History of treatment for a rare type of blood cancer: Acute promyelocytic leukaemia

APL was first recognised as its own disease (separate from AML) by a Swedish physician called Leif Hillestad in 1957, who also gave the disease its name.

At this time, APL was treated no differently from any other form of AML and, as a result, the average survival time for a patient with APL was less than a week. It is now known that immediately administering intensive chemotherapy upon diagnosis of APL can exacerbate bleeding and increase the risk of early death. Today, prognosis for patients has drastically improved, with the average 10-year survival rate for someone diagnosed with APL currently standing at around 85%.

The first major contribution to the treatment of APL came from J. Bernard and his team of physicians from France who, in 1973, discovered that the disease was particularly sensitive to anthracyclines (a type of chemotherapy drug that is extracted from streptomyces bacteria). They reported a massive improvement in the rates of complete remission in patients, rising from 13% to 57%.

ATRA stands for all-trans retinoic acid, which is a compound similar in structure to vitamin A. ATRA works very specifically as a treatment for APL by acting on and resolving the faulty “fusion gene”, PML/RARA, which is the cause of nearly all cases of APL.

The discovery of the effects of ATRA as a treatment option for APL has proven to be the biggest breakthrough treatment in its history and has completely revolutionised the outcome for patients facing this rare disease.

People with the faulty PML/RARA fusion gene are unable to properly produce a protein known as retinoic acid, which is needed to help promyelocytes (a type of immature white blood cell) mature properly. It’s this lack of retinoic acid in patients with APL that is causing promyelocytes to build up in the bone marrow. ATRA works to combat this by binding specifically to the faulty PML/RARA fusion gene to enable them to properly synthesise retinoic acid. This then allows promyelocytes to mature correctly.

Unfortunately, some people with APL experience a relapse even after reaching a state of remission following treatment with ATRA and chemotherapy. The treatment options for these patients was extremely bleak at one time, but the emergence of a final treatment has brought hope: arsenic trioxide.

Although most think of it as a poison, the therapeutic benefits of low doses of arsenic compounds have been known for over 2,000 years, particularly in ancient Asia where they were originally used to cure certain ailments such as ulcers or abscesses. Perhaps more surprisingly, arsenic was first shown to have anti-leukemic qualities back in 1880 in America.

Over a century later, in 1995, a group of Chinese scientists noted that APL was particularly responsive to arsenic trioxide (ATO). The first large clinical trial that looked at the effect of arsenic trioxide (ATO) on relapsed APL patients (no longer responding to chemotherapy or ATRA) found that 85% of patients achieved a complete remission when treated with ATO alone.

Furthermore, in June of last year, NICE (National Institute of Health and Care Excellence) approved NHS funding for the use of arsenic trioxide in combination with ATRA for relapsed patients, as well as patients who have just been newly diagnosed. In one trial that compared the combination of ATRA with arsenic trioxide with the standard treatment (ATRA and anthracyclines), after five years, 97.5% of patients had event-free survival following treatment with arsenic trioxide plus ATRA. It is thought that the use of ATO and ATRA in untreated patients will significantly reduce the number of people relapsing with APL.