Sep 28 2004
Arsenic trioxide – a highly poisonous substance best known as an effective weed killer or pesticide and notorious for being a favourite ‘weapon’ of choice in murder mystery novels, is being re-invented as a treatment for a rare type of leukaemia.
It is already licensed as an orphan drug (the term for drugs intended to treat rare conditions) for patients who have relapsed after initial therapy for acute promyeloctytic leukaemia (APL).
But now, a research team led by Dr. Ardeshir Ghavamzadeh and Dr. Kamran Alimoghaddam at Tehran University of Medical Sciences in Iran, are running a trial of its use in newly diagnosed APL patients who have received no prior therapy, and they are impressed enough with its effectiveness to suggest that it should now be considered as a first-line treatment for APL. They also believe it is likely to prove effective in other cancers such as multiple myeloma.
Dr. Ghavamzadeh, professor of medicine at Tehran University, reported at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva that two courses of the drug achieved complete remission in over 90% of the 63 patients in a Phase II study being carried out at the city’s Hematology, Oncology and Bone Marrow Transplant Center. 88.5% of patients were still alive with a mean survival time to date of nearly 34 months. Of 11 patients who relapsed, eight went back into remission after a third cycle of treatment. Six patients in the trial have died.
APL accounts for around 10% of acute myeloid leukaemias and affects an estimated 20,000 people worldwide each year. It is a cancer of the white blood cells, characterized by a rapid accumulation of abnormal white cells in the bone marrow and the blood, resulting in anaemia, bleeding and susceptibility to infections. It occurs in people of all ages, although it is more common in older people. The five-year survival rate for patients receiving the current optimum treatment of chemotherapy plus ATRA (All Trans-Retinoic Acid – a vitamin A-based substance) is between 60 and 80 percent.
"There have been a few studies done using arsenic trioxide on a limited number of newly diagnosed patients, but we are the first group to suggest that it is acceptable as a first-line treatment," said Dr. Ghavamzadeh. "The results are comparable to ATRA with chemotherapy and in our study it has actually proved to be better than ATRA with chemotherapy. What this means is that we now have the possibility of offering APL patients a new first-line treatment that avoids conventional chemotherapy. It also means that if we have this drug and other effective drugs such as ATRA available as well, most patients will be able to avoid the need for bone marrow transplants."
Arsenic compounds have been used in medicine for thousands of years, dating back to the ancient Chinese and the Romans, but it was the Chinese in the 1980s that first tried it in leukaemia after finding it was the active ingredient in some traditional Chinese preparations.
The drug works by causing changes in cancer cells, inducing apoptosis – programmed cell death. It also appears to correct the gene responsible for making a flawed protein (the PML–RAR fusion protein) that causes APL.
The research team used RT-PCR techniques to confirm the diagnosis of APL by identifying the rogue gene in their study patients. This further enabled them to establish a new classification for acute myeloid leukaemia (AML). Part of the disease process in APL is due to a translocation involving chromosomes 15 and 17. Their results from the RT-PCR analysis suggested that AML should be reclassified by dividing it into two groups – APL with t(15-17) and t(15,17) negative AML. t(15-17) negative AML would then be sub-divided in line with the World Health Organization’s histologic classification system. The researchers believe that this would make sense because t(15-17) positive AML and t(15-17) negative AML have a totally different prognosis and need a different treatment approach.