Removing the fear: Thalidomide’s evolution

Despite its dark past, thalidomide has staged a therapeutic comeback like no other. Kate Woods investigates.

DR MELITA Kenealy is a Melbourne haematologist with a particular interest in myelodysplastic syndrome (MDS). The disease, which typically affects people in their 60s, is characterised by anaemia, neutropenia and thrombocytopenia leading to acute leukaemia in about one in three patients. 

While there are very few treatment options available to patients with this disease, one drug that has had some success is thalidomide.

“But as soon as you tell a patient that you want to start them on thalidomide, the first thing they say is: Isn’t that a really bad drug?”

What many patients don’t understand, explains Dr Kenealy, is that thalidomide has been used frequently and with very good outcomes in treating a number of haematological diseases. 

“When you explain these benefits to patients, explain that monitoring processes are in place...and explain the care taken in order to keep it from people who may become pregnant, most people’s concerns disappear pretty quickly,” she says.

A terrible history

Thalidomide is one of the world’s most well-known drugs, but for all the wrong reasons. Introduced in 1956 as a sedative to combat insomnia and then as an antiemetic taken by thousands of pregnant women worldwide to ease morning sickness, teratogenic effects were discovered in 1961 and it was withdrawn from the market.

Commentators have suggested that the thalidomide story is “one of the biggest medical tragedies of modern times”,1 with estimates indicating that between 10,000 and 20,000 children in 46 countries were affected by thalidomide induced limb defects during the five years the drug was marketed. 

But less well known is the fact that thalidomide has also made one of the greatest medical comebacks of modern times, gradually transforming into an extremely useful drug for a wide range of conditions.

The renaissance began in the mid-1960s when an Israeli dermatologist trialled thalidomide in patients with erythema nodosum leprosum (ENL).2

Although he was attracted by thalidomide’s sedative properties, he discovered it actually had a dramatic effect on skin lesions, improving and even resolving them within two days of treatment.

Of course confirmatory studies followed, and before too long it was back on the market, approved by a number of countries for ENL.

Researchers in various medical specialties continued to investigate all possible benefits of the drugs, but it wasn’t until the late 1990s that one of the biggest discoveries was made: thalidomide worked extremely well for treating multiple myeloma.

The discovery occurred when Beth Wolmer, the wife of a US cardiologist extremely ill with multiple myeloma, contacted a doctor by the name of Dr Bart Barlogie. 

Mrs Wolmer had been looking for an effective intervention for her husband, and after talking to researchers at Harvard Medical School, she believed thalidomide might be able to treat her husband’s myeloma by slowing angiogenesis.3 Dr Barlogie agreed to try using the drug to treat Mr Wolmer, but the therapy failed shortly thereafter and he died. 

Thalidomide did, however, successful help treat another of Dr Barlogie’s patients. 

Spurred on by this result, Dr Barlogie set up a trial in 84 previously treated patients with refractory multiple myeloma and found bone marrow changes and a significant reduction in blood and urine paraprotein levels among thalidomide users.4

“These results caused an explosion of research into thalidomide in myeloma,” says Professor Miles Prince, a haematologist at the Peter MacCallum Cancer Centre.

Many of these research studies occurred in Australia, and all confirmed that thalidomide was  clinically effective in inhibiting the growth of multiple myeloma cells and controlling the micro-environment.

Mechanism unknown

“Australia was the first country to approve thalidomide for myeloma and to include it on the PBS,” says Professor Prince.

“Since then it has moved from approval as an end-stage treatment, to cornerstone of front line therapy in myeloma. 

“Virtually every patient with myeloma, young or old, now receives thalidomide as part of induction treatment.”

Thalidomide’s exact mechanism of action and those of its immunomodulatory derivatives – lenalidomide and pomalidomide – have yet to be clearly identified. 5

However, researchers believe it is related to its immune modulating properties (it decreases the levels of cytokines, TNF-a and IFN-y), and anti-inflammatory (it inhibits the chemotaxic of lymphocytes and neutrophils) and anti-angiogenic properties. 

Mild and well known teratogenicity is its most severe toxicity, but this complex drug is also associated with peripheral neuropathy, somnolence, constipation, rash and deep vein thrombosis. 

“Nerve damage is the other major issue. In fact about 50–70% of patients can’t take it for more than a year because of this effect,” says Professor Prince.

As both lenalidomide and pomalidomide are proving more efficient and less toxic than thalidomide, these next generation IMiDs will take over about 90% of current thalidomide use for myeloma in the future, he adds.

“Thalidomide is going to be used less and less in the future, but it has provided an exciting step into the next era of thalidomide derivatives. It has saved hundreds of years of life.

“The statistics show that in 1999 myeloma had a medium survival of three years. In 2011 it had a medium survival of seven years.” 

Unfortunately its effect in other cancers has not been as dramatic. 

“It has been used in brain tumours, and there are a few reports suggesting they may have some benefit in prostate cancer. But these are exceptions rather than the rule.” 

It has also been trialled in HIV and AIDS after US researchers demonstrated that thalidomide inhibited TNF-a, a cytokine known to be elevated in people with HIV/AIDS.4

But while these studies confirmed that thalidomide was effective against aphthous ulcers and the symptoms of wasting syndrome, it did not improve T4 cell counts or reduce HIV replication.6

Its role in gastroenterologic conditions might be more significant however, with a recent Chinese study showing that thalidomide showed promise for the treatment of refractory gastrointestinal bleeding from vascular malformation.7

In the study of more than 50 patients, the rate of bleeding episodes fell by half in more than 70% of subjects receiving thalidomide. Rates of hospitalisation and blood transfusions were also significantly reduced. No severe adverse effects were observed.

“While we will need to see bigger and larger confirmatory trials before we can jump to any conclusions, these findings maybe setting the stage for another major indication for thalidomide,” says Professor Prince.

Dermatology is the other area where thalidomide has shown itself to be an effective treatment for a host of skin conditions. 

Patients with diseases such as aphthous stomatitis, Behçet disease, pyoderma gangrenosum, chronic discoid lupus erythematosus, systemic lupus erythematosus, lichen planus, prurigo nodularis and sarcoidosis have all shown some improvement as a result of taking the drug.

Associate Professor Chris Baker is the director of dermatology at St Vincent’s Hospital in Melbourne.

He says a number of patients are treated at his photobiology clinic with thalidomide, but not as first-line therapy.

“In some conditions such as actinic prurigo, thalidomide is extremely effective. But it is only used when other options have been exhausted and obviously is used with great care.

“In other conditions like prurigo nodularis and lupus, it is invariably effective, but again, it is often all we have left to offer patients because we have exhausted all other options.”

He says while he has never had a patient who has outright refused to take thalidomide on his suggestion, patients do usually display some degree of surprise that the drug is still being used today. 

“But because we are offering thalidomide to patients who are severely affected by their skin condition, who are just so pleased to hear there is another treatment option, resistance is rarely offered. 

“Obviously we are all very aware of the unfortunate, terrible history that thalidomide has had, and so we prescribe with precaution; we provide patients with a lot of information and we make sure careful monitoring ensues.”

Dr Kenealy, a consultant haematologist at Cabrini Health, warns that as thalidomide is now an old drug, the next 20 years will not be as bright as the last 20. 

“Thalidomide has really revolutionised treatments in multiple myeloma and has also been the basis of a huge amount of development,” she says. 

“People have truly benefited from this drug and we shouldn’t forget that.”