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Reducing chemo drug’s cardiac side effects
Investigators have identified compounds that appear to prevent the cardiac damage caused by the chemotherapy drug doxorubicin.
The compounds target MDH2, an enzyme key to the generation of cellular energy in mitochondria.
And preclinical experiments showed that inhibiting MDH2 could prevent doxorubicin-induced damage to cardiac cells without reducing the drug’s antitumor effects.
The investigators detailed these experiments in Science Translational Medicine.
“Doxorubicin-induced cardiomyopathy limits the amount of the drug a patient can receive—which limits the ability to treat cancer—and even low, safer doses can lead to heart failure in up to 8% of patients,” explained study author Randall Peterson, PhD, of Massachusetts General Hospital in Charlestown.
“Finding an effective cardioprotective drug—essentially separating the good and bad effects of this form of chemotherapy—could increase the beneficial effects of doxorubicin against cancer while reducing the rate of heart failure in treated patients.”
To conduct a broad search for potential protective compounds, Dr Peterson and his colleagues developed a zebrafish model of doxorubicin-induced heart failure. They used this model to screen 3000 molecules from 2 chemical libraries for the ability to prevent the kind of cardiac damage caused by the drug.
Eight of the tested chemicals reduced damage to the hearts of zebrafish embryos, and two compounds—visnagin and diphenylurea—were the most potent in preventing both structural and functional damage.
Further in vitro and in vivo experiments revealed that either compound almost completely prevented the death of cardiac cells caused by doxorubicin. In mouse models of both high- and low-dose doxorubicin treatment, visnagin—a natural compound synthesized by the toothpick weed—was able to maintain cardiac function.
Investigation into the possible mechanism behind visnagin’s protective ability showed that the compound binds to and inhibits the action of MDH2, an enzyme essential to the generation of cellular energy by mitochondria.
Other agents that block MDH2 activity also protected zebrafish against doxorubicin-induced cardiac damage. And tests in both cellular and animal models of several types of cancer showed that neither visnagin nor diphenylurea reduced the antitumor action of doxorubicin.
“We are still trying to determine exactly how inhibition of MDH2 protects the heart, but one intriguing idea is that doxorubicin may kill cardiac and tumor cells in different ways,” Dr Peterson said. “Given the intense energy requirements of the beating heart, we speculate that cardiac cells may be especially susceptible to metabolic disturbance caused by doxorubicin and that inhibiting MDH2 may correct the metabolic imbalance and prevent the cells from dying.”
“It remains to be seen if visnagin’s protective effects are restricted to doxorubicin or if it can protect the heart from other kinds of damage. We are pursuing this question by testing its ability to protect heart muscle from oxygen deprivation during heart attacks and from the effects of other heart-damaging chemotherapy drugs.” 
Investigators have identified compounds that appear to prevent the cardiac damage caused by the chemotherapy drug doxorubicin.
The compounds target MDH2, an enzyme key to the generation of cellular energy in mitochondria.
And preclinical experiments showed that inhibiting MDH2 could prevent doxorubicin-induced damage to cardiac cells without reducing the drug’s antitumor effects.
The investigators detailed these experiments in Science Translational Medicine.
“Doxorubicin-induced cardiomyopathy limits the amount of the drug a patient can receive—which limits the ability to treat cancer—and even low, safer doses can lead to heart failure in up to 8% of patients,” explained study author Randall Peterson, PhD, of Massachusetts General Hospital in Charlestown.
“Finding an effective cardioprotective drug—essentially separating the good and bad effects of this form of chemotherapy—could increase the beneficial effects of doxorubicin against cancer while reducing the rate of heart failure in treated patients.”
To conduct a broad search for potential protective compounds, Dr Peterson and his colleagues developed a zebrafish model of doxorubicin-induced heart failure. They used this model to screen 3000 molecules from 2 chemical libraries for the ability to prevent the kind of cardiac damage caused by the drug.
Eight of the tested chemicals reduced damage to the hearts of zebrafish embryos, and two compounds—visnagin and diphenylurea—were the most potent in preventing both structural and functional damage.
Further in vitro and in vivo experiments revealed that either compound almost completely prevented the death of cardiac cells caused by doxorubicin. In mouse models of both high- and low-dose doxorubicin treatment, visnagin—a natural compound synthesized by the toothpick weed—was able to maintain cardiac function.
Investigation into the possible mechanism behind visnagin’s protective ability showed that the compound binds to and inhibits the action of MDH2, an enzyme essential to the generation of cellular energy by mitochondria.
Other agents that block MDH2 activity also protected zebrafish against doxorubicin-induced cardiac damage. And tests in both cellular and animal models of several types of cancer showed that neither visnagin nor diphenylurea reduced the antitumor action of doxorubicin.
“We are still trying to determine exactly how inhibition of MDH2 protects the heart, but one intriguing idea is that doxorubicin may kill cardiac and tumor cells in different ways,” Dr Peterson said. “Given the intense energy requirements of the beating heart, we speculate that cardiac cells may be especially susceptible to metabolic disturbance caused by doxorubicin and that inhibiting MDH2 may correct the metabolic imbalance and prevent the cells from dying.”
“It remains to be seen if visnagin’s protective effects are restricted to doxorubicin or if it can protect the heart from other kinds of damage. We are pursuing this question by testing its ability to protect heart muscle from oxygen deprivation during heart attacks and from the effects of other heart-damaging chemotherapy drugs.”
Investigators have identified compounds that appear to prevent the cardiac damage caused by the chemotherapy drug doxorubicin.
The compounds target MDH2, an enzyme key to the generation of cellular energy in mitochondria.
And preclinical experiments showed that inhibiting MDH2 could prevent doxorubicin-induced damage to cardiac cells without reducing the drug’s antitumor effects.
The investigators detailed these experiments in Science Translational Medicine.
“Doxorubicin-induced cardiomyopathy limits the amount of the drug a patient can receive—which limits the ability to treat cancer—and even low, safer doses can lead to heart failure in up to 8% of patients,” explained study author Randall Peterson, PhD, of Massachusetts General Hospital in Charlestown.
“Finding an effective cardioprotective drug—essentially separating the good and bad effects of this form of chemotherapy—could increase the beneficial effects of doxorubicin against cancer while reducing the rate of heart failure in treated patients.”
To conduct a broad search for potential protective compounds, Dr Peterson and his colleagues developed a zebrafish model of doxorubicin-induced heart failure. They used this model to screen 3000 molecules from 2 chemical libraries for the ability to prevent the kind of cardiac damage caused by the drug.
Eight of the tested chemicals reduced damage to the hearts of zebrafish embryos, and two compounds—visnagin and diphenylurea—were the most potent in preventing both structural and functional damage.
Further in vitro and in vivo experiments revealed that either compound almost completely prevented the death of cardiac cells caused by doxorubicin. In mouse models of both high- and low-dose doxorubicin treatment, visnagin—a natural compound synthesized by the toothpick weed—was able to maintain cardiac function.
Investigation into the possible mechanism behind visnagin’s protective ability showed that the compound binds to and inhibits the action of MDH2, an enzyme essential to the generation of cellular energy by mitochondria.
Other agents that block MDH2 activity also protected zebrafish against doxorubicin-induced cardiac damage. And tests in both cellular and animal models of several types of cancer showed that neither visnagin nor diphenylurea reduced the antitumor action of doxorubicin.
“We are still trying to determine exactly how inhibition of MDH2 protects the heart, but one intriguing idea is that doxorubicin may kill cardiac and tumor cells in different ways,” Dr Peterson said. “Given the intense energy requirements of the beating heart, we speculate that cardiac cells may be especially susceptible to metabolic disturbance caused by doxorubicin and that inhibiting MDH2 may correct the metabolic imbalance and prevent the cells from dying.”
“It remains to be seen if visnagin’s protective effects are restricted to doxorubicin or if it can protect the heart from other kinds of damage. We are pursuing this question by testing its ability to protect heart muscle from oxygen deprivation during heart attacks and from the effects of other heart-damaging chemotherapy drugs.”
Weak magnetic fields not responsible for leukemia, study suggests
Research first carried out in the 1970s revealed an association between living near overhead power lines and an increased risk of childhood leukemia.
Although some later studies failed to find such a link, the International Agency for Research on Cancer has categorized low-frequency magnetic fields as “possibly carcinogenic.”
However, a mechanism for this association has never been found, and, now, researchers have ruled out one of the prime candidates.
The team studied the effects of weak magnetic fields (WMFs) on key human proteins, including those
crucial for health, and found they have no detectable impact.
The researchers detailed this discovery in the Journal of the Royal Society Interface.
Alex Jones, PhD, of The University of Manchester in the UK, and his colleagues looked at how WMFs affect flavoproteins, which are key to processes vital for healthy human function, such as the nervous system, DNA repair, and the biological clock.
If these proteins malfunction, there are serious knock-on effects for human health. But after subjecting flavoproteins to WMFs in the lab, the researchers found that WMFs have no detectable impact on these proteins.
“There is still some concern among the public about this potential link, which has been found in some studies into cases of childhood leukemia, but without any clear mechanism for why,” Dr Jones said.
“Flavoproteins transfer electrons from one place to another. Along the path the electrons take, very short-lived chemical species known as radical pairs are often created. Biochemical reactions involving radical pairs are considered the most plausible candidates for sensitivity to WMFs, but for them to be so, the reaction conditions have to be right. This research suggests that the correct conditions for biochemical effects of WMFs are likely to be rare in human biology.”
“More work on other possible links will need to be done,” noted study author Nigel Scrutton, PhD, also of the University of Manchester.
“But this study definitely takes us nearer to the point where we can say that power lines, mobile phones, and other similar devices are likely to be safe for humans.”
Research first carried out in the 1970s revealed an association between living near overhead power lines and an increased risk of childhood leukemia.
Although some later studies failed to find such a link, the International Agency for Research on Cancer has categorized low-frequency magnetic fields as “possibly carcinogenic.”
However, a mechanism for this association has never been found, and, now, researchers have ruled out one of the prime candidates.
The team studied the effects of weak magnetic fields (WMFs) on key human proteins, including those
crucial for health, and found they have no detectable impact.
The researchers detailed this discovery in the Journal of the Royal Society Interface.
Alex Jones, PhD, of The University of Manchester in the UK, and his colleagues looked at how WMFs affect flavoproteins, which are key to processes vital for healthy human function, such as the nervous system, DNA repair, and the biological clock.
If these proteins malfunction, there are serious knock-on effects for human health. But after subjecting flavoproteins to WMFs in the lab, the researchers found that WMFs have no detectable impact on these proteins.
“There is still some concern among the public about this potential link, which has been found in some studies into cases of childhood leukemia, but without any clear mechanism for why,” Dr Jones said.
“Flavoproteins transfer electrons from one place to another. Along the path the electrons take, very short-lived chemical species known as radical pairs are often created. Biochemical reactions involving radical pairs are considered the most plausible candidates for sensitivity to WMFs, but for them to be so, the reaction conditions have to be right. This research suggests that the correct conditions for biochemical effects of WMFs are likely to be rare in human biology.”
“More work on other possible links will need to be done,” noted study author Nigel Scrutton, PhD, also of the University of Manchester.
“But this study definitely takes us nearer to the point where we can say that power lines, mobile phones, and other similar devices are likely to be safe for humans.”
Research first carried out in the 1970s revealed an association between living near overhead power lines and an increased risk of childhood leukemia.
Although some later studies failed to find such a link, the International Agency for Research on Cancer has categorized low-frequency magnetic fields as “possibly carcinogenic.”
However, a mechanism for this association has never been found, and, now, researchers have ruled out one of the prime candidates.
The team studied the effects of weak magnetic fields (WMFs) on key human proteins, including those
crucial for health, and found they have no detectable impact.
The researchers detailed this discovery in the Journal of the Royal Society Interface.
Alex Jones, PhD, of The University of Manchester in the UK, and his colleagues looked at how WMFs affect flavoproteins, which are key to processes vital for healthy human function, such as the nervous system, DNA repair, and the biological clock.
If these proteins malfunction, there are serious knock-on effects for human health. But after subjecting flavoproteins to WMFs in the lab, the researchers found that WMFs have no detectable impact on these proteins.
“There is still some concern among the public about this potential link, which has been found in some studies into cases of childhood leukemia, but without any clear mechanism for why,” Dr Jones said.
“Flavoproteins transfer electrons from one place to another. Along the path the electrons take, very short-lived chemical species known as radical pairs are often created. Biochemical reactions involving radical pairs are considered the most plausible candidates for sensitivity to WMFs, but for them to be so, the reaction conditions have to be right. This research suggests that the correct conditions for biochemical effects of WMFs are likely to be rare in human biology.”
“More work on other possible links will need to be done,” noted study author Nigel Scrutton, PhD, also of the University of Manchester.
“But this study definitely takes us nearer to the point where we can say that power lines, mobile phones, and other similar devices are likely to be safe for humans.”
Discovery could help predict, prevent therapy-related AML
Credit: Rhoda Baer
A new study challenges the view that cancer treatment is a direct cause of therapy-related acute myeloid leukemia (AML).
The research suggests that mutations in p53 can accumulate in hematopoietic stem cells (HSCs) as a person ages, years before a cancer diagnosis.
If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which can then lead to AML.
The findings, reported in Nature, open up new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve really understood very little about therapy-related AML and why it is so difficult to treat,” said study author Daniel Link, MD, of Washington University in St Louis, Missouri.
“This gives us some important clues for further studies aimed at treatment and prevention.”
Dr Link and his colleagues began this research by sequencing the genomes of 22 patients with therapy-related AML. The patients had similar numbers and types of mutations in their leukemia cells as other patients who developed AML without prior exposure to chemotherapy or radiation, an indication that cancer treatment does not cause widespread DNA damage.
“This is contrary to what physicians and scientists have long accepted as fact,” said study author Richard K. Wilson, PhD, of The Genome Institute at Washington University.
“It led us to consider a novel hypothesis: p53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.”
When therapy-related AML occurs, it typically develops 1 to 5 years after treatment with chemotherapy or radiation. Its incidence varies by cancer type. For example, 10% of lymphoma patients who relapse after chemotherapy go on to develop therapy-related AML, compared to 0.1% of breast cancer patients.
The researchers knew that patients with therapy-related AML are more likely than other AML patients to have a high rate of p53 mutations in their blood cells.
But the team was surprised to find that nearly 50% of 19 healthy subjects (aged 68 to 89 with no history of cancer or chemotherapy) had mutations in one copy of p53, an indicator that many people acquire mutations in this gene as they age.
The finding encouraged the researchers to dig further. They scoured the US to find bone marrow samples from patients with therapy-related AML that had been stored before the patients developed leukemia.
“We wanted to know whether we could go back in time—before a patient is diagnosed with therapy-related AML—to find the exact p53 mutation that caused them to develop leukemia years later,” Dr Link said.
The researchers found 7 bone marrow samples that fit the criteria. In 4 samples, they detected specific mutations in p53 that were present at very low rates in blood cells or bone marrow 3 to 6 years before the patients developed AML.
In the 3 cases in which p53 mutations could not be found, the researchers said it’s possible the mutations were present but at rates too low to be detected, or it may be that other age-related mutations contributed to the onset of therapy-related AML.
In related work in mice, the team showed that chemotherapy causes HSCs with mutations in p53 to divide rapidly, which gives them a competitive advantage. But that was not the case in HSCs with both copies of the gene intact.
The researchers suspect the early accumulation of p53 mutations in HSCs likely contributes to the frequent chromosomal and genetic abnormalities seen in patients with therapy-related AML and their poor responses to chemotherapy. The team believes other age-related mutations may be involved in the disease as well.
“We’re already conducting follow-up studies to look for other age-related mutations that may be at play in therapy-related AML,” Dr Link said. “As individuals, we’re not genetically homogeneous throughout our lives. Our DNA is constantly changing as we age, and we know this plays an important role in the development of cancer.”
“With advanced genomics, we can investigate the interplay between aging and the random accumulation of mutations, as a means to improve the diagnosis, treatment, and prevention of cancer.”
Credit: Rhoda Baer
A new study challenges the view that cancer treatment is a direct cause of therapy-related acute myeloid leukemia (AML).
The research suggests that mutations in p53 can accumulate in hematopoietic stem cells (HSCs) as a person ages, years before a cancer diagnosis.
If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which can then lead to AML.
The findings, reported in Nature, open up new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve really understood very little about therapy-related AML and why it is so difficult to treat,” said study author Daniel Link, MD, of Washington University in St Louis, Missouri.
“This gives us some important clues for further studies aimed at treatment and prevention.”
Dr Link and his colleagues began this research by sequencing the genomes of 22 patients with therapy-related AML. The patients had similar numbers and types of mutations in their leukemia cells as other patients who developed AML without prior exposure to chemotherapy or radiation, an indication that cancer treatment does not cause widespread DNA damage.
“This is contrary to what physicians and scientists have long accepted as fact,” said study author Richard K. Wilson, PhD, of The Genome Institute at Washington University.
“It led us to consider a novel hypothesis: p53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.”
When therapy-related AML occurs, it typically develops 1 to 5 years after treatment with chemotherapy or radiation. Its incidence varies by cancer type. For example, 10% of lymphoma patients who relapse after chemotherapy go on to develop therapy-related AML, compared to 0.1% of breast cancer patients.
The researchers knew that patients with therapy-related AML are more likely than other AML patients to have a high rate of p53 mutations in their blood cells.
But the team was surprised to find that nearly 50% of 19 healthy subjects (aged 68 to 89 with no history of cancer or chemotherapy) had mutations in one copy of p53, an indicator that many people acquire mutations in this gene as they age.
The finding encouraged the researchers to dig further. They scoured the US to find bone marrow samples from patients with therapy-related AML that had been stored before the patients developed leukemia.
“We wanted to know whether we could go back in time—before a patient is diagnosed with therapy-related AML—to find the exact p53 mutation that caused them to develop leukemia years later,” Dr Link said.
The researchers found 7 bone marrow samples that fit the criteria. In 4 samples, they detected specific mutations in p53 that were present at very low rates in blood cells or bone marrow 3 to 6 years before the patients developed AML.
In the 3 cases in which p53 mutations could not be found, the researchers said it’s possible the mutations were present but at rates too low to be detected, or it may be that other age-related mutations contributed to the onset of therapy-related AML.
In related work in mice, the team showed that chemotherapy causes HSCs with mutations in p53 to divide rapidly, which gives them a competitive advantage. But that was not the case in HSCs with both copies of the gene intact.
The researchers suspect the early accumulation of p53 mutations in HSCs likely contributes to the frequent chromosomal and genetic abnormalities seen in patients with therapy-related AML and their poor responses to chemotherapy. The team believes other age-related mutations may be involved in the disease as well.
“We’re already conducting follow-up studies to look for other age-related mutations that may be at play in therapy-related AML,” Dr Link said. “As individuals, we’re not genetically homogeneous throughout our lives. Our DNA is constantly changing as we age, and we know this plays an important role in the development of cancer.”
“With advanced genomics, we can investigate the interplay between aging and the random accumulation of mutations, as a means to improve the diagnosis, treatment, and prevention of cancer.”
Credit: Rhoda Baer
A new study challenges the view that cancer treatment is a direct cause of therapy-related acute myeloid leukemia (AML).
The research suggests that mutations in p53 can accumulate in hematopoietic stem cells (HSCs) as a person ages, years before a cancer diagnosis.
If and when cancer develops, these mutated cells are more resistant to treatment and multiply at an accelerated pace after exposure to chemotherapy or radiation therapy, which can then lead to AML.
The findings, reported in Nature, open up new avenues for research to predict which patients are at risk of developing therapy-related AML and to find ways to prevent it.
“Until now, we’ve really understood very little about therapy-related AML and why it is so difficult to treat,” said study author Daniel Link, MD, of Washington University in St Louis, Missouri.
“This gives us some important clues for further studies aimed at treatment and prevention.”
Dr Link and his colleagues began this research by sequencing the genomes of 22 patients with therapy-related AML. The patients had similar numbers and types of mutations in their leukemia cells as other patients who developed AML without prior exposure to chemotherapy or radiation, an indication that cancer treatment does not cause widespread DNA damage.
“This is contrary to what physicians and scientists have long accepted as fact,” said study author Richard K. Wilson, PhD, of The Genome Institute at Washington University.
“It led us to consider a novel hypothesis: p53 mutations accumulate randomly as part of the aging process and are present in blood stem cells long before a patient is diagnosed with therapy-related AML.”
When therapy-related AML occurs, it typically develops 1 to 5 years after treatment with chemotherapy or radiation. Its incidence varies by cancer type. For example, 10% of lymphoma patients who relapse after chemotherapy go on to develop therapy-related AML, compared to 0.1% of breast cancer patients.
The researchers knew that patients with therapy-related AML are more likely than other AML patients to have a high rate of p53 mutations in their blood cells.
But the team was surprised to find that nearly 50% of 19 healthy subjects (aged 68 to 89 with no history of cancer or chemotherapy) had mutations in one copy of p53, an indicator that many people acquire mutations in this gene as they age.
The finding encouraged the researchers to dig further. They scoured the US to find bone marrow samples from patients with therapy-related AML that had been stored before the patients developed leukemia.
“We wanted to know whether we could go back in time—before a patient is diagnosed with therapy-related AML—to find the exact p53 mutation that caused them to develop leukemia years later,” Dr Link said.
The researchers found 7 bone marrow samples that fit the criteria. In 4 samples, they detected specific mutations in p53 that were present at very low rates in blood cells or bone marrow 3 to 6 years before the patients developed AML.
In the 3 cases in which p53 mutations could not be found, the researchers said it’s possible the mutations were present but at rates too low to be detected, or it may be that other age-related mutations contributed to the onset of therapy-related AML.
In related work in mice, the team showed that chemotherapy causes HSCs with mutations in p53 to divide rapidly, which gives them a competitive advantage. But that was not the case in HSCs with both copies of the gene intact.
The researchers suspect the early accumulation of p53 mutations in HSCs likely contributes to the frequent chromosomal and genetic abnormalities seen in patients with therapy-related AML and their poor responses to chemotherapy. The team believes other age-related mutations may be involved in the disease as well.
“We’re already conducting follow-up studies to look for other age-related mutations that may be at play in therapy-related AML,” Dr Link said. “As individuals, we’re not genetically homogeneous throughout our lives. Our DNA is constantly changing as we age, and we know this plays an important role in the development of cancer.”
“With advanced genomics, we can investigate the interplay between aging and the random accumulation of mutations, as a means to improve the diagnosis, treatment, and prevention of cancer.”
FDA approves first supplemental test for HTLV-I/II
Credit: Daniel Gay
The US Food and Drug Administration (FDA) has approved the first supplemental test for human T-cell lymphotropic virus-I/II (HTLV-I/II).
The test, MP Diagnostics HTLV Blot 2.4, is a qualitative enzyme immunoassay intended for use as an additional, more specific test for human serum or plasma specimens that have previously tested positive for HTLV-I/II.
MP Diagnostics HTLV Blot 2.4 can confirm infection with HTLV and differentiate between HTLV-I and HTLV-II.
The HTLVs are a group of human retroviruses known to cause diseases such as adult T-cell leukemia/lymphoma and myelopathy. HTLV can be transmitted from person to person through breastfeeding, unprotected sexual contact, or transfusion of blood from an infected donor.
Therefore, the FDA requires that donated blood be tested for HTLV-I/II antibodies. Currently, there are 2 FDA-licensed screening tests for HTLV-I/II. If a test is positive, the donation is discarded, and the donor is notified of his or her deferral.
The MP Diagnostics HTLV Blot 2.4 can provide blood establishments with additional information to convey to the donor. Specifically, the test can confirm HTLV infection and determine which virus type is causing the infection, HTLV-I or HTLV-II.
“The approval of MP Diagnostics HTLV Blot 2.4 will help blood establishments better counsel donors who have had positive results on an FDA-licensed HTLV-I/II screening test,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
MP Diagnostics HTLV Blot 2.4 is manufactured by MP Biomedicals Asia Pacific Pte. Ltd. in Singapore, a company of MP Biomedicals LLC in Santa Ana, California. For more information on the test, visit the MP Biomedicals website.
Credit: Daniel Gay
The US Food and Drug Administration (FDA) has approved the first supplemental test for human T-cell lymphotropic virus-I/II (HTLV-I/II).
The test, MP Diagnostics HTLV Blot 2.4, is a qualitative enzyme immunoassay intended for use as an additional, more specific test for human serum or plasma specimens that have previously tested positive for HTLV-I/II.
MP Diagnostics HTLV Blot 2.4 can confirm infection with HTLV and differentiate between HTLV-I and HTLV-II.
The HTLVs are a group of human retroviruses known to cause diseases such as adult T-cell leukemia/lymphoma and myelopathy. HTLV can be transmitted from person to person through breastfeeding, unprotected sexual contact, or transfusion of blood from an infected donor.
Therefore, the FDA requires that donated blood be tested for HTLV-I/II antibodies. Currently, there are 2 FDA-licensed screening tests for HTLV-I/II. If a test is positive, the donation is discarded, and the donor is notified of his or her deferral.
The MP Diagnostics HTLV Blot 2.4 can provide blood establishments with additional information to convey to the donor. Specifically, the test can confirm HTLV infection and determine which virus type is causing the infection, HTLV-I or HTLV-II.
“The approval of MP Diagnostics HTLV Blot 2.4 will help blood establishments better counsel donors who have had positive results on an FDA-licensed HTLV-I/II screening test,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
MP Diagnostics HTLV Blot 2.4 is manufactured by MP Biomedicals Asia Pacific Pte. Ltd. in Singapore, a company of MP Biomedicals LLC in Santa Ana, California. For more information on the test, visit the MP Biomedicals website.
Credit: Daniel Gay
The US Food and Drug Administration (FDA) has approved the first supplemental test for human T-cell lymphotropic virus-I/II (HTLV-I/II).
The test, MP Diagnostics HTLV Blot 2.4, is a qualitative enzyme immunoassay intended for use as an additional, more specific test for human serum or plasma specimens that have previously tested positive for HTLV-I/II.
MP Diagnostics HTLV Blot 2.4 can confirm infection with HTLV and differentiate between HTLV-I and HTLV-II.
The HTLVs are a group of human retroviruses known to cause diseases such as adult T-cell leukemia/lymphoma and myelopathy. HTLV can be transmitted from person to person through breastfeeding, unprotected sexual contact, or transfusion of blood from an infected donor.
Therefore, the FDA requires that donated blood be tested for HTLV-I/II antibodies. Currently, there are 2 FDA-licensed screening tests for HTLV-I/II. If a test is positive, the donation is discarded, and the donor is notified of his or her deferral.
The MP Diagnostics HTLV Blot 2.4 can provide blood establishments with additional information to convey to the donor. Specifically, the test can confirm HTLV infection and determine which virus type is causing the infection, HTLV-I or HTLV-II.
“The approval of MP Diagnostics HTLV Blot 2.4 will help blood establishments better counsel donors who have had positive results on an FDA-licensed HTLV-I/II screening test,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
MP Diagnostics HTLV Blot 2.4 is manufactured by MP Biomedicals Asia Pacific Pte. Ltd. in Singapore, a company of MP Biomedicals LLC in Santa Ana, California. For more information on the test, visit the MP Biomedicals website.
FDA approves drug for HCM
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.
HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.
Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.
The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.
Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment.
The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L; adverse events grade < 1) within 10 days of the first dose of denosumab.
Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL).
The primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.
The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Potential safety risks
Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.
Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.
Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.
Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.
Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.
Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.
Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.
For more information on denosumab (XGEVA), visit www.xgeva.com.
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.
HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.
Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.
The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.
Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment.
The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L; adverse events grade < 1) within 10 days of the first dose of denosumab.
Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL).
The primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.
The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Potential safety risks
Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.
Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.
Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.
Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.
Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.
Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.
Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.
For more information on denosumab (XGEVA), visit www.xgeva.com.
The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.
HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.
Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.
The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.
Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment.
The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL (2.9 mmol/L; adverse events grade < 1) within 10 days of the first dose of denosumab.
Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL).
The primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.
The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Potential safety risks
Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.
Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.
Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.
Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.
Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.
Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.
Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.
For more information on denosumab (XGEVA), visit www.xgeva.com.
Encapsulating doxorubicin can reduce heart damage
Credit: USDA
VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.
Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.
Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.
Pigs that received epirubicin were excluded due to low survival rates.
“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”
“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”
“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”
The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.
The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.
“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.
The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.
“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.
“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”
The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.
Credit: USDA
VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.
Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.
Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.
Pigs that received epirubicin were excluded due to low survival rates.
“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”
“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”
“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”
The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.
The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.
“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.
The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.
“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.
“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”
The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.
Credit: USDA
VIENNA—Encapsulating the anthracycline doxorubicin in a liposome can reduce the risk of developing heart damage, according to a study presented at EuroEcho-Imaging 2014.
Researchers administered doxorubicin encased in a liposome to a small group of pigs and compared cardiac outcomes to those in pigs that received unmanipulated doxorubicin or epirubicin.
Pigs that received encapsulated doxorubicin still developed cardiotoxicity, but at lower rates than pigs that received traditional doxorubicin.
Pigs that received epirubicin were excluded due to low survival rates.
“[M]any chemotherapies—in particular, anthracyclines—cause cardiac side effects that can lead to cardiomyopathy and severe heart failure,” said study investigator Jutta Bergler-Klein, MD, of the Medical University of Vienna in Austria. “Cardiotoxicity can occur acutely or up to 30 years after chemotherapy and is the second most common cause of death in cancer patients, after secondary malignancy in childhood cancer survivors.”
“Liposomal encapsulation is a new technique which wraps the chemotherapy drug in a fatty cover called a liposome. More of the drug reaches the cancer cells because there is less degradation, and there are fewer side effects on healthy cells because the fat cover acts as a barrier.”
“The drug stays in the bloodstream longer, allowing higher cumulative doses to be given. We tested whether non-pegylated liposome encapsulation of the anthracycline doxorubicin (called Myocet) could decrease its cardiotoxicity compared to conventional doxorubicin or epirubicin, another anthracycline.”
The study included 24 pigs that were randomized to receive the human dose-equivalent of Myocet, conventional doxorubicin, or epirubicin in 3 cycles. The epirubicin group was excluded from the final analyses because of low survival levels.
The researchers assessed cardiac function by echocardiography and MRI at baseline and follow-up (after about 3 months). Laboratory follow-up included hematology, renal function, and measurement of the cardiac enzymes troponin and BNP.
“The dose, imaging methodology, and blood parameters simulate the monitoring that patients on this treatment would receive and produces valuable translational data,” Dr Bergler-Klein said.
The researchers found that the group receiving Myocet had better diastolic and systolic function in the left and right ventricles, compared to conventional doxorubicin. The Myocet group also had less fibrosis in the myocardium, as shown by MRI and histology staining.
“Our study shows that doxorubicin encapsulated in a liposome had fewer cardiac side effects than doxorubicin given in the conventional way,” Dr Bergler-Klein said.
“We did find cardiac toxicity in the Myocet group as well, despite the fact that the pigs were young, healthy, and received anthracyclines for only a short period. This emphasizes how important it is for all cancer patients taking anthracyclines to receive cardiac monitoring using echocardiography and biomarkers, and MRI where indicated.”
“Many patients who recover after chemotherapy have asymptomatic heart damage, which can become symptomatic as they get older. When heart problems are picked up early, patients can be given preventive treatment, including ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to prevent the progression to overt heart failure.”
The researchers are now conducting gene-expression profiling on the histology samples, hoping to explain the better outcome and cardiac function after Myocet therapy. They have found differences in the expression of genes that control energy use and the metabolic state, with better regulation in the Myocet group.
Disordered methylation compromises CLL treatment
Credit: Christoph Bock
New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.
The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.
In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.
The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.
“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.
“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”
To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.
They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.
They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.
“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.
“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”
To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.
“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”
The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.
The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.
Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.
The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.
“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.
“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”
“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”
Credit: Christoph Bock
New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.
The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.
In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.
The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.
“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.
“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”
To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.
They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.
They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.
“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.
“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”
To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.
“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”
The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.
The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.
Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.
The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.
“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.
“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”
“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”
Credit: Christoph Bock
New research suggests disordered methylation is one of the defining characteristics of cancer and helps tumors adapt to changing circumstances.
The study, published in Cancer Cell, showed that disordered methylation has a direct bearing on the effectiveness of cancer therapy.
In patients with chronic lymphocytic leukemia (CLL), researchers found that treatment produced shorter remissions if the tumor tissue showed signs of highly disordered methylation.
The findings indicate that such disorganization can actually benefit tumors and render them less vulnerable to anticancer drugs.
“The behavior of a cancer cell is dictated not only by genetics . . . but also by epigenetics,” said study author Catherine Wu, MD, of the Dana-Farber Cancer Institute in Boston.
“We know that tumors are composed of many subgroups of cells, each with its own array of gene mutations. In this study, we wanted to see if that type of genetic diversity coincides with epigenetic diversity. In other words, does the range of methylation patterns mirror the genetic variety we find in tumors?”
To find out, the researchers used bisulfite sequencing, which allows scientists to track the presence or absence of methyl groups at specific rungs on the DNA ladder.
They also devised a simple measure called PDR—percent discordant reads—for quantifying the extent of irregular methylation within a tissue sample. The higher the PDR, the more variability in how the methyl groups are arranged.
They measured the PDR and the amount of genetic diversity in 104 CLL samples and 27 samples of normal B cells.
“We thought the epigenetic structure would map right onto the genetic structure,” said study author Alexander Meissner, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.
“That is, the degree of genetic diversity in each sample would match the variation in methylation marks in an organized fashion.”
To the researchers’ surprise, the methylation patterns showed a tremendous degree of random disarray.
“We know that individual tumors are checkered with genetically distinct groups of cells,” Dr Meissner explained. “Bisulfite sequencing enabled us to see that the placement of methyl groups across tumor cell DNA also varies substantially among cells in the same tumor. In fact, disorderly methylation pervades the entire tumor.”
The results revealed that the diversity within individual tumors apparently proceeds along two independent, yet interrelated tracks: one resulting in a genetic hodgepodge of cell groups, the other resulting in haphazard methylation.
The methylation irregularities, technically known as “local methylation disorder,” were highly evident in CLL and other types of cancer.
Because methyl groups control the expression of genes, disorderly methylation might be expected to cause wildly inconsistent gene activity even within a single tumor. This, in fact, is what the researchers found.
The disruption of methylation machinery might seem hazardous to tumor survival, but the researchers theorize that tumors can turn the disorderliness to their own advantage.
“Just as in the case of genetic heterogeneity within tumors, increased random variation of the epigenetic profile may augment the diversity of malignant cells,” said study author Dan Landau, MD, PhD, of Dana-Farber and the Broad Institute.
“The ability of cancers to maintain high levels of diversity is an effective hedging strategy, enabling them to better adapt to therapy, as well as enhancing the ‘trial and error’ process in search of better evolutionary trajectories.”
“Cancer survives through some wildly inventive ways,” Dr Wu added. “Methylation disorder is one of the ways it creates the conditions that enable it to adapt.”
CLL drug can fight AML too, study suggests
Credit: FDA
SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.
This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.
Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.
The drug appeared to be particularly active in patients with IDH mutations.
Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.
The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.
The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.
The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.
The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.
The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.
Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.
No patients died as a result of treatment-related adverse events.
Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.
AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.
Credit: FDA
SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.
This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.
Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.
The drug appeared to be particularly active in patients with IDH mutations.
Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.
The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.
The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.
The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.
The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.
The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.
Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.
No patients died as a result of treatment-related adverse events.
Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.
AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.
Credit: FDA
SAN FRANCISCO—A BCL2 inhibitor that previously proved active against chronic lymphocytic leukemia has shown activity in certain patients with acute myelogenous leukemia (AML) as well.
This phase 2 trial was the first use of the inhibitor, ABT-199 (or venetoclax), in patients with relapsed or refractory AML.
Five of 32 patients treated with ABT-199 achieved a complete response (CR) or CR with incomplete blood count recovery (CRi), and several more had stable disease.
The drug appeared to be particularly active in patients with IDH mutations.
Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, presented these results at the 2014 ASH Annual Meeting (abstract 118). The research was funded by AbbVie, Inc., the company developing ABT-199.
The trial was launched on the basis of preclinical studies showing that ABT-199 could kill AML cell lines, patients’ AML cells, and patient-derived AML cells implanted in mice.
The researchers enrolled 32 AML patients, 30 of whom had relapsed or refractory disease. Patients had a median age of 71 (range, 19 to 84), and half were male.
The overall response rate was 15.5%, with 1 patient achieving a CR and 4 patients achieving a CRi. The researchers noted that 3 of the patients who had a CR/CRi had IDH mutations. Two of these patients also achieved minimal residual disease negativity.
The team said these results suggest single-agent ABT-199 can have considerable clinical activity in patients with relapsed or refractory AML, and patients with mutations in IDH genes may be particularly sensitive to the drug.
The researchers also found the median bone marrow blast count in evaluable patients decreased 36% after treatment with ABT-199. And 6 patients (19%) had at least a 50% reduction in bone marrow blasts.
Common adverse events following treatment (occurring in at least 25% of patients) included nausea, diarrhea, fatigue, neutropenia, and vomiting. Grade 3 and 4 adverse events (occurring in 3 or more patients) included febrile neutropenia, anemia, and pneumonia.
No patients died as a result of treatment-related adverse events.
Furthermore, the maximum-tolerated dose was not reached, leaving open the possibility of higher doses in further trials. The next step is to carry out trials combining ABT-199 with other agents. These trials are currently opening at several sites.
AbbVie said ABT-199 will be studied in combination with common AML treatments, and the company is developing ABT-199 for, and evaluating the drug in, several hematologic malignancies.
Method may predict likelihood of GVHD
Credit: Darren Baker
Researchers say that computer modeling of next-generation DNA sequencing data can help us understand the variable outcomes of stem cell transplant and provide a theoretical framework to make transplant a possibility for more patients who don’t have a related donor.
The team analyzed data obtained from whole-exome sequencing of 9 donor-recipient pairs (DRPs) and found it’s possible to predict the risk of graft-vs-host disease (GVHD).
This finding could one day help physicians tailor immunosuppressive therapies to possibly improve transplant outcomes.
The investigators say their data provide evidence that the way a patient’s immune system rebuilds itself following transplant is representative of a dynamical system, a system in which the current state determines what future state will follow.
“The immune system seems chaotic, but that is because there are so many variables involved,” said Amir Toor, MD, of the Virginia Commonwealth University in Richmond.
“We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor’s immune system will graft to a patient.”
Dr Toor and his colleagues describe this work in two articles in Frontiers in Immunology.
In the first paper, the researchers recount how they used whole-exome sequencing to examine variation in minor histocompatibility antigens (mHAs) of transplant DRPs.
Using advanced computer-based analysis, the investigators examined potential interactions between mHAs and HLAs and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.
These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients do not develop GVHD remains a mystery.
The researchers offer an explanation for this seeming paradox in a companion article. In this paper, they suggest that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplant, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.
In previous research, Dr Toor and his colleagues discovered a fractal pattern in the DNA of recipients’ T-cell repertoires. (Fractals are self-similar patterns that repeat themselves at every scale.)
Based on their data, the researchers believe that the presentation of mHAs following transplant helps shape the development of T-cell clonal families.
Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is supported by data from clinical studies showing immune suppression soon after transplant improves outcomes in unrelated DRPs.
The investigators suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient’s future risk of GVHD.
“Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants,” Dr Toor said. “The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach.”
“We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients.”
Credit: Darren Baker
Researchers say that computer modeling of next-generation DNA sequencing data can help us understand the variable outcomes of stem cell transplant and provide a theoretical framework to make transplant a possibility for more patients who don’t have a related donor.
The team analyzed data obtained from whole-exome sequencing of 9 donor-recipient pairs (DRPs) and found it’s possible to predict the risk of graft-vs-host disease (GVHD).
This finding could one day help physicians tailor immunosuppressive therapies to possibly improve transplant outcomes.
The investigators say their data provide evidence that the way a patient’s immune system rebuilds itself following transplant is representative of a dynamical system, a system in which the current state determines what future state will follow.
“The immune system seems chaotic, but that is because there are so many variables involved,” said Amir Toor, MD, of the Virginia Commonwealth University in Richmond.
“We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor’s immune system will graft to a patient.”
Dr Toor and his colleagues describe this work in two articles in Frontiers in Immunology.
In the first paper, the researchers recount how they used whole-exome sequencing to examine variation in minor histocompatibility antigens (mHAs) of transplant DRPs.
Using advanced computer-based analysis, the investigators examined potential interactions between mHAs and HLAs and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.
These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients do not develop GVHD remains a mystery.
The researchers offer an explanation for this seeming paradox in a companion article. In this paper, they suggest that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplant, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.
In previous research, Dr Toor and his colleagues discovered a fractal pattern in the DNA of recipients’ T-cell repertoires. (Fractals are self-similar patterns that repeat themselves at every scale.)
Based on their data, the researchers believe that the presentation of mHAs following transplant helps shape the development of T-cell clonal families.
Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is supported by data from clinical studies showing immune suppression soon after transplant improves outcomes in unrelated DRPs.
The investigators suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient’s future risk of GVHD.
“Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants,” Dr Toor said. “The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach.”
“We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients.”
Credit: Darren Baker
Researchers say that computer modeling of next-generation DNA sequencing data can help us understand the variable outcomes of stem cell transplant and provide a theoretical framework to make transplant a possibility for more patients who don’t have a related donor.
The team analyzed data obtained from whole-exome sequencing of 9 donor-recipient pairs (DRPs) and found it’s possible to predict the risk of graft-vs-host disease (GVHD).
This finding could one day help physicians tailor immunosuppressive therapies to possibly improve transplant outcomes.
The investigators say their data provide evidence that the way a patient’s immune system rebuilds itself following transplant is representative of a dynamical system, a system in which the current state determines what future state will follow.
“The immune system seems chaotic, but that is because there are so many variables involved,” said Amir Toor, MD, of the Virginia Commonwealth University in Richmond.
“We have found evidence of an underlying order. Using next-generation DNA sequencing technology, it may be possible to account for many of the molecular variables that eventually determine how well a donor’s immune system will graft to a patient.”
Dr Toor and his colleagues describe this work in two articles in Frontiers in Immunology.
In the first paper, the researchers recount how they used whole-exome sequencing to examine variation in minor histocompatibility antigens (mHAs) of transplant DRPs.
Using advanced computer-based analysis, the investigators examined potential interactions between mHAs and HLAs and discovered a high level of mHA variation in HLA-matched DRPs that could potentially contribute to GVHD.
These findings may help explain why many HLA-matched recipients experience GVHD, but why some HLA-mismatched recipients do not develop GVHD remains a mystery.
The researchers offer an explanation for this seeming paradox in a companion article. In this paper, they suggest that by inhibiting peptide generation through immunosuppressive therapies in the earliest weeks following stem cell transplant, antigen presentation to donor T cells could be diminished, which reduces the risk of GVHD as the recipients reconstitute their T-cell repertoire.
In previous research, Dr Toor and his colleagues discovered a fractal pattern in the DNA of recipients’ T-cell repertoires. (Fractals are self-similar patterns that repeat themselves at every scale.)
Based on their data, the researchers believe that the presentation of mHAs following transplant helps shape the development of T-cell clonal families.
Thus, inhibiting this antigen presentation through immunosuppressive therapies in patients who have high mHA variation can potentially reduce the risk of GVHD by influencing the development of their T-cell repertoire. This is supported by data from clinical studies showing immune suppression soon after transplant improves outcomes in unrelated DRPs.
The investigators suggest that an equation such as the logistic model of growth, a mathematical formula used to explain population growth, could be employed to predict the evolution of T-cell clones and determine a patient’s future risk of GVHD.
“Currently, we rely on population-based outcomes derived from probabilistic studies to determine the best way to perform stem cell transplants,” Dr Toor said. “The development of accurate mathematical models that account for the key variables influencing transplant outcomes may allow us to treat patients using a systematic and personalized approach.”
“We plan to keep exploring this concept in hopes that we can tailor the transplantation process to each individual in order to improve outcomes and make transplantation an option for more patients.”
Team identifies cells responsible for metastasis in MM
SAN FRANCISCO—Multiple myeloma (MM) is driven to spread by only a subset of the myeloma cells within a patient’s body, according to research presented at the 2014 ASH Annual Meeting.
Attacking those cells with targeted drugs may degrade MM’s ability to spread throughout the bone marrow, study investigators said.
The team had used a mouse model of MM to track which of 15 subclones of myeloma cells spread beyond their initial site in the animals’ hind legs.
By labeling the different subgroups with fluorescent dyes, the researchers determined that just one of the subclones was responsible for disease metastasis.
They then compared the pattern of gene abnormalities in the initial myeloma tissue and the metastatic tumors. And they found that 238 genes were significantly less active in the latter group, comprising a gene signature of metastatic myeloma.
“Out of all the genes that were differently expressed in the 2 groups, we found 11 that played a functional role in metastasis and therefore may be drivers of the disease,” said study investigator Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.
If future studies confirm that role, the genes may become targets for therapies that inhibit MM metastasis, she added.
Dr Ghobrial and her colleagues presented this research in a poster session at ASH (abstract 3370).
SAN FRANCISCO—Multiple myeloma (MM) is driven to spread by only a subset of the myeloma cells within a patient’s body, according to research presented at the 2014 ASH Annual Meeting.
Attacking those cells with targeted drugs may degrade MM’s ability to spread throughout the bone marrow, study investigators said.
The team had used a mouse model of MM to track which of 15 subclones of myeloma cells spread beyond their initial site in the animals’ hind legs.
By labeling the different subgroups with fluorescent dyes, the researchers determined that just one of the subclones was responsible for disease metastasis.
They then compared the pattern of gene abnormalities in the initial myeloma tissue and the metastatic tumors. And they found that 238 genes were significantly less active in the latter group, comprising a gene signature of metastatic myeloma.
“Out of all the genes that were differently expressed in the 2 groups, we found 11 that played a functional role in metastasis and therefore may be drivers of the disease,” said study investigator Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.
If future studies confirm that role, the genes may become targets for therapies that inhibit MM metastasis, she added.
Dr Ghobrial and her colleagues presented this research in a poster session at ASH (abstract 3370).
SAN FRANCISCO—Multiple myeloma (MM) is driven to spread by only a subset of the myeloma cells within a patient’s body, according to research presented at the 2014 ASH Annual Meeting.
Attacking those cells with targeted drugs may degrade MM’s ability to spread throughout the bone marrow, study investigators said.
The team had used a mouse model of MM to track which of 15 subclones of myeloma cells spread beyond their initial site in the animals’ hind legs.
By labeling the different subgroups with fluorescent dyes, the researchers determined that just one of the subclones was responsible for disease metastasis.
They then compared the pattern of gene abnormalities in the initial myeloma tissue and the metastatic tumors. And they found that 238 genes were significantly less active in the latter group, comprising a gene signature of metastatic myeloma.
“Out of all the genes that were differently expressed in the 2 groups, we found 11 that played a functional role in metastasis and therefore may be drivers of the disease,” said study investigator Irene Ghobrial, MD, of the Dana-Farber Cancer Institute in Boston.
If future studies confirm that role, the genes may become targets for therapies that inhibit MM metastasis, she added.
Dr Ghobrial and her colleagues presented this research in a poster session at ASH (abstract 3370).