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Making better pediatric chemo treatments, and delivering them to more children
By Grant Burningham / Thu Apr 4, 2019
On her first Christmas Eve, when Janel Long-Boyle, PharmD, PhD, was a few months old, her two-year-old sister, Jenny, took a toddler-sized fall. But within minutes, Jenny was covered in deep bruises. At the hospital, doctors found an elevated white blood cell count under a microscope, a marker of pediatric leukemia.
During leukemia, white blood cells lose the ability to die, causing them to accumulate. Then they starve the other cells in the body of nutrients. Left alone, the disease kills, sometimes in months.
The fact that Jenny is alive and has children of her own is a medical miracle, but it is one that belongs to an earlier era of medicine. A medical trial of chemotherapy, a category of drugs that eliminate fast-dividing cells, saved her life. But even now, Jenny lives with many of the side effects of that brutal, years-long chemotherapy regimen.
Janel Long-Boyle, a faculty member in the UCSF School of Pharmacy's Department of Clinical Pharmacy, has spent her career advancing the drugs that saved her sister into the modern era. In the process, she’s enabled doctors to safely treat younger patients with these toxic, temperamental, and ultimately lifesaving drugs, even bringing new hope to babies as young as two months old. Her work on individualized treatments now enables some of the most-exciting gene therapy treatments for newborns.
The early days of pediatric chemotherapy
When Long-Boyle’s sister got sick in the 1970s, she was lucky to qualify for a clinical trial for her case of leukemia, especially considering her young age.
To survive, Jenny went through several rounds of chemotherapy. First, there was induction therapy, which entailed a massive amount of chemo drugs intended to force the disease into remission. Then she went through consolidation therapy, which targets cancer cells in the central nervous system. And finally, there was maintenance therapy, consisting of three additional years of chemotherapy to prevent the cancer from recurring.
Jenny and her family spent so much time in hospitals with other sick children and their families that Long-Boyle remembers being shocked when she went to kindergarten and all the students had hair.
Hair loss is a symptom of the stress chemotherapy drugs put your on your body. With children, chemotherapy is particularly dangerous. Chemotherapy drugs stop cells from dividing, which kills cancer cells, but they also kill other fast-dividing cells in the body, like the cells in the lining of the stomach, hair follicles, and fingernails. In the developing body, where every organ is growing, chemotherapy can cause even more widespread and lasting damage.
Chemotherapy drugs are also toxic to the nervous system, and children, particularly infants, are left with a heightened risk for lifelong cognitive effects after undergoing treatment. Chemotherapy can also, counterintuitively, increase young cancer patients’ risk of adulthood cancers, and its impact on the liver, heart, and other organs also raises their risk of diabetes, hypertension, and cardiovascular disease later in life.
After college, Long-Boyle worked in a laboratory studying adult bone marrow transplants, which require chemotherapy. At this point, her sister was having trouble getting pregnant. Long-Boyle reviewed her sister’s charts and was shocked by the doses her sibling endured as a child.
“She got chemo doses we would never give today,” said Long-Boyle. “The drugs haven’t really changed; we’ve gotten much better at using them.”
Better chemotherapy for kids
Jenny went on to have two children in high-risk pregnancies that carried an extreme risk of heart failure. Although she never had heart problems, she did develop thyroid cancer. Thankfully, Jenny was able to beat this second bout of cancer.
For Long-Boyle, Jenny’s ongoing health challenges had become a constant reminder of the challenges chemotherapy survivors face, and, in part, led her to pursue a Doctor of Pharmacy (PharmD). Even as she worked on her PharmD, though, Long-Boyle believed she would someday return to the lab, a path that would ultimately lead her to a PhD in experimental and clinical pharmacology.
She also started dreaming of a better understanding of chemotherapy and cancer treatments that could be tailored to individual patients, reducing side-effects and long-term impacts.
Chemotherapy regimens are a balancing act. On one hand, clinicians are wary of giving too little medicine, which might fail to completely eliminate cancer cells. On the other, the chemotherapy drugs that oncologists prescribe can be outright poisonous at high doses. An effective dose can be very close to a dose that does serious organ damage, or even kills.
Long-Boyle soon became an expert not only on pediatric chemotherapy but also the quantitative side of pharmacology—the mathematical science that helps determine the proper dose of a given drug for a given patient.
As she collected data on disease outcomes and medication levels for hundreds of children, Long-Boyle crafted algorithms to make sense of it all. She would take patient-specific variables like age, weight, organ function, and genetics, and then mathematically model what an ideal amount of chemotherapy would be for particular patients.
Eventually, Long-Boyle was able to incorporate these algorithms into giant Excel spreadsheets, designed to help clinicians easily calculate precise chemotherapy doses for children.
These lab-brewed spreadsheets opened chemotherapy regimens to younger and younger patients. But the technology was hard to use.
“Hospitals would send me back the spreadsheet and I would make changes based on new news, or new dosing information,” Long-Boyle said. “But then I would have to validate each change. I needed the help of someone who could do something more sophisticated.”
A tech solution
That more sophisticated solution came from two UCSF alumni who were already trying to usher in an age of precision medicine, where doctors pick ideal treatments based on individualized patient factors like genetics. After learning about Long-Boyle’s efforts to improve pediatric chemotherapy regimens, Ron Keizer, PharmD, PhD, and Sirj Goswami, PhD, committed themselves to making Long-Boyle’s unreliable spreadsheets a thing of the past.
The two had already founded InsightRX with the hope of making precision medicine easier to access. Their company takes complicated equations for drug doses and makes them available to health care institutions through a secure and reliable website.
Keizer was a postdoctoral fellow who worked in the lab of Rada Savic, PhD, a faculty member in the Department of Bioengineering and Therapeutic Sciences (BTS), a joint department of the UCSF Schools of Pharmacy and Medicine, and Goswami studied under Savic and Kathy Giacomini, PhD, another BTS faculty member.
InsightRX Nova software now gives dosing recommendations for 50 different medications. They picked up Long-Boyle’s equations for busulfan, a cancer drug, because it had immediate impact.
“It was sort of a primitive model, but it was designed to improve itself as more data was added from additional patients” Long-Boyle said. “As more patients’ data gets in the app, its reassesses the model and improves it. The model now performs very well in a much more broad spectrum of patients.”
The software is now available at UCSF hospitals and is already changing the model of care. “When I was in graduate school, my research advisors would say that we would never get doses this personalized. They said it was too complex,” Long-Boyle said. “Now it’s part of standard care.”
The uses for chemotherapy have evolved far beyond cancer. Now that chemotherapy drugs can be used on younger cancer patients, thanks to Long-Boyle and the InsightRX team, these drugs can also be used treat other pediatric diseases.
For example, severe combined immunodeficiency (SCID), an inherited disease that prevents young children from developing a healthy immune system, can now be treated with a combination of chemotherapy and bone marrow transplants, similar to the regimens used to treat pediatric leukemia.
Thanks to the work of Jennifer Puck, MD, and Morton Cowan, MD, faculty members in the School of Medicine at UCSF, screening for SCID happens at birth. That means doctors can catch diseases early and treat babies using chemotherapy as young as two months old.
UCSF recently started gene therapy trials for SCID babies that use Long-Boyle’s busulfan algorithm.
InsightRX’s technology has made Long-Boyle’s life a little easier, but she’s filled her free time offering help to other pharmacists and oncologists. She’s still the leading expert on chemotherapy in babies, and that means her phone is always ringing.
Long-Boyle’s work has also made her a hero to her mother, who remembers the brutal years of chemotherapy with her sister. She’s truly not in it for the money. She’s never gotten a copyright on any of the algorithms she developed, and she continues to freely share them with the world.
“Don’t tell my husband,” she said, “but if there’s a baby that needs help, I’m going to do it, whether or not I get paid.”
About the School: The UCSF School of Pharmacy aims to solve the most pressing health care problems and strives to ensure that each patient receives the safest, most effective treatments. Our discoveries seed the development of novel therapies, and our researchers consistently lead the nation in NIH funding. The School’s doctor of pharmacy (PharmD) degree program, with its unique emphasis on scientific thinking, prepares students to be critical thinkers and leaders in their field.