Vicky F
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Arsenic; the deadly poison and unlikely hero of leukaemia treatment.

Vicky F
Posted by
12 Jun 2015

This weekend I'm attending the European Haematology Association (EHA) in a swelteringly hot Vienna, Austria. The conference is the second biggest haematology meeting in the world covering all different blood-based disorders with a major focus on leukaemia.  Scientists and doctors come together to present their work, discuss breakthroughs and advances in treatment and to set up scientific collaborations.  Throughout the conference, I'll be writing a couple of blogs keeping you up to date with the most important breakthroughs in leukaemia understanding and treatment.

Every year at EHA, there is a specially chosen lecture given on an important historical breakthrough in haematology.  This year, the lecture was given by Professor Hugues de Thé on the treatment of acute promyelocytic leukaemia (APL) and how he and his team discovered and used the first ever drug which was able to directly target the DNA mutation in the blood cells which caused leukaemia.

APL is caused by the fusion protein PML-RARA (discovered by Dr Janet Rowley) which is formed when two bits of DNA, which should normally be separate and distinct, get fused together during cell division and then behave abnormally.  This happens in lots of different types of leukaemia, such as chronic myeloid leukaemia (CML) and some types of acute lymphoblastic leukaemia (ALL), which have the BCR-ABL fusion protein, and some childhood ALLs, where the fusion protein TEL-AML1 is the most commonly found DNA mutation.

In the early 1970s, APL treatment had a success rate of just 20%, using drugs called anthracyclines, which have numerous side effects and are particularly toxic to the heart.  In the early 1980s it was found that by using a drug called retinoic acid, a closely related compound to vitamin A, people with APL achieved complete remissions for the first time.  The retinoid acid binds directly to the RARA (Retinoic Acid Receptor Alpha) bit of the fusion protein and degrades it making the APL cells mature.

This in itself was a massive breakthrough for treating patients with APL, but many patients eventually became resistant to ATRA and often relapsed. The treatment protocol was further improved by treating with arsenic, well known for it's role as a deadly poison.  Arsenic given in low doses as the compound arsenic trioxide was found to bind directly to the PML part of the fusion protein and combined with retinoic acid, in the present day almost all patients achieve remission from APL, with around 90% surviving five years or more after diagnosis.

Many patients with APL still receieve some conventional chemotherapy in addition to the retinoid acid and arsenic, but this may shortly change. On Sunday 14th June at EHA, Professor Alan Burnett from Cardiff University reported new results from the AML 17 clinical trial for APL, showing that patients receiving just arsenic trioxide and retinoic acid did just as well as those who also received extra chemotherapy and experienced less toxic effects from the treatments.  The trial will now be expanded to more patients to confirm these promising early results.

The use of arsenic as a treatment may not be limited only to APL. Professor de Thé shared exciting new research showing that targeting the PML protein in other types of leukaemia and cancer might be an exciting new treatment strategy.  He used the example of NPM1 mutated cells (a frequent mutation in leukaemia, especially AML where 30% of people have an NPM1 mutation) and showed that in lab experiments, arsenic trioxide and retinoic acid combine to kill cells with mutated NPM1.

A truly remarkable story of research saving lives and an example of a disease which was universally deadly fifty years ago, now being entirely treatable in the majority of patients.