The Treatment of Chronic Myelogenous Leukaemia with Imatinib (Glivec/Gleevec): binding site mechanisms

Introduction

Chronic Myelogenous Leukaemia is a disorder of the blood that results from a genetic mutation. Tyrosine is one of twenty amino acids used in the construction of cellular proteins. These proteins are involved in signal transduction pathways controlled by the phosphorylation of tyrosine by cytoplasmic tyrosine kinase. Tyrosine kinase in the nucleus is linked to cell cycle arrest and apoptosis during the first gap stage of the cell cycle when abnormalities occur. Under normal conditions, tyrosine kinase is encoded by the Abl gene on chromosome 9.

Chronic Myelogenous/Myeloid Leukaemia

Chronic Myelogenous Leukaemia is a triphasic disorder of the blood, whereby abnormal cells multiply and increase in number. The proportion of abnormal cells is a determining feature of each phase of the disease, as indicated below.

 
  • Chronic Phase – This phase is characterized by higher levels of white blood cells than normal in both the blood and bone marrow, although less than ten percent of these cells are abnormal. At this stage, although half of all patients report no symptoms, some reported symptoms are fatigue, pain or feeling full.
  • Accelerated phase – White blood cell levels are further increased in this phase, and abnormal cells now constitute between ten and nineteen percent of these white cells. Symptoms may become more noticeable now, and include fatigue, bruising, fever, night sweats, bone pain and abdominal pain.
  • Blast crisis phase – At this stage, twenty percent or more of the white blood cells in the blood and marrow are abnormal, and symptoms are significantly worse, including fatigue, bleeding, significant weight loss and complications from infections

 

In majority of cases of Chronic Myelogenous Leukaemia, the cause is attributed to a mutation in the Abl-gene coding for tyrosine kinase. The mutation responsible is a reciprocal translocation of genetic material between chromosomes 9 and 22, which results in the Abl-gene being located in the Breakpoint Cluster Region (BCR) of chromosome 22. Chromosome 22 is significantly shorter as a result of the translocation, and is referred to as the Philadelphia Chromosome. The resulting Bcr-Abl gene produces a cytoplasmic tyrosine kinase that is able to phosphorylate tyrosine in signaling pathways, but cannot be limited in its action; it also encodes a nucleic tyrosine kinase that is unable to trigger apoptosis in faulty cells, meaning these cells can continue to proliferate unchecked.

If left untreated, this condition progresses from the chronic phase to the blast crisis phase within three to five years, and treatment with drugs aims to keep the patient in the chronic phase of the disease until bone marrow transplant becomes a viable option.

Historical Treatment

There are three key treatments that were used prior to the introduction of Glivec. These were:

 

  • Busulfan – Introduced in 1953, this is an oral alkylating agent.
  • Hydroxyurea – This is an oral inhibitor of ribonucleotide reductase, so could affect the DNA replication. It has been shown to be good for white blood cell control; however it rarely induces a cytogenetic response.
  • Interferon-_ – This was introduced as a treatment in the 1980’s, and was the most effective. It is a naturally occurring glycoprotein, whose mechanism of action is unknown, although it is known to inhibit cell proliferation.

Glivec

The molecule includes several nitrogen atoms and an oxygen atom which enables bonding with several protein residues in the active site, as shown below. In normal circumstances, the tyrosine kinase binds with adenosine triphosphate (ATP) molecules to release a terminal phosphate group and bind it to a tyrosine residue. The phosphorylation of these tyrosine residues allows transmission of intracellular messages. In chronic myelogenous leukaemia, Imatinib binds with the ATP segment of the tyrosine kinase binding sites, competitively blocking its activity. This prevents the messages travelling through the cell to enable replication and proliferation, halting the advance of the cancer.

Glivec molecule

Effectiveness in Clinical Trials

 Imatinib was tested in a number of clinical trials, both individually as a treatment and in comparison with interferon, the previous treatment of choice for chronic myelogenous leukaemia. Measurements were taken to establish the haematologic and cytogenetic responses when treatment was given.

 
  • Haematologic response: When the number of blood cells (white, red and platelets) have started to return towards the normal range.
  • Cytogenetic response: Indicates a decrease in the number of cells with the Philadelphia chromosome in the bone marrow or blood.

Druker et al published research in 2001 into the efficacy and safety of Imatinib. Patients received varying daily doses of Imatinib from 25mg to 1000mg. All patients receiving doses of 140mg or more showed a haematologic response. The cytogenetic responses vary, however these still increase with the higher doses.

Kantarjian et al (2002) published results of a trial they completed over several treatment centres in the United States with 454 patients, with chronic phase chronic myelogenous leukaemia. The figures shown below demonstrate the numbers with a haematologic response (95%) and a major cytogenetic response (60%). This is a significant effect shown by this drug.

 

Talpaz et al (2002) examined use of Imatinib in the accelerated phase, and although not as effective as when used in the chronic phase, it still shows a haematologic response for 82% of patients, however the cytogenetic response is limited to 48% (half of these having a major response).

 

The use of Imatinib in the blast crisis phase is also examined by Sawyers et al (2002) where the effects are further diminished; the haematologic response is 52% and the cytogenetic response is 31%.

 

Hughes et al (2003) and O’Brien et al (2003) both looked at the molecular responses of chronic myelogenous leukaemia to both interferon with cytarabine and Imatinib in comparison. Both studies concentrated on the chronic phase. O’Brien et al (2003) showed that Imatinib demonstrated a greater haematologic and cytogenetic response than interferon. The results from Hughes et al’s (2003) study also showed a greater response to Imatinib than to interferon.

 

References

 DRUKER, B.J., TALPAZ, M., RESTA, D.J., PENG, B., BUCHDUNGER, E., FORD, J.M., LYDON, N.B., KANTARJIAN, H., CAPDEVILLE, R., OHNO-JONES, S., SAWYERS, C.L. (2001) ‘Efficacy and Safety of a specific inhibitor of the BCR-ABL tyrosine kinase in Chronic Myeloid Leukaemia’ The New England Journal of Medicine 344:pp1031-1037.

HUGHES, T.P., KAEDA, J., BRANFORD, S., RUDZKI, Z., HOCHHAUS, A., HESLEY, M.L., GATHMANN, I., BOLTON, A.E., VAN HOOMISSEN, I.C., GOLDMAN,J.M., RADICH, J.P. (2003) The New England Journal of Medicine 349:pp1423-1432.

KANTARJIAN, H.M., SAWYERS, C.L., HOCHHAUS, A., GUILHOT, F.,  SCHIFFER, C.A., GAMBACORTI-PASSERINI, C., NIEDERWIESER, D., RESTA, D., CAPDEVILLE, R., ZOELLNER, U., TALPAZ, M., DRUKER, B.J. (2002) ‘Haematologic and Cytogenetic responses to Imatinib Mesylate in Chronic Myelogenous Leukaemia’ The New England Journal of Medicine 346:pp645-652.

O’BRIEN, S.G., GUILHOT, F., LARSON, R.A., GATHMANN, I., BACCARANI, M., CERVANTES, F., CORNELISSON, J.J., FISCHER, T., HOCHHAUS, A., HUGHES, T., LECHNER, K., NIELSON, J.L., ROUSSELOT, P., REIFFERS, J., SAGLIO, G., SHEPHERD, J., SIMONSSON, B., GRATWOHL, A., GOLDMAN, J.M., KANTARJIAN, H.M., TAYLOR, K., VERHOEF, G., BOLTON, A.E., CAPDEVILLE, R., DRUKER, B.J. (2003) ‘Imatinib compared with Interferon and low-dose Cytarabine for newly diagnosed chronic-phase Chronic Myeloid Leukaemia’ The New England Journal of Medicine 348:pp 994-1004.

SAWYERS, C.L., HOCHHAUS, A., FELDMAN, E., GOLDMAN, J.M., MILLER, C.B., OTTMANN, O.G., SCHIFFER, C.A., TALPAZ, M., GUILHOT, F., DEININGER, M.W.N., FISCHER, T., O’BRIEN, S.G., STONE, R., GAMBACORTI-PASSERINI, C., RUSSELL, N.H., REIFFERS, J.J., SHEA, T.C., CHAPUIS, B. COUTRE, S., TURA, S., MORRA, E., LARSON, R.A., SAVEN, A., PESCHEL, C., GRATWOHL, A., MANDELLI, F., BEN-AM, M., GATHMANN, I., CAPDEVILLE, R., PAQUETTE, R.L., DRUKER, B.J. (2002) ‘Imatinib induces haematologic and cytogenetic responses in patients with chronic myelogenous leukaemia in myeloid blast crisis: results of a phase II study’ Blood 99:pp3530-3539.

TALPAZ, M., SILVER, R.T., DRUKER, B.J., GOLDMAN, J.M., GAMBACORTI-PASSERINI, C., GUILHOT, F., SCHIFFER, C.A., FISCHER, T., DEININGER, M.W.N., LENNARD, A.L., HOCHHAUS, A., OTTMANN, O.G., GRATWOHL, A., BACCARINI, M., STONE, R., TURA, S., MAHON, F.X., FERNANDES-REECE, S., GATHMANN, I., CAPDEVILLE, R., KANTARJIAN, H.M., SAWYERS, C.L (2002) ‘Imatinib induces durable haematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukaemia: results of a phase 2 study’ Blood 99:pp1928-1936.

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