Operation Flush Clean

A drug being used for the first time in India 
offers hope to leukaemia patients, reports Biplab Das 

When a bone marrow test showed no signs of leukaemic cells, 34-year-old Kasturi Sengupta heaved a sigh of relief. To be absolutely certain, she then consulted a haemato-oncologist, Dr. Asis Mukherjee, at the Kothari Institute of Medical Science. That is when the bad news came. She was diagnosed with acute promyelocytic leukaemia (APL), a rare form of blood cancer. 

A slew of anti-cancer drugs and chemotherapy followed which steadily mopped up the leukaemic cells from her blood and bone marrow. But they just could not write off her genetic anomaly, the root cause of APL, which made Kausturi more towards the disorder. "With residual genetic anomaly, there is always a possibility of a relapse," says Mukherjee. 

Intrigued by Kasturi's case, Mukherjee devised a novel therapy in an attempt to avoid future relapses. He is being assisted by Dr. S. Pattanayak, Dr. S. Mukherjee and Dr. M. K. Das, all from Kothari Institute. 

Recently, Mukherjee and his colleagues have started to administer Trisenox, chemically known as arsenic trioxide, to Kasturi. The drug has been proved to eliminate traces of genetic defects. Incidentally, Kasturi is the first recipient of this drug in India. 

APL occurs due to an unexpected exchange of genetic material between chromosomes 15 and 17. This process, called translocation, turns on specific genes present in promyelocyte cells, which are precursors of a type of white blood cells called neutrophils. Once these oncogenes are activated, they not only arrest the development of promyelocyte cells but also render them malignant. This triggers their unbridled proliferation in the blood and bone marrow, leading to APL. As the oncogene codes for PML RAR alpha (promyelocytic leukaemia retinoic acid receptor alpha) protein, it is called the PML RAR alpha gene. 

"Trisenox stops translocation and induces apoptosis [programmed cell death] in malignant promyelocyte cells," Mukherjee points out. However, this annihilation mechanism does not interfere with neighbouring healthy cells, and the dead cells are neatly scavenged out. 

The drug is administered intravenously over a period of one to two hours. The prescribed single dose is 15 mg for every kilogram of a patient's body weight. The therapy will be administered for five days a week for five weeks. "Altogether we will provide the patient with 25 doses of Trisenox injections," says Dr. Mukherjee. 

According to him, this step is the second phase of APL treatment. Usually induction treatment, which includes anti-cancer drugs and chemotherapy, precedes Trisenox therapy. Only if induction therapy fails should this method be introduced. "With the help of the anti-cancer drug, ATRA (all trans retinoic acid), malignant promyelocyte cells are driven towards maturity and then mercilessly killed by anthracycline, a chemotherapeutic agent," says Mukherjee. 

But, studies have revealed that induction therapy fails to clean up cancer genes. Thirty to forty per cent of the cancer genes still lurk and threaten to reinitiate APL within two years. "Trisenox as a part of consolidation treatment seals the fate of those harmful residual genes," Mukherjee adds with some satisfaction. 

He admits that there are a few side effects. During treatment, a patient may suffer from APL differntiation syndrome, which manifests in the form of high fever and weight gain. "If it becomes life-threatening, intervention therapy is needed," he adds. This involves the administration of a steroid called dexomehtasone. 

There are more risks. Trisenox contains arsenic, which itself is a carginogen. Although the drug is diluted to a great extent to reduce arsenic toxicity, excess dosage can cause much harm, especially to the liver. "Once Trisenox regimen is over, it's important to keep the liver in good shape," says Mukherjee. 

Trisenox should not be used in APL patients with renal failure. If the arsenic starts getting deposited inside the body, it can prove lethal for the patient. The symptoms of arsenic toxicity are convulsions and muscle weakness. "If such a situation occurs, Trisenox should be discontinued and intervention therapy should be resorted to," Mukherjee suggests. 

Pregnant women should never be given the drug because it causes foetal damage. Studies in pregnant mice, hamsters and primates have shown that inorganic arsenic compounds cross the placental barrier when given orally or by injection. Another study showed that patients who became pregnant while receiving Trisenox often had miscarriages. Since the residual arsenic is also secreted in human milk, a breast-fed infant runs a great risk of toxicity if the mother is on Trisenox. 

But the side effects are a minor worry compared to the cost of the therapy. The drug has to be imported and a single regimen of 25 doses costs around Rs 5 lakh. "If it is produced in India, the cost will be whittled down to mere Rs 5,000," concludes Mukherjee. "This shouldn't be a problem as we have no dearth of arsenic deposits in India." Are the pharmaceutical giants listening?