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FDA changes deferral policy for MSM blood donors
Photo by Михаило Јовановић
The US Food and Drug Administration (FDA) has issued a final guidance outlining updated blood donor deferral recommendations.
As part of the guidance, the FDA is changing its recommendation that men who have sex with men (MSM) be indefinitely deferred from donating blood—a policy that has been in place for approximately 30 years.
Now, the agency is recommending that MSMs be deferred for 12 months since their last sexual contact with another man.
The FDA’s guidance also reflects a change in the rationale for deferring potential blood donors with hemophilia or related clotting disorders who have received clotting factor concentrates.
The FDA recommends that blood establishments make corresponding revisions to donor educational materials, donor history questionnaires, and accompanying materials, as well as donor requalification and product management procedures.
MSM deferral
The FDA said its recommendation regarding MSM blood donors reflects the most current scientific evidence and will help ensure continued safety of the blood supply by reducing the risk of human immunodeficiency virus (HIV) transmission by blood and blood products.
The agency also said this recommendation better aligns the deferral period for MSMs with the deferral period for other men and women at increased risk for HIV infection, such as those who had a recent blood transfusion or those who have been accidentally exposed to the blood of another individual.
Before issuing this guidance, the FDA reviewed its policies regarding HIV transmission through blood products to determine appropriate changes based on the most recent scientific evidence. The agency examined a variety of studies, epidemiologic data, and shared experiences from other countries that have made recent MSM deferral policy changes.
“In reviewing our policies to help reduce the risk of HIV transmission through blood products, we rigorously examined several alternative options, including individual risk assessment,” said Peter Marks, MD, PhD, deputy director of the FDA’s Center for Biologics Evaluation and Research.
“Ultimately, the 12-month deferral window is supported by the best available scientific evidence, at this point in time, relevant to the US population. We will continue to actively conduct research in this area and further revise our policies as new data emerge.”
Several countries, including the UK and Australia, currently have 12-month deferral policies for MSM blood donors.
During the change in Australia from an indefinite blood donor deferral policy for MSMs to a 12-month deferral, studies evaluating over 8 million units of donated blood were performed using a national blood surveillance system. These studies (CR Seed et al, Transfusion 2010; TTA Lucky et al, Transfusion 2014) show no change in risk to the blood supply with use of the 12-month deferral.
A study conducted in the UK produced similar results, although it also suggested that 3 in 10 MSMs don’t comply with the 12-month deferral policy.
And a study conducted in Canada, which recently shortened its MSM deferral period to 5 years, showed no change in risk to the blood supply with the 5-year deferral as compared to indefinite deferral. Based on these results, Canadian regulators are considering changing to a 12-month deferral period as well.
Patients with clotting disorders
The FDA’s new guidance also reflects a change in the rationale for deferring patients with hemophilia or related clotting disorders who have received clotting factor concentrates. Previously, potential donors with hemophilia or related clotting disorders were deferred due to the increased risk of HIV transmission to potential recipients.
Based on new scientific evidence, these potential donors are still deferred, but not due to the risk of HIV transmission—instead, for their own protection due to potential harm from large needles used during the donation process.
FDA policies and actions
Throughout the process of updating blood donor deferral policies over the past several years, the FDA has worked with other government agencies, considered input from external advisory committees, reviewed comments from stakeholders to its May 2015 draft guidance, and examined the most recent available scientific evidence to support the current policy revision.
The FDA has also implemented a nationally representative safety monitoring system for the blood supply with assistance from the National Heart, Lung and Blood Institute at the National Institutes of Health. This system will provide information to help inform future actions the FDA may take on blood donor policies.
The FDA said it will continue to reevaluate and update its blood donor deferral policies as new scientific information becomes available. 
Photo by Михаило Јовановић
The US Food and Drug Administration (FDA) has issued a final guidance outlining updated blood donor deferral recommendations.
As part of the guidance, the FDA is changing its recommendation that men who have sex with men (MSM) be indefinitely deferred from donating blood—a policy that has been in place for approximately 30 years.
Now, the agency is recommending that MSMs be deferred for 12 months since their last sexual contact with another man.
The FDA’s guidance also reflects a change in the rationale for deferring potential blood donors with hemophilia or related clotting disorders who have received clotting factor concentrates.
The FDA recommends that blood establishments make corresponding revisions to donor educational materials, donor history questionnaires, and accompanying materials, as well as donor requalification and product management procedures.
MSM deferral
The FDA said its recommendation regarding MSM blood donors reflects the most current scientific evidence and will help ensure continued safety of the blood supply by reducing the risk of human immunodeficiency virus (HIV) transmission by blood and blood products.
The agency also said this recommendation better aligns the deferral period for MSMs with the deferral period for other men and women at increased risk for HIV infection, such as those who had a recent blood transfusion or those who have been accidentally exposed to the blood of another individual.
Before issuing this guidance, the FDA reviewed its policies regarding HIV transmission through blood products to determine appropriate changes based on the most recent scientific evidence. The agency examined a variety of studies, epidemiologic data, and shared experiences from other countries that have made recent MSM deferral policy changes.
“In reviewing our policies to help reduce the risk of HIV transmission through blood products, we rigorously examined several alternative options, including individual risk assessment,” said Peter Marks, MD, PhD, deputy director of the FDA’s Center for Biologics Evaluation and Research.
“Ultimately, the 12-month deferral window is supported by the best available scientific evidence, at this point in time, relevant to the US population. We will continue to actively conduct research in this area and further revise our policies as new data emerge.”
Several countries, including the UK and Australia, currently have 12-month deferral policies for MSM blood donors.
During the change in Australia from an indefinite blood donor deferral policy for MSMs to a 12-month deferral, studies evaluating over 8 million units of donated blood were performed using a national blood surveillance system. These studies (CR Seed et al, Transfusion 2010; TTA Lucky et al, Transfusion 2014) show no change in risk to the blood supply with use of the 12-month deferral.
A study conducted in the UK produced similar results, although it also suggested that 3 in 10 MSMs don’t comply with the 12-month deferral policy.
And a study conducted in Canada, which recently shortened its MSM deferral period to 5 years, showed no change in risk to the blood supply with the 5-year deferral as compared to indefinite deferral. Based on these results, Canadian regulators are considering changing to a 12-month deferral period as well.
Patients with clotting disorders
The FDA’s new guidance also reflects a change in the rationale for deferring patients with hemophilia or related clotting disorders who have received clotting factor concentrates. Previously, potential donors with hemophilia or related clotting disorders were deferred due to the increased risk of HIV transmission to potential recipients.
Based on new scientific evidence, these potential donors are still deferred, but not due to the risk of HIV transmission—instead, for their own protection due to potential harm from large needles used during the donation process.
FDA policies and actions
Throughout the process of updating blood donor deferral policies over the past several years, the FDA has worked with other government agencies, considered input from external advisory committees, reviewed comments from stakeholders to its May 2015 draft guidance, and examined the most recent available scientific evidence to support the current policy revision.
The FDA has also implemented a nationally representative safety monitoring system for the blood supply with assistance from the National Heart, Lung and Blood Institute at the National Institutes of Health. This system will provide information to help inform future actions the FDA may take on blood donor policies.
The FDA said it will continue to reevaluate and update its blood donor deferral policies as new scientific information becomes available.
Photo by Михаило Јовановић
The US Food and Drug Administration (FDA) has issued a final guidance outlining updated blood donor deferral recommendations.
As part of the guidance, the FDA is changing its recommendation that men who have sex with men (MSM) be indefinitely deferred from donating blood—a policy that has been in place for approximately 30 years.
Now, the agency is recommending that MSMs be deferred for 12 months since their last sexual contact with another man.
The FDA’s guidance also reflects a change in the rationale for deferring potential blood donors with hemophilia or related clotting disorders who have received clotting factor concentrates.
The FDA recommends that blood establishments make corresponding revisions to donor educational materials, donor history questionnaires, and accompanying materials, as well as donor requalification and product management procedures.
MSM deferral
The FDA said its recommendation regarding MSM blood donors reflects the most current scientific evidence and will help ensure continued safety of the blood supply by reducing the risk of human immunodeficiency virus (HIV) transmission by blood and blood products.
The agency also said this recommendation better aligns the deferral period for MSMs with the deferral period for other men and women at increased risk for HIV infection, such as those who had a recent blood transfusion or those who have been accidentally exposed to the blood of another individual.
Before issuing this guidance, the FDA reviewed its policies regarding HIV transmission through blood products to determine appropriate changes based on the most recent scientific evidence. The agency examined a variety of studies, epidemiologic data, and shared experiences from other countries that have made recent MSM deferral policy changes.
“In reviewing our policies to help reduce the risk of HIV transmission through blood products, we rigorously examined several alternative options, including individual risk assessment,” said Peter Marks, MD, PhD, deputy director of the FDA’s Center for Biologics Evaluation and Research.
“Ultimately, the 12-month deferral window is supported by the best available scientific evidence, at this point in time, relevant to the US population. We will continue to actively conduct research in this area and further revise our policies as new data emerge.”
Several countries, including the UK and Australia, currently have 12-month deferral policies for MSM blood donors.
During the change in Australia from an indefinite blood donor deferral policy for MSMs to a 12-month deferral, studies evaluating over 8 million units of donated blood were performed using a national blood surveillance system. These studies (CR Seed et al, Transfusion 2010; TTA Lucky et al, Transfusion 2014) show no change in risk to the blood supply with use of the 12-month deferral.
A study conducted in the UK produced similar results, although it also suggested that 3 in 10 MSMs don’t comply with the 12-month deferral policy.
And a study conducted in Canada, which recently shortened its MSM deferral period to 5 years, showed no change in risk to the blood supply with the 5-year deferral as compared to indefinite deferral. Based on these results, Canadian regulators are considering changing to a 12-month deferral period as well.
Patients with clotting disorders
The FDA’s new guidance also reflects a change in the rationale for deferring patients with hemophilia or related clotting disorders who have received clotting factor concentrates. Previously, potential donors with hemophilia or related clotting disorders were deferred due to the increased risk of HIV transmission to potential recipients.
Based on new scientific evidence, these potential donors are still deferred, but not due to the risk of HIV transmission—instead, for their own protection due to potential harm from large needles used during the donation process.
FDA policies and actions
Throughout the process of updating blood donor deferral policies over the past several years, the FDA has worked with other government agencies, considered input from external advisory committees, reviewed comments from stakeholders to its May 2015 draft guidance, and examined the most recent available scientific evidence to support the current policy revision.
The FDA has also implemented a nationally representative safety monitoring system for the blood supply with assistance from the National Heart, Lung and Blood Institute at the National Institutes of Health. This system will provide information to help inform future actions the FDA may take on blood donor policies.
The FDA said it will continue to reevaluate and update its blood donor deferral policies as new scientific information becomes available.
Antibody shows promise for treating CLL
Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).
Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.
But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.
Investigators reported these results in The Journal of Clinical Investigation.
They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.
“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”
The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.
In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.
In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.
In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.
In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.
In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.
The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.
Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.
Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.
But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.
Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).
Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.
But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.
Investigators reported these results in The Journal of Clinical Investigation.
They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.
“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”
The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.
In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.
In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.
In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.
In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.
In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.
The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.
Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.
Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.
But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.
Preclinical research suggests a humanized monoclonal antibody called cirmtuzumab (UC-961) might be an effective treatment for chronic lymphocytic leukemia (CLL).
Experiments revealed that the Wnt5a protein acts on the tumor-surface proteins ROR1 and ROR2 to accelerate the proliferation and spread of CLL cells.
But cirmtuzumab, which is specific for ROR1, can block the effects of Wnt5a and inhibit the growth and spread of CLL cells both in vitro and in vivo.
Investigators reported these results in The Journal of Clinical Investigation.
They noted that ROR1 and ROR2 are considered orphan receptors, which are expressed primarily during embryonic development. The expression of these proteins, particularly ROR1, becomes suppressed during fetal development and is negligible on normal adult tissues. However, CLL and many solid tissue cancers re-express these orphan receptors.
“Our findings show that ROR1 and ROR2 team up to stimulate tumor cell growth and metastasis in response to Wnt5a, which appears overexpressed in patients with CLL and can act as a survival/growth factor for leukemia cells,” said study author Thomas J. Kipps, MD, PhD, of Moores Cancer Center at the University of California, San Diego.
“By blocking the capacity of Wnt5a to stimulate tumor cells, cirmtuzumab can inhibit the growth and spread of cancer cells. We now have better insight into how cirmtuzumab works against leukemia cells. This should help find better ways to treat patients who have other cancers with cirmtuzumab, which currently is being evaluated in a phase 1 clinical trial for patients with CLL.”
The JCI paper follows a series of related findings by Dr Kipps and his colleagues in recent years.
In 2008, they reported that patients vaccinated with their own CLL cells could make antibodies against ROR1, some of which had the ability to reduce CLL cell survival. They found ROR1 on CLL cells but not on all normal adult tissues examined.
In 2012, the investigators reported finding ROR1 on many different types of cancer, particularly cancers that appear less differentiated and more likely to spread to other parts in the body. Because this protein was not found on normal adult tissues, these findings made ROR1 a new target for anticancer drug research.
In June 2013, the team linked ROR1 to a process used in early development, suggesting cancer cells hijack an embryological process called epithelial-mesenchymal transition to spread or metastasize more quickly.
In January 2014, the investigators reported expression of ROR1 resulted in a faster-developing, more aggressive form of CLL in mice.
In September 2014, the team launched a phase 1 trial of cirmtuzumab in patients with CLL. The trial is ongoing.
In November 2014, the investigators described cellular experiments indicating that cirmtuzumab might be effective against cancer stem cells, which appear responsible for the relapse and spread of cancer after conventional therapy.
The latest research more precisely defines the roles of ROR1 and ROR2 in CLL development.
Both are evolutionarily conserved proteins that are found in many species and are most active in the early stages of embryogenesis when cells are migrating to form organs and parts of the body. The lack of either during this process results in severe developmental abnormalities.
Low levels of ROR2 remain in some adult tissues, but ROR1 is found only in cancer cells. The investigators found that, in response to signaling by Wnt5a, ROR1 and ROR2 come together to signal the growth and migration of CLL cells.
But treating mice with cirmtuzumab disrupted the process, inhibiting the engraftment of CLL cells and slowing or stopping the disease from spreading.
Anemia tied to cognitive impairment
A population-based study conducted in Germany has suggested a link between anemia and mild cognitive impairment (MCI).
Researchers found that subjects with anemia, defined as hemoglobin <13 g/dL in men and <12 g/dL in women, performed worse on cognitive tests than their nonanemic peers.
And MCI occurred almost twice as often in subjects with anemia than in subjects with normal hemoglobin levels.
This study was published in the Journal of Alzheimer’s Disease.
About MCI
MCI represents an intermediate and possibly modifiable stage between normal cognitive aging and dementia. Although individuals with MCI have an increased risk of developing dementia or Alzheimer’s disease, they can also remain stable for many years or even revert to a cognitively normal state over time. This modifiable characteristic makes the concept of MCI a promising target in the prevention of dementia.
The following 4 criteria are used to diagnose MCI. First, subjects must report a decline in cognitive performance over the past 2 years. Second, they must show a cognitive impairment in objective cognitive tasks that is greater than one would expect taking their age and education into consideration.
Third, the impairment must not be as pronounced as in demented individuals since people with MCI can perform normal daily living activities or are only slightly impaired in carrying out complex instrumental functions. Fourth, the cognitive impairment has to be insufficient to fulfil criteria for dementia.
The concept of MCI distinguishes between amnestic MCI (aMCI) and non-amnestic MCI (naMCI). In the former, impairment in the memory domain is evident, most likely reflecting Alzheimer’s disease pathology. In the latter, impairment in non-memory domains is present, mainly reflecting vascular pathology but also frontotemporal dementia or dementia with Lewy bodies.
Study details
The Heinz Nixdorf Recall study is an observational, population-based, prospective study in which researchers examined 4814 subjects between 2000 and 2003. Subjects were 50 to 80 years of age and lived in the metropolitan Ruhr Area. Both genders were equally represented.
After 5 years, the researchers conducted a second examination with 92% of the subjects taking part. The publication includes cross-sectional results of the second examination.
First, 163 subjects with anemia and 3870 without anemia were included to compare their performance in all cognitive subtests.
The subjects took verbal memory tests, which were used to gauge immediate recall and delayed recall. They were also tested on executive functioning, which included problem-solving/speed of processing, verbal fluency, visual spatial organization, and the clock drawing test.
In the initial analysis, anemic subjects showed more pronounced cardiovascular risk profiles and lower cognitive performance in all administered cognitive subtests. After adjusting for age, anemic subjects showed a significantly lower performance in the immediate recall task (P=0.009) and the verbal fluency task (P=0.004).
Next, the researchers compared 579 subjects diagnosed with MCI—299 with aMCI and 280 with naMCI—to 1438 cognitively normal subjects to determine the association between anemia at follow-up and MCI.
The team found that MCI occurred more often in anemic than non-anemic subjects. The unadjusted odds ratio (OR) was 2.59 (P<0.001). The OR after adjustment for age, gender, and years of education was 2.15 (P=0.002).
In a third analysis, the researchers adjusted for the aforementioned variables as well as body mass index, high-sensitivity C-reactive protein, glomerular filtration rate, cholesterol, serum iron, hypertension, diabetes mellitus, history of coronary heart disease, history of stroke, history of cancer, APOE4, smoking, severe depressive symptoms, and use of antidepressants. The OR after adjustment for these factors was 1.92 (P=0.04).
Similar results were found for aMCI and naMCI. The researchers said this suggests that having a low hemoglobin level may contribute to cognitive impairment via different pathways.
The team believes that, overall, their study results indicate that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. They said the association between anemia and MCI has important clinical relevance because—depending on etiology—anemia can be treated effectively, and this might provide means to prevent or delay cognitive decline.
A population-based study conducted in Germany has suggested a link between anemia and mild cognitive impairment (MCI).
Researchers found that subjects with anemia, defined as hemoglobin <13 g/dL in men and <12 g/dL in women, performed worse on cognitive tests than their nonanemic peers.
And MCI occurred almost twice as often in subjects with anemia than in subjects with normal hemoglobin levels.
This study was published in the Journal of Alzheimer’s Disease.
About MCI
MCI represents an intermediate and possibly modifiable stage between normal cognitive aging and dementia. Although individuals with MCI have an increased risk of developing dementia or Alzheimer’s disease, they can also remain stable for many years or even revert to a cognitively normal state over time. This modifiable characteristic makes the concept of MCI a promising target in the prevention of dementia.
The following 4 criteria are used to diagnose MCI. First, subjects must report a decline in cognitive performance over the past 2 years. Second, they must show a cognitive impairment in objective cognitive tasks that is greater than one would expect taking their age and education into consideration.
Third, the impairment must not be as pronounced as in demented individuals since people with MCI can perform normal daily living activities or are only slightly impaired in carrying out complex instrumental functions. Fourth, the cognitive impairment has to be insufficient to fulfil criteria for dementia.
The concept of MCI distinguishes between amnestic MCI (aMCI) and non-amnestic MCI (naMCI). In the former, impairment in the memory domain is evident, most likely reflecting Alzheimer’s disease pathology. In the latter, impairment in non-memory domains is present, mainly reflecting vascular pathology but also frontotemporal dementia or dementia with Lewy bodies.
Study details
The Heinz Nixdorf Recall study is an observational, population-based, prospective study in which researchers examined 4814 subjects between 2000 and 2003. Subjects were 50 to 80 years of age and lived in the metropolitan Ruhr Area. Both genders were equally represented.
After 5 years, the researchers conducted a second examination with 92% of the subjects taking part. The publication includes cross-sectional results of the second examination.
First, 163 subjects with anemia and 3870 without anemia were included to compare their performance in all cognitive subtests.
The subjects took verbal memory tests, which were used to gauge immediate recall and delayed recall. They were also tested on executive functioning, which included problem-solving/speed of processing, verbal fluency, visual spatial organization, and the clock drawing test.
In the initial analysis, anemic subjects showed more pronounced cardiovascular risk profiles and lower cognitive performance in all administered cognitive subtests. After adjusting for age, anemic subjects showed a significantly lower performance in the immediate recall task (P=0.009) and the verbal fluency task (P=0.004).
Next, the researchers compared 579 subjects diagnosed with MCI—299 with aMCI and 280 with naMCI—to 1438 cognitively normal subjects to determine the association between anemia at follow-up and MCI.
The team found that MCI occurred more often in anemic than non-anemic subjects. The unadjusted odds ratio (OR) was 2.59 (P<0.001). The OR after adjustment for age, gender, and years of education was 2.15 (P=0.002).
In a third analysis, the researchers adjusted for the aforementioned variables as well as body mass index, high-sensitivity C-reactive protein, glomerular filtration rate, cholesterol, serum iron, hypertension, diabetes mellitus, history of coronary heart disease, history of stroke, history of cancer, APOE4, smoking, severe depressive symptoms, and use of antidepressants. The OR after adjustment for these factors was 1.92 (P=0.04).
Similar results were found for aMCI and naMCI. The researchers said this suggests that having a low hemoglobin level may contribute to cognitive impairment via different pathways.
The team believes that, overall, their study results indicate that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. They said the association between anemia and MCI has important clinical relevance because—depending on etiology—anemia can be treated effectively, and this might provide means to prevent or delay cognitive decline.
A population-based study conducted in Germany has suggested a link between anemia and mild cognitive impairment (MCI).
Researchers found that subjects with anemia, defined as hemoglobin <13 g/dL in men and <12 g/dL in women, performed worse on cognitive tests than their nonanemic peers.
And MCI occurred almost twice as often in subjects with anemia than in subjects with normal hemoglobin levels.
This study was published in the Journal of Alzheimer’s Disease.
About MCI
MCI represents an intermediate and possibly modifiable stage between normal cognitive aging and dementia. Although individuals with MCI have an increased risk of developing dementia or Alzheimer’s disease, they can also remain stable for many years or even revert to a cognitively normal state over time. This modifiable characteristic makes the concept of MCI a promising target in the prevention of dementia.
The following 4 criteria are used to diagnose MCI. First, subjects must report a decline in cognitive performance over the past 2 years. Second, they must show a cognitive impairment in objective cognitive tasks that is greater than one would expect taking their age and education into consideration.
Third, the impairment must not be as pronounced as in demented individuals since people with MCI can perform normal daily living activities or are only slightly impaired in carrying out complex instrumental functions. Fourth, the cognitive impairment has to be insufficient to fulfil criteria for dementia.
The concept of MCI distinguishes between amnestic MCI (aMCI) and non-amnestic MCI (naMCI). In the former, impairment in the memory domain is evident, most likely reflecting Alzheimer’s disease pathology. In the latter, impairment in non-memory domains is present, mainly reflecting vascular pathology but also frontotemporal dementia or dementia with Lewy bodies.
Study details
The Heinz Nixdorf Recall study is an observational, population-based, prospective study in which researchers examined 4814 subjects between 2000 and 2003. Subjects were 50 to 80 years of age and lived in the metropolitan Ruhr Area. Both genders were equally represented.
After 5 years, the researchers conducted a second examination with 92% of the subjects taking part. The publication includes cross-sectional results of the second examination.
First, 163 subjects with anemia and 3870 without anemia were included to compare their performance in all cognitive subtests.
The subjects took verbal memory tests, which were used to gauge immediate recall and delayed recall. They were also tested on executive functioning, which included problem-solving/speed of processing, verbal fluency, visual spatial organization, and the clock drawing test.
In the initial analysis, anemic subjects showed more pronounced cardiovascular risk profiles and lower cognitive performance in all administered cognitive subtests. After adjusting for age, anemic subjects showed a significantly lower performance in the immediate recall task (P=0.009) and the verbal fluency task (P=0.004).
Next, the researchers compared 579 subjects diagnosed with MCI—299 with aMCI and 280 with naMCI—to 1438 cognitively normal subjects to determine the association between anemia at follow-up and MCI.
The team found that MCI occurred more often in anemic than non-anemic subjects. The unadjusted odds ratio (OR) was 2.59 (P<0.001). The OR after adjustment for age, gender, and years of education was 2.15 (P=0.002).
In a third analysis, the researchers adjusted for the aforementioned variables as well as body mass index, high-sensitivity C-reactive protein, glomerular filtration rate, cholesterol, serum iron, hypertension, diabetes mellitus, history of coronary heart disease, history of stroke, history of cancer, APOE4, smoking, severe depressive symptoms, and use of antidepressants. The OR after adjustment for these factors was 1.92 (P=0.04).
Similar results were found for aMCI and naMCI. The researchers said this suggests that having a low hemoglobin level may contribute to cognitive impairment via different pathways.
The team believes that, overall, their study results indicate that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. They said the association between anemia and MCI has important clinical relevance because—depending on etiology—anemia can be treated effectively, and this might provide means to prevent or delay cognitive decline.
Potential new alternative in CML when TKI therapy fails
ASH Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—ABL001, an allosteric inhibitor of BCR-ABL1, has shown early evidence of single-agent activity in a multicenter, first-in-human, first-in-class trial of heavily treated patients with chronic myeloid leukemia (CML) that is resistant to or intolerant of prior tyrosine kinase inhibitors (TKIs), even at the lowest dose evaluated.
ABL001 and classical TKIs exhibit complementary mutation profiles, with ABL001 showing activity against TKI resistance mutations.
When combined with nilotinib in a mouse model of CML, ABL001 prevented the emergence of resistant disease even after treatment was discontinued.
“This produces a new therapeutic concept—that of allosteric inhibition,” said Oliver G. Ottmann, MD, of Cardiff University in the UK.
The ABL001 binding site is located in a region remote from the kinase domain and has the potential to combine with TKIs for greater pharmacologic control of BCR-ABL1.
“This obviously has the opportunity both for combining different treatments and for overcoming resistance to one or the other,” Dr Ottmann added.
Based on preliminary pharmacokinetic data and preclinical evidence, investigators proceeded to evaluate ABL001 in a phase 1 dose-escalation and dose-expansion study.
Their primary objective was to determine the maximum tolerated dose (MTD) in humans and the recommended dose for expansion (RDE). Secondary objectives were to evaluate the safety, tolerability, preliminary anti-CML activity, and pharmacokinetic and pharmacodynamic profile.
Dr Ottmann presented the findings during the 2015 ASH Annual Meeting as abstract 138.*
Study design
Patients received ABL001 orally as a single agent twice a day (BID) continuously until disease progression, unacceptable toxicity, consent withdrawal, or death.
The dose-escalation schema followed a Bayesian logistic regression model based on dose-limiting toxicities during cycle 1. Doses ranged from 10 mg to 200 mg BID.
A subsequent dose-expansion phase was planned to augment the data generated in the dose-escalation phase and to include patients with Ph-positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy.
Dr Ottmann noted that there were 2 protocol amendments. The first amendment was made to include a once-daily (QD) dosing of ABL001 at 120 mg and 200 mg. The second amendment was made to evaluate the combination of 40 mg of ABL001 BID with nilotinib at 300 mg BID.
Inclusion/exclusion criteria
Patients had to be at least 18 years old with CML in chronic or accelerated phase. They had to have failed at least 2 prior TKIs or be intolerant of TKIs. Their performance status had to be 0–2.
Patients were excluded from the trial if they had an absolute neutrophil count less than 500/mm3, a platelet count less than 50,000/mm3, bilirubin level more than 1.5 x the upper limit of normal (ULN) or more than 3.0 x ULN in patients with Gilberts syndrome.
Their aspartate aminotransferase or alanine aminotransferase could not be above 3 x ULN, and creatinine could not be above 1.5 x ULN.
Patients were also excluded if they needed treatment with strong inhibitors or inducers of CYP3A4 or its substrates with narrow therapeutic index.
Patient demographics
Fifty-nine patients were enrolled on the trial at the time of the presentation and they had “typical” characteristics of patients at this stage, Dr Ottmann said.
Their median age was 56 (range, 23–78). Almost two-thirds (61%) were male and 39% female.
All but 1 patient had an ECOG performance status of 0, and patients had a median of 3.5 (range, 2–5) prior lines of therapy. Twenty-four patients (41%) had 2 prior TKIs, and 35 (59%) had 3 or more TKIs. Forty-five patients (76%) were resistant and 14 (24%) were intolerant to their prior TKI.
All but 1 patient had chronic phase CML, 18 (31%) were TKD nonmutated, 14 (24%) were mutated, and 17 (46%) were not evaluable.
Patient disposition
Of the 43 patients in the monotherapy BID cohort, 1 was treated at the 10 mg dose level, 5 at the 20 mg level, 12 at the 40 mg level, 12 at the 80 mg level, 8 at the 150 mg level, and 5 at the 200 mg level. They had a median duration of drug exposure ranging from 25 weeks to 67 weeks.
Of the 11 patients in the monotherapy QD group, 5 were treated at the 120 mg dose level and 6 at the 200 mg level. Their drug exposure was a median of 26 weeks for those receiving 120 mg and 9.8 weeks for those receiving the 200 mg dose.
And the 5 patients in the ABL001-plus-nilotinib group had a median of 6.3 weeks of drug exposure.
“We had a remarkably low rate of discontinuation to date,” Dr Ottmann pointed out.
Ten patients discontinued therapy, all in the monotherapy BID group, 1 at 10 mg, 2 at 40 mg, 2 at 80 mg, 3 at 150 mg, and 2 at 200 mg.
Seven patients discontinued for adverse events. Two patients withdrew consent, and 1 patient in the 40 mg group had disease progression, which is “quite remarkable in a phase 1,” Dr Ottmann said.
Pharmacokinetic profile
ABL001 is rapidly absorbed in a median of 2 to 3 hours, and there is a dose-proportional increase in exposure following single and repeated dosing.
The drug has an approximately 2-fold or lower accumulation on repeated dosing and a short elimination half-life of 5 to 6 hours.
Safety
“We have excellent tolerability,” Dr Ottmann said, with a small number of grade 3/4 adverse events (AEs).
Grade 3/4 AEs considered to be drug-related were mostly associated with hematologic suppression. Four patients (7%) had thrombocytopenia, 4 (7%) neutropenia, 3 (5%) anemia, 4 (7%) lipase increase, and 1 (2%) hypercholesterolemia.
AEs of all grades suspected of being related to the study drug and occurring in 5% or more of patients included thrombocytopenia (19%), neutropenia (15%), anemia (10%), nausea/vomiting/diarrhea (29%), arthralgia/myalgia (20%), rash (17%), fatigue (15%), lipase increase (14%), headache (14%), pruritus (10%), dry skin (7%), hypophosphatemia (7%), and acute pancreatitis (5%).
“The pancreatitis was reversible upon interruption or discontinuation of the drug,” Dr Ottmann explained.
There were 5 dose-limiting toxicities. Two patients had grade 3 lipase elevation in the 40 mg BID and 200 mg QD cohorts. One patient had grade 2 myalgia/arthralgia at 80 mg BID, 1 patient had a grade 3 acute coronary event at 150 mg BID, and 1 patient had a grade 3 bronchospasm at 200 mg BID.
No deaths occurred on the study, and the dose escalation is still ongoing.
Response
Twenty-nine patients with 3 months or more of follow-up were evaluable for response.
Twelve patients, who at baseline had hematologic relapse, achieved complete hematologic response within 2 months, and 8 who had cytogenetic relapse at baseline achieved a complete cytogenetic response within 3 to 6 months.
Of the 29 patients who had molecular relapse at baseline, 10 (34.5%) achieved a molecular response within 6 months, 7 (24.1%) had 1 log or more reduction in BCR-ABL1, 9 (31.0%) had less than a log reduction, and 3 (10.3%) had no reduction.
“The obvious question from the preclinical data,” Dr Ottmann said, “is do the mutations respond?”
And ABL001 has shown clinical activity across TKI-resistant mutations, such as V299L, F317L, and Y253H.
“So to conclude,” he said, “we have a new class, a new therapeutic category of drug, ABL001, which is quite well tolerated in extremely heavily treated patients with CML. We do consider this a promising approach.”
The trial was sponsored by Novartis.
*Data in the abstract differ from the presentation.
ASH Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—ABL001, an allosteric inhibitor of BCR-ABL1, has shown early evidence of single-agent activity in a multicenter, first-in-human, first-in-class trial of heavily treated patients with chronic myeloid leukemia (CML) that is resistant to or intolerant of prior tyrosine kinase inhibitors (TKIs), even at the lowest dose evaluated.
ABL001 and classical TKIs exhibit complementary mutation profiles, with ABL001 showing activity against TKI resistance mutations.
When combined with nilotinib in a mouse model of CML, ABL001 prevented the emergence of resistant disease even after treatment was discontinued.
“This produces a new therapeutic concept—that of allosteric inhibition,” said Oliver G. Ottmann, MD, of Cardiff University in the UK.
The ABL001 binding site is located in a region remote from the kinase domain and has the potential to combine with TKIs for greater pharmacologic control of BCR-ABL1.
“This obviously has the opportunity both for combining different treatments and for overcoming resistance to one or the other,” Dr Ottmann added.
Based on preliminary pharmacokinetic data and preclinical evidence, investigators proceeded to evaluate ABL001 in a phase 1 dose-escalation and dose-expansion study.
Their primary objective was to determine the maximum tolerated dose (MTD) in humans and the recommended dose for expansion (RDE). Secondary objectives were to evaluate the safety, tolerability, preliminary anti-CML activity, and pharmacokinetic and pharmacodynamic profile.
Dr Ottmann presented the findings during the 2015 ASH Annual Meeting as abstract 138.*
Study design
Patients received ABL001 orally as a single agent twice a day (BID) continuously until disease progression, unacceptable toxicity, consent withdrawal, or death.
The dose-escalation schema followed a Bayesian logistic regression model based on dose-limiting toxicities during cycle 1. Doses ranged from 10 mg to 200 mg BID.
A subsequent dose-expansion phase was planned to augment the data generated in the dose-escalation phase and to include patients with Ph-positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy.
Dr Ottmann noted that there were 2 protocol amendments. The first amendment was made to include a once-daily (QD) dosing of ABL001 at 120 mg and 200 mg. The second amendment was made to evaluate the combination of 40 mg of ABL001 BID with nilotinib at 300 mg BID.
Inclusion/exclusion criteria
Patients had to be at least 18 years old with CML in chronic or accelerated phase. They had to have failed at least 2 prior TKIs or be intolerant of TKIs. Their performance status had to be 0–2.
Patients were excluded from the trial if they had an absolute neutrophil count less than 500/mm3, a platelet count less than 50,000/mm3, bilirubin level more than 1.5 x the upper limit of normal (ULN) or more than 3.0 x ULN in patients with Gilberts syndrome.
Their aspartate aminotransferase or alanine aminotransferase could not be above 3 x ULN, and creatinine could not be above 1.5 x ULN.
Patients were also excluded if they needed treatment with strong inhibitors or inducers of CYP3A4 or its substrates with narrow therapeutic index.
Patient demographics
Fifty-nine patients were enrolled on the trial at the time of the presentation and they had “typical” characteristics of patients at this stage, Dr Ottmann said.
Their median age was 56 (range, 23–78). Almost two-thirds (61%) were male and 39% female.
All but 1 patient had an ECOG performance status of 0, and patients had a median of 3.5 (range, 2–5) prior lines of therapy. Twenty-four patients (41%) had 2 prior TKIs, and 35 (59%) had 3 or more TKIs. Forty-five patients (76%) were resistant and 14 (24%) were intolerant to their prior TKI.
All but 1 patient had chronic phase CML, 18 (31%) were TKD nonmutated, 14 (24%) were mutated, and 17 (46%) were not evaluable.
Patient disposition
Of the 43 patients in the monotherapy BID cohort, 1 was treated at the 10 mg dose level, 5 at the 20 mg level, 12 at the 40 mg level, 12 at the 80 mg level, 8 at the 150 mg level, and 5 at the 200 mg level. They had a median duration of drug exposure ranging from 25 weeks to 67 weeks.
Of the 11 patients in the monotherapy QD group, 5 were treated at the 120 mg dose level and 6 at the 200 mg level. Their drug exposure was a median of 26 weeks for those receiving 120 mg and 9.8 weeks for those receiving the 200 mg dose.
And the 5 patients in the ABL001-plus-nilotinib group had a median of 6.3 weeks of drug exposure.
“We had a remarkably low rate of discontinuation to date,” Dr Ottmann pointed out.
Ten patients discontinued therapy, all in the monotherapy BID group, 1 at 10 mg, 2 at 40 mg, 2 at 80 mg, 3 at 150 mg, and 2 at 200 mg.
Seven patients discontinued for adverse events. Two patients withdrew consent, and 1 patient in the 40 mg group had disease progression, which is “quite remarkable in a phase 1,” Dr Ottmann said.
Pharmacokinetic profile
ABL001 is rapidly absorbed in a median of 2 to 3 hours, and there is a dose-proportional increase in exposure following single and repeated dosing.
The drug has an approximately 2-fold or lower accumulation on repeated dosing and a short elimination half-life of 5 to 6 hours.
Safety
“We have excellent tolerability,” Dr Ottmann said, with a small number of grade 3/4 adverse events (AEs).
Grade 3/4 AEs considered to be drug-related were mostly associated with hematologic suppression. Four patients (7%) had thrombocytopenia, 4 (7%) neutropenia, 3 (5%) anemia, 4 (7%) lipase increase, and 1 (2%) hypercholesterolemia.
AEs of all grades suspected of being related to the study drug and occurring in 5% or more of patients included thrombocytopenia (19%), neutropenia (15%), anemia (10%), nausea/vomiting/diarrhea (29%), arthralgia/myalgia (20%), rash (17%), fatigue (15%), lipase increase (14%), headache (14%), pruritus (10%), dry skin (7%), hypophosphatemia (7%), and acute pancreatitis (5%).
“The pancreatitis was reversible upon interruption or discontinuation of the drug,” Dr Ottmann explained.
There were 5 dose-limiting toxicities. Two patients had grade 3 lipase elevation in the 40 mg BID and 200 mg QD cohorts. One patient had grade 2 myalgia/arthralgia at 80 mg BID, 1 patient had a grade 3 acute coronary event at 150 mg BID, and 1 patient had a grade 3 bronchospasm at 200 mg BID.
No deaths occurred on the study, and the dose escalation is still ongoing.
Response
Twenty-nine patients with 3 months or more of follow-up were evaluable for response.
Twelve patients, who at baseline had hematologic relapse, achieved complete hematologic response within 2 months, and 8 who had cytogenetic relapse at baseline achieved a complete cytogenetic response within 3 to 6 months.
Of the 29 patients who had molecular relapse at baseline, 10 (34.5%) achieved a molecular response within 6 months, 7 (24.1%) had 1 log or more reduction in BCR-ABL1, 9 (31.0%) had less than a log reduction, and 3 (10.3%) had no reduction.
“The obvious question from the preclinical data,” Dr Ottmann said, “is do the mutations respond?”
And ABL001 has shown clinical activity across TKI-resistant mutations, such as V299L, F317L, and Y253H.
“So to conclude,” he said, “we have a new class, a new therapeutic category of drug, ABL001, which is quite well tolerated in extremely heavily treated patients with CML. We do consider this a promising approach.”
The trial was sponsored by Novartis.
*Data in the abstract differ from the presentation.
ASH Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—ABL001, an allosteric inhibitor of BCR-ABL1, has shown early evidence of single-agent activity in a multicenter, first-in-human, first-in-class trial of heavily treated patients with chronic myeloid leukemia (CML) that is resistant to or intolerant of prior tyrosine kinase inhibitors (TKIs), even at the lowest dose evaluated.
ABL001 and classical TKIs exhibit complementary mutation profiles, with ABL001 showing activity against TKI resistance mutations.
When combined with nilotinib in a mouse model of CML, ABL001 prevented the emergence of resistant disease even after treatment was discontinued.
“This produces a new therapeutic concept—that of allosteric inhibition,” said Oliver G. Ottmann, MD, of Cardiff University in the UK.
The ABL001 binding site is located in a region remote from the kinase domain and has the potential to combine with TKIs for greater pharmacologic control of BCR-ABL1.
“This obviously has the opportunity both for combining different treatments and for overcoming resistance to one or the other,” Dr Ottmann added.
Based on preliminary pharmacokinetic data and preclinical evidence, investigators proceeded to evaluate ABL001 in a phase 1 dose-escalation and dose-expansion study.
Their primary objective was to determine the maximum tolerated dose (MTD) in humans and the recommended dose for expansion (RDE). Secondary objectives were to evaluate the safety, tolerability, preliminary anti-CML activity, and pharmacokinetic and pharmacodynamic profile.
Dr Ottmann presented the findings during the 2015 ASH Annual Meeting as abstract 138.*
Study design
Patients received ABL001 orally as a single agent twice a day (BID) continuously until disease progression, unacceptable toxicity, consent withdrawal, or death.
The dose-escalation schema followed a Bayesian logistic regression model based on dose-limiting toxicities during cycle 1. Doses ranged from 10 mg to 200 mg BID.
A subsequent dose-expansion phase was planned to augment the data generated in the dose-escalation phase and to include patients with Ph-positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy.
Dr Ottmann noted that there were 2 protocol amendments. The first amendment was made to include a once-daily (QD) dosing of ABL001 at 120 mg and 200 mg. The second amendment was made to evaluate the combination of 40 mg of ABL001 BID with nilotinib at 300 mg BID.
Inclusion/exclusion criteria
Patients had to be at least 18 years old with CML in chronic or accelerated phase. They had to have failed at least 2 prior TKIs or be intolerant of TKIs. Their performance status had to be 0–2.
Patients were excluded from the trial if they had an absolute neutrophil count less than 500/mm3, a platelet count less than 50,000/mm3, bilirubin level more than 1.5 x the upper limit of normal (ULN) or more than 3.0 x ULN in patients with Gilberts syndrome.
Their aspartate aminotransferase or alanine aminotransferase could not be above 3 x ULN, and creatinine could not be above 1.5 x ULN.
Patients were also excluded if they needed treatment with strong inhibitors or inducers of CYP3A4 or its substrates with narrow therapeutic index.
Patient demographics
Fifty-nine patients were enrolled on the trial at the time of the presentation and they had “typical” characteristics of patients at this stage, Dr Ottmann said.
Their median age was 56 (range, 23–78). Almost two-thirds (61%) were male and 39% female.
All but 1 patient had an ECOG performance status of 0, and patients had a median of 3.5 (range, 2–5) prior lines of therapy. Twenty-four patients (41%) had 2 prior TKIs, and 35 (59%) had 3 or more TKIs. Forty-five patients (76%) were resistant and 14 (24%) were intolerant to their prior TKI.
All but 1 patient had chronic phase CML, 18 (31%) were TKD nonmutated, 14 (24%) were mutated, and 17 (46%) were not evaluable.
Patient disposition
Of the 43 patients in the monotherapy BID cohort, 1 was treated at the 10 mg dose level, 5 at the 20 mg level, 12 at the 40 mg level, 12 at the 80 mg level, 8 at the 150 mg level, and 5 at the 200 mg level. They had a median duration of drug exposure ranging from 25 weeks to 67 weeks.
Of the 11 patients in the monotherapy QD group, 5 were treated at the 120 mg dose level and 6 at the 200 mg level. Their drug exposure was a median of 26 weeks for those receiving 120 mg and 9.8 weeks for those receiving the 200 mg dose.
And the 5 patients in the ABL001-plus-nilotinib group had a median of 6.3 weeks of drug exposure.
“We had a remarkably low rate of discontinuation to date,” Dr Ottmann pointed out.
Ten patients discontinued therapy, all in the monotherapy BID group, 1 at 10 mg, 2 at 40 mg, 2 at 80 mg, 3 at 150 mg, and 2 at 200 mg.
Seven patients discontinued for adverse events. Two patients withdrew consent, and 1 patient in the 40 mg group had disease progression, which is “quite remarkable in a phase 1,” Dr Ottmann said.
Pharmacokinetic profile
ABL001 is rapidly absorbed in a median of 2 to 3 hours, and there is a dose-proportional increase in exposure following single and repeated dosing.
The drug has an approximately 2-fold or lower accumulation on repeated dosing and a short elimination half-life of 5 to 6 hours.
Safety
“We have excellent tolerability,” Dr Ottmann said, with a small number of grade 3/4 adverse events (AEs).
Grade 3/4 AEs considered to be drug-related were mostly associated with hematologic suppression. Four patients (7%) had thrombocytopenia, 4 (7%) neutropenia, 3 (5%) anemia, 4 (7%) lipase increase, and 1 (2%) hypercholesterolemia.
AEs of all grades suspected of being related to the study drug and occurring in 5% or more of patients included thrombocytopenia (19%), neutropenia (15%), anemia (10%), nausea/vomiting/diarrhea (29%), arthralgia/myalgia (20%), rash (17%), fatigue (15%), lipase increase (14%), headache (14%), pruritus (10%), dry skin (7%), hypophosphatemia (7%), and acute pancreatitis (5%).
“The pancreatitis was reversible upon interruption or discontinuation of the drug,” Dr Ottmann explained.
There were 5 dose-limiting toxicities. Two patients had grade 3 lipase elevation in the 40 mg BID and 200 mg QD cohorts. One patient had grade 2 myalgia/arthralgia at 80 mg BID, 1 patient had a grade 3 acute coronary event at 150 mg BID, and 1 patient had a grade 3 bronchospasm at 200 mg BID.
No deaths occurred on the study, and the dose escalation is still ongoing.
Response
Twenty-nine patients with 3 months or more of follow-up were evaluable for response.
Twelve patients, who at baseline had hematologic relapse, achieved complete hematologic response within 2 months, and 8 who had cytogenetic relapse at baseline achieved a complete cytogenetic response within 3 to 6 months.
Of the 29 patients who had molecular relapse at baseline, 10 (34.5%) achieved a molecular response within 6 months, 7 (24.1%) had 1 log or more reduction in BCR-ABL1, 9 (31.0%) had less than a log reduction, and 3 (10.3%) had no reduction.
“The obvious question from the preclinical data,” Dr Ottmann said, “is do the mutations respond?”
And ABL001 has shown clinical activity across TKI-resistant mutations, such as V299L, F317L, and Y253H.
“So to conclude,” he said, “we have a new class, a new therapeutic category of drug, ABL001, which is quite well tolerated in extremely heavily treated patients with CML. We do consider this a promising approach.”
The trial was sponsored by Novartis.
*Data in the abstract differ from the presentation.
CHMP recommends FVIII product for hemophilia A
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended BAY 81-8973, a recombinant factor VIII (FVIII) compound, for approval in the European Union.
BAY 81-8973 is an unmodified, full-length, recombinant FVIII compound intended for the treatment and prophylaxis of bleeding in hemophilia A patients of all ages.
The CHMP’s recommendation has been relayed to the European Commission, which is expected to make a decision regarding BAY 81-8973 in the coming weeks.
If approved, BAY 81-8973 will be marketed for the aforementioned indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.
The CHMP’s recommendation is based on results from the LEOPOLD trials, which were presented at the National Hemophilia Foundation’s 67th Annual Meeting last August.
LEOPOLD trials
The LEOPOLD Clinical Development Program consists of 3 multinational clinical trials designed to evaluate the pharmacokinetics, efficacy, and safety of BAY 81-8973 in subjects with severe hemophilia A (<1% FVIII:C).
LEOPOLD I is an open-label, cross-over, phase 3 study of males ages 12 to 65. The objectives were to demonstrate the efficacy and safety of BAY 81-8973 when used as prophylaxis, for the treatment of bleeding episodes, and for maintaining hemostasis during surgery. In LEOPOLD I, investigators assigned subjects to either the 2- or 3-times-weekly dosing regimens based on each patient’s phenotype, prior bleeding history and other factors.
LEOPOLD II is a randomized, cross-over, open-label trial conducted in male subjects ages 12 to 65. In this phase 3 study, 80 subjects were randomized to receive BAY 81-8973 either as a low-dose prophylaxis regimen (20-30 IU/kg; n=28) twice per week, high-dose prophylaxis (30-40 IU/kg; n=31) 3 times a week, or on-demand (n=21).
The primary objective was to demonstrate the superiority of prophylaxis over on-demand therapy, with the primary endpoint being bleeding frequency at 12 months.
LEOPOLD Kids is an open-label, non-randomized, phase 3 study. Part A is designed to evaluate the efficacy and safety of BAY 81-8973 for prophylaxis, treatment of bleeds, and surgical management in previously treated children at least 12 years of age with twice or 3 times per week or every other day prophylaxis regimens. Part B of the study, which involves previously untreated patients, is ongoing.
Bayer HealthCare AG has submitted marketing applications for BAY 81-8973 in the US and several other countries and is pursuing regulatory approvals worldwide.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended BAY 81-8973, a recombinant factor VIII (FVIII) compound, for approval in the European Union.
BAY 81-8973 is an unmodified, full-length, recombinant FVIII compound intended for the treatment and prophylaxis of bleeding in hemophilia A patients of all ages.
The CHMP’s recommendation has been relayed to the European Commission, which is expected to make a decision regarding BAY 81-8973 in the coming weeks.
If approved, BAY 81-8973 will be marketed for the aforementioned indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.
The CHMP’s recommendation is based on results from the LEOPOLD trials, which were presented at the National Hemophilia Foundation’s 67th Annual Meeting last August.
LEOPOLD trials
The LEOPOLD Clinical Development Program consists of 3 multinational clinical trials designed to evaluate the pharmacokinetics, efficacy, and safety of BAY 81-8973 in subjects with severe hemophilia A (<1% FVIII:C).
LEOPOLD I is an open-label, cross-over, phase 3 study of males ages 12 to 65. The objectives were to demonstrate the efficacy and safety of BAY 81-8973 when used as prophylaxis, for the treatment of bleeding episodes, and for maintaining hemostasis during surgery. In LEOPOLD I, investigators assigned subjects to either the 2- or 3-times-weekly dosing regimens based on each patient’s phenotype, prior bleeding history and other factors.
LEOPOLD II is a randomized, cross-over, open-label trial conducted in male subjects ages 12 to 65. In this phase 3 study, 80 subjects were randomized to receive BAY 81-8973 either as a low-dose prophylaxis regimen (20-30 IU/kg; n=28) twice per week, high-dose prophylaxis (30-40 IU/kg; n=31) 3 times a week, or on-demand (n=21).
The primary objective was to demonstrate the superiority of prophylaxis over on-demand therapy, with the primary endpoint being bleeding frequency at 12 months.
LEOPOLD Kids is an open-label, non-randomized, phase 3 study. Part A is designed to evaluate the efficacy and safety of BAY 81-8973 for prophylaxis, treatment of bleeds, and surgical management in previously treated children at least 12 years of age with twice or 3 times per week or every other day prophylaxis regimens. Part B of the study, which involves previously untreated patients, is ongoing.
Bayer HealthCare AG has submitted marketing applications for BAY 81-8973 in the US and several other countries and is pursuing regulatory approvals worldwide.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended BAY 81-8973, a recombinant factor VIII (FVIII) compound, for approval in the European Union.
BAY 81-8973 is an unmodified, full-length, recombinant FVIII compound intended for the treatment and prophylaxis of bleeding in hemophilia A patients of all ages.
The CHMP’s recommendation has been relayed to the European Commission, which is expected to make a decision regarding BAY 81-8973 in the coming weeks.
If approved, BAY 81-8973 will be marketed for the aforementioned indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.
The CHMP’s recommendation is based on results from the LEOPOLD trials, which were presented at the National Hemophilia Foundation’s 67th Annual Meeting last August.
LEOPOLD trials
The LEOPOLD Clinical Development Program consists of 3 multinational clinical trials designed to evaluate the pharmacokinetics, efficacy, and safety of BAY 81-8973 in subjects with severe hemophilia A (<1% FVIII:C).
LEOPOLD I is an open-label, cross-over, phase 3 study of males ages 12 to 65. The objectives were to demonstrate the efficacy and safety of BAY 81-8973 when used as prophylaxis, for the treatment of bleeding episodes, and for maintaining hemostasis during surgery. In LEOPOLD I, investigators assigned subjects to either the 2- or 3-times-weekly dosing regimens based on each patient’s phenotype, prior bleeding history and other factors.
LEOPOLD II is a randomized, cross-over, open-label trial conducted in male subjects ages 12 to 65. In this phase 3 study, 80 subjects were randomized to receive BAY 81-8973 either as a low-dose prophylaxis regimen (20-30 IU/kg; n=28) twice per week, high-dose prophylaxis (30-40 IU/kg; n=31) 3 times a week, or on-demand (n=21).
The primary objective was to demonstrate the superiority of prophylaxis over on-demand therapy, with the primary endpoint being bleeding frequency at 12 months.
LEOPOLD Kids is an open-label, non-randomized, phase 3 study. Part A is designed to evaluate the efficacy and safety of BAY 81-8973 for prophylaxis, treatment of bleeds, and surgical management in previously treated children at least 12 years of age with twice or 3 times per week or every other day prophylaxis regimens. Part B of the study, which involves previously untreated patients, is ongoing.
Bayer HealthCare AG has submitted marketing applications for BAY 81-8973 in the US and several other countries and is pursuing regulatory approvals worldwide.
A microfluidic biochip for blood cell counts
Researchers say they have created a biosensor capable of counting blood cells electrically using only a drop of blood.
The microfluidic device can measure red blood cell, platelet, and white blood cell counts using as little as 11 µL of blood.
The device electrically counts the different types of blood cells based on their size and membrane properties.
To count leukocyte and its differentials, red blood cells are selectively lysed, and the remaining white blood cells are individually counted. Specific cells like neutrophils can be counted using multi-frequency analysis, which probes the membrane properties of the cells.
For red blood cells and platelets, 1 µL of whole blood is diluted with PBS on-chip, and the cells are counted electrically. The total time for measurement is under 20 minutes.
The researchers described this device in TECHNOLOGY.
“Our biosensor exhibits the potential to improve patient care in a spectrum of settings,” said Rashid Bashir, PhD, of the University of Illinois at Urbana-Champaign.
He noted that the device could be particularly useful in resource-limited settings where laboratory tests are often inaccessible due to costs, poor prevalence of laboratory facilities, and the difficulty of follow-up upon receiving results that take days to process.
“There exists a huge potential to translate our biosensor commercially for blood cell count applications,” added Umer Hassan, PhD, of the University of Illinois at Urbana-Champaign.
“The translation of our technology will result in minimal to no experience requirement for device operation. Even patients can perform the test at the comfort of their home and share the results with their primary care physicians via electronic means too.”
“The technology is scalable, and, in future, we plan to apply it to many other potential applications in the areas of animal diagnostics, blood transfusion analysis, ER/ICU applications, and blood cell counting for chemotherapy management,” Dr Bashir said.
The researchers are now working to further develop a portable prototype of the cell counter.
“The cartridges will be disposable and the size of a credit card,” Dr Umer said. “The base unit or the reader will be portable and possibly hand-held. Our technology has the potential to reduce the cost of the test to less than $10, as compared to $100 or more currently charged.”
Researchers say they have created a biosensor capable of counting blood cells electrically using only a drop of blood.
The microfluidic device can measure red blood cell, platelet, and white blood cell counts using as little as 11 µL of blood.
The device electrically counts the different types of blood cells based on their size and membrane properties.
To count leukocyte and its differentials, red blood cells are selectively lysed, and the remaining white blood cells are individually counted. Specific cells like neutrophils can be counted using multi-frequency analysis, which probes the membrane properties of the cells.
For red blood cells and platelets, 1 µL of whole blood is diluted with PBS on-chip, and the cells are counted electrically. The total time for measurement is under 20 minutes.
The researchers described this device in TECHNOLOGY.
“Our biosensor exhibits the potential to improve patient care in a spectrum of settings,” said Rashid Bashir, PhD, of the University of Illinois at Urbana-Champaign.
He noted that the device could be particularly useful in resource-limited settings where laboratory tests are often inaccessible due to costs, poor prevalence of laboratory facilities, and the difficulty of follow-up upon receiving results that take days to process.
“There exists a huge potential to translate our biosensor commercially for blood cell count applications,” added Umer Hassan, PhD, of the University of Illinois at Urbana-Champaign.
“The translation of our technology will result in minimal to no experience requirement for device operation. Even patients can perform the test at the comfort of their home and share the results with their primary care physicians via electronic means too.”
“The technology is scalable, and, in future, we plan to apply it to many other potential applications in the areas of animal diagnostics, blood transfusion analysis, ER/ICU applications, and blood cell counting for chemotherapy management,” Dr Bashir said.
The researchers are now working to further develop a portable prototype of the cell counter.
“The cartridges will be disposable and the size of a credit card,” Dr Umer said. “The base unit or the reader will be portable and possibly hand-held. Our technology has the potential to reduce the cost of the test to less than $10, as compared to $100 or more currently charged.”
Researchers say they have created a biosensor capable of counting blood cells electrically using only a drop of blood.
The microfluidic device can measure red blood cell, platelet, and white blood cell counts using as little as 11 µL of blood.
The device electrically counts the different types of blood cells based on their size and membrane properties.
To count leukocyte and its differentials, red blood cells are selectively lysed, and the remaining white blood cells are individually counted. Specific cells like neutrophils can be counted using multi-frequency analysis, which probes the membrane properties of the cells.
For red blood cells and platelets, 1 µL of whole blood is diluted with PBS on-chip, and the cells are counted electrically. The total time for measurement is under 20 minutes.
The researchers described this device in TECHNOLOGY.
“Our biosensor exhibits the potential to improve patient care in a spectrum of settings,” said Rashid Bashir, PhD, of the University of Illinois at Urbana-Champaign.
He noted that the device could be particularly useful in resource-limited settings where laboratory tests are often inaccessible due to costs, poor prevalence of laboratory facilities, and the difficulty of follow-up upon receiving results that take days to process.
“There exists a huge potential to translate our biosensor commercially for blood cell count applications,” added Umer Hassan, PhD, of the University of Illinois at Urbana-Champaign.
“The translation of our technology will result in minimal to no experience requirement for device operation. Even patients can perform the test at the comfort of their home and share the results with their primary care physicians via electronic means too.”
“The technology is scalable, and, in future, we plan to apply it to many other potential applications in the areas of animal diagnostics, blood transfusion analysis, ER/ICU applications, and blood cell counting for chemotherapy management,” Dr Bashir said.
The researchers are now working to further develop a portable prototype of the cell counter.
“The cartridges will be disposable and the size of a credit card,” Dr Umer said. “The base unit or the reader will be portable and possibly hand-held. Our technology has the potential to reduce the cost of the test to less than $10, as compared to $100 or more currently charged.”
Myeloma drug could treat sickle cell disease, team says
and a normal one
Image by Betty Pace
Preclinical research suggests a drug used to treat multiple myeloma (MM) might also prove effective in the treatment of sickle cell disease (SCD).
Researchers say this study is the first to reveal how the drug, pomalidomide, increases the production of fetal hemoglobin, which is known to interfere with the sickling of red blood cells.
“We knew the drug would make fetal hemoglobin, but we didn’t know to what extent or how,” said Lionel Blanc, PhD, of the Feinstein Institute for Medical Research in Manhasset, New York.
He and his colleagues reported their findings in Blood.
The researchers’ in vitro experiments revealed that pomalidomide reverses γ-globin silencing during adult erythropoiesis, and the drug delays the maturation of early erythroid precursors without impairing terminal differentiation.
The team also found that pomalidomide selectively targets BCL11A and SOX6 to induce γ-globin synthesis, the drug’s mechanism of action during erythropoiesis is independent of IKZF1 degradation, and pomalidomide partially reprograms adult erythroid progenitors to a fetal-like state.
Finally, the researchers discovered that pomalidomide’s mechanism of action is conserved in cells from SCD patients, and treatment with pomalidomide leads to γ-globin production in MM patients.
“We can also say something else—that hydroxyurea, the only FDA-approved drug for sickle cell anemia, was less effective than pomalidomide and appeared to act through a different mechanism of action,” Dr Blanc said.
“The current therapy is good, but not everyone responds equally to hydroxyurea, and what we hope with pomalidomide is to improve this.”
Dr Blanc and his colleagues plan to launch a clinical trial in the near future to test pomalidomide in young adults with SCD.
and a normal one
Image by Betty Pace
Preclinical research suggests a drug used to treat multiple myeloma (MM) might also prove effective in the treatment of sickle cell disease (SCD).
Researchers say this study is the first to reveal how the drug, pomalidomide, increases the production of fetal hemoglobin, which is known to interfere with the sickling of red blood cells.
“We knew the drug would make fetal hemoglobin, but we didn’t know to what extent or how,” said Lionel Blanc, PhD, of the Feinstein Institute for Medical Research in Manhasset, New York.
He and his colleagues reported their findings in Blood.
The researchers’ in vitro experiments revealed that pomalidomide reverses γ-globin silencing during adult erythropoiesis, and the drug delays the maturation of early erythroid precursors without impairing terminal differentiation.
The team also found that pomalidomide selectively targets BCL11A and SOX6 to induce γ-globin synthesis, the drug’s mechanism of action during erythropoiesis is independent of IKZF1 degradation, and pomalidomide partially reprograms adult erythroid progenitors to a fetal-like state.
Finally, the researchers discovered that pomalidomide’s mechanism of action is conserved in cells from SCD patients, and treatment with pomalidomide leads to γ-globin production in MM patients.
“We can also say something else—that hydroxyurea, the only FDA-approved drug for sickle cell anemia, was less effective than pomalidomide and appeared to act through a different mechanism of action,” Dr Blanc said.
“The current therapy is good, but not everyone responds equally to hydroxyurea, and what we hope with pomalidomide is to improve this.”
Dr Blanc and his colleagues plan to launch a clinical trial in the near future to test pomalidomide in young adults with SCD.
and a normal one
Image by Betty Pace
Preclinical research suggests a drug used to treat multiple myeloma (MM) might also prove effective in the treatment of sickle cell disease (SCD).
Researchers say this study is the first to reveal how the drug, pomalidomide, increases the production of fetal hemoglobin, which is known to interfere with the sickling of red blood cells.
“We knew the drug would make fetal hemoglobin, but we didn’t know to what extent or how,” said Lionel Blanc, PhD, of the Feinstein Institute for Medical Research in Manhasset, New York.
He and his colleagues reported their findings in Blood.
The researchers’ in vitro experiments revealed that pomalidomide reverses γ-globin silencing during adult erythropoiesis, and the drug delays the maturation of early erythroid precursors without impairing terminal differentiation.
The team also found that pomalidomide selectively targets BCL11A and SOX6 to induce γ-globin synthesis, the drug’s mechanism of action during erythropoiesis is independent of IKZF1 degradation, and pomalidomide partially reprograms adult erythroid progenitors to a fetal-like state.
Finally, the researchers discovered that pomalidomide’s mechanism of action is conserved in cells from SCD patients, and treatment with pomalidomide leads to γ-globin production in MM patients.
“We can also say something else—that hydroxyurea, the only FDA-approved drug for sickle cell anemia, was less effective than pomalidomide and appeared to act through a different mechanism of action,” Dr Blanc said.
“The current therapy is good, but not everyone responds equally to hydroxyurea, and what we hope with pomalidomide is to improve this.”
Dr Blanc and his colleagues plan to launch a clinical trial in the near future to test pomalidomide in young adults with SCD.
Osteoarticular pain affects CML patients stopping TKI
Photo courtesy of ASH
ORLANDO, FL—Cases of musculoskeletal pain have been reported after patients stop taking tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML).
TKI discontinuation trials—notably, the STOP imatinib (STIM) trials and EURO-SKI trial—have been conducted to assess the feasibility of maintaining molecular remission once patients discontinue a TKI.
However, none of the studies collected low-grade events before or after patients discontinued TKI therapy.
So investigators collected data from the STIM2 study and EUROSKI trial and recorded all events from the time of TKI discontinuation.
They discovered that about 23% of patients who stopped TKI therapy experienced a withdrawal syndrome (WS) consisting largely of musculoskeletal pain, regardless of the TKI they were taking.
Philippe Rousselot, MD, PhD, of University of Versailles St-Quentin-en-Yvelines, Versailles, France, discussed this finding at the 2015 ASH Annual Meeting as abstract 137.*
Dr Rousselot noted that investigators first reported the TKI WS in 2014 in CML patients enrolled on the EURO-SKI trial who were discontinuing imatinib (Richter et al, JCO 2014).
A team of French investigators undertook the current observational study to estimate the prevalence of the WS and to identify clinical factors associated with it.
They collected, prospectively, the adverse events from all 428 French patients who were enrolled in the STIM2 (n=204) and EURO-SKI (n=224) trials. And they compared patients who stopped taking TKIs and had a painful WS to those who stopped TKIs and did not have a painful syndrome.
Patient characteristics
Patient characteristics were well balanced between the STIM2 and EURO-SKI groups, with the exception of the median time on TKI before discontinuation. In the STIM2 group, patients were a median of 77.4 months on TKI therapy. In the EURO-SKI group, the median time on a TKI was 100.4 months (P<0.001).
In all, there were 208 male and 220 female patients included. They were a median age of 64 (range, 53–73) and 63 (range, 53–70) years in the STIM2 and EURO-SKI groups, respectively.
Sokal scores were also comparable between the cohorts, with most patients falling in the low and intermediate ranges.
Prevalence and characteristics of WS
Overall, 326 patients (76.2%) were without WS and 102 (23.8%) had WS. In the STIM2 cohort, 193 patients (86.2%) were without WS and 31 (13.8%) had WS. In the EURO-SKI cohort, 133 patients (65.2%) were without WS and 71 (34.8%) had WS.
“And these differences [between cohorts] are significant,” Dr Rousselot pointed out.
Investigators analyzed clinical characteristics of WS in 40 patients and determined that the median time from TKI discontinuation to WS was 21 days, and the median duration of WS was 7 months (range, 3–30).
Pain was located in the shoulder and spine for 67% of the patients and elsewhere in 33%. About two-thirds of patients (62.5%) experienced grade 1–2 pain, and 37.5% experienced grade 3–4 pain.
Nineteen patients resumed TKI therapy, “because of loss of MMR [major molecular response] or loss of clinical response,” Dr Rousselot said.
And the pain disappeared in 52.6% of them when they resumed TKI therapy. The median duration of TKI therapy before WS pain disappeared was 3 weeks.
Risk factors for WS
Investigators determined that CML duration, time on a TKI, and previous history of osteoarticular symptoms were risk factors for WS.
Patients without WS had CML for a shorter time—a mean of 8.7 ± 3.1 months, compared to 9.7 ± 3.8 for those with WS (P=0.02).
Patients without WS were also on a TKI for a shorter time—a median of 81.2 months (range, 61.2–108.0), compared to 97.3 months (range, 73.7–122.9) for those with WS (P<0.001).
Patients with a previous history of osteoarticular symptoms were more likely to experience WS—22.9%, compared to 9.8% without a previous history (P=0.002).
Most patients were receiving imatinib—323 without WS and 100 with WS. The 1 patient receiving dasatinib had no WS. And of the 4 patients receiving nilotinib, 2 had WS and 2 didn’t.
And so the type of TKI therapy—dasatinib, imatinib, or nilotinib—was not significant (P=0.42).
Investigators performed a multivariate analysis adjusted for gender, CML duration, and Sokal score, and 2 risk factors emerged: previous history of osteoarticular symptoms (relative risk: 2.08) and time on TKI (relative risk: 2.23).
Discussion
Dr Rousselot compared the Richter trial (Richter et al, JCO 2014) to the current study and noted that the Richter trial, with an enrollment of 50 patients, had a WS prevalence of 30%. But the current trial had a prevalence of 24%.
The difference in WS may be due to time on TKI, Dr Rousselot said, as patients in the Richter trial were on TKI treatment for a longer period of time.
“The time of onset is the same [in both trials],” Dr Rousselot said, as are the TKI used, location of pain, and duration of pain.
“So what we can say is [with] shorter TKI treatment . . . , we have a higher risk of molecular relapse but a lower risk of withdrawal syndrome.”
And with longer TKI treatment, the converse appears to be true. It reduces the risk of molecular relapse but raises the risk of withdrawal syndrome.
*Data in the abstract differ from the presentation.
Photo courtesy of ASH
ORLANDO, FL—Cases of musculoskeletal pain have been reported after patients stop taking tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML).
TKI discontinuation trials—notably, the STOP imatinib (STIM) trials and EURO-SKI trial—have been conducted to assess the feasibility of maintaining molecular remission once patients discontinue a TKI.
However, none of the studies collected low-grade events before or after patients discontinued TKI therapy.
So investigators collected data from the STIM2 study and EUROSKI trial and recorded all events from the time of TKI discontinuation.
They discovered that about 23% of patients who stopped TKI therapy experienced a withdrawal syndrome (WS) consisting largely of musculoskeletal pain, regardless of the TKI they were taking.
Philippe Rousselot, MD, PhD, of University of Versailles St-Quentin-en-Yvelines, Versailles, France, discussed this finding at the 2015 ASH Annual Meeting as abstract 137.*
Dr Rousselot noted that investigators first reported the TKI WS in 2014 in CML patients enrolled on the EURO-SKI trial who were discontinuing imatinib (Richter et al, JCO 2014).
A team of French investigators undertook the current observational study to estimate the prevalence of the WS and to identify clinical factors associated with it.
They collected, prospectively, the adverse events from all 428 French patients who were enrolled in the STIM2 (n=204) and EURO-SKI (n=224) trials. And they compared patients who stopped taking TKIs and had a painful WS to those who stopped TKIs and did not have a painful syndrome.
Patient characteristics
Patient characteristics were well balanced between the STIM2 and EURO-SKI groups, with the exception of the median time on TKI before discontinuation. In the STIM2 group, patients were a median of 77.4 months on TKI therapy. In the EURO-SKI group, the median time on a TKI was 100.4 months (P<0.001).
In all, there were 208 male and 220 female patients included. They were a median age of 64 (range, 53–73) and 63 (range, 53–70) years in the STIM2 and EURO-SKI groups, respectively.
Sokal scores were also comparable between the cohorts, with most patients falling in the low and intermediate ranges.
Prevalence and characteristics of WS
Overall, 326 patients (76.2%) were without WS and 102 (23.8%) had WS. In the STIM2 cohort, 193 patients (86.2%) were without WS and 31 (13.8%) had WS. In the EURO-SKI cohort, 133 patients (65.2%) were without WS and 71 (34.8%) had WS.
“And these differences [between cohorts] are significant,” Dr Rousselot pointed out.
Investigators analyzed clinical characteristics of WS in 40 patients and determined that the median time from TKI discontinuation to WS was 21 days, and the median duration of WS was 7 months (range, 3–30).
Pain was located in the shoulder and spine for 67% of the patients and elsewhere in 33%. About two-thirds of patients (62.5%) experienced grade 1–2 pain, and 37.5% experienced grade 3–4 pain.
Nineteen patients resumed TKI therapy, “because of loss of MMR [major molecular response] or loss of clinical response,” Dr Rousselot said.
And the pain disappeared in 52.6% of them when they resumed TKI therapy. The median duration of TKI therapy before WS pain disappeared was 3 weeks.
Risk factors for WS
Investigators determined that CML duration, time on a TKI, and previous history of osteoarticular symptoms were risk factors for WS.
Patients without WS had CML for a shorter time—a mean of 8.7 ± 3.1 months, compared to 9.7 ± 3.8 for those with WS (P=0.02).
Patients without WS were also on a TKI for a shorter time—a median of 81.2 months (range, 61.2–108.0), compared to 97.3 months (range, 73.7–122.9) for those with WS (P<0.001).
Patients with a previous history of osteoarticular symptoms were more likely to experience WS—22.9%, compared to 9.8% without a previous history (P=0.002).
Most patients were receiving imatinib—323 without WS and 100 with WS. The 1 patient receiving dasatinib had no WS. And of the 4 patients receiving nilotinib, 2 had WS and 2 didn’t.
And so the type of TKI therapy—dasatinib, imatinib, or nilotinib—was not significant (P=0.42).
Investigators performed a multivariate analysis adjusted for gender, CML duration, and Sokal score, and 2 risk factors emerged: previous history of osteoarticular symptoms (relative risk: 2.08) and time on TKI (relative risk: 2.23).
Discussion
Dr Rousselot compared the Richter trial (Richter et al, JCO 2014) to the current study and noted that the Richter trial, with an enrollment of 50 patients, had a WS prevalence of 30%. But the current trial had a prevalence of 24%.
The difference in WS may be due to time on TKI, Dr Rousselot said, as patients in the Richter trial were on TKI treatment for a longer period of time.
“The time of onset is the same [in both trials],” Dr Rousselot said, as are the TKI used, location of pain, and duration of pain.
“So what we can say is [with] shorter TKI treatment . . . , we have a higher risk of molecular relapse but a lower risk of withdrawal syndrome.”
And with longer TKI treatment, the converse appears to be true. It reduces the risk of molecular relapse but raises the risk of withdrawal syndrome.
*Data in the abstract differ from the presentation.
Photo courtesy of ASH
ORLANDO, FL—Cases of musculoskeletal pain have been reported after patients stop taking tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML).
TKI discontinuation trials—notably, the STOP imatinib (STIM) trials and EURO-SKI trial—have been conducted to assess the feasibility of maintaining molecular remission once patients discontinue a TKI.
However, none of the studies collected low-grade events before or after patients discontinued TKI therapy.
So investigators collected data from the STIM2 study and EUROSKI trial and recorded all events from the time of TKI discontinuation.
They discovered that about 23% of patients who stopped TKI therapy experienced a withdrawal syndrome (WS) consisting largely of musculoskeletal pain, regardless of the TKI they were taking.
Philippe Rousselot, MD, PhD, of University of Versailles St-Quentin-en-Yvelines, Versailles, France, discussed this finding at the 2015 ASH Annual Meeting as abstract 137.*
Dr Rousselot noted that investigators first reported the TKI WS in 2014 in CML patients enrolled on the EURO-SKI trial who were discontinuing imatinib (Richter et al, JCO 2014).
A team of French investigators undertook the current observational study to estimate the prevalence of the WS and to identify clinical factors associated with it.
They collected, prospectively, the adverse events from all 428 French patients who were enrolled in the STIM2 (n=204) and EURO-SKI (n=224) trials. And they compared patients who stopped taking TKIs and had a painful WS to those who stopped TKIs and did not have a painful syndrome.
Patient characteristics
Patient characteristics were well balanced between the STIM2 and EURO-SKI groups, with the exception of the median time on TKI before discontinuation. In the STIM2 group, patients were a median of 77.4 months on TKI therapy. In the EURO-SKI group, the median time on a TKI was 100.4 months (P<0.001).
In all, there were 208 male and 220 female patients included. They were a median age of 64 (range, 53–73) and 63 (range, 53–70) years in the STIM2 and EURO-SKI groups, respectively.
Sokal scores were also comparable between the cohorts, with most patients falling in the low and intermediate ranges.
Prevalence and characteristics of WS
Overall, 326 patients (76.2%) were without WS and 102 (23.8%) had WS. In the STIM2 cohort, 193 patients (86.2%) were without WS and 31 (13.8%) had WS. In the EURO-SKI cohort, 133 patients (65.2%) were without WS and 71 (34.8%) had WS.
“And these differences [between cohorts] are significant,” Dr Rousselot pointed out.
Investigators analyzed clinical characteristics of WS in 40 patients and determined that the median time from TKI discontinuation to WS was 21 days, and the median duration of WS was 7 months (range, 3–30).
Pain was located in the shoulder and spine for 67% of the patients and elsewhere in 33%. About two-thirds of patients (62.5%) experienced grade 1–2 pain, and 37.5% experienced grade 3–4 pain.
Nineteen patients resumed TKI therapy, “because of loss of MMR [major molecular response] or loss of clinical response,” Dr Rousselot said.
And the pain disappeared in 52.6% of them when they resumed TKI therapy. The median duration of TKI therapy before WS pain disappeared was 3 weeks.
Risk factors for WS
Investigators determined that CML duration, time on a TKI, and previous history of osteoarticular symptoms were risk factors for WS.
Patients without WS had CML for a shorter time—a mean of 8.7 ± 3.1 months, compared to 9.7 ± 3.8 for those with WS (P=0.02).
Patients without WS were also on a TKI for a shorter time—a median of 81.2 months (range, 61.2–108.0), compared to 97.3 months (range, 73.7–122.9) for those with WS (P<0.001).
Patients with a previous history of osteoarticular symptoms were more likely to experience WS—22.9%, compared to 9.8% without a previous history (P=0.002).
Most patients were receiving imatinib—323 without WS and 100 with WS. The 1 patient receiving dasatinib had no WS. And of the 4 patients receiving nilotinib, 2 had WS and 2 didn’t.
And so the type of TKI therapy—dasatinib, imatinib, or nilotinib—was not significant (P=0.42).
Investigators performed a multivariate analysis adjusted for gender, CML duration, and Sokal score, and 2 risk factors emerged: previous history of osteoarticular symptoms (relative risk: 2.08) and time on TKI (relative risk: 2.23).
Discussion
Dr Rousselot compared the Richter trial (Richter et al, JCO 2014) to the current study and noted that the Richter trial, with an enrollment of 50 patients, had a WS prevalence of 30%. But the current trial had a prevalence of 24%.
The difference in WS may be due to time on TKI, Dr Rousselot said, as patients in the Richter trial were on TKI treatment for a longer period of time.
“The time of onset is the same [in both trials],” Dr Rousselot said, as are the TKI used, location of pain, and duration of pain.
“So what we can say is [with] shorter TKI treatment . . . , we have a higher risk of molecular relapse but a lower risk of withdrawal syndrome.”
And with longer TKI treatment, the converse appears to be true. It reduces the risk of molecular relapse but raises the risk of withdrawal syndrome.
*Data in the abstract differ from the presentation.
Fear really does curdle blood, study suggests
Photo by Graham Colm
Horror movies may actually be “blood-curdling,” according to a study published in The BMJ.
The research showed that watching a scary movie was associated with an increase in the clotting protein factor VIII (FVIII).
Study subjects were more likely to experience an increase in FVIII while watching a horror film than an educational film.
So using the term “blood-curdling” to describe feeling extreme fear may be justified, researchers said.
The term dates back to medieval times and is based on the concept that fear would “run the blood cold” or “curdle” the blood, but the validity of this theory has never been studied.
So Banne Nemeth, MD, of Leiden University Medical Centre in The Netherlands, and his colleagues set out to assess whether acute fear can curdle blood.
Their study involved 24 healthy volunteers age 30 or younger. Fourteen subjects were assigned to watch a frightening movie followed by a non-threatening educational movie, and 10 were assigned to watch the movies in reverse order.
The movies were viewed more than a week apart at the same time of day and in a comfortable and relaxed environment. Both lasted approximately 90 minutes.
Before and after each movie (within 15 minutes), blood samples were taken and analyzed for markers of clotting activity.
After each movie, participants rated the fear they experienced using a visual analogue fear scale ranging from 0 (no fear at all) to 10 (worst fear imaginable). They also reported whether they had already seen the movie and completed a general questionnaire on lifestyle and favorite movie genre.
The horror movie was perceived to be more frightening than the educational movie, with a 5.4 mean difference in fear rating scores.
The difference in FVIII levels before and after watching the movies was higher for the horror movie than for the educational movie. The mean difference of differences was 11.1 IU/dL (95% confidence interval: 1.2 to 21.0 IU/dL).
FVIII levels increased in 12 (57%) subjects during the horror movie and in 3 (14%) during the educational movie. FVIII levels decreased in 18 (86%) participants during the educational movie and in 9 (43%) during the horror movie.
However, the researchers found no effect of either movie on thrombin-antithrombin complexes, D-dimer, or prothrombin fragments 1+2. They said this suggests that although acute fear may trigger coagulation, it does not lead to actual clot formation.
The team pointed out some study limitations but concluded that, in young and healthy adults, “watching blood-curdling movies is associated with an increase in blood coagulant factor VIII without actual thrombin formation.”
The researchers believe this phenomenon may confer an important evolutionary benefit by preparing the body for blood loss during life-threatening situations.
Photo by Graham Colm
Horror movies may actually be “blood-curdling,” according to a study published in The BMJ.
The research showed that watching a scary movie was associated with an increase in the clotting protein factor VIII (FVIII).
Study subjects were more likely to experience an increase in FVIII while watching a horror film than an educational film.
So using the term “blood-curdling” to describe feeling extreme fear may be justified, researchers said.
The term dates back to medieval times and is based on the concept that fear would “run the blood cold” or “curdle” the blood, but the validity of this theory has never been studied.
So Banne Nemeth, MD, of Leiden University Medical Centre in The Netherlands, and his colleagues set out to assess whether acute fear can curdle blood.
Their study involved 24 healthy volunteers age 30 or younger. Fourteen subjects were assigned to watch a frightening movie followed by a non-threatening educational movie, and 10 were assigned to watch the movies in reverse order.
The movies were viewed more than a week apart at the same time of day and in a comfortable and relaxed environment. Both lasted approximately 90 minutes.
Before and after each movie (within 15 minutes), blood samples were taken and analyzed for markers of clotting activity.
After each movie, participants rated the fear they experienced using a visual analogue fear scale ranging from 0 (no fear at all) to 10 (worst fear imaginable). They also reported whether they had already seen the movie and completed a general questionnaire on lifestyle and favorite movie genre.
The horror movie was perceived to be more frightening than the educational movie, with a 5.4 mean difference in fear rating scores.
The difference in FVIII levels before and after watching the movies was higher for the horror movie than for the educational movie. The mean difference of differences was 11.1 IU/dL (95% confidence interval: 1.2 to 21.0 IU/dL).
FVIII levels increased in 12 (57%) subjects during the horror movie and in 3 (14%) during the educational movie. FVIII levels decreased in 18 (86%) participants during the educational movie and in 9 (43%) during the horror movie.
However, the researchers found no effect of either movie on thrombin-antithrombin complexes, D-dimer, or prothrombin fragments 1+2. They said this suggests that although acute fear may trigger coagulation, it does not lead to actual clot formation.
The team pointed out some study limitations but concluded that, in young and healthy adults, “watching blood-curdling movies is associated with an increase in blood coagulant factor VIII without actual thrombin formation.”
The researchers believe this phenomenon may confer an important evolutionary benefit by preparing the body for blood loss during life-threatening situations.
Photo by Graham Colm
Horror movies may actually be “blood-curdling,” according to a study published in The BMJ.
The research showed that watching a scary movie was associated with an increase in the clotting protein factor VIII (FVIII).
Study subjects were more likely to experience an increase in FVIII while watching a horror film than an educational film.
So using the term “blood-curdling” to describe feeling extreme fear may be justified, researchers said.
The term dates back to medieval times and is based on the concept that fear would “run the blood cold” or “curdle” the blood, but the validity of this theory has never been studied.
So Banne Nemeth, MD, of Leiden University Medical Centre in The Netherlands, and his colleagues set out to assess whether acute fear can curdle blood.
Their study involved 24 healthy volunteers age 30 or younger. Fourteen subjects were assigned to watch a frightening movie followed by a non-threatening educational movie, and 10 were assigned to watch the movies in reverse order.
The movies were viewed more than a week apart at the same time of day and in a comfortable and relaxed environment. Both lasted approximately 90 minutes.
Before and after each movie (within 15 minutes), blood samples were taken and analyzed for markers of clotting activity.
After each movie, participants rated the fear they experienced using a visual analogue fear scale ranging from 0 (no fear at all) to 10 (worst fear imaginable). They also reported whether they had already seen the movie and completed a general questionnaire on lifestyle and favorite movie genre.
The horror movie was perceived to be more frightening than the educational movie, with a 5.4 mean difference in fear rating scores.
The difference in FVIII levels before and after watching the movies was higher for the horror movie than for the educational movie. The mean difference of differences was 11.1 IU/dL (95% confidence interval: 1.2 to 21.0 IU/dL).
FVIII levels increased in 12 (57%) subjects during the horror movie and in 3 (14%) during the educational movie. FVIII levels decreased in 18 (86%) participants during the educational movie and in 9 (43%) during the horror movie.
However, the researchers found no effect of either movie on thrombin-antithrombin complexes, D-dimer, or prothrombin fragments 1+2. They said this suggests that although acute fear may trigger coagulation, it does not lead to actual clot formation.
The team pointed out some study limitations but concluded that, in young and healthy adults, “watching blood-curdling movies is associated with an increase in blood coagulant factor VIII without actual thrombin formation.”
The researchers believe this phenomenon may confer an important evolutionary benefit by preparing the body for blood loss during life-threatening situations.
A potential target for IDH1-mutant cancers
acute myeloid leukemia
Researchers say they have identified a potential therapeutic target for IDH1-mutant malignancies.
Preclinical experiments showed that tumors characterized by IDH1 mutations are “extremely vulnerable” to depletion of NAD+, a metabolic cofactor.
“Our finding . . . supports the proposal that medications that can decrease levels of this metabolite, which are in development, have the potential to specifically treat these cancers,” said Daniel Cahill, MD, PhD, of Massachusetts General Hospital in Boston.
Dr Cahill and his colleagues described their research in Cancer Cell.
IDH1 and IDH2 are known to play essential roles in cellular metabolism, including the processes by which cells convert glucose and other nutrients into ATP, providing the energy needed for cellular survival.
In 2008, researchers discovered that IDH1 mutations are involved in several cancers. The gene is mutated in around 20% of adult gliomas, in more than 10% of acute myeloid leukemias, and in a smaller percentage of other cancers.
One clear result of IDH1 mutation is a 100-fold elevation in levels of the metabolite 2-HG, which is known to mediate several properties that lead to tumor development. Drugs that decrease levels of 2-HG are currently under development.
Dr Cahill and his colleagues wanted to find additional ways of blocking the mutation’s effects, so they inhibited mutant IDH1 in tumor cells. They were surprised to find that this reduced 2-HG levels, but, in many cases, that reduction did not halt cell growth.
Detailed metabolic profiling of IDH1-mutant cells revealed that inhibiting the mutated enzyme greatly increased levels of NAD+, a cofactor that plays a role in several cellular energy processes.
Additional experiments showed that depletion of NAD+ induced the death of IDH1-mutant tumor cells and inhibited tumor growth in an animal model of glioma.
“Accumulation of excess 2-HG is known to drive several changes leading to tumor development, but our results indicate that simply depleting 2-HG levels was not sufficient to halt the growth of several types of later-stage IDH1-mutant tumors,” said Hiroaki Wakimoto, MD, PhD, of Massachusetts General Hospital.
“In addition, we found that mutant IDH1 reduces expression of an enzyme that maintains NAD+ levels, rendering IDH1-mutant tumor cells highly sensitive to direct NAD+ depletion. Several drugs that inhibit the synthesis of NAD+ are already in clinical trials, and these agents may prove useful for patients with IDH-mutant cancers. While we primarily focused on IDH1-mutant gliomas, we also found evidence that NAD+ inhibition could slow the growth of other types of cancer with this mutation.”
acute myeloid leukemia
Researchers say they have identified a potential therapeutic target for IDH1-mutant malignancies.
Preclinical experiments showed that tumors characterized by IDH1 mutations are “extremely vulnerable” to depletion of NAD+, a metabolic cofactor.
“Our finding . . . supports the proposal that medications that can decrease levels of this metabolite, which are in development, have the potential to specifically treat these cancers,” said Daniel Cahill, MD, PhD, of Massachusetts General Hospital in Boston.
Dr Cahill and his colleagues described their research in Cancer Cell.
IDH1 and IDH2 are known to play essential roles in cellular metabolism, including the processes by which cells convert glucose and other nutrients into ATP, providing the energy needed for cellular survival.
In 2008, researchers discovered that IDH1 mutations are involved in several cancers. The gene is mutated in around 20% of adult gliomas, in more than 10% of acute myeloid leukemias, and in a smaller percentage of other cancers.
One clear result of IDH1 mutation is a 100-fold elevation in levels of the metabolite 2-HG, which is known to mediate several properties that lead to tumor development. Drugs that decrease levels of 2-HG are currently under development.
Dr Cahill and his colleagues wanted to find additional ways of blocking the mutation’s effects, so they inhibited mutant IDH1 in tumor cells. They were surprised to find that this reduced 2-HG levels, but, in many cases, that reduction did not halt cell growth.
Detailed metabolic profiling of IDH1-mutant cells revealed that inhibiting the mutated enzyme greatly increased levels of NAD+, a cofactor that plays a role in several cellular energy processes.
Additional experiments showed that depletion of NAD+ induced the death of IDH1-mutant tumor cells and inhibited tumor growth in an animal model of glioma.
“Accumulation of excess 2-HG is known to drive several changes leading to tumor development, but our results indicate that simply depleting 2-HG levels was not sufficient to halt the growth of several types of later-stage IDH1-mutant tumors,” said Hiroaki Wakimoto, MD, PhD, of Massachusetts General Hospital.
“In addition, we found that mutant IDH1 reduces expression of an enzyme that maintains NAD+ levels, rendering IDH1-mutant tumor cells highly sensitive to direct NAD+ depletion. Several drugs that inhibit the synthesis of NAD+ are already in clinical trials, and these agents may prove useful for patients with IDH-mutant cancers. While we primarily focused on IDH1-mutant gliomas, we also found evidence that NAD+ inhibition could slow the growth of other types of cancer with this mutation.”
acute myeloid leukemia
Researchers say they have identified a potential therapeutic target for IDH1-mutant malignancies.
Preclinical experiments showed that tumors characterized by IDH1 mutations are “extremely vulnerable” to depletion of NAD+, a metabolic cofactor.
“Our finding . . . supports the proposal that medications that can decrease levels of this metabolite, which are in development, have the potential to specifically treat these cancers,” said Daniel Cahill, MD, PhD, of Massachusetts General Hospital in Boston.
Dr Cahill and his colleagues described their research in Cancer Cell.
IDH1 and IDH2 are known to play essential roles in cellular metabolism, including the processes by which cells convert glucose and other nutrients into ATP, providing the energy needed for cellular survival.
In 2008, researchers discovered that IDH1 mutations are involved in several cancers. The gene is mutated in around 20% of adult gliomas, in more than 10% of acute myeloid leukemias, and in a smaller percentage of other cancers.
One clear result of IDH1 mutation is a 100-fold elevation in levels of the metabolite 2-HG, which is known to mediate several properties that lead to tumor development. Drugs that decrease levels of 2-HG are currently under development.
Dr Cahill and his colleagues wanted to find additional ways of blocking the mutation’s effects, so they inhibited mutant IDH1 in tumor cells. They were surprised to find that this reduced 2-HG levels, but, in many cases, that reduction did not halt cell growth.
Detailed metabolic profiling of IDH1-mutant cells revealed that inhibiting the mutated enzyme greatly increased levels of NAD+, a cofactor that plays a role in several cellular energy processes.
Additional experiments showed that depletion of NAD+ induced the death of IDH1-mutant tumor cells and inhibited tumor growth in an animal model of glioma.
“Accumulation of excess 2-HG is known to drive several changes leading to tumor development, but our results indicate that simply depleting 2-HG levels was not sufficient to halt the growth of several types of later-stage IDH1-mutant tumors,” said Hiroaki Wakimoto, MD, PhD, of Massachusetts General Hospital.
“In addition, we found that mutant IDH1 reduces expression of an enzyme that maintains NAD+ levels, rendering IDH1-mutant tumor cells highly sensitive to direct NAD+ depletion. Several drugs that inhibit the synthesis of NAD+ are already in clinical trials, and these agents may prove useful for patients with IDH-mutant cancers. While we primarily focused on IDH1-mutant gliomas, we also found evidence that NAD+ inhibition could slow the growth of other types of cancer with this mutation.”