A new study of acute lymphoblastic leukemia (ALL), a blood cancer that primarily affects young children, has revealed that the disease has two distinct subtypes, and provides preliminary evidence that approximately 13% of ALL cases may be successfully treated with targeted drugs proven highly effective in the treatment of lymphomas in adults. The study was published in Cancer Cell (2015; 27(3):409-425).

Usually emerging in children age 2 to 5 years, ALL occurs when the proliferation of lymphocytes spirals out of control. The current standard of care for ALL employs high doses of chemotherapy that usually cure the disease, but may also have serious long-term effects on brain development, bone growth, and fertility, so there is an unmet need for better therapies.

In addition to discovering the two ALL subtypes, the researchers, led by scientists from University of California San Francisco (UCSF) and Oregon Health & Science University (OHSU) in Portland, developed a simple lab test that determines whether patients fall into the less-common subtype that may respond to targeted therapy. One author of the new study, affiliated with MD Anderson Cancer Center in Houston, Texas, is already using this new test to recruit patients for a phase 1 clinical trial evaluating the use of targeted drugs for ALL.


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“We hope patients in this newly identified subset can be treated with these targeted drugs, which have worked very well in patients with lymphoma and which are powerfully effective in the mouse experiments we have conducted on ALL,” said co-senior author Markus Müschen, MD, PhD, of UCSF and a member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). “These drugs have essentially no side-effects and relatively few effects on quality of life.”

Müschen said the new work grew out of a line of research on new treatments for lymphoma, which usually affects adults. That work showed that various forms of lymphoma respond well to treatment with ibrutinib or idelalisib, two drugs that precisely target the B-cell antigen receptor, a protein found in white blood cells.

“Because B-cells are also involved in ALL, we essentially recapitulated these studies, starting out with the basic science by studying genetic components of the B-cell antigen receptor in mice,” said Müschen. “We were surprised to find that, depending on the initial cancer-causing mutation, B-cell antigen receptor signaling is sometimes present in ALL, which suggested that ALL might also respond to the drugs that had been used in lymphoma.”

The group found that cells that exhibit B-cell antigen receptor signaling also express very high levels of a protein known as BCL-6. They found that their test for BCL-6 expression may have sufficient sensitivity and specificity to select patients for targeted therapy.

“Children are given high doses of chemotherapy for ALL because they are considered more resilient than adults, but there are long-term consequences that may not be obvious in childhood,” Müschen said. “Our idea is that by adding these new drugs we can reduce the amount of conventional chemotherapy or even replace it. In our experiments with mice, both combination therapy with low-dose chemotherapy and single-agent targeted therapy each worked very well. The new clinical trial using the BCL-6 biomarker should begin to bring us the answers.”