One man’s mission to revive a forgotten, life-saving cancer drug

For the past decade, Dutch immunologist Jacques (Sjaak) Neefjes has been on a mission to bring back a cancer drug that has been off the market in Europe since 2004. “I’m still baffled that a drug that could have helped thousands of people was taken off the market,” Neefjes says. Why it was removed seems a mystery, but as far as he can tell, it was simply a lack of demand.

His latest research shows that this drug, aclarubicin, can improve survival in people with acute myeloid leukemia (AML) much better than other forms of chemotherapy. If it had been available in Europe in the past 20 years, Neefjes estimates it could have helped 100,000 people.

But while the math sounds simple, Neefjes’ research path has been anything but smooth. In his efforts to revive aclarubicin, he has smuggled small amounts out of China, found old samples in a Finnish freezer and funded part of his work with an inheritance from a Dutch MP who was murdered 10 years ago.

“It’s been a tough battle,” Neefjes says. And it’s far from over. Next, he needs to produce enough of the drug to start clinical trials for AML patients in Europe.

AML is a blood cancer in which the bone marrow quickly produces abnormal cells instead of healthy blood cells. Chemotherapy is a common treatment, but the side effects of some of these drugs can be quite severe. In particular, a group of chemotherapy drugs called anthracyclines can cause heart damage. This includes drugs such as doxorubicin and daunorubicin, which are used in the UK and Europe. “Normally, these drugs are only given four or five times to prevent heart problems,” says Neefjes. That may not be enough to put the cancer into remission, so researchers are looking for alternatives.

In 2013, Neefjes’ PhD student Baoxu Pang discovered that doxorubicin works in two different ways: it damages DNA and it changes the way genes are turned on and off. The gene switch was mainly responsible for killing cancer cells, while the cardiotoxic side effects were linked to DNA damage.

Aclarubicin is also an anthracycline and is used in China and Japan as a cancer treatment. On a trip to China, Pang got a small amount of aclarubicin and took it back to the Netherlands in his suitcase. “In China, you can just get it at the pharmacy with a prescription,” says Neefjes.

From this small sample, Pang found that aclarubicin caused no DNA damage at all. That meant it wouldn’t have the same cardiotoxic effects as other anthracyclines. That alone would be a good reason to bring aclarubicin back to Europe, but they needed more evidence – and more aclarubicin.

Neefjes found a researcher in Finland who had once produced aclarubicin on a commercial scale, decades ago. “She still had the bacteria needed to produce it in her freezer,” he says.

However, there was no funding to scale up production. “There is no patent on this compound, so the industry is not interested in it,” says Neefjes. Because the patent on aclarubicin has expired, there is no incentive for pharmaceutical companies to invest in it, since all competitors are also free to produce the drug. That leaves small grants, charity, and independent funding—and for Neefjes, some of his initial funding came from a tragic and unexpected source.

Neefjes’ mother-in-law was former Dutch Minister of Health Els Borst. In 2014, she was murdered in her home because of her stance on euthanasia. Borst was a driving force behind Dutch legislation that allows euthanasia under certain conditions. She was also a strong advocate for patients throughout her career. For Neefjes and his wife Andra, it was a fitting tribute to use her legacy to support research into reviving a forgotten cancer drug.

With the Borst legacy and the bacteria from Finland, Neefjes was able to produce more aclarubicin in India for his research in the Netherlands. Another boost for the project came in 2020, when Neefjes won the prestigious Dutch Spinoza Prize for his research, with an amount of €2.5 million.

Meanwhile, Neefjes also began collaborating with clinician Junmin Li in Shanghai, who routinely used aclarubicin to treat AML. Li’s patient records showed that aclarubicin improved the five-year survival rate of AML patients by 23 percent compared with other chemotherapy drugs. “Even the Chinese group was surprised to see the results,” Neefjes says. Li hadn’t yet crunched the numbers on his own patient data.

However, these promising data are not enough to bring aclarubicin back to Europe. The next step is clinical trials, and that could present entirely new obstacles, both for Neefjes and for other aclarubicin researchers.

Jay Sarthy is an assistant professor at the University of Washington and a pediatric oncologist at Seattle Children’s Hospital in the United States. He hopes to use aclarubicin to treat childhood cancer. “I’ve seen time and time again that children have severe toxicity from chemotherapy,” Sarthy says. “So a safer drug like this needs to be explored.”

In his research so far, Sarthy has found that aclarubicin, which has never been available in the United States, could work as a treatment for pediatric leukemias and lymphomas. “We immediately started preparing for a clinical trial.” But the lack of a patent means that pharmaceutical companies have not been interested in funding aclarubicin trials. “Support from charities has been crucial,” Sarthy says.

Another challenge is finding enough people willing to participate in clinical trials, especially for AML.

“It’s a very busy environment at the moment,” says Steven Knapper, a clinical haematologist at Cardiff University and the University Hospital of Wales.

AML is relatively rare, so any new drugs in development will compete for the same group of patients for clinical trials. “There’s a tendency to move to newer treatments,” Knapper says. That is, drugs developed in recent years that target the root cause of AML, rather than relatively established chemotherapy drugs like aclarubicin. There would have to be demand for aclarubicin to make a trial feasible.

That question seems to be coming. “Fewer side effects are so important,” says Veronica van Nederveen, chair of Patiëntenstem.nu.

Van Nederveen, who herself has undergone chemotherapy to treat breast cancer, notes that the cardiotoxic effect of drugs like doxorubicin can even lead to some people needing a heart transplant. “If you have a chemotherapy drug that has fewer and less severe side effects, I think people will be lining up for clinical trials.”