Genes predict response of adult leukemia patients to chemotherapy

Genes can indicate which adult leukemia patients will respond to therapy and what the duration of their remission will be, according to a new study published in the April 1, 2004, issue of Blood, the official journal of the American Society of Hematology.

Researchers from the Dana-Farber Cancer Institute in Boston, Mass., and the University “La Sapienza” in Rome studied 33 patients that had all been recently diagnosed with adult T-cell acute lymphocytic leukemia (T-ALL), a type of cancer in which the body makes too many T lymphocytes.

“The present study investigates, for the first time, the identification of gene expression profiles associated with both short-term and long-term outcome in adult patients with T-ALL. While approximately 70 percent of pediatric patients with T-ALL have excellent long-term response to intensive chemotherapy, adult patients have a much less favorable outcome. Previously, this poor prognosis of adult T-ALL patients had not been attributed to specific genetic signatures,” according to Jerome Ritz, M.D., of the Dana-Farber Cancer Institute, co-senior author of the study. Robin Foa, M.D., from the University “La Sapienza,” also served as senior author.

Using microarray technology, a technique that can evaluate the expression of thousands of genes at once, researchers were able to compare the gene expression profiles of the patients who responded to chemotherapy to those who did not. Through gene expression profiling – a determination of which genes in a cell or group of cells are active – the scientists identified a single gene, IL-8, that was highly expressed in T-ALL cells that were resistant to treatment. Researchers also discovered a set of 30 genes that were highly expressed in leukemic cells from patients who achieved complete remission.

A model based on the expression of three genes – AHNAK, TTK, and CD2 – was also found to be highly predictive of the duration of remission, correctly classifying 71 percent of outcomes. The model was later verified by T-ALL samples taken from a separate group of 18 patients. Two conventional measures for predicting a patient’s outcome – the white blood cell count and the degree of differentiation (a comparison of the similarity between cancerous cells and their normal counterparts) – were also examined and appeared to be less predictive than the three-gene expression model.

The results of the study may help doctors customize a T-ALL patient’s treatment plan based on the individual’s predicted response to therapy using these methods. Further exploration of these genes may also lead to new therapeutic targets for adult T-ALL.

According to Donald Miller, M.D., Ph.D., Professor in the Division of Hematology at the University of Louisville and Director of the James Graham Brown Cancer Center in Louisville, Ky., “This work represents one of the first applications of genomics to an important clinical problem. It provides strong evidence that genetic analysis will help us provide better care to patients with leukemia and other malignant diseases.”

This work was supported by the National Institutes of Health grant CA66996, the Ted and Eileen Pasquarello Research Fund, the Associazione Italiana per la Ricerca sul Cancro, the Instituto Superiore di Sanita, the Ministero dell’Istruzione, dell’Universita e della Ricerca Scientifica (MIUR), the Progetto FIRB, and the Associazione per le Leucemie Acute dell’adulto “Cristina Bassi” e Fondazione Cassa di Risparmio di Genova e Imperia.

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