Acute-leukemia sign may signal need for different therapy

Sep 19 2005

A type of chromosome change that was thought to predict a good response to treatment in patients with acute myeloid leukemia (AML) might actually signal the need for a different therapy to achieve the best outcome.

The findings from this new study may alert doctors that they need to change their treatment approach for certain AML patients.

The study compared AML patients whose cancer cells showed chromosome changes known as the 8;21 translocation with patients whose cancer cells showed chromosome damage known as inversion 16.

Currently, AML patients with either the 8;21 translocation or the inversion 16 abnormalities receive the same therapy. They also tend to experience complete remission and have a better overall survival than do patients with most other subtypes of AML.

But this study found that when the two groups of patients are compared with each other – and when ethnicity, sex and other chromosome changes are considered – patients with the 8;21 abnormality fare significantly worse than do patients with inversion 16 when they receive similar therapy.

Furthermore, the researchers were surprised to find that nonwhite AML patients with the 8;21 translocation were almost six times less likely to achieve complete remission following the initial therapy than were whites.

The findings were published in a recent issue of the Journal of Clinical Oncology. They come from a Cancer and Leukemia Group B (CALGB) study initiated by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSU CCC-James).

The study is part of a larger CALGB cytogenetic trial chaired by Clara D. Bloomfield, professor of internal medicine and the William G. Pace III Professor in Cancer Research, OSU Cancer Scholar and senior adviser to the OSU Cancer Program.

"It's widely believed that AML cases with these abnormalities have the same outcome," says Bloomfield, "but our findings indicate that they don't. Furthermore, nonwhites with the 8;21 translocation can do extremely poorly.

"While our data need to be verified, they strongly indicate that we must stop thinking about the 8;21 group as having a highly favorable type of leukemia and start asking what we might do to increase the cure rate among those patients. They may require a transplant or an experimental therapy after they achieve remission."

Bloomfield was the first some years ago to determine that AML patients with the 8;12 translocation and inversion 16 abnormalities was particularly sensitive to a particular chemotherapy regimen and tended to have better outcomes than did many other AML patients.

"These findings indicate that patients with the 8;21 translocation do worse because, once they relapse, the disease doesn't respond well to additional therapy," says first author Guido Marcucci, associate professor of internal medicine and a hematologist with the OSU CCC-James.

"We need to begin reporting the outcomes of these patients as separate subgroups of AML, and we may need to offer them different treatments."

This retrospective study analyzed the clinical characteristics and outcomes of 312 AML patients, 144 of whom had cancer cells with the 8;21 translocation and 168 of whom had inversion 16.

Of the 8;21-translocation patients, 100 were white (69 percent), 27 were African American (19 percent) and 12 were other ethnicities. Of the inversion-16 patients, 136 were white (82 percent), 13 were African American (8 percent) and 17 were of other ethnicities (10 percent).

The data showed that patients with the 8;21 abnormality were 1.5 times more likely to die of their disease than were patients with inversion 16.

In addition, nonwhite patients with the 8;21 translocation plus other abnormalities did extremely poorly, with 20 percent achieving long-term survival.

Among the patients who relapsed, those with the 8;21-translocation had significantly shorter survival than did the inversion-16 patients.

However, when the 8;21 translocation was the sole chromosomal abnormality among nonwhites, at least 50 percent are cured; and 76 percent of nonwhite patients were cured when the 8;21 translocation and a second abnormality, the loss of a portion of chromosome 9, were both present.

Whites with the 8;21 translocation showed 40 percent to 50 percent long-term survival in all cases.

Within the inversion-16 group, whites and nonwhites achieved complete remission equally. However, relapse was less likely in patients whose cancer cells had an extra chromosome 22 compared with patients whose cancer cells lacked an extra chromosome 22.

"Our findings need to be confirmed," Bloomfield says. "But clearly, we want to learn more about why therapy is failing some patients so we can determine how to improve it."

To put the above in context, about 55 percent of adult AML cases show chromosomal abnormalities. These have long been recognized as important predictors of treatment outcome. Certain of these abnormalities signal a poor response to therapy, while others signal a good response and a greater likelihood of complete remission or cure.

A chromosome inversion happens when a chromosome breaks in two places and the resulting fragment (or fragments) becomes inverted. The inversion 16 occurs when the two ends of chromosome 16 break off and become reversed.

A translocation occurs when a piece of one chromosome becomes attached to another chromosome.

http://www.osu.edu/