Royal North Shore Hospital
St Leonards, NSW
Tyrosine kinase (TK) receptors are receptors that cross the entire cell membrane. The intracellular portion of the receptor switches on a communication cascade within the cell. This enables activation and coordination of biochemical changes within the cell that allows the cell to undergo changes such as growth, proliferation and prevention of cell death depending on which pathway is activated. Normally, the process of activation is regulated by substances within the cell, that is, they stop the receptor from continuing to initiate the signalling pathway. In some disease states, the TK receptor becomes permanently switched on so that the end products of the pathway, such as proliferation, go on unimpeded. If the receptor is mutated or activated by an abnormal substance that doesn’t respond to the normal regulatory substances, the cell may continue to signal for growth and proliferation. Chronic myeloid leukaemia (CML) and gastrointestinal stromal cell tumours (GIST) are two examples of diseases with TK receptor abnormalities.
Imatinib is a novel small molecule that functions as a tyrosine kinase inhibitor. Specifically it inhibits the tyrosine kinase receptor for BCR-ABL, c-kit, stem cell factor (SCF) and platelet derived growth factor (PDGF)1. The drug is taken orally, presented as 100mg capsules. It has a peak plasma concentration within two to three hours of administration and is metabolised by the liver. The major cytochrome pathway of metabolism is with CYP3A42. The disadvantage of this is that it is susceptible to induction or inhibition of metabolism with other drugs also metabolised by the same route. Elimination is largely faecal. Carcinogenicity studies have not been completed, however it is teratogenic in rat models and should be avoided by pregnant and lactating women2. To avoid GI upset, it is recommended that the drug is taken with a full glass of water and that it be taken at meal times with food.
Generally the drug is well tolerated with minimal side effects. The most commonly reported adverse effects are fluid retention and oedema (the probability of this increases with both increasing age and dose), nausea, diarrhea and dyspepsia, neutropenia and thrombocytopenia (grade three and four in blast and accelerated phase CML), rash and myalgias2. For patients with severe neutropenia and thrombocytopenia, dose reductions or interruption of treatment are recommended. For other nonhaematological toxicities, the drug should be ceased until the event has resolved or been appropriately treated. For patient safety, monitoring for adverse effects and toxicities is vital while the patient remains on the drug. In solid tumours (eg GIST) haemorrhage into the tumour may reflect rapid response to therapy.
Chronic myeloid leukaemia
CML is a disorder in which one line of myeloid cells undergoes massive expansion. There are three phases of the disease: the chronic phase, the accelerated phase and the blast crisis. BCR-ABL is a constitutively activated TK receptor in CML. It is the product of the Philadelphia chromosome, the genetic abnormality that causes CML. Both invitro and invivo studies have shown that activation of this receptor alone results in an increase in cell cycling, proliferation, cell viability through a reduction in apoptosis and genetic instability3. Because of this single mutation, ideal treatments should be aimed at disabling this receptor. Imatinib binds to the ABL portion of the receptor thereby blocking its ability to be activated. Three phase II, open label studies have been reported, investigating the use of this drug in the three different phases of the disease, and recent approval for marketing in Australia is based on these results. Comparative studies with standard therapy (Interferon/ cytarabine) are underway to evaluate cost-benefit ratios and use in earlier phase CML. Whether it will replace transplantation as curative therapy is unknown at present.
a) Chronic Phase CML
Five hundred and thirty-two patients who had previously failed interferon treatment were entered in the trial. The median time from diagnosis was 32 months. The median time of treatment with interferon was 14 months4. All patients received 400mg of Imatinib. In patients who had previous haematologic resistance, 28% had a complete response with a further 26% having a partial response. In patients who had cytogenetic resistance 53% had a complete response and 36% had a partial response. Patients who had discontinued interferon treatment due to intolerable side effects rather than resistance had the best responses with 69% complete response and 38% partial response.
b) Accelerated Phase CML
Two hundred and thirty-three patients were treated with either 400mg or 600mg daily5. The criteria for accelerated phase was well defined. Ninety-one percent of patients achieved a haematological response; 44% complete haematological response (CHR) with recovery of peripheral blood counts; 19% CHR without peripheral blood count recovery and 28% improved blood counts only. The 12 month durable response rate was 64% with 75% 12 month survival.
c) Blastic Phase CML
Sixty patients were evaluable following treatment with 400mg or 600mg of Imatinib6. In previously untreated patients the response was 48% at four weeks and 47% at eight weeks. In previously treated patients, the response rate was 38% at four weeks and 33% at eight weeks.
Gastrointestinal stromal cell tumour
GIST is a rare soft tissue sarcoma arising usually from the stomach. This tumour expresses a trans membrane TK receptor for stem cell factor known as KIT (CD117). Normally this receptor is activated when stem cell factor is bound to it. In GIST, mutations in the c-kit gene lead to automatic activation of the receptor, bypassing the need for stem cell factor binding7. Preclinical research has demonstrated that constant signalling from the mutated receptor results in an increase in cellular proliferation and a reduction in cell death. While the incidence of this tumour is small, it has been notoriously resistant to all forms of treatment apart from surgery. To date, overall response rates to standard chemotherapy and radiotherapy have been less than 5%. For patients with advanced, unresectable or metastatic disease the outlook has been very grim with overall survival less than two years. This year has seen the first reports of promising data using Imatinib for patients with unresectable or metastatic GIST.
A single case report from Finland prompted the rapid development of two trials looking at effective dosages and response to this drug for stromal cell tumours7. Imatinib binds to several different types of the c-kit receptor, with the same “switching off” of downstream signalling pathways that had previously been seen in CML patients. The preliminary results from an ongoing international study looking at two different doses of Imatinib in advanced or metastatic GIST, were presented at the annual meeting of the American Society of Clinical Oncology earlier in the year, reporting 145 evaluable patients. Most of the patients had received prior therapy with a less than 1% response rate at the time of entry into the study. Overall response rates to Imatinib were impressive with 59% achieving a partial response and 26% having stable disease. The drug was generally well tolerated with 21% having serious adverse toxicites, including gastrointestinal bleeding8. PET scans demonstrate a rapid reduction in metabolic activity of the tumour after commencing Imatinib, with shrinkage on CT following more slowly. Receptor mutations were correlated with response. While these results are very promising the investigators stressed that it was very early days and the medium and long term outcomes are still unknown. A current European Organisation for Research and Treatment of Cancer trial comparing 400mg and 800mg per day has included Australian patients through the Australian Gastro Intestinal Trials Group. GIST is not yet an approved indication for use in Australia.
3. BJ Druker, M Talpaz, DJ Resta, B Peng, E Buchdunger, JM Ford, NB Lyndon, H Kantarjian, R Capdeville, S Ohno-Jones and CL Sawyers. “Efficacy and safety of a specific inhibitor of the BCR_ABL tyrosine kinase in chronic myeloid leukaemia”. N Engl J Med, 344, 14 (2001):1031-1037.
4. H Kantarjian, C Sawyers, A Hochhaus, et al. “Phase II study of STI571, a tyrosine kinase inhibitor, in patients with resistant or refractory Philadelphia chromosome-positive chronic myeloid leukaemia”. Blood, 96 (2000):470a.
5. M Talpaz, RT Silver, B Druker, R Paquette, JM Goldman, SF Reese, R Capdeville. “A phase II study of STI571 in adult patients with Philadelphia chromosome positive chronic myeloid leukaemia in accelerated phase”. Blood, 96 (2000):469a.
6. BJ Druker, CL Sawyers, H Kantarjian, DJ Resta, S Fernandes Reese, JM Ford, R Capdeville and M Talpaz. “Activity of a specific inhibitor of the BCR ABL tyrosine kinase in the blast crisis of chronic myeloid leukaemia and acute lymphoblastic leukaemia with Philadelphia chromosome”. N Engl J Med, 344, 14 (2001):1038-1042.
7. H Joensuu, PJ Roberts, M Sarlomo-Rikala, LC Anderson, P Tervahartiala, D Tuveson, SL Silberman, R Capdeville, S Dimitrijevic, B Druker, GD Demetri. “Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumour”. N Engl J Med, 344, 14 (2001):1052-1056.
8. CD Blanke, M von Mehren, H Joensuu, PJ Roberts, B Eisenberg, et al. “Evaluation of the safety and efficacy of an oral molecularly targeted therapy, STI571 in patients with unresectable or metastatic GIST expressing C-KIT”. Proc ASCO 37 (2001):32.