Anticancer agent - nilotinib
In leukaemia, immature or abnormal white blood cells are overproduced, which suppresses the production of normal white cells, red blood cells and platelets.
In leukaemia, immature or abnormal white blood cells are overproduced, which suppresses the production of normal white cells, red blood cells and platelets.
About a fifth of all leukaemias are of the chronic myeloid forms, which results from a proliferation of the cells that are formed in the myeloid areas of the bone marrow. The initial chronic phase, lasting maybe five years, is followed by another year or so of accelerated phase, and then the blastic stage where life expectancy is just three to six months.
Treatment of the disease was revolutionised by the introduction of imatinib (Glivec) from Novartis, which binds with the ATP binding site of tyrosine kinase, acting on the Philadephia chromosome that is abnormal in most patients with CML. However, resistance to the drug is now being reported, particularly in the advanced stages of the disease. Further drugs that act by the same mechanism are under development, including Novartis's nilotinib, which is structurally related to imatinib, and has potential in treating resistant CML.
Numerous clinical trials have been carried out, including a Phase I/II trial in patients with late stage resistant CML or Philadelphia-positive acute lymphoblastic leukaemia.1 A total of 119 patients were given the drug orally at doses between 50 and 1200mg once a day, or 400 or 600mg twice a day. Thirteen of the 33 patients in the blastic stage had a haematological response and nine a cytogenic response. Of the 46 patients in the accelerated phase, the figures were 33 and 22 respectively. Only two of the 13 with ALL responded.
Another Phase II trial has been carried out in 24 patients, three-quarters of whom had imatinib-resistant or intolerant CML in blast crisis, and the remainder relapsed or refractory Philadelphia-positive ALL.2 Seven of the CML patients had a haematological response and three a cytogenic response, while two of the ALL patients experienced a complete remission. Some patients suffered thrombocytopenia or neutropoenia, but otherwise the adverse effects were largely mild to moderate, and included fever, nausea, vomiting, rash, fatigue, headache and diarrhoea.
It has also been investigated in the chronic phase of CML. The drug was given in twice-daily doses of 400mg to 22 patients with imatinib-resistant or intolerant disease for a median of 124 days.3 Fourteen had a haematological response, 10 of which were complete responses, and six more a cytogenic response. Similar adverse event profiles were observed to previous studies.
Trials are continuing, and the drug has been submitted in both the US and Europe for treating imatinib-resistant or intolerant Philadelphia-positive CML patients.