Mutations Predict Quick Recurrence Of Acute Leukemia

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The presence of mutations in a particular gene may forecast the quick return of acute leukemia in some people with the disease, a new study shows.

Researchers at The Ohio State University Comprehensive Cancer Center examined the prognostic importance of mutations in a gene called Wilms tumor 1 (WT1). The study involved 196 patients under age 60 with acute myeloid leukemia (AML) whose leukemic cells had normal-looking chromosomes, a characteristic present in nearly half of adult AML cases.

The study suggests that cases of normal-chromosome AML with mutations in WT1 are likely to recur an average of nine months following treatment, that the recurrent disease will respond poorly to therapy, and that this influence is not altered by other molecular markers.

“Based on these results, we recommend that new clinical trials in this patient population include testing for WT1 mutations to confirm their prognostic importance, and, ultimately, to develop therapies that target this gene,” says principal investigator Dr. Clara D. Bloomfield, an AML specialist at Ohio State’s Comprehensive Cancer Center.

The study is published online in a recent issue of the Journal of Clinical Oncology.

“This finding was totally unexpected, and it suggests that the WT1 gene could be one of the strongest prognostic markers in AML patients with normal chromosomes,” says co-author Dr. Guido Marcucci, associate professor of internal medicine and a leukemia specialist. “It predicts a higher risk of relapse and death even when other molecular markers or clinical variables are considered.”

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Bloomfield, Marcucci and their colleagues designed this retrospective study to assess the frequency and prognostic value of WT1 mutations in normal-chromosome AML in conjunction with other genetic markers.

Patients in the study were intensively treated with an autologous stem-cell transplant through two clinical trials sponsored by the Cancer and Leukemia Group B (CALGB), a national clinical cooperative group. Twenty-one of these patients had mutations in the WT1 gene.

Bloomfield and her colleagues found that, three years after treatment, patients with WT1 mutations had poorer disease-free survival compared with patients having normal WT1 genes – 13 percent and 50 percent, respectively – and poorer overall survival – 10 percent and 56 percent, respectively.

In addition, while 16 of the 21 patients with WT1 mutations had a complete remission, the disease recurred within nine months in 14 of these patients and all but two died within 17 months (the remaining five did not achieve complete remission).

Based on their data, the researchers estimated that the risk of death was more than three times higher in patients with WT1 mutations compared with those having normal WT1 genes.

Last, the risk of relapse and death predicted by WT1 mutations were not influenced by the presence or absence of mutations in other marker genes.

Funding from National Cancer Institute and the Coleman Leukemia Research Foundation supported this research.

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