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New Genetic Defect Signals Need for Aggressive Leukemia Treatment

New Genetic Defect Signals Need for Aggressive Leukemia Treatment

Researchers looking at a group of leukemia patients have found that a genetic defect that they discovered 2 years ago serves as an early warning signal, calling for a more aggressive approach to treatment in these patients.

The defect is a duplication of a small part of the ALL1 gene. Patients who have this defect relapse three times faster than those who do not have the alteration, and their survival is slightly more than half that of patients who do not have the defect.

The scientists reported their discovery in Cancer Research.

The genetic defect appears in patients suffering from acute myeloid leukemia (AML), a cancer that afflicts about 1 in 100,000 people. The disease increases as the population ages and the prognosis of patients with the disease worsens with age. Perhaps 40% of those with AML can be cured using appropriate therapies. Without treatment, AML can kill in a few months.

 “This is one of only a few instances where we’ve cloned a gene and then figured out what it means in terms of an individual patient’s disease. What’s more, this gene defect is a sign of a poor prognosis. Finding it allows us to better plan a patient’s treatment,” explained Michael Caligiuri, codirector of the division of hematology and oncology and associate director for clinical cancer research for Ohio State University’s Comprehensive Cancer Center (CCC). The study was led by Caligiuri and Dr. Clara Bloomfield, director of the CCC and of the division of hematology and oncology.

In approximately 55% of AML cases, the patient’s chromosomes show distinctive changes that can be linked to the disease. The remaining 45% of patients, however, show normal cytogenetics; ie, they have no obvious chromosomal changes.

Closer Examination Reveals Defect in Patients With “Normal” Chromosomes

This particular defect appears in patients who have normal cytogenetics, Caligiuri said. This means that a typical inspection of the patient’s chromosomes shows none of the chromosomal changes that signal the cause of AML.

Caligiuri and his colleagues examined 98 patients diagnosed with AML but who had normal chromosomes. In 11 of these patients, a closer examination showed that a short segment of the ALL1 gene had been duplicated and spliced back into the gene. The prognosis of all of these patients was more serious than that of patients lacking this defect.

Patients with the defect remained in remission from the disease just over 7 months, while those without the defect maintained remission for nearly 2 years. The survival time for patients who had the defect was just under 14 months, as compared with an average survival of 20 months in patients without the defect.

“This means that about 5 percent of patients with AML have this defect and need to be treated quickly and aggressively,” Caligiuri said, adding that patients with the defect probably should undergo an allogeneic bone marrow transplant while in first remission, if that option is a possibility.

Effects of Aggressive Therapy to Be Tested

The researchers are now beginning a larger, more comprehensive prospective trial intended to validate their retrospective study. Next, they will test the effectiveness of aggressive therapy in patients with the ALL1 defect. Caligiuri speculates that a screening test for the defect, now available at Ohio State, should be widely available this year.

The international collaboration was funded by the Leukemia Society of America, the Lady Tata Memorial Fund, the Cancer Society of Finland, and the Coleman Leukemia Research Fund.

 
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