Within the past 25 years, increased understanding of the molecular mechanisms involved in the pathogenesis of haematological and oncological neoplasms has led to the concept of rationally designed small molecules that specifically interact with the malignant clone but spare the normal tissue. This concept has been named ‘targeted therapy’. Imatinib mesylate (Gleevec/Glivec, Novartis Pharmaceuticals, Basel, Switzerland) represents one such compound that has revolutionised the therapy of chronic myeloid leukaemia (CML) and now serves as a paradigm for targeted therapies.

CML is a monoclonal stem cell disorder accounting for approximately 20% of adult leukaemias.1 The median age at first diagnosis is 60 years and the male to female ratio is almost even (1:1.4). Typically, CML develops in three phases. The vast majority of patients (>80%) are diagnosed in the initial chronic phase, which – in the absence of any treatment – lasts for approximately three to six years, before patients enter into the advanced and often terminal stages of the disease called the accelerated phase and/or blast crisis, respectively.2

Typical haematological features of chronic-phase CML are an increase of total leukocyte count, expansion of myeloid progenitor cells in the peripheral blood and bone marrow, thrombocytosis and splenomegaly. Progression of CML into the accelerated phase can be defined as any of the following:

• blast cells in blood or bone marrow between 15 and 29%;

• blast cells plus promyelocytes in the peripheral blood or bone marrow above 30% with fewer than 30% blasts;

• basophils in the peripheral blood above 20%; or

• persistent thrombocytopaenia.3

Blast crisis CML, commonly associated with a median survival of less than six months, is marked by more than 30% myeloblasts in either bone marrow or blood.

The pivotal genetic abnormality of CML is a reciprocal, balanced chromosomal t(9;22)(q34;q11) translocation also known as the Philadelphia chromosome, which is restricted to the malignant clone and which can be detected cytogenetically or by fluorescent in situ hybridisation (FISH) analysis in more than 90% of patients with CML.4

This chromosomal alteration fuses the Abelson (ABL) tyrosine kinase gene, originally located on chromosome nine, with the breakpoint cluster region (BCR) gene, originally located on chromosome 22, resulting in the BCR-ABL oncogene.5,6

In CML patients the BCR-ABL oncogene generates the p210 BCR-ABL tyrosine kinase that activates specific pathways resulting in the leukaemic phenotype. In summary, CML is defined as a monoclonal, haematopoietic stem cell disorder caused by the constitutively activated, highly oncogenic p210 BCR-ABL kinase.

Imatinib Mesylate

The concept of targeted therapy as a treatment modality of malignant diseases is based on small molecules – kinase inhibitors – aiming at cancer-specific target structures of the malignant cell.

Unprecedented therapeutic success was observed when imatinib (Glivec/Gleevec, Novartis Pharma AG), a 2-phenylaminopyrimidine derivative with a low molecular weight of 589.7kD, was designed and developed.7,8 Imatinib is acting as a competitive inhibitor of adenosinetriphosphate (ATP)-dependent phosphorylation of BCR-ABL, freezing the oncoprotein in the inactive and closed conformation, resulting in BCRABL dephosphorylation and inactivation.8–10 The specific structure of the ABL catalytic domain, which is incorporated in BCR-ABL, shows a bilobate structure with a smaller N-terminal and a larger C-terminal lobe. The cleft separating these two lobes contains – among other amino acids that are critical for catalysis – an ATP-binding loop (P-loop) as well as the activation loop (A-loop). In the closed and inactive conformation of BCR-ABL, ATP and substrate binding is prevented through sealing of the catalytic centre of the kinase by the A-loop. In contrast, when BCR-ABL turns into the open and active conformation, the A-loop swings away from the catalytic centre, allowing access to the catalytic centre.11

Pre-clinical models, both in cell culture systems and mouse models, demonstrated activity of this compound as well as showing proof of principal in terms of BCR-ABL dephosphorylation.8,11,12 Upon dephosphorylation of BCR-ABL, imatinib reconstitutes apoptosis, normalises cellular proliferation in cell culture systems and results in the prevention and regression of BCR-ABL positive tumour growth in a mouse model system.8,13