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June 2011
June 2011

Experimental treatment for childhood leukemia shows promise

Researchers at University of California San Francisco (UCSF) have identified an experimental drug that lessens symptoms of a rare form of childhood leukemia called Juvenile Myelomonocytic Leukemia, or JMML, that offers significant insight into the cellular development of the disease. The results of the study were published in the March 30 issue of the journal Science Translational Medicine.

Gary Kupfer, MD, is the chief of pediatric hematology/oncology at Yale-New Haven Children's Hospital and associate professor of pediatrics and pathology at Yale School of Medicine.

What the news means to you

Leukemia is the most common childhood cancer, affecting more than 3,500 children in the United States every year. Leukemia is classified as either acute or chronic. In acute leukemia, white blood cells are released from the bone marrow into the bloodstream before they mature, where they reproduce rapidly. In chronic leukemias, the blood cells are a bit more mature and multiply at a much slower rate.

Leukemia can occur at any age, although it is most commonly seen in children between two and six years of age. The disease occurs slightly more frequently in males than in females, and is more commonly seen in Caucasian children than in African-American children, or children of other races.

Juvenile Myelomonocytic Leukemia is an aggressive blood cancer usually diagnosed in children younger than five years and accounts for one to two percent of all childhood leukemia cases. JMML develops in the bone marrow and leads to an elevated white blood cell count that interferes with the bone marrow's ability to produce healthy red blood cells. The abnormal increase in white blood cells occurs when genetic changes, or mutations, arise in the genes that encode proteins in a cellular signaling network called the Ras pathway. This network, controlled by the Ras protein, is a critical regulator of cell growth and a frequent target of cancerous mutations.

The symptoms associated with JMML can occur over a period of weeks to months. Treatment for JMML usually begins by addressing the visible symptoms such as anemia, bleeding, and/or infection.

In the UCSF study, researchers treated genetically engineered mice to have JMML with a drug that inhibits a signaling protein called MEK (mitogen activated extracellular kinase). The most significant feature of the findings was that the treatment helped the mice not by making the cancer cells go away, but by forcing them to act like normal cells, despite their mutation. Within one week of starting treatment, leukemia symptoms, including anemia, had reversed in almost all of the mice. The mice treated with the MEK inhibitor produced more red blood cells and fewer white blood cells than the mice that did not receive the MEK inhibitor.

This is the first time a MEK inhibitor has been investigated as a treatment for JMML. Although the drug did not produce a cure, it alleviated the symptoms of leukemia as long as the treatment was continued and delayed the development of a more aggressive disease.

One concern is that given the presence of persistent mutations in these cells, it would be only a matter of time before cells acquire further changes that result in resistance to the drug as well as boosting the proliferative capacity, sending the patients back into a leukemic state. This is particularly true with respect to any aspect of the Ras pathway.

Currently, JMML is curable only through bone marrow transplantation (BMT), in which healthy blood stem cells are extracted from a matched donor and intravenously transplanted into the patient. Still, there are many problems associated with BMT, including side effects of the treatment and the immediate difficulty of getting a patient to the point of transplant. While not a curative treatment, the use of the new Ras inhibitor could prove to be an important tool in enabling patients to get to transplant and suggesting avenues of post-transplant therapy.

At Yale-New Haven Children's Hospital, we offer the latest advances in diagnosing and treating childhood cancer and blood disorders, such as leukemia, lymphoma, brain tumors, bone tumors, solid tumors such as Wilms' tumor, neuroblastoma, rhabdomyosarcoma and kidney tumors. This report highlights the potential of our new pediatric BMT unit that is scheduled to open in July.

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