use of more sensitive tests to screen for the presence of the bcr-abl fusion gene has led to renewed interest in this procedure.

 

 

Glivec and CML Treatment

Glivec (imatinib) is approved as first-line treatment for CML (chronic myeloid leukaemia), and is the world’s most-often prescribed therapy for the condition. Glivec revolutionises treatment by targeting the molecular cause of CML.  Indicated as therapy for patients with CML in blast crisis, accelerated phase, or in chronic phase after failure of IFN-α therapy, Glivec prolongs progression-free survival in most patients, providing significant clinical benefit to patients in all phases of CML. Unlike traditional therapies, Glivec also prolongs disease free survival for patients even in advanced phases.

Mechanism of Action and Cellular Selectivity

Glivec, a derivative of 2-phenylaminopyrimidine is a small molecule antagonist with activity against protein tyrosine kinases and was chosen because of its potent and specific inhibition of Bcr-Abl. Glivec acts specifically by blocking the binding site for ATP in the Abl kinase. This inhibits the ability of Abl to transfer phosphate groups from ATP and phosphorylate tyrosine residues on substrate proteins, which in turn prevents the transduction of energy signals necessary for Abl-induced cellular proliferation and apoptosis. Thus, the specific signal transduction pathway abnormally activated in the leukaemic transformation process is inactivated by Glivec while the normal pathways are unaffected. Wild-type Abl is also inhibited by Glivec, but due to redundancy in signal transduction pathways, this phenomenon does not appear clinically to alter normal processes. In vitro assays determined the concentration of inhibitor that resulted in a 50% reduction (IC50) in tyrosine phosphorylation. In addition to being a potent inhibitor of Abl and Bcr-Abl intracellular tyrosine kinases, Glivec also has been shown to selectively inhibit 2 other tyrosine kinases: the PDGF-R and c-Kit, the receptor for stem cell factor or Steel factor. Until recently, CML has had few treatment options and, for the most part, these succeeded only in delaying disease progression by up to a few years.

Efficacy

the current 5-year follow-up of the IRIS trial demonstrats in patients with chronic phase CML that 98% achieve an haematological response (HR) and 87% attain a complete cytogenetic response (CR). In addition, the annual rate of progression gradually declines with a rate of 0.6% in the 5th year of treatment. After 5 years of therapy 89% of the patietns are still alive with only 4.6% died of their leukemia. The literature in CML has shown that there may be a correlation between attaining a CR and improved survival. HRs and CRs have been attained with Glivec in all phases of CML, and improved time to progression and estimated survival has been shown with Glivec in advanced phase CML. Studies with Glivec are on-going, especially to investigate the optimal starting dose as well as a survival benefit of Glivec has not yet been established.

Dosage

Glivec is supplied as 100-mg capsules and is dosed at 400 mg daily for patients with chronic phase CML. For patients with advanced disease, 600 mg daily is the recommended starting dose.
Dose increase from 400 mg to 600 mg in patients with chronic phase disease, or from 600 mg to 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 neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory HR after at least 3 months of treatment; or loss of a previously achieved HR.

Side-Effects

Glivec is generally well tolerated. The majority of undesirable effects are 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. In all trials (n=1027), the most frequently reported adverse events (grade 1 to 2) were lower limb oedema (19%), rash (15%), and dyspepsia (12%). The incidence of these side-effects occurring as a severe event (grade 3 or 4) was <1% except for rash (2%) and nausea (3%).

Limited data are available on the reproductive effects (if any) of Imatinib. The manufacturer has indicated that women of childbearing age taking imatinib should use effective contraception. Women should not breastfeed while taking imatinib.
 
Read about the importance of Ongoing Management for patients with CML.