Leukemia is the name given to cancer of the blood forming cells in the bone marrow. One common type is chronic myeloid leukemia (CML), which occurs in about 6,000 people a year in the USA. About a quarter of them die within two years, and a further quarter die each following year. There are three phases of CML - an initial chronic phase, then an accelerated phase, and finally a "blast crisis", in which immature bone marrow cells appear in the bloodstream. Once a blast crisis occurs, average survival is only two months, although chemotherapy can sometimes extend this by some months. The treatment of choice is a bone marrow transplant, but this procedure carries severe and sometimes dangerous side effects, and often a suitable donor is lacking. The chemo drug normally used, interferon alfa, also has many severe side effects.

The leukemic cells in CML have an abnormal chromosome, called the Philadelphia chromosome, which is associated with the formation of an enzyme called BCR-ABL. This enzyme "turns on" the cancer process in the bone marrow cells. This protein is found in all cases of CML as well as in 20% of cases of another common type, acute lymphoblastic leukemia (ALL). A new drug has been developed that prevents the action of BCR-ABL, and this has now been studied in two clinical trials in CML and ALL patients.

In the first study, 83 patients in the chronic phase of CML who could not be adequately treated with interferon Alfa were divided into groups of 3 to 6 patients. Each group was given successively increasing doses of STI571, starting with 25 mg daily in the first group, and increasing up to 1000 mg daily. Starting with a new group at the next dose level was only allowed if there were no adverse effects after 28 days treatment in the lower dose group.

Patients were followed carefully with frequent blood counts, bone marrow exams, and other lab tests. If the white blood cell count (WBC) was reduced by half, and stayed that way for two weeks, the patient was said to have had a "hematologic response". A "complete hematologic response" was declared when the WBC fell and stayed for 4 weeks below 10,000/mm, and the platelet count fell below 450/mm. A third measure of effectiveness was the percentage of bone marrow cells carrying the Philadelphia chromosome.

The patients' ages ranged from 19 to 76 years, and they had had CML for an average of 3.8 years. Hematologic responses were seen in all the patients who were given 140 mg or more of STI571. With doses of 300 mg and above, all but one of 54 patients had complete hematologic responses. These usually occurred within two weeks of starting treatment, and were maintained well beyond the 4-week mark. Roughly half the patients had some degree of response in the bone marrow, shown by a striking reduction in the percentage of cells with the Philadelphia chromosome.

Side effects were not severe -- chiefly nausea, muscle pains, swelling of the ankles and diarrhea. Liver function tests were increased slightly in 10% of the patients, but not so badly that the treatment had to be completely stopped.

In the second study, 58 patients in blast crisis (38 CML, 20 ALL) were given STI571. Over half of them had a hematologic response, and in as many as 20% there was a complete hematologic response. Again, roughly half the subjects had a strikingly reduced number of Philadelphia chromosomes in their bone marrow cells. At the time the report was written, some of the subjects remained in remission 100 to 350 days after starting treatment with STI571. However, all but one of the 20 ALL patients had relapsed at the time of writing.

Again, side effects were not severe, except in a few instances. The commonest, which were related to the dose level and were mostly mild-to-moderate, were nausea, vomiting, and swelling of the ankles. Liver function tests were increased in a number of subjects, but not seriously so. Sixteen of the patients died in this study due to progression of their disease, but none of the deaths was considered to be due to STI571 treatment.

These results are most encouraging. In the first study, although patients in the initial phase of CML were treated, they were in fact fairly advanced, having been diagnosed on average 3.8 years previously. In the second study, where the leukemias were in their final, severe stage, STI571 was somewhat more successful in the patients with CML than in those with ALL.

The two studies, taken together, show that this drug is able to reverse quite rapidly the blood abnormalities found in CML, while being very non-toxic, compared with other chemotherapy drugs. There is reason to believe that STI571 represents a true breakthrough in the treatment of these types of leukemia, and, indeed, may also prove effective in other cancers where the BCR-ABL enzyme is involved.

STI571 is marketed by Novartis Pharmaceuticals in the USA under the name Gleevec (and by Novartis as Glivec in other countries). To learn more, click here to go to the Novartis Oncology website for Gleevec.