Leukaemia drug lifts hope

By KATHERINE HOBY

A new leukaemia drug is being hailed by researchers and medical professionals as "a significant breakthrough" in the treatment of cancer.

Peter Browett, Auckland School of Medicine associate professor of haematology, said the aim of cancer research was to develop a drug or treatment strategy that specifically targeted and killed the cancer cell while leaving normal cells relatively unharmed.

The recent discovery of the drug STI571, now called Glivec, may have fulfilled that goal in the treatment of a type of cancer called chronic myeloid leukaemia.

Chronic myeloid leukaemia is one of the blood and bone marrow cancers, which results in a proliferation of abnormal white cells in the blood and, in some patients, enlargement of the spleen.

It occurs in all age groups, although the peak incidence is in people aged between 45 and 55. Fifteen to 20 patients are diagnosed with this condition each year in Auckland.

Present treatments are good at controlling the condition for a period of time but only allogeneic bone marrow transplantation, where patients are given very high doses of chemotherapy followed by reinfusion of matched bone marrow cells, offers the prospect of a long-term cure.

Unfortunately, this treatment option is available to only 30 per cent of patients, either because their age would make the transplant too risky or because a suitable donor cannot be found.

A characteristic feature of chronic myeloid leukaemia is a unique genetic change called the Philadelphia chromosome. This abnormal chromosome is found only in the leukaemia cells, and results in production of a powerful enzyme that drives the proliferation of abnormal white blood cells.

For this reason, scientists felt that it was likely to be a very good target for an anti-leukaemia agent. The new drug STI571 was designed to be a specific inhibitor of the enzyme produced by the Philadelphia chromosome (as shown in the graphic below).

Because this enzyme is found only in leukaemia cells, STI571 does not appear to affect normal cells in the bone marrow and elsewhere in the body.

This contrasts with many of the traditional anti-cancer drugs, which kill both cancer and normal cells.

The STI571 drug is one of the first targeted anti-cancer drugs to go into clinical trial, and early results have been very encouraging.

Over 500 patients with chronic myeloid leukaemia who had not responded to conventional therapy have now been treated with STI571. Over 90 per cent have seen their white blood cell counts and spleen size return to normal, and in nearly one-third of patients, the Philadelphia chromosome, a sensitive marker of the leukaemia, cannot be detected in the bone marrow.

Investigators in the Faculty of Medical and Health Sciences, University of Auckland and the Department of Haematology, Auckland Hospital, have also been involved in trials with STI571.

In their present study, which is a collaboration with investigators in Australia and North America, patients newly diagnosed with chronic myeloid leukaemia have been randomised between the best treatment available (interferon-alpha and cytosine arabinoside) and STI571.

This trial has now closed to further accrual, and preliminary results may be available this year.

Patients on STI571 take 4-6 capsules daily and side-effects to date have been minimal: mainly mild nausea, muscle cramps and slight swelling of the ankles.

At present, it is available only to patients who are on clinical trials, although approval is likely to be given by the FDA this year, and this may be followed by registration in other countries, including New Zealand.

The main role of STI571 at present is in the treatment of chronic myeloid leukaemia, although internationally it is also being studied in other cancers.

Fact file

* Chronic myeloid leukaemia is one of the blood cancers, and affects 1 to 2 people per 100,000 population a year. Bone marrow transplants are the only potentially curative treatment at present but are an option for only 30 per cent of patients with the condition.

* An abnormal chromosome called the Philadelphia chromosome is associated with cases of chronic myeloid leukaemia. The Philadelphia chromosome results in the formation of a novel fusion gene called bcr-abl.

* The product of the bcr-abl fusion gene is a powerful enzyme (a tyrosine kinase) which causes increased proliferation of abnormal white blood cells in the bone marrow and blood.

* The bcr-abl fusion gene and enzyme is found only in leukaemia cells. It is not present in normal cells and is therefore an ideal target for leukaemia therapy.

* STI571, now called Glivec, was designed to inhibit the bcr-abl tyrosine kinase, and has been shown in laboratory experiments to kill leukaemia cells that contain the Philadelphia chromosome.

* ST571 (Glivec) is in clinical trial and results have been encouraging. Ninety per cent response rates have been observed in patients who have not responded to conventional treatment with interferon-alpha. A significant reduction in the number of Philadelphia chromosome positive cells in bone marrow was seen in nearly 50 per cent of patients.

* STI571 (Glivec) is taken as a tablet. Side effects - mild nausea, skin rashes, muscle cramps, and mild oedema - have been minimal.