Treatment, outcomes poorer in AML with chromosome abnormality
Chromoanagenesis found in majority of patients with high-risk profile
Chromoanagenesis — an abnormal rearrangement of DNA within the chromosomes of certain cells, including blood cells — links with limited treatment response and poorer outcomes in people with acute myeloid leukemia (AML), a study reported.
Research has shown that chromoanagenesis is “widespread” in cancer. In a study by scientists at MD Anderson Cancer Center in Texas, chromoanagenesis (called CAG in their study) was detected in about two-thirds of AML patients who had high-risk chromosomal profiles.
Detecting “markers like CAG, which is associated with a lower median survival rate and a lower response to therapy, holds the promise that more people with devastating diseases like AML could potentially have access to appropriate therapy sooner,” Erik Holmlin, president and CEO of Bionano, said in a company press release.
Bionano developed a technique to accurately assess CAG, which was used by the MD Anderson researchers in “Chromoanagenesis Is Frequently Associated With Highly Complex Karyotypes, Extensive Clonal Heterogeneity, and Treatment Refractoriness in Acute Myeloid Leukemia,” a study published in the American Journal of Hematology.
Chromoanagenesis is the complex rearrangement of DNA in chromosomes
AML is an aggressive form of blood cancer that, like all leukemias, occurs when immature blood cells begin to grow out of control in the bone marrow. Most often, AML cells move from the marrow into the blood and can spread to other parts of the body.
Mutations in the DNA of blood cells are thought to cause AML, including in genes that control how cells grow and divide, whether they die when they’re supposed to, or repair mistakes in DNA.
CAG refers to catastrophic genetic events characterized by complex and large-scale rearrangements of DNA within chromosomes — the structures in cells that hold genetic information — involving the breaking and rejoining of chromosome parts. These events have been reported in various solid tumors and blood cancers, and they are associated with an aggressive clinical course.
Researchers investigated CAG frequency in AML patients at their Houston center using optical genome mapping, or OGM, a technique developed by Bionano that provides a complete assessment of chromosomal architecture.
“The critical mass of publications underscoring the concordance of OGM with traditional cytogenetics [study of chromosomes] has been established,” Holmlin said.
Among the 410 adult patients evaluated (59% men), 292 were newly diagnosed with AML and 118 who had refractory/relapsed (treatment-resistant) disease. CAG was identified by chromosomal abnormalities and/or changes in gene copy number within one or more chromosomal regions.
Changes in chromosomal regions found in 16% of 410 adults with AML
According to OGM findings, CAG was found in 65 patients (16%), including 42 (14%) recently diagnosed adults.
In the newly diagnosed group, 90% of patients with CAG had a highly complex karyotype, defined as at least five unrelated chromosome abnormalities when examined under a microscope (karyotyping). In comparison, 9% of the newly diagnosed without CAG also had a highly complex karyotype.
In total, CAG was found in about two-thirds (63%) of newly diagnosed adults with a highly complex karyotype, with similar frequencies observed in the refractory/relapsed group.
Likewise, 66 newly diagnosed patients had a monosomal karyotype, defined as two or more monosomies (when one of their two chromosome copies is missing), or one monosomy with a structural abnormality. Of these, 39 (93%) had CAG, and 27 (11%) did not. CAG was present in 59% of these patients with a monosomal karyotype, with a high frequency also seen in refractory/relapsed patients with CAG.
More newly diagnosed patients with CAG had extensive clonal heterogeneity than those without CAG (74% vs. 4%); clonal heterogeneity refers to multiple distinct cancer cell populations, or clones, that have accumulated different mutations. About 3 out of 4 patients (76%) with extensive clonal heterogeneity had CAG.
Mutations in the tumor-suppressor gene TP53 or that gene’s loss, which are often linked with more aggressive cancer, were more common in both patient groups with CAG compared with patients without this chromosomal rearrangement (92% vs. 9%). Among the newly diagnosed, more CAG-positive patients also had a so-called TP53 “double hit,” meaning both TP53 gene copies showed alterations, than did those without CAG (50% vs. 3.2%).
Among those with newly diagnosed disease, CAG was found in significantly more patients with gene amplification, which refers to an increase in gene copy number in a region of a chromosome (52% vs. 1%). Among 13 refractory/relapsed patients showing gene amplification, 10 had CAG.
Overall, CAG was detected in about two-thirds of AML patients who showed high-risk chromosomal abnormalities or karyotypes.
Among 36 adults with AML and CAG, half didn’t respond to chemotherapy
Among the 42 newly diagnosed patients with CAG, 36 underwent treatment. Of them, half (50%) showed no response, 10 (28%) showed a partial response, and eight (22%) achieved a complete response. Further, overall survival in newly diagnosed patients with CAG was significantly shorter than that of those without CAG — a median of five vs. 14 months, the researchers noted.
In adjusted statistical analyses, older age and a highly complex karyotype significantly impacted overall survival. But CAG, monosomal karyotype, and TP53 mutations didn’t appear to be independent risk factors for survival in AML.
“We report the first study to utilize OGM for the detection of CAG in AML,” the researchers wrote. “Patients with AML associated with CAG are highly refractory to conventional chemotherapy and have a shorter [overall survival].”
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