Leukemia and Lymphoma: The TOTAL Package

A new precision medicine study aims to push leukemia and lymphoma survival rates ever higher while reducing side effects.

By Elizabeth Jane Walker; Photos by Seth Dixon

The word sliced through Wendi Brantner like a sharpened blade: leukemia. At that moment, the universe contracted, explanations muffled by the roar of a mother’s frantic heartbeat.

“I didn’t cry; I was just trying to breathe,” Wendi recalls. “Your whole life changes in one second.”

Looking back, there had been clues: worrisome bruises, a lackluster appetite, night sweats. But 12-year-old Brooke and her parents had discounted those minor ailments. Then a scooter mishap required X-rays to rule out a broken arm.

“Please check her blood while she’s here,” Wendi told the doctor.

The arm was not broken, but Brooke’s blood sample teemed with immature white blood cells. Wendi and her husband, Mark, rushed their daughter to the St. Jude Children’s Research Hospital affiliate in their hometown, where clinicians diagnosed acute lymphoblastic leukemia (ALL).

“We’re sending you to the mother ship,” the staff told the Brantners. “You’re leaving for Memphis tomorrow.”

Success builds on success

Brooke and her family learned she would be one of the first four patients to enter Total Therapy Study 17 for children with leukemia or lymphoma. This new clinical trial represents the culmination of a half-century of innovative research and clinical care.

Fifty-five years ago, most medical centers offered single-drug treatments that saved about four out of every 100 patients. Then St. Jude scientists announced a “total” strategy that involved a combination of anti-cancer drugs. The revolutionary protocol yielded cures, and the world took note.

During the ensuing years, each iteration in the Total Therapy series built upon knowledge gleaned from preceding studies. Today, St. Jude leads the world in the research and treatment of ALL. The 17th trial in the series is designed to save more children while improving their quality of life during treatment and beyond.

“At St. Jude, we have 94 percent survival, but we want to increase it to 100 percent,” explains oncologist Hiroto Inaba, MD, PhD, who heads Total 17. “To reach 100 percent, we must take a new approach.”

That tactic incorporates precision medicine—a discipline that uses genetic factors to tailor therapy. By harnessing technology and melding it with phenomenal research and clinical care, Inaba and his colleagues intend to further increase survival rates while reducing long-term side effects.

Every child who enrolls in Total 17 will undergo genomic testing of both normal tissue and leukemia cells to guide therapy.

 

Practical genomics

Every child who enrolls in Total 17 will undergo genomic testing of both normal tissue and leukemia cells to guide therapy.

Genes in normal tissues determine our eye and hair color, as well as many other traits. But genes can also predispose children to cancer or regulate medication response.

Years ago, St. Jude researchers discovered that children with a certain variant genetic type could not clear a common chemotherapy drug from their bodies, so the medication could build to dangerously high levels. For those patients, a much smaller dose had the same effect that a larger dose would have in children with common genetic profiles. As a result, St. Jude developed a genetic test that is now used by hospitals worldwide to screen children before administering that drug.

Total 17 will incorporate this kind of new testing for several medications, including a drug that can cause neurological problems such as foot-drop more frequently in children with a specific genetic type.

“Genomics will also change the chemotherapy,” Inaba explains. “Leukemia cells carry abnormal genetic changes—so-called mutations—that produce cancerous cells and promote their growth. Using genomic data of leukemia cells, we can identify many abnormal mutations that may be targetable by new agents. If a patient has these lesions or is not responding well to treatment, we can add those agents to therapy to improve the responses.” 

Hiroto Inaba and Brooke Brantner

By harnessing technology and melding it with phenomenal research and clinical care, Hiroto Inaba, MD, PhD, and his colleagues intend to increase survival rates while reducing long-term side effects for children such as 12-year-old Brooke Brantner.

Allergy avoidance

One important medication for ALL treatment is called asparaginase. But some children develop severe allergies to that drug. Those reactions can range from skin rashes to low blood pressure or respiratory problems. In such cases, the medication can stop working and response to chemotherapy may worsen. Alternative medicine is available and important for these patients, but it only works for a few days instead of for two or three weeks—meaning it must be given every few days to be effective.

“If you can prevent those allergies, the drug works better without severe side effects and it decreases hospital visits,” Inaba explains.

Allergies are caused by antibody formation, so clinicians hope to avoid allergic reactions by dispensing a drug called rituximab to children like Brooke, who has a type of ALL that affects B cells. Rituximab prevents antibodies from forming.

“This method has not been used in other trials,” Inaba says. “We hope that by giving rituximab early in therapy we can prevent antibody formation and the allergic reactions.”

Early response

Success builds upon early vigilance. That’s why evaluations occur early and often in Total 17. After the second and sixth weeks of therapy, clinicians conduct tests to find out whether cancer cells persist.

“With a microscope, we can detect maybe one out of 20 cells,” Inaba explains. “But if even 1 percent is there, the cancer will come back. With our detection level, we can find one out of 10,000 to a million cells. This is a more sensitive way to identify who is a high-risk patient and who can be cured with standard agents.”

If leukemic cells remain, a patient with B-cell ALL receives immunotherapy, which is a treatment that marshals the patient’s own immune system to eradicate cancer cells. If leukemic cells continue to persist after immunotherapy, then the child may require a bone marrow transplant.

Problem prevention

One crucial aspect of Total 17 is the emphasis on quality-of-life issues. St. Jude staff are determined to enable survivors to thrive into adulthood.

Several years ago, St. Jude completely stopped giving brain irradiation to children with ALL. Instead, all patients with that disease receive chemotherapy given through the spinal fluid. This has remarkably improved issues with IQ, memory, growth and the occurrence of second cancers. However, attention problems have persisted. To combat attention issues, St. Jude will test the use of computer software designed to increase attention and working memory.

In addition, through genomic testing, scientists are able to determine which patients require more chemotherapy administered into the spinal fluid. If a child has lower-risk disease, that individual will receive lower frequencies of treatment, thus avoiding the potential for attention problems.

Because the steroids used in treatment may affect bone density, clinicians will use an intervention that requires the patient to stand on a vibrating plate—a therapy that may prevent bone density loss. 

Charles Gawad and Veronica Gonzalez-Pena

As part of the Total 17 clinical trial, Veronica Gonzalez-Pena, PhD (left), and Chuck Gawad, MD, PhD, both of Oncology, sequence both the normal and leukemic cells of patients.

Kiri Ness and Brooke Brantner

Kiri Ness, PhD, of St. Jude Epidemiology and Cancer Control, helps Brooke Brantner understand how standing on a vibrating plate could help prevent bone density loss. 

Finding cures more quickly

As the largest clinical trial ever run by St. Jude, Total 17 aims to treat 1,000 children—a massive undertaking that requires the collaboration of institutions throughout the U.S. By enrolling many children in the study, scientists can accrue data more quickly and share their findings worldwide.

“ALL is now divided into more than 20 subgroups,” Inaba explains. “To study that, we need a large number of patients. I think such a high-quality, meticulous study can only be done by St. Jude. Our strength is the quality of our genomic testing and our dedicated patient care. But we also want to prove that the St. Jude way can be exportable to other institutions.”

Attitude of gratitude

After completing the first month of therapy, Brooke remains upbeat and optimistic. Today, she colors an intricate picture during a seven-hour chemotherapy infusion. Although fighting fatigue, the sixth-grader is talkative.

“Mommy, the only thing that has energy is my mouth,” says Brooke, who anticipates the day she can return to a normal life of riding bicycles and hanging out with friends; petting her dog, Snickers; and snuggling with her black cats, Perky, Ninja and Allison.

Although Wendi also anticipates that future homecoming, she says she appreciates the excellent medical care her daughter is receiving.

“This has been the most amazing experience,” she says. “You don’t feel sadness here; you feel hope and love and comfort. I’m so grateful to be here, and I couldn’t imagine a better place for Brooke.” 

From Promise, Summer 2017

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