A little card with a big task: Saving lives from CML

Researchers develop low-cost, paper-based diagnostic for use in low-income countries
Leukemia researchers (from left to right) Lan Beppu, Dr. Olga Sala-Torra and Jordan Smith in Dr. Jerry Radich's laboratory at Fred Hutchinson Cancer Research Center. The research team has developed a low-cost way to diagnose CML using dried blood spots on a paper card. Photo by Robert Hood / Fred Hutch News Service

This is the story of a molecule that made a long journey.

The molecule started out its life coursing through the blood of a person in Burkina Faso in West Africa, someone with an as-yet-undiagnosed leukemia. Along with its fellow mutant molecules in the blood, this molecule, a leukemia-specific RNA, spurred the out-of-control division of white blood cells that led to that person’s cancer.

The molecule was taken from the patient’s arm as part of a blood sample and a tiny drop of that blood was spotted onto a small, rectangular card of paper.

It sat on a laboratory bench for weeks on that card, as the liquid that buoyed the molecule dried out, leaving four rusty brown spots, each no larger than a dime.

The card was slipped into an envelope addressed to Dr. Olga Sala-Torra at Fred Hutchinson Cancer Research Center, stamped with Burkina Faso postage and dropped into a mailbox.

Several weeks and 7,000 miles later, it arrived in Seattle at Sala-Torra’s desk, part of the Fred Hutch laboratory of leukemia researcher and diagnostic expert Dr. Jerry Radich. Sala-Torra and her colleagues captured and recognized that molecule, known as BCR-ABL, thus for the first time identifying the disease of its original host human — chronic myeloid leukemia, or CML.

And by naming that person’s disease, a chain of events was started that would save her life.

Radich is leading a research team at the Hutch working to improve CML diagnostics — and lower their cost — in low- and middle-income countries. They’ve developed a method, supported initially by the fundraising bike ride Obliteride, to diagnose CML accurately from dried blood spots on special paper shipped by “snail mail” — at a tiny fraction of the price of FedEx-ing fresh tubes of blood halfway around the world to clinics that could analyze them.

Radich lab members have received those cards from countries all over the world. They’ve come from Asia, Eastern Europe, Africa. They arrive by mail or tucked into colleagues’ luggage as they travel from international conferences or clinic visits back to Seattle. They spend days or weeks or even months in transit to the Seattle laboratory bench.

But once patients are diagnosed through Radich’s laboratory, they’re connected with treatment through a Seattle-area non-profit, The Max Foundation, which partners with Novartis and other pharmaceutical companies to provide cancer drugs for free to patients in need outside the U.S in certain low and middle income countries.

Leuekmia researcher and diagnostic expert Dr. Jerry Radich. Fred Hutch file

‘We can’t get patients in the program’

Untreated, CML is a slow-moving but sure death sentence:  patients will likely die within 10 years. But thanks to treatments known as tyrosine kinase inhibitors, led by the approval of the breakthrough drug Gleevec in 2001, CML patients in the U.S. and other Western countries are living healthier lives, and may even reach a normal lifespan, Radich said.  

“It’s a spectacular gift” for CML patients, he said.

That is, provided those patients have access to and can pay for the drugs which must be taken continuously to keep the cancerous cells in check. Costs for the drug vary by country, but in the U.S., where the drug is called Gleevec, the price can top $100,000 per year without insurance.

But for those in many low-income countries, the treatment is free. In 2002, The Max Foundation formed a partnership with Novartis, Gleevec’s manufacturer, to provide access to the drug (which is known as Glivec outside the U.S.) at no cost to patients diagnosed with CML in 80 low- and middle-income countries around the world — for life.

The key word in that sentence, for the patients in need, is diagnosed.

In the U.S., many cancer diagnoses are relatively routine — even for a relatively rare cancer like CML, which is diagnosed in slightly more than 8,000 people in the U.S. per year, according to the American Cancer Society. But in countries without the money to pay for expensive diagnostic machines, without trained doctors and technicians, without even reliable sources of electricity, accurate diagnoses can be hard to come by.

Radich met Pat Garcia-Gonzalez, CEO of The Max Foundation, about 10 years ago through a former patient of his. Radich’s laboratory was running the diagnostics for all tyrosine kinase inhibitor clinical trials in the U.S. at the time, diagnosing patients enrolled in the studies led by Novartis.

When Garcia-Gonzalez asked Radich if he could help diagnose CML patients from outside the U.S., the Fred Hutch researcher had to admit he had never done any global health work before. But he said it wasn’t a hard decision to partner with her.

“We were doing thousands [of diagnoses] a year anyway. The idea of putting those in the pipeline as well, it was a no-brainer,” Radich said. “It was all benefit and no possible downside.”

But the cost to ship fresh blood samples from around the world to diagnostic labs like Radich’s turned out to be prohibitive for many of the patients Garcia-Gonzalez was trying to reach.

Pat Garcia-Gonzalez, CEO of The Max Foundation. Photo by Kim Hildebrand Photography

By 2009, The Max Foundation had been connecting patients around the world with free Glivec for going-on seven years. That’s when Garcia-Gonzalez traveled to Africa for the first time in her life, to attend a conference in Tanzania. She was excited to meet some of the doctors she’d corresponded with by email, she said.

She met an Ethiopian physician there, and inquired about the 200 patients in his country she knew were receiving Glivec through her foundation’s partnership. The doctor exclaimed how his patients were thriving and were so grateful. And then he gently let her know that for those 200 patients in his country who’d been diagnosed, there were another 400 who couldn’t afford the $600 it would cost to ship their blood samples to Germany or Seattle for diagnosis. They didn’t own homes, he said, while many of the 200 had sold their houses just to pay for their diagnoses.

Garcia-Gonzalez’s jaw dropped, she said.

“I was so naïve and I felt so bad,” she said. “Here you have a pharmaceutical company with this amazing drug, that is very expensive but they’re giving it for free with no limits for all the patients who need it — and we can’t get patients in the program because they can’t get diagnosed.”

After that trip, she discovered that, of the 80 countries The Max Foundation served, 50 of them were in similar straits. Patients were having a hard time affording the shipping costs to have their blood sent to a diagnostic laboratory, such as the one in Germany, that could give the patients the accurate diagnosis needed to qualify for Novartis’ program.

She started telling this story to everyone she knew and asking for ideas. Garcia-Gonzalez and Radich met up at a U.S. conference shortly after her trip, and he told her about work his research team had been doing with the company Cepheid to develop an automated diagnostic assay for CML. Cepheid makes “plug and play” diagnostic machines that require less training and expertise to accurately diagnose CML and other diseases. With Radich’s help, Garcia-Gonzalez shortly convinced Cepheid to provide the machines and supplies at a discount, when ordered through The Max Foundation in countries with a high burden of CML.

Low-tech with an impact

What started out as a sideline project soon turned into a major career focus for Radich. His lab’s other research is aimed at developing new, cutting-edge technologies to identify cancerous cells at incredibly minute levels. Those projects’ ultimate goal is to improve treatment by spotting those patients most likely to relapse as early as possible in their cancer’s return.

It’s a body of work that Radich hopes will bear fruit for cancer patients in the long run. But in the meantime, the low-tech side of his lab is making an immediate impact on patients around the world, for people thousands of miles away whom Radich will never meet, he said.

It is incredibly fulfilling, he said. “The bang for our buck is much more immediate.”

A few years ago, Jordan Smith, a technician from Radich’s lab, traveled to Tashkent, Uzbekistan, to help install a Cepheid machine in a hospital there. During his week-long trip to Uzbekistan, Smith helped diagnose dozens of local people with CML — people who likely would have died and are now connected with lifesaving therapies.

Of the original list of 50 countries that couldn’t afford diagnoses, the Cepheid partnership has now provided this aid in 22, Garcia-Gonzalez said. Some of the machines came through The Max Foundation, some were made available through other international partnerships to diagnose other diseases. Once the machines were bought and in place, with the discounts, the price per diagnosis dropped from $600 to about $50, she said.

But many of the countries couldn’t afford the machines or the supplies for them, even at the discounted price. Or they didn’t have reliable enough sources of electricity to run the machines. So the researchers had to come up with another solution to add to their diagnostic toolkit.

‘One tiny technology’

The diagnosis itself goes back to that singular molecule, BCR-ABL, which 95 percent of CML patients carry in their blood cells. Unlike many other cancers, CML is driven, diagnosed, and can be defeated by that single mutant protein.

“It’s unique among cancers,” Radich said.

BCR-ABL is created when two normal genes, BCR and ABL, are fused. It can happen by random chance. When the mutation crops up in blood cells, the resulting fused protein drives the out-of-control division of white blood cells. CML diagnoses rely on detecting that fused gene’s RNA (the message molecule that translates DNA to protein). The fused gene itself is too large to easily assess in a diagnostic test, but the gene’s RNA is much smaller.

CML can be detected with a relatively simple laboratory procedure, known as PCR, that signals the presence of the mutant RNA.

When the researchers were looking for other low-cost ways to diagnose CML, especially for those regions without easy access to diagnostic machines, they were inspired by a simple concept — the newborn “heel stick” test, which uses blood from a newborn baby’s heel spotted onto a paper card and shipped to central genetic testing laboratories to screen for inherited disorders. Those tests look for DNA, not RNA, but Radich thought they might be able to get the test working accurately enough to work on RNA.

It started out as a short-term, low-investment project in his lab for some summer interns. But relatively quickly, it was clear the blood spots would work.

“It was a rare project in that, within a summer, from idea to possibility, it came together,” said Smith, the technician in Radich’s lab who worked on the paper blood spot project as well.

With funding from Obliteride, Fred Hutch’s fundraising bike ride, the research team scaled up the project. Their collaborators in Adelaide, Australia, tested samples from patients in their lab and sent spotted cards to Radich’s lab in Seattle by ground mail. The cards took an average of six weeks to reach them, Radich said. One took three months. But they all worked to reveal the presence of CML with the required accuracy.

Since then, the team has diagnosed about 40 other patients around the world with CML using the paper product, through The Max Foundation. These are all people who wouldn’t have otherwise had access to testing — and thus no access to the no-cost treatment. The tests still cost $50 to $100 per person, Radich said, but they don’t require the initial investment in the diagnostic equipment or access to a specialized lab. His team does the diagnoses using their own Cepheid machine.

Like Radich, the other Hutch researchers working on this project hadn’t worked on global health projects before. But they are all inspired by the impact their work is having.

“It’s nice to see that what you do here has a direct translation in somebody else’s life, far away, so fast,” Sala-Torra said.

“It utilizes the infrastructure that we’ve built here at the Hutch,” Smith added. “Just with one tiny technology, a piece of paper, it extends that infrastructure so that people in far-flung regions can access the things we’ve done here.”

Next, the team wants to scale up their testing. Once they secure additional funding to support the diagnostic work, Radich wants to start a project with a goal to diagnose one person/day — or maybe more — for the next year.

As Garcia-Gonzalez puts it, “every test is saving a life.”

Dr. Jerry Radich and his laboratory team at Fred Hutch. Fred Hutch file

Learn more and follow our progress at Spot On CML.

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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