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University of Minnesota researchers work to eliminate relapsed leukemia

By Susan Haberle

“The cancer is back.” Those are difficult words to hear as an adult but even more devastating when they apply to your child. University of Minnesota cancer researchers are working to eliminate that phrase from the vocabulary of parents who have children with leukemia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer diagnosis. According to the National Cancer Institute (NCI), it represents 23 percent of cancer in children under the age of 15. Happily, the NCI reports that more than 95 percent of children with ALL attain remission, and up to 85 percent survive without recurrence for at least five years. But that’s not good enough for the University of Minnesota.

Despite this good outcome for the majority of children diagnosed with ALL, 20% still continue to relapse with their leukemia. “A significant proportion of the relapsed ALL patients will die of the disease despite our best efforts,” says Michael Verneris, M.D., associate professor of pediatrics with the University of Minnesota Medical School, Division of Hematology-Oncology and Blood and Marrow Transplantation. It is very hard to cure leukemia once relapse occurs. Relapsing leukemia poses a greater danger to children because of the intensity and potential side effects of treatment, which often includes a combination of chemotherapy, radiation and bone marrow transplant.

Working with Verneris to eliminate relapsed leukemia— both ALL and acute myeloid leukemia (AML)—is Michael Burke, M.D., assistant professor of pediatrics with the University of Minnesota Medical School, Division of Hematology-Oncology and Blood and Marrow Transplantation at the University of Minnesota Amplatz Children’s Hospital. The work they are doing is being supported by funds from Children’s Cancer Research Fund.

Fewer children are relapsing today due to the ability of doctors to identify high-risk patients at diagnoses. This allows doctors to start patients on a more tailored and intensified regimen. High-risk patients include infants, teenagers, and patients who have a particular molecular abnormality identified through the leukemia DNA. Prior to finding these abnormalities, it puzzled doctors why these patients relapsed. Researchers continue to look for additional clues within the DNA to understand how patients will respond to treatment. The other very important indicator is a patient’s early response to treatment, even within the first week.

“The ability to follow a patient’s response through very sensitive measures is dramatically changing practice. Literally by watching the patient’s response, it becomes clear within the first week, two weeks, first month of therapy on what is going to happen to most of these patients,” says Verneris.

Researchers and doctors are unsure why leukemia returns. According to Dr. Burke, there are three general theories. The first is a hypothesis centered on patients who relapse during therapy. It is thought the disease is never eliminated due to a more resistant “mother cell,” which isn’t killed despite chemotherapy killing all the “daughter cells.” In other cases, a patient born with DNA defects, or mutations, may be exposed to an infection or toxin which causes cancer to develop. Chemotherapy may eliminate the cancer but not the initial DNA mutation and, therefore, the patient is at risk to develop a second leukemia. The third general theory is that some patients simply develop a resistance to the drugs used.

Currently, transplants with bone marrow or umbilical cord blood are primarily used for relapsed patients. Using the FACS Canto machine that was provided by supporters of Children’s Cancer Research Fund, Dr. Verneris and his team are working to identify the minute amounts of leukemia that might be present in patients before and after bone marrow transplantation. The goal of this work is to identify better ways to monitor response to therapy, to identify patients who are at high risk for treatment failure, and then to tailor treatments accordingly.

“The greatest strides will be in tailored treatments,” says Burke. “In the early 80s, people realized that not all leukemia was the same. They didn’t understand T-cell or B-cell ALL. We know now that we can’t treat all patients the same. We need to identify the family tree, where the leukemia originated, and what it will respond to.”

“At the heart of it is personalized medicine,” Burke says. “We are taking small steps, but this is the way of the future.” Current ALL treatment takes three years. Based on new data, the treatment will be dictated by what is best for each patient.

Both Dr. Verneris and Dr. Burke stress the importance of clinical trials. The improved therapies over the past years are due to doctors trying different drug combinations during patients’ treatments. Based on clinical trials at the University of Minnesota, researchers are moving forward in an international consortium called Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) for early studies of new drugs in pediatric patients with relapsed leukemia. “If these trials are successful, we could make huge strides based on the work done here,” says Burke. “It is still early but very exciting.”

Verneris, along with John Wagner, M.D., professor of pediatrics and director of the University of Minnesota Medical School’s Division of Pediatric Hematology-Oncology and Blood and Marrow Transplantation, led a recent research team that addressed leukemia recurrence. Funding from the NCI and Children’s Cancer Research Fund enabled a study showing that patients with acute leukemia, both ALL and AML, had significantly reduced risk of relapse when transplanted with two units of umbilical cord blood instead of one unit. A national, randomized study is now being conducted to validate the observations and may impact standard treatments for children and adults worldwide.

According to Burke, the research to help children with leukemia also helps adults because it gives physicians a better understanding of the molecular methods of relapse and helps them find drugs to make leukemia more susceptible to treatment. Surprising to many people, children often can undergo more intensive therapies and toxicities than adults can handle. Dr. Burke often assists other oncologists treating adult patients based on the successful treatments with children.

The number one goal is always to cure patients of leukemia, but doctors also have to understand the many long-term side effects of the therapy. Now doctors are examining survivors to adjust the initial treatments for leukemia patients currently being diagnosed.

“One of the most morbid complications of ALL therapy is the development of bone necrosis that leads to joint replacements in kids,” Burke says. “This is horribly painful. It happens in 10 to 20 percent of cases and can be life-altering,” he adds. National clinical trials are being planned for children with ALL to test new drugs to prevent relapse and also to test the use of cholesterol altering “statins” to prevent and treat bone necrosis.

“Because of what Children’s Cancer Research Fund provides, we can spend more time thinking about and exploring new ideas,” says Verneris. “This allows us breadth so we can dig deeper and become international experts. One of our biggest needs is to bridge the oncology/hematology and bone marrow transplant communities.”

It’s all about collaboration. “Part of our mission is to pull people together,” says Verneris. He and Burke both sit on committees to understand the complicated relationship between the two disciplines. They plan to visit with most of the 30 investigators at the University of Minnesota who conduct leukemia work to learn what they are working on and how they can jointly take the research to the next level.

“Some people are doing lab-intensive, early-stage work,” Verneris says. “If we can provide investigators with primary cells from patients, they would love it. We can supply patient samples to make their research better. We can also take their work and bring it back into the clinic. Taking science to the clinic or taking the clinic back to the lab – that is extraordinary. Because of Children’s Cancer Research Fund’s support, we can do these things.”

“There are so many good ideas and projects at this university,” says Verneris. “We want to embrace these ideas, capture what’s happening here, and move it forward.”

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