January 13, 2012 — New research into the behavior of leukemic cells during and after treatment has led to some "very interesting and provocative" observations about they way acute myeloid leukemia (AML) evolves, according to one of the researchers involved.
Although there are no immediate therapeutic implications from the research, the study opens up a "Pandora's box of questions, and we will need to test various new hypotheses," senior author John DiPersio, MD, PhD, chief of the division of oncology at the Washington University School of Medicine, St Louis, Missouri, said in an interview.
The research was published online January 11 in Nature.
The study involved 8 patients with AML, all of whom received cytarabine and anthracycline for induction therapy and additional cytotoxic chemotherapy for consolidation. All 8 patients subsequently relapsed.
The researchers sequenced the genomes of leukemic cells taken before and after chemotherapy, and compared them with each other and with healthy cells taken from each patient before chemotherapy (to act as a control).
The results suggest that chemotherapy damages the DNA in leukemic cells and leads to new mutations. "The mutations in AML patients who have relapsed are different from those present in the primary tumor, and they are more likely to have a tell-tale signature of DNA damage," Dr. DiPersio said in a statement.
"This suggests that the mutations in relapsed cells are influenced by the chemotherapy drugs the patients receive," he added.
However, causality has not been proven, Dr. DiPersio emphasized to Medscape Medical News. The new mutations observed in relapse occurred after the patients received chemotherapy, but it is not proven that they were caused by chemotherapy, he elaborated.
That is suspected to be the case, but to prove it they will have to study other drugs that have different modes of action, he said, such as hypomethylating agents like azacitidine and the novel agent lenalidomide, which are already used in the treatment of AML in elderly patients.
Different Mutations on Relapse
Chemotherapy offers a very successful treatment for AML, Dr. DiPersio continued. In patients younger than 60 years of age, it results in a cure in more than 40% of patients. However, for the other patients, a remission is usually followed at some stage by a relapse, sometimes several relapses, and eventually death.
It is this relapse phenomenon that the new research helps explain. The genome sequencing revealed 2 major patterns of evolution of leukemic cells.
In this study, all 8 patients studied had a single founding clone of cells, all with the same mutations. In all cases, chemotherapy failed to eradicate the founding clone, the cluster of leukemic cells that drive the disease.
The genome sequencing revealed that in some patients, this founding clone developed new mutations that enabled it to survive chemotherapy and to evolve into a new clone. However, in other patients, a subclone broke off from the founding clone, developed new mutations, and evolved to become the dominant clone at relapse.
"It's the same tumor coming back but with a twist," explained coauthor Richard Wilson, PhD, director of the Genome Institute at Washington University School of Medicine.
"It's always the founding clone or a subclone that comes back with new mutations that give the cells new strategies for surviving attack by whatever drugs are thrown at them. This makes a lot of sense, but it's been hard to prove without whole-genome sequencing," he added in a statement.
"Our preconceived notion of the clonal evolution of AML and other cancers has been altered by our study, which suggests that it is much more complicated and dynamic than we initially suspected, and can even be affected by the therapy that is given to treat the disease," Dr. DiPersio explained.
"Chemotherapy drugs are absolutely necessary to get leukemia patients into remission, but we also pay a price in terms of DNA damage," coauthor Timothy Ley, MD, professor of oncology at Washington University, said in a statement.
The findings reach beyond AML, he suggested. Chemotherapy might contribute to disease progression and relapse in many different cancers, he said, "which is why our long-term goal is to find targeted therapies based on the mutations specific to a patients' cancer, rather than to use drugs that further damage DNA."
The study was funded by the National Human Genome Research Institute, the National Cancer Institute, and the Barnes-Jewish Hospital Foundation. The authors have disclosed no relevant financial relationships.
Nature. Published online January 11, 2012. Abstract
Although there are no immediate therapeutic implications from the research, the study opens up a "Pandora's box of questions, and we will need to test various new hypotheses," senior author John DiPersio, MD, PhD, chief of the division of oncology at the Washington University School of Medicine, St Louis, Missouri, said in an interview.
The research was published online January 11 in Nature.
The study involved 8 patients with AML, all of whom received cytarabine and anthracycline for induction therapy and additional cytotoxic chemotherapy for consolidation. All 8 patients subsequently relapsed.
The researchers sequenced the genomes of leukemic cells taken before and after chemotherapy, and compared them with each other and with healthy cells taken from each patient before chemotherapy (to act as a control).
The results suggest that chemotherapy damages the DNA in leukemic cells and leads to new mutations. "The mutations in AML patients who have relapsed are different from those present in the primary tumor, and they are more likely to have a tell-tale signature of DNA damage," Dr. DiPersio said in a statement.
"This suggests that the mutations in relapsed cells are influenced by the chemotherapy drugs the patients receive," he added.
However, causality has not been proven, Dr. DiPersio emphasized to Medscape Medical News. The new mutations observed in relapse occurred after the patients received chemotherapy, but it is not proven that they were caused by chemotherapy, he elaborated.
That is suspected to be the case, but to prove it they will have to study other drugs that have different modes of action, he said, such as hypomethylating agents like azacitidine and the novel agent lenalidomide, which are already used in the treatment of AML in elderly patients.
Different Mutations on Relapse
Chemotherapy offers a very successful treatment for AML, Dr. DiPersio continued. In patients younger than 60 years of age, it results in a cure in more than 40% of patients. However, for the other patients, a remission is usually followed at some stage by a relapse, sometimes several relapses, and eventually death.
It is this relapse phenomenon that the new research helps explain. The genome sequencing revealed 2 major patterns of evolution of leukemic cells.
In this study, all 8 patients studied had a single founding clone of cells, all with the same mutations. In all cases, chemotherapy failed to eradicate the founding clone, the cluster of leukemic cells that drive the disease.
The genome sequencing revealed that in some patients, this founding clone developed new mutations that enabled it to survive chemotherapy and to evolve into a new clone. However, in other patients, a subclone broke off from the founding clone, developed new mutations, and evolved to become the dominant clone at relapse.
"It's the same tumor coming back but with a twist," explained coauthor Richard Wilson, PhD, director of the Genome Institute at Washington University School of Medicine.
"It's always the founding clone or a subclone that comes back with new mutations that give the cells new strategies for surviving attack by whatever drugs are thrown at them. This makes a lot of sense, but it's been hard to prove without whole-genome sequencing," he added in a statement.
"Our preconceived notion of the clonal evolution of AML and other cancers has been altered by our study, which suggests that it is much more complicated and dynamic than we initially suspected, and can even be affected by the therapy that is given to treat the disease," Dr. DiPersio explained.
"Chemotherapy drugs are absolutely necessary to get leukemia patients into remission, but we also pay a price in terms of DNA damage," coauthor Timothy Ley, MD, professor of oncology at Washington University, said in a statement.
The findings reach beyond AML, he suggested. Chemotherapy might contribute to disease progression and relapse in many different cancers, he said, "which is why our long-term goal is to find targeted therapies based on the mutations specific to a patients' cancer, rather than to use drugs that further damage DNA."
The study was funded by the National Human Genome Research Institute, the National Cancer Institute, and the Barnes-Jewish Hospital Foundation. The authors have disclosed no relevant financial relationships.
Nature. Published online January 11, 2012. Abstract
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