Acute-leukemia Sign May Signal Need For Different Therapy

The study compared AML patients whosecancer cells showed chromosome changes known as the 8;21 translocationwith patients whose cancer cells showed chromosome damage known asinversion 16.

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

But this study found that when the two groups of patientsare compared with each other – and when ethnicity, sex and otherchromosome changes are considered – patients with the 8;21 abnormalityfare significantly worse than do patients with inversion 16 when theyreceive similar therapy.

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

Thefindings were published in a recent issue of the Journal of ClinicalOncology. They come from a Cancer and Leukemia Group B (CALGB) studyinitiated by researchers at The Ohio State University ComprehensiveCancer Center – Arthur G. James Cancer Hospital and Richard J. SoloveResearch Institute (OSU CCC-James).

The study is part of a largerCALGB cytogenetic trial chaired by Clara D. Bloomfield, professor ofinternal medicine and the William G. Pace III Professor in CancerResearch, OSU Cancer Scholar and senior adviser to the OSU CancerProgram.

“It's widely believed that AML cases with theseabnormalities have the same outcome,” says Bloomfield, “but ourfindings indicate that they don't. Furthermore, nonwhites with the 8;21translocation can do extremely poorly.

“While our data need to beverified, they strongly indicate that we must stop thinking about the8;21 group as having a highly favorable type of leukemia and startasking what we might do to increase the cure rate among those patients.They may require a transplant or an experimental therapy after theyachieve remission.”

Bloomfield was the first some years ago todetermine that AML patients with the 8;12 translocation and inversion16 abnormalities was particularly sensitive to a particularchemotherapy regimen and tended to have better outcomes than did manyother AML patients.

“These findings indicate that patients withthe 8;21 translocation do worse because, once they relapse, the diseasedoesn't respond well to additional therapy,” says first author GuidoMarcucci, associate professor of internal medicine and a hematologistwith the OSU CCC-James.

“We need to begin reporting the outcomesof these patients as separate subgroups of AML, and we may need tooffer them different treatments.”

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

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

The data showed that patients with the8;21 abnormality were 1.5 times more likely to die of their diseasethan were patients with inversion 16.

In addition, nonwhitepatients with the 8;21 translocation plus other abnormalities didextremely poorly, with 20 percent achieving long-term survival.

Amongthe patients who relapsed, those with the 8;21-translocation hadsignificantly shorter survival than did the inversion-16 patients.

However,when the 8;21 translocation was the sole chromosomal abnormality amongnonwhites, at least 50 percent are cured; and 76 percent of nonwhitepatients were cured when the 8;21 translocation and a secondabnormality, 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.

Withinthe inversion-16 group, whites and nonwhites achieved completeremission equally. However, relapse was less likely in patients whosecancer cells had an extra chromosome 22 compared with patients whosecancer cells lacked an extra chromosome 22.

“Our findings need tobe confirmed,” Bloomfield says. “But clearly, we want to learn moreabout why therapy is failing some patients so we can determine how toimprove it.”

To put the above in context, about 55 percent ofadult AML cases show chromosomal abnormalities. These have long beenrecognized as important predictors of treatment outcome. Certain ofthese abnormalities signal a poor response to therapy, while otherssignal a good response and a greater likelihood of complete remissionor cure.

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

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

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