Treating Leukemia in the Brain: Advances and Challenges in Pediatric Oncology

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• The Brain Leukemia Challenge
• Historical Treatment and Toxicity
• Modern Treatment Approaches
• Long-Term Consequences for Survivors
• Current Research Focus on Biology
• Metabolic Enzyme Discovery
• Immune Evasion in the Brain
• Future Treatment Goals

The Brain Leukemia Challenge

Leukemia spread to the brain is a major problem in pediatric oncology. Dr. Shai Izraeli, MD, explains that children with leukemia often already have leukemic cells in the brain or its meningeal coverings at the time of diagnosis. This infiltration is a significant cause of treatment failure, as relapses frequently occur in this sanctuary site.

Historical Treatment and Toxicity

Before the 1970s, childhood leukemia was largely incurable. Dr. Shai Izraeli, MD, notes that while new medications achieved remission in the bone marrow, leukemia returned in the brain in 75% of children. The initial solution was preventive radiotherapy to the brain, which increased the cure rate to about 40-50%. However, this came at an enormous cost to neurodevelopment, causing an average decrease of 10 IQ points.

Modern Treatment Approaches

Modern protocols have largely abandoned prophylactic brain irradiation due to its severe toxicity. Dr. Shai Izraeli, MD, states that radiotherapy is now reserved for cases where leukemia is discovered in the brain. Current standard care involves administering very high doses of systemic chemotherapy and injecting medication directly into the spinal canal (intrathecal chemotherapy) to treat or prevent central nervous system (CNS) leukemia.

Long-Term Consequences for Survivors

Despite advances, the treatments for brain leukemia carry long-term consequences. Dr. Shai Izraeli, MD, observes that even children who grow into normal adulthood, including some professors, often suffer from a decreased intellectual capacity. Furthermore, survivors face an increased risk of developing secondary tumors in the brain later in life, highlighting the critical need for less toxic therapies.

Current Research Focus on Biology

The huge challenge today is twofold, according to Dr. Izraeli. First, researchers must identify better biomarkers to determine which patients need more or less CNS-directed therapy. Second, and more crucially, they must understand the unique biology of why leukemia cells survive in the brain, an environment that is hostile to most cells.

Metabolic Enzyme Discovery

Dr. Shai Izraeli, MD, leads collaborative research to understand how leukemic cells survive in the brain's "desert," which lacks food, glucose, oxygen, and fatty acids. His team, working with groups in Glasgow, the Technion, and the City of Hope, recently discovered a key enzyme involved in fatty acid metabolism. Leukemia cells use this enzyme to produce their own fat for survival, presenting a promising new therapeutic target to inhibit and specifically kill brain leukemia.

Immune Evasion in the Brain

Another reason leukemia cells thrive in the brain is their ability to evade the immune system. Dr. Izraeli references a publication showing that natural killer (NK) immune cells, which are critical for killing cancer cells, do not effectively enter the brain. This creates a protected sanctuary where leukemic cells can escape immune surveillance and proliferate.

Future Treatment Goals

The ultimate goal is to treat brain leukemia more smartly and with less toxicity. Dr. Shai Izraeli, MD, emphasizes that because 50% of all leukemia relapses occur in the brain, solving this problem is paramount. His research into the metabolic adaptations and immune evasion tactics of leukemic cells in the CNS is paving the way for precision medicine approaches that could one day cure leukemia in the brain without damaging healthy brain tissue.

Full Transcript

Dr. Anton Titov, MD: As more children with leukemia are cured, prevention and successful treatment of leukemia infiltration in the brain, without toxicity, is a very important goal. How can precision medicine be used to treat leukemic infiltration of the brain in pediatric patients?

Leading cancer expert, spread of leukemia to the brain is a major problem. Children with leukemia often already have leukemia cells in the brain at the time of diagnosis. Leukemia cells spread to the meningeal coverings and in the brain.

You co-authored a paper about treating leukemia in the brain more effectively. Because relapses of leukemia often also happen in the brain.

Dr. Shai Izraeli, MD: Child leukemia in the brain is a very important problem in treatment of leukemia in children. Before the 1970s, children with leukemia were not cured. Then came several effective cancer medications. Leukemia disappeared from the bone marrow, but it came back in the brain in 75% of the children.

Then we realized that you have to do preventive therapy to the brain in every child with leukemia. The way to do preventive cancer therapy was radiotherapy. Now about 40 to 50% of children were cured from leukemia, but the cost in brain development retardation was enormous.

It was an average of 10 points of decrease in IQ after radiotherapy to the brain. Today we almost never irradiate the brain. We sometimes do radiotherapy when leukemia is discovered in the brain, but we give chemotherapy to the brain.

We give very high doses of certain cancer medications into the vein. We also inject the spinal canal with cancer medications against leukemia. This also has toxic effects.

Now we have some clinical trials 10 to 20 years later. The children cured from leukemia are now normal adults. I know some professors who were cured from leukemia, but in general they suffer from a decrease in their intellectual capacity.

Dr. Anton Titov, MD: Children who survived leukemia and grew up into adulthood also have an increase of secondary tumors in the brain.

Dr. Shai Izraeli, MD: Our huge challenge today is two-fold. One problem is to identify better biomarkers in leukemia. We must know who needs more and who needs less cancer therapy to the brain.

Then we also must understand the biology of leukemia better. We have to understand why leukemia cells live in the brain.

Dr. Anton Titov, MD: Could we treat brain leukemia more smartly?

Dr. Shai Izraeli, MD: That's what we in Schneider Hospital do. We treat brain leukemia. We collaborate with other cancer research groups.

We work with pediatric oncology specialists in Glasgow with Dr. Chris Halsey, and in the Technion with Dr. Eyal Gottlieb, in the City of Hope in Los Angeles. We have a whole group that collaborates on the clinical trial of CNS leukemia.

We just presented at the American Society of Hematology a discovery of an enzyme that has to do with the metabolism of fatty acids in leukemia. Leukemic cells need fatty acids in order to survive in the brain.

Actually, the brain is a very bad place for a blood cell. That's why usually there are no blood cells in the brain. It's like a desert. The brain has no food for cells.

We found that leukemia cells have a method to start producing fat in the cells. We hope maybe we can inhibit this cancer enzyme. Then we can specifically cure leukemia in the brain.

It's a very big challenge, but that's one of the cancer research areas we focus on in metastatic pediatric leukemia. The environment is also more hypoxic in the brain. The brain is not a good place for cancer cells to live in.

There is almost no food, no glucose, no protein, no vitamins, no fatty acids anywhere in the brain. There is no oxygen, but the leukemic cells escape to the brain.

We showed in another publication that one of the reasons leukemia cells grow in the brain is because they can escape from some of the immune cells. We showed that the natural killer immune cells don't enter the brain.

But we have to kill cancer cells in the brain, because today leukemia relapses fortunately are so rare. About 50% of all relapses of leukemia happen in the brain.

Dr. Anton Titov, MD: Again, you don't need to be a scientist or leukemia physician to understand that leukemia in the brain is not a good thing.