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NICE recommends eculizumab for aHUS despite cost
Credit: Globovision
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending eculizumab (Soliris) to treat atypical hemolytic uremic syndrome (aHUS), despite the drug’s high cost.
NICE estimates that eculizumab will cost the National Health Service (NHS) up to £58 million in the first year, rising to £82 million after 5 years.
The drug is currently funded by NHS England through interim specialized commissioning arrangements.
Eculizumab is ‘breakthrough’ for aHUS
aHUS is an extremely rare but life-threatening disease that causes inflammation of blood vessels and the formation of blood clots throughout the body. Patients with aHUS are at constant risk of sudden and progressive damage to, and failure of, vital organs.
Roughly 10% to 15% of patients die in the initial, acute phase of aHUS. The majority of patients—up to 70%—develop end-stage kidney failure requiring dialysis. And 1 in 5 patients has aHUS affecting organs other than the kidneys, most commonly the brain or heart.
Eculizumab inhibits the disease by blocking pro-thrombotic and pro-inflammatory processes, which can lead to cellular damage in small blood vessels throughout the body, renal failure, and damage to other organs.
“Eculizumab radically improves the quality of life of the small number of people with aHUS,” said NICE Chief Executive Sir Andrew Dillon.
“From the available evidence and from the testimony of clinicians and patients, families, and carers, it is clear that eculizumab is a significant breakthrough in the management of aHUS. The drug offers people with the disease the possibility of avoiding end-stage renal failure, dialysis, and kidney transplantation, as well as other organ damage.”
Breakthrough comes with considerable cost
Eculizumab costs £3150 per 30 mL vial (excluding value-added tax). The net budget impact of eculizumab based on the developer’s predicted rate of uptake over a 5-year period is confidential.
However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an illustration of the possible budget impact of eculizumab for aHUS, using information available in the public domain.
This is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.
If all of these adult patients with aHUS are treated with eculizumab, the budget impact for the first year would be £57.8 million.
If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 per million), the budget impact will rise to £62.5 million in year 2. That assumes all new patients are treated, and all existing patients continue to be treated at the maintenance cost of £327,600 per year.
Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients), and £82 million in year 5 (230 existing and 20 new patients).
Conditions of the recommendation
The expert committee advising NICE on eculizumab believes the budget impact of recommending the drug for aHUS in relation to the benefits it offers would be lower if the potential for dose adjustment and treatment discontinuation was taken into account, according to Sir Dillon.
“Therefore, the draft guidance recommends that eculizumab is funded only if important conditions are met,” he said. “These include coordinating the use of eculizumab through an expert center and putting in place systems for monitoring how many people are diagnosed with aHUS, how many receive the drug, at what dose, and for how long.”
“The program also needs to develop protocols for starting and stopping treatment with eculizumab for clinical reasons and introduce a research program to collect data to evaluate when stopping treatment or adjusting the dose of the drug might occur.”
Given that the budget impact of eculizumab for treating aHUS will be considerable, the draft guidance also recommends that NHS England and the drug’s developer, Alexion, should consider what opportunities might exist to reduce the overall cost of eculizumab to the NHS.
NICE has not yet issued final guidance to the NHS. These decisions may change after consultation. The public can comment on the preliminary recommendations, which will be available until midday on September 25.
Comments received during this consultation period will be considered by the advisory committee at its meeting in October and, following this meeting, the next draft guidance will be issued. 
Credit: Globovision
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending eculizumab (Soliris) to treat atypical hemolytic uremic syndrome (aHUS), despite the drug’s high cost.
NICE estimates that eculizumab will cost the National Health Service (NHS) up to £58 million in the first year, rising to £82 million after 5 years.
The drug is currently funded by NHS England through interim specialized commissioning arrangements.
Eculizumab is ‘breakthrough’ for aHUS
aHUS is an extremely rare but life-threatening disease that causes inflammation of blood vessels and the formation of blood clots throughout the body. Patients with aHUS are at constant risk of sudden and progressive damage to, and failure of, vital organs.
Roughly 10% to 15% of patients die in the initial, acute phase of aHUS. The majority of patients—up to 70%—develop end-stage kidney failure requiring dialysis. And 1 in 5 patients has aHUS affecting organs other than the kidneys, most commonly the brain or heart.
Eculizumab inhibits the disease by blocking pro-thrombotic and pro-inflammatory processes, which can lead to cellular damage in small blood vessels throughout the body, renal failure, and damage to other organs.
“Eculizumab radically improves the quality of life of the small number of people with aHUS,” said NICE Chief Executive Sir Andrew Dillon.
“From the available evidence and from the testimony of clinicians and patients, families, and carers, it is clear that eculizumab is a significant breakthrough in the management of aHUS. The drug offers people with the disease the possibility of avoiding end-stage renal failure, dialysis, and kidney transplantation, as well as other organ damage.”
Breakthrough comes with considerable cost
Eculizumab costs £3150 per 30 mL vial (excluding value-added tax). The net budget impact of eculizumab based on the developer’s predicted rate of uptake over a 5-year period is confidential.
However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an illustration of the possible budget impact of eculizumab for aHUS, using information available in the public domain.
This is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.
If all of these adult patients with aHUS are treated with eculizumab, the budget impact for the first year would be £57.8 million.
If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 per million), the budget impact will rise to £62.5 million in year 2. That assumes all new patients are treated, and all existing patients continue to be treated at the maintenance cost of £327,600 per year.
Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients), and £82 million in year 5 (230 existing and 20 new patients).
Conditions of the recommendation
The expert committee advising NICE on eculizumab believes the budget impact of recommending the drug for aHUS in relation to the benefits it offers would be lower if the potential for dose adjustment and treatment discontinuation was taken into account, according to Sir Dillon.
“Therefore, the draft guidance recommends that eculizumab is funded only if important conditions are met,” he said. “These include coordinating the use of eculizumab through an expert center and putting in place systems for monitoring how many people are diagnosed with aHUS, how many receive the drug, at what dose, and for how long.”
“The program also needs to develop protocols for starting and stopping treatment with eculizumab for clinical reasons and introduce a research program to collect data to evaluate when stopping treatment or adjusting the dose of the drug might occur.”
Given that the budget impact of eculizumab for treating aHUS will be considerable, the draft guidance also recommends that NHS England and the drug’s developer, Alexion, should consider what opportunities might exist to reduce the overall cost of eculizumab to the NHS.
NICE has not yet issued final guidance to the NHS. These decisions may change after consultation. The public can comment on the preliminary recommendations, which will be available until midday on September 25.
Comments received during this consultation period will be considered by the advisory committee at its meeting in October and, following this meeting, the next draft guidance will be issued.
Credit: Globovision
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending eculizumab (Soliris) to treat atypical hemolytic uremic syndrome (aHUS), despite the drug’s high cost.
NICE estimates that eculizumab will cost the National Health Service (NHS) up to £58 million in the first year, rising to £82 million after 5 years.
The drug is currently funded by NHS England through interim specialized commissioning arrangements.
Eculizumab is ‘breakthrough’ for aHUS
aHUS is an extremely rare but life-threatening disease that causes inflammation of blood vessels and the formation of blood clots throughout the body. Patients with aHUS are at constant risk of sudden and progressive damage to, and failure of, vital organs.
Roughly 10% to 15% of patients die in the initial, acute phase of aHUS. The majority of patients—up to 70%—develop end-stage kidney failure requiring dialysis. And 1 in 5 patients has aHUS affecting organs other than the kidneys, most commonly the brain or heart.
Eculizumab inhibits the disease by blocking pro-thrombotic and pro-inflammatory processes, which can lead to cellular damage in small blood vessels throughout the body, renal failure, and damage to other organs.
“Eculizumab radically improves the quality of life of the small number of people with aHUS,” said NICE Chief Executive Sir Andrew Dillon.
“From the available evidence and from the testimony of clinicians and patients, families, and carers, it is clear that eculizumab is a significant breakthrough in the management of aHUS. The drug offers people with the disease the possibility of avoiding end-stage renal failure, dialysis, and kidney transplantation, as well as other organ damage.”
Breakthrough comes with considerable cost
Eculizumab costs £3150 per 30 mL vial (excluding value-added tax). The net budget impact of eculizumab based on the developer’s predicted rate of uptake over a 5-year period is confidential.
However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an illustration of the possible budget impact of eculizumab for aHUS, using information available in the public domain.
This is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.
If all of these adult patients with aHUS are treated with eculizumab, the budget impact for the first year would be £57.8 million.
If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 per million), the budget impact will rise to £62.5 million in year 2. That assumes all new patients are treated, and all existing patients continue to be treated at the maintenance cost of £327,600 per year.
Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients), and £82 million in year 5 (230 existing and 20 new patients).
Conditions of the recommendation
The expert committee advising NICE on eculizumab believes the budget impact of recommending the drug for aHUS in relation to the benefits it offers would be lower if the potential for dose adjustment and treatment discontinuation was taken into account, according to Sir Dillon.
“Therefore, the draft guidance recommends that eculizumab is funded only if important conditions are met,” he said. “These include coordinating the use of eculizumab through an expert center and putting in place systems for monitoring how many people are diagnosed with aHUS, how many receive the drug, at what dose, and for how long.”
“The program also needs to develop protocols for starting and stopping treatment with eculizumab for clinical reasons and introduce a research program to collect data to evaluate when stopping treatment or adjusting the dose of the drug might occur.”
Given that the budget impact of eculizumab for treating aHUS will be considerable, the draft guidance also recommends that NHS England and the drug’s developer, Alexion, should consider what opportunities might exist to reduce the overall cost of eculizumab to the NHS.
NICE has not yet issued final guidance to the NHS. These decisions may change after consultation. The public can comment on the preliminary recommendations, which will be available until midday on September 25.
Comments received during this consultation period will be considered by the advisory committee at its meeting in October and, following this meeting, the next draft guidance will be issued.
Recommendations for managing SCD lack supporting evidence
Credit: St Jude Children’s
Research Hospital
A new set of guidelines includes some strong recommendations for managing patients with sickle cell disease (SCD) that are not supported by high-quality evidence, according to researchers.
The group reviewed the medical literature to examine the quality of evidence supporting each of the guideline’s recommendations.
And they discovered a lack of randomized controlled trials in SCD patients that have left “extensive” gaps in our knowledge of the disease.
So while the guidelines do provide some helpful advice for managing patients with SCD, they also leave healthcare professionals with some uncertainties, according to the researchers.
The National Heart, Lung, and Blood Institute convened an expert panel to develop the guidelines, which are now available on the institute’s website.
Barbara P. Yawn, MD, of the Olmsted Medical Center in Rochester, Minnesota, and her colleagues examined the quality of evidence supporting the guidelines and reported their results in JAMA alongside a related editorial. Several examples of guideline recommendations and supporting evidence follow.
Health management recommendations
The guidelines strongly recommend oral penicillin prophylaxis twice daily until age 5 years in all children with HbSS to prevent invasive pneumococcal infection. And this recommendation is supported by moderate-quality evidence.
But the guidelines also strongly recommend referral to an ophthalmologist for dilated eye examination to screen for retinopathy beginning at age 10 years, and the quality of evidence supporting this recommendation is poor.
Acute SCD complications
The guidelines strongly recommend rapid initiation of parenteral opioids in adults and children with a vaso-occlusive crisis associated with severe pain, a suggestion supported by high-quality evidence.
However, the guidelines also strongly recommend treating SCD patients with acute chest syndrome with an intravenous cephalosporin, an oral macrolide antibiotic, and supplemental oxygen (to maintain oxygen saturation of >95%), as well as closely monitoring patients for bronchospasm, acute anemia, and hypoxemia. And this is supported by low-quality evidence.
Chronic complications
A strong recommendation supported by high-quality evidence is to treat avascular necrosis with analgesics and consult physical therapy and orthopedic departments for assessment and follow-up.
A strong recommendation supported by low-quality evidence is to evaluate all children and adults with SCD and intermittent or chronic hip pain for avascular necrosis by history, physical examination, radiography, and magnetic resonance imaging, as needed.
Use of hydroxyurea
Dr Yawn and her colleagues found that strong recommendations for hydroxyurea are all supported by moderate- or high-quality evidence.
A strong recommendation supported by high-quality evidence is to initiate hydroxyurea in adults who have at least 3 moderate-to-severe pain crises associated with SCD during a 12-month period.
A strong recommendation supported by moderate-quality evidence is to initiate hydroxyurea in adults who have sickle cell-associated pain that interferes with daily activities and quality of life.
Transfusion therapy
For this category, the only strong recommendation supported by high-quality evidence is to transfuse a child with a transcranial Doppler reading greater than 200 cm/s.
The guidelines strongly recommend transfusing red blood cells in adults and children with SCD to bring the hemoglobin level to 10 g/dL prior to undergoing a surgical procedure involving general anesthesia, but this is supported by moderate-quality evidence.
A strong recommendation supported by low-quality evidence is to perform an exchange transfusion in a patient with symptomatic, severe acute chest syndrome (defined by an oxygen saturation less than 90% despite supplemental oxygen).
Conclusions
Dr Yawn and her colleagues said this investigation confirms that developing guidelines for managing SCD is challenging because high-quality evidence is limited in virtually every area related to SCD management.
Therefore, the guidelines leave healthcare professionals with some uncertainties about managing SCD patients. But the researchers hope their analysis will prompt new research that might provide more definitive guidance.
Credit: St Jude Children’s
Research Hospital
A new set of guidelines includes some strong recommendations for managing patients with sickle cell disease (SCD) that are not supported by high-quality evidence, according to researchers.
The group reviewed the medical literature to examine the quality of evidence supporting each of the guideline’s recommendations.
And they discovered a lack of randomized controlled trials in SCD patients that have left “extensive” gaps in our knowledge of the disease.
So while the guidelines do provide some helpful advice for managing patients with SCD, they also leave healthcare professionals with some uncertainties, according to the researchers.
The National Heart, Lung, and Blood Institute convened an expert panel to develop the guidelines, which are now available on the institute’s website.
Barbara P. Yawn, MD, of the Olmsted Medical Center in Rochester, Minnesota, and her colleagues examined the quality of evidence supporting the guidelines and reported their results in JAMA alongside a related editorial. Several examples of guideline recommendations and supporting evidence follow.
Health management recommendations
The guidelines strongly recommend oral penicillin prophylaxis twice daily until age 5 years in all children with HbSS to prevent invasive pneumococcal infection. And this recommendation is supported by moderate-quality evidence.
But the guidelines also strongly recommend referral to an ophthalmologist for dilated eye examination to screen for retinopathy beginning at age 10 years, and the quality of evidence supporting this recommendation is poor.
Acute SCD complications
The guidelines strongly recommend rapid initiation of parenteral opioids in adults and children with a vaso-occlusive crisis associated with severe pain, a suggestion supported by high-quality evidence.
However, the guidelines also strongly recommend treating SCD patients with acute chest syndrome with an intravenous cephalosporin, an oral macrolide antibiotic, and supplemental oxygen (to maintain oxygen saturation of >95%), as well as closely monitoring patients for bronchospasm, acute anemia, and hypoxemia. And this is supported by low-quality evidence.
Chronic complications
A strong recommendation supported by high-quality evidence is to treat avascular necrosis with analgesics and consult physical therapy and orthopedic departments for assessment and follow-up.
A strong recommendation supported by low-quality evidence is to evaluate all children and adults with SCD and intermittent or chronic hip pain for avascular necrosis by history, physical examination, radiography, and magnetic resonance imaging, as needed.
Use of hydroxyurea
Dr Yawn and her colleagues found that strong recommendations for hydroxyurea are all supported by moderate- or high-quality evidence.
A strong recommendation supported by high-quality evidence is to initiate hydroxyurea in adults who have at least 3 moderate-to-severe pain crises associated with SCD during a 12-month period.
A strong recommendation supported by moderate-quality evidence is to initiate hydroxyurea in adults who have sickle cell-associated pain that interferes with daily activities and quality of life.
Transfusion therapy
For this category, the only strong recommendation supported by high-quality evidence is to transfuse a child with a transcranial Doppler reading greater than 200 cm/s.
The guidelines strongly recommend transfusing red blood cells in adults and children with SCD to bring the hemoglobin level to 10 g/dL prior to undergoing a surgical procedure involving general anesthesia, but this is supported by moderate-quality evidence.
A strong recommendation supported by low-quality evidence is to perform an exchange transfusion in a patient with symptomatic, severe acute chest syndrome (defined by an oxygen saturation less than 90% despite supplemental oxygen).
Conclusions
Dr Yawn and her colleagues said this investigation confirms that developing guidelines for managing SCD is challenging because high-quality evidence is limited in virtually every area related to SCD management.
Therefore, the guidelines leave healthcare professionals with some uncertainties about managing SCD patients. But the researchers hope their analysis will prompt new research that might provide more definitive guidance.
Credit: St Jude Children’s
Research Hospital
A new set of guidelines includes some strong recommendations for managing patients with sickle cell disease (SCD) that are not supported by high-quality evidence, according to researchers.
The group reviewed the medical literature to examine the quality of evidence supporting each of the guideline’s recommendations.
And they discovered a lack of randomized controlled trials in SCD patients that have left “extensive” gaps in our knowledge of the disease.
So while the guidelines do provide some helpful advice for managing patients with SCD, they also leave healthcare professionals with some uncertainties, according to the researchers.
The National Heart, Lung, and Blood Institute convened an expert panel to develop the guidelines, which are now available on the institute’s website.
Barbara P. Yawn, MD, of the Olmsted Medical Center in Rochester, Minnesota, and her colleagues examined the quality of evidence supporting the guidelines and reported their results in JAMA alongside a related editorial. Several examples of guideline recommendations and supporting evidence follow.
Health management recommendations
The guidelines strongly recommend oral penicillin prophylaxis twice daily until age 5 years in all children with HbSS to prevent invasive pneumococcal infection. And this recommendation is supported by moderate-quality evidence.
But the guidelines also strongly recommend referral to an ophthalmologist for dilated eye examination to screen for retinopathy beginning at age 10 years, and the quality of evidence supporting this recommendation is poor.
Acute SCD complications
The guidelines strongly recommend rapid initiation of parenteral opioids in adults and children with a vaso-occlusive crisis associated with severe pain, a suggestion supported by high-quality evidence.
However, the guidelines also strongly recommend treating SCD patients with acute chest syndrome with an intravenous cephalosporin, an oral macrolide antibiotic, and supplemental oxygen (to maintain oxygen saturation of >95%), as well as closely monitoring patients for bronchospasm, acute anemia, and hypoxemia. And this is supported by low-quality evidence.
Chronic complications
A strong recommendation supported by high-quality evidence is to treat avascular necrosis with analgesics and consult physical therapy and orthopedic departments for assessment and follow-up.
A strong recommendation supported by low-quality evidence is to evaluate all children and adults with SCD and intermittent or chronic hip pain for avascular necrosis by history, physical examination, radiography, and magnetic resonance imaging, as needed.
Use of hydroxyurea
Dr Yawn and her colleagues found that strong recommendations for hydroxyurea are all supported by moderate- or high-quality evidence.
A strong recommendation supported by high-quality evidence is to initiate hydroxyurea in adults who have at least 3 moderate-to-severe pain crises associated with SCD during a 12-month period.
A strong recommendation supported by moderate-quality evidence is to initiate hydroxyurea in adults who have sickle cell-associated pain that interferes with daily activities and quality of life.
Transfusion therapy
For this category, the only strong recommendation supported by high-quality evidence is to transfuse a child with a transcranial Doppler reading greater than 200 cm/s.
The guidelines strongly recommend transfusing red blood cells in adults and children with SCD to bring the hemoglobin level to 10 g/dL prior to undergoing a surgical procedure involving general anesthesia, but this is supported by moderate-quality evidence.
A strong recommendation supported by low-quality evidence is to perform an exchange transfusion in a patient with symptomatic, severe acute chest syndrome (defined by an oxygen saturation less than 90% despite supplemental oxygen).
Conclusions
Dr Yawn and her colleagues said this investigation confirms that developing guidelines for managing SCD is challenging because high-quality evidence is limited in virtually every area related to SCD management.
Therefore, the guidelines leave healthcare professionals with some uncertainties about managing SCD patients. But the researchers hope their analysis will prompt new research that might provide more definitive guidance.
Synthetic platelets can augment natural clotting
bacteria needed to create
the platelet-like particles
Credit: Gary Meek
Researchers say they’ve developed a new class of synthetic platelet-like particles that can augment natural blood clotting.
The particles are based on soft and deformable hydrogel materials and measure about 1 micron in diameter.
Testing in animal models and a simulated circulatory system suggested the particles are effective at slowing bleeding and can safely circulate in the bloodstream.
The particles have been tested in human blood but not in clinical trials.
Ashley Brown, PhD, of the Georgia Institute of Technology and Emory University in Atlanta, and her colleagues described the research involving these particles in Nature Materials.
The team noted that, when fibrinogen proteins receive the right signals from thrombin, they polymerize at the site of bleeding to form a clot. The synthetic platelet-like particles use the same trigger, so they are activated only when the body’s natural clotting process is initiated.
To create that trigger, the researchers employed molecular evolution. They developed an antibody that could be attached to the hydrogel particles to change their form when they encounter thrombin-activated fibrin. The resulting antibody has a high affinity for the polymerized form of fibrin and a low affinity for the precursor material.
“Fibrin production is on the back end of the clotting process, so we feel that it is a safer place to try to interact with it,” said study author Thomas Barker, PhD, of Georgia Tech and Emory University.
“The specificity of this material provides a very important advantage in triggering clotting at just the right time.”
The researchers tested the platelet-like particles in an animal model and a microfluidic chamber designed to simulate conditions within the body’s circulatory system.
The team used the chamber to study normal human blood, as well as blood that had been depleted of its natural platelets. In platelet-rich blood, clots formed as expected, and blood without platelets did not form clots. When the platelet-like particles were added to the platelet-depleted blood, it was able to clot.
The researchers also tested blood from infants who had received anticoagulant treatment prior to undergoing open heart surgery. When platelet-like particles were added to this blood, it was able to form clots.
Finally, the team performed safety testing on blood from hemophilia patients. Because their blood lacked the triggers needed to cause fibrin formation, the particles had no effect.
What ultimately happens to the particles circulating in the bloodstream will be the topic of future research, Dr Brown said. Particles of similar size and composition are normally eliminated from the body.
While the platelet-like particles lack many features of natural platelets, the researchers were surprised to find one property in common. Clots formed by natural platelets begin to contract over a period of hours, beginning the body’s repair process. Clots formed from the synthetic particles also contract, but over a longer period of time.
These particles were originally developed to be used on the battlefield by wounded soldiers, who might self-administer them using a device about the size of a smartphone. But the researchers believe the particles could also reduce the need for platelet transfusions in patients undergoing chemotherapy or bypass surgery, and in those with certain blood disorders.
“For a patient with insufficient platelets due to bleeding or an inherited disorder, physicians often have to resort to platelet transfusions, which can be difficult to obtain,” said study author Wilbur Lam, MD, PhD, of the Georgia Institute of Technology and Emory University.
“These particles could potentially be a way to obviate the need for a transfusion. Though they don’t have all the assets of natural platelets, a number of intriguing experiments have shown that the particles help augment the clotting process.”
bacteria needed to create
the platelet-like particles
Credit: Gary Meek
Researchers say they’ve developed a new class of synthetic platelet-like particles that can augment natural blood clotting.
The particles are based on soft and deformable hydrogel materials and measure about 1 micron in diameter.
Testing in animal models and a simulated circulatory system suggested the particles are effective at slowing bleeding and can safely circulate in the bloodstream.
The particles have been tested in human blood but not in clinical trials.
Ashley Brown, PhD, of the Georgia Institute of Technology and Emory University in Atlanta, and her colleagues described the research involving these particles in Nature Materials.
The team noted that, when fibrinogen proteins receive the right signals from thrombin, they polymerize at the site of bleeding to form a clot. The synthetic platelet-like particles use the same trigger, so they are activated only when the body’s natural clotting process is initiated.
To create that trigger, the researchers employed molecular evolution. They developed an antibody that could be attached to the hydrogel particles to change their form when they encounter thrombin-activated fibrin. The resulting antibody has a high affinity for the polymerized form of fibrin and a low affinity for the precursor material.
“Fibrin production is on the back end of the clotting process, so we feel that it is a safer place to try to interact with it,” said study author Thomas Barker, PhD, of Georgia Tech and Emory University.
“The specificity of this material provides a very important advantage in triggering clotting at just the right time.”
The researchers tested the platelet-like particles in an animal model and a microfluidic chamber designed to simulate conditions within the body’s circulatory system.
The team used the chamber to study normal human blood, as well as blood that had been depleted of its natural platelets. In platelet-rich blood, clots formed as expected, and blood without platelets did not form clots. When the platelet-like particles were added to the platelet-depleted blood, it was able to clot.
The researchers also tested blood from infants who had received anticoagulant treatment prior to undergoing open heart surgery. When platelet-like particles were added to this blood, it was able to form clots.
Finally, the team performed safety testing on blood from hemophilia patients. Because their blood lacked the triggers needed to cause fibrin formation, the particles had no effect.
What ultimately happens to the particles circulating in the bloodstream will be the topic of future research, Dr Brown said. Particles of similar size and composition are normally eliminated from the body.
While the platelet-like particles lack many features of natural platelets, the researchers were surprised to find one property in common. Clots formed by natural platelets begin to contract over a period of hours, beginning the body’s repair process. Clots formed from the synthetic particles also contract, but over a longer period of time.
These particles were originally developed to be used on the battlefield by wounded soldiers, who might self-administer them using a device about the size of a smartphone. But the researchers believe the particles could also reduce the need for platelet transfusions in patients undergoing chemotherapy or bypass surgery, and in those with certain blood disorders.
“For a patient with insufficient platelets due to bleeding or an inherited disorder, physicians often have to resort to platelet transfusions, which can be difficult to obtain,” said study author Wilbur Lam, MD, PhD, of the Georgia Institute of Technology and Emory University.
“These particles could potentially be a way to obviate the need for a transfusion. Though they don’t have all the assets of natural platelets, a number of intriguing experiments have shown that the particles help augment the clotting process.”
bacteria needed to create
the platelet-like particles
Credit: Gary Meek
Researchers say they’ve developed a new class of synthetic platelet-like particles that can augment natural blood clotting.
The particles are based on soft and deformable hydrogel materials and measure about 1 micron in diameter.
Testing in animal models and a simulated circulatory system suggested the particles are effective at slowing bleeding and can safely circulate in the bloodstream.
The particles have been tested in human blood but not in clinical trials.
Ashley Brown, PhD, of the Georgia Institute of Technology and Emory University in Atlanta, and her colleagues described the research involving these particles in Nature Materials.
The team noted that, when fibrinogen proteins receive the right signals from thrombin, they polymerize at the site of bleeding to form a clot. The synthetic platelet-like particles use the same trigger, so they are activated only when the body’s natural clotting process is initiated.
To create that trigger, the researchers employed molecular evolution. They developed an antibody that could be attached to the hydrogel particles to change their form when they encounter thrombin-activated fibrin. The resulting antibody has a high affinity for the polymerized form of fibrin and a low affinity for the precursor material.
“Fibrin production is on the back end of the clotting process, so we feel that it is a safer place to try to interact with it,” said study author Thomas Barker, PhD, of Georgia Tech and Emory University.
“The specificity of this material provides a very important advantage in triggering clotting at just the right time.”
The researchers tested the platelet-like particles in an animal model and a microfluidic chamber designed to simulate conditions within the body’s circulatory system.
The team used the chamber to study normal human blood, as well as blood that had been depleted of its natural platelets. In platelet-rich blood, clots formed as expected, and blood without platelets did not form clots. When the platelet-like particles were added to the platelet-depleted blood, it was able to clot.
The researchers also tested blood from infants who had received anticoagulant treatment prior to undergoing open heart surgery. When platelet-like particles were added to this blood, it was able to form clots.
Finally, the team performed safety testing on blood from hemophilia patients. Because their blood lacked the triggers needed to cause fibrin formation, the particles had no effect.
What ultimately happens to the particles circulating in the bloodstream will be the topic of future research, Dr Brown said. Particles of similar size and composition are normally eliminated from the body.
While the platelet-like particles lack many features of natural platelets, the researchers were surprised to find one property in common. Clots formed by natural platelets begin to contract over a period of hours, beginning the body’s repair process. Clots formed from the synthetic particles also contract, but over a longer period of time.
These particles were originally developed to be used on the battlefield by wounded soldiers, who might self-administer them using a device about the size of a smartphone. But the researchers believe the particles could also reduce the need for platelet transfusions in patients undergoing chemotherapy or bypass surgery, and in those with certain blood disorders.
“For a patient with insufficient platelets due to bleeding or an inherited disorder, physicians often have to resort to platelet transfusions, which can be difficult to obtain,” said study author Wilbur Lam, MD, PhD, of the Georgia Institute of Technology and Emory University.
“These particles could potentially be a way to obviate the need for a transfusion. Though they don’t have all the assets of natural platelets, a number of intriguing experiments have shown that the particles help augment the clotting process.”
Cancer centers may not allow for dignified deaths
Credit: NCI and
Mathews Media Group
A new study suggests many patients in cancer centers do not experience a dignified death.
Study investigators surveyed physicians and nurses in 16 hospitals belonging to 10 cancer centers in Baden-Württemberg, Germany.
The results revealed a need for cancer centers to invest more in palliative care services, adequate rooms for dying patients, staff training in end-of-life care, and advance-care-planning standards.
Karin Jors, of the University Medical Center Freiburg, and her colleagues reported these findings in Cancer.
Previous research has shown that hospitals are often ill-prepared to provide care for dying patients.
To investigate whether the circumstances for dying on cancer center wards allow for a dignified death, Jors and her colleagues surveyed physicians and nurses in German cancer centers.
Among 1131 survey respondents, 57% believed that patients could die with dignity on their ward.
Half of the surveyed staff members indicated that they rarely have enough time to care for dying patients, and 55% found the rooms available for dying patients unsatisfactory.
Only 19% of respondents felt they had been well-prepared to care for dying patients, and only 6% of physicians felt that way.
On the other hand, physicians perceived the circumstances for dying patients much more positively than nurses, especially regarding communication and life-prolonging measures.
While 72% of physicians reported that patients can usually die a dignified death on their ward, only 52% of nurses shared this opinion.
Palliative care staff reported much better conditions for dying patients than staff from other wards, with 95% of palliative care staff indicating that patients die with dignity on their wards.
“In our aging society, it is predicted that the number of hospital deaths will continue to rise in the coming years, and many of these deaths will be attributable to cancer,” Jors said.
“For this reason, it is particularly important that cancer centers strive to create a comfortable, dignified experience for dying patients and their families. Above all, this requires that staff members are provided with the adequate resources to care for these patients.”
The investigators therefore encourage the integration of palliative care into standard oncology care, beginning as early as diagnosis. They also believe physicians and nurses would benefit from increased education and training in end-of-life care.
Credit: NCI and
Mathews Media Group
A new study suggests many patients in cancer centers do not experience a dignified death.
Study investigators surveyed physicians and nurses in 16 hospitals belonging to 10 cancer centers in Baden-Württemberg, Germany.
The results revealed a need for cancer centers to invest more in palliative care services, adequate rooms for dying patients, staff training in end-of-life care, and advance-care-planning standards.
Karin Jors, of the University Medical Center Freiburg, and her colleagues reported these findings in Cancer.
Previous research has shown that hospitals are often ill-prepared to provide care for dying patients.
To investigate whether the circumstances for dying on cancer center wards allow for a dignified death, Jors and her colleagues surveyed physicians and nurses in German cancer centers.
Among 1131 survey respondents, 57% believed that patients could die with dignity on their ward.
Half of the surveyed staff members indicated that they rarely have enough time to care for dying patients, and 55% found the rooms available for dying patients unsatisfactory.
Only 19% of respondents felt they had been well-prepared to care for dying patients, and only 6% of physicians felt that way.
On the other hand, physicians perceived the circumstances for dying patients much more positively than nurses, especially regarding communication and life-prolonging measures.
While 72% of physicians reported that patients can usually die a dignified death on their ward, only 52% of nurses shared this opinion.
Palliative care staff reported much better conditions for dying patients than staff from other wards, with 95% of palliative care staff indicating that patients die with dignity on their wards.
“In our aging society, it is predicted that the number of hospital deaths will continue to rise in the coming years, and many of these deaths will be attributable to cancer,” Jors said.
“For this reason, it is particularly important that cancer centers strive to create a comfortable, dignified experience for dying patients and their families. Above all, this requires that staff members are provided with the adequate resources to care for these patients.”
The investigators therefore encourage the integration of palliative care into standard oncology care, beginning as early as diagnosis. They also believe physicians and nurses would benefit from increased education and training in end-of-life care.
Credit: NCI and
Mathews Media Group
A new study suggests many patients in cancer centers do not experience a dignified death.
Study investigators surveyed physicians and nurses in 16 hospitals belonging to 10 cancer centers in Baden-Württemberg, Germany.
The results revealed a need for cancer centers to invest more in palliative care services, adequate rooms for dying patients, staff training in end-of-life care, and advance-care-planning standards.
Karin Jors, of the University Medical Center Freiburg, and her colleagues reported these findings in Cancer.
Previous research has shown that hospitals are often ill-prepared to provide care for dying patients.
To investigate whether the circumstances for dying on cancer center wards allow for a dignified death, Jors and her colleagues surveyed physicians and nurses in German cancer centers.
Among 1131 survey respondents, 57% believed that patients could die with dignity on their ward.
Half of the surveyed staff members indicated that they rarely have enough time to care for dying patients, and 55% found the rooms available for dying patients unsatisfactory.
Only 19% of respondents felt they had been well-prepared to care for dying patients, and only 6% of physicians felt that way.
On the other hand, physicians perceived the circumstances for dying patients much more positively than nurses, especially regarding communication and life-prolonging measures.
While 72% of physicians reported that patients can usually die a dignified death on their ward, only 52% of nurses shared this opinion.
Palliative care staff reported much better conditions for dying patients than staff from other wards, with 95% of palliative care staff indicating that patients die with dignity on their wards.
“In our aging society, it is predicted that the number of hospital deaths will continue to rise in the coming years, and many of these deaths will be attributable to cancer,” Jors said.
“For this reason, it is particularly important that cancer centers strive to create a comfortable, dignified experience for dying patients and their families. Above all, this requires that staff members are provided with the adequate resources to care for these patients.”
The investigators therefore encourage the integration of palliative care into standard oncology care, beginning as early as diagnosis. They also believe physicians and nurses would benefit from increased education and training in end-of-life care.
WHO supports study of blood transfusions for Ebola
Credit: Elise Amendola
Experts from the World Health Organization (WHO) have identified several interventions that should be the focus of clinical evaluation for treating and preventing Ebola.
Transfusions of blood products from Ebola survivors topped this list.
Of course, such blood preparations, like the other interventions the WHO discussed, have not been approved to treat or prevent Ebola.
However, they could be available before the year is out, according to WHO estimates. The organization is exploring options to conduct clinical trials of blood products in Ebola patients.
Previous studies have suggested blood transfusions from Ebola survivors might prevent or treat Ebola virus infection. However, it is unclear whether antibodies in the plasma of survivors are sufficient to treat or prevent the disease.
Safety is also a concern, although the WHO said transfusions should be safe if they are provided by well-managed blood banks. Still, there is a risk of transmitting blood-borne pathogens and a theoretical concern about antibody-dependent enhancement of Ebola virus infection.
“[T]here was a lot of discussion and emphasis on blood, on blood transfusion, whole-blood transfusion, as well as on plasma that can be purified from convalescent serum,” said Marie-Paule Kieny, Assistant Director-General at the WHO.
“There was consensus that this has a good chance to work and that, also, this is something that can be produced now from the affected countries themselves.”
The experts also agreed that the international community needs to help affected countries create the necessary infrastructure to draw blood safely and prepare the blood products safely.
Aside from blood transfusions, the WHO experts mentioned 2 potential Ebola vaccines that should be a priority. Safety studies of these vaccines—based on vesicular stomatitis virus (VSV-EBO) and chimpanzee adenovirus (ChAd-EBO)—are beginning in the US and are slated to begin in Africa and Europe in mid-September.
If proven safe, a vaccine could be available in November 2014 for priority use in healthcare workers.
The WHO experts also discussed the availability and evidence supporting the use of novel therapeutic drugs, including monoclonal antibodies, RNA-based drugs, and small antiviral molecules. They considered the potential use of existing drugs approved for other diseases and conditions as well.
Of the novel products discussed, some have shown great promise in monkey models. Others have been used in a few Ebola patients and appear safe, but the numbers are too small to permit any definitive conclusions about efficacy.
Existing supplies of all experimental medicines are limited, the WHO said. While many efforts are underway to accelerate production, supplies will not be sufficient for several months to come. The prospects of having augmented supplies of vaccines rapidly look slightly better.
The WHO also cautioned that the investigation of the aforementioned interventions should not detract attention from measures to prevent Ebola from spreading.
Credit: Elise Amendola
Experts from the World Health Organization (WHO) have identified several interventions that should be the focus of clinical evaluation for treating and preventing Ebola.
Transfusions of blood products from Ebola survivors topped this list.
Of course, such blood preparations, like the other interventions the WHO discussed, have not been approved to treat or prevent Ebola.
However, they could be available before the year is out, according to WHO estimates. The organization is exploring options to conduct clinical trials of blood products in Ebola patients.
Previous studies have suggested blood transfusions from Ebola survivors might prevent or treat Ebola virus infection. However, it is unclear whether antibodies in the plasma of survivors are sufficient to treat or prevent the disease.
Safety is also a concern, although the WHO said transfusions should be safe if they are provided by well-managed blood banks. Still, there is a risk of transmitting blood-borne pathogens and a theoretical concern about antibody-dependent enhancement of Ebola virus infection.
“[T]here was a lot of discussion and emphasis on blood, on blood transfusion, whole-blood transfusion, as well as on plasma that can be purified from convalescent serum,” said Marie-Paule Kieny, Assistant Director-General at the WHO.
“There was consensus that this has a good chance to work and that, also, this is something that can be produced now from the affected countries themselves.”
The experts also agreed that the international community needs to help affected countries create the necessary infrastructure to draw blood safely and prepare the blood products safely.
Aside from blood transfusions, the WHO experts mentioned 2 potential Ebola vaccines that should be a priority. Safety studies of these vaccines—based on vesicular stomatitis virus (VSV-EBO) and chimpanzee adenovirus (ChAd-EBO)—are beginning in the US and are slated to begin in Africa and Europe in mid-September.
If proven safe, a vaccine could be available in November 2014 for priority use in healthcare workers.
The WHO experts also discussed the availability and evidence supporting the use of novel therapeutic drugs, including monoclonal antibodies, RNA-based drugs, and small antiviral molecules. They considered the potential use of existing drugs approved for other diseases and conditions as well.
Of the novel products discussed, some have shown great promise in monkey models. Others have been used in a few Ebola patients and appear safe, but the numbers are too small to permit any definitive conclusions about efficacy.
Existing supplies of all experimental medicines are limited, the WHO said. While many efforts are underway to accelerate production, supplies will not be sufficient for several months to come. The prospects of having augmented supplies of vaccines rapidly look slightly better.
The WHO also cautioned that the investigation of the aforementioned interventions should not detract attention from measures to prevent Ebola from spreading.
Credit: Elise Amendola
Experts from the World Health Organization (WHO) have identified several interventions that should be the focus of clinical evaluation for treating and preventing Ebola.
Transfusions of blood products from Ebola survivors topped this list.
Of course, such blood preparations, like the other interventions the WHO discussed, have not been approved to treat or prevent Ebola.
However, they could be available before the year is out, according to WHO estimates. The organization is exploring options to conduct clinical trials of blood products in Ebola patients.
Previous studies have suggested blood transfusions from Ebola survivors might prevent or treat Ebola virus infection. However, it is unclear whether antibodies in the plasma of survivors are sufficient to treat or prevent the disease.
Safety is also a concern, although the WHO said transfusions should be safe if they are provided by well-managed blood banks. Still, there is a risk of transmitting blood-borne pathogens and a theoretical concern about antibody-dependent enhancement of Ebola virus infection.
“[T]here was a lot of discussion and emphasis on blood, on blood transfusion, whole-blood transfusion, as well as on plasma that can be purified from convalescent serum,” said Marie-Paule Kieny, Assistant Director-General at the WHO.
“There was consensus that this has a good chance to work and that, also, this is something that can be produced now from the affected countries themselves.”
The experts also agreed that the international community needs to help affected countries create the necessary infrastructure to draw blood safely and prepare the blood products safely.
Aside from blood transfusions, the WHO experts mentioned 2 potential Ebola vaccines that should be a priority. Safety studies of these vaccines—based on vesicular stomatitis virus (VSV-EBO) and chimpanzee adenovirus (ChAd-EBO)—are beginning in the US and are slated to begin in Africa and Europe in mid-September.
If proven safe, a vaccine could be available in November 2014 for priority use in healthcare workers.
The WHO experts also discussed the availability and evidence supporting the use of novel therapeutic drugs, including monoclonal antibodies, RNA-based drugs, and small antiviral molecules. They considered the potential use of existing drugs approved for other diseases and conditions as well.
Of the novel products discussed, some have shown great promise in monkey models. Others have been used in a few Ebola patients and appear safe, but the numbers are too small to permit any definitive conclusions about efficacy.
Existing supplies of all experimental medicines are limited, the WHO said. While many efforts are underway to accelerate production, supplies will not be sufficient for several months to come. The prospects of having augmented supplies of vaccines rapidly look slightly better.
The WHO also cautioned that the investigation of the aforementioned interventions should not detract attention from measures to prevent Ebola from spreading.
Drug shows early promise for hematologic malignancies
A drug that targets mitochondrial function is largely safe and can be active in heavily pretreated patients with hematologic malignancies, a phase 1 trial indicates.
The drug, CPI-613, prompted responses in only 4 of 21 evaluable patients. However, 2 of those responses lasted more than 2 years.
CPI-613 was generally well-tolerated and did not induce bone marrow suppression. Four patients experienced renal failure, but it was reversed in 3 of them.
These results appear in Clinical Cancer Research.
“This drug is selectively taken up by cancer cells and then shuts down the production of energy in the mitochondria,” said study author Timothy Pardee, MD, PhD, of the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, North Carolina.
“This is the first drug to inhibit mitochondria in this way, and, if it proves effective in further clinical trials, it will open up a whole new approach to fighting cancer.”
Dr Pardee and his colleagues evaluated CPI-613 in 26 patients with relapsed or refractory hematologic malignancies—11 with acute myeloid leukemia, 6 with non-Hodgkin lymphoma, 4 with multiple myeloma, 4 with myelodysplastic syndrome (MDS), and 1 with Hodgkin lymphoma.
The median patient age was 65 years (range, 19-81), and the median number of prior therapies was 3 (range, 1-9).
Treatment dosing and toxicity
Patients received CPI-613 as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.
When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3780 mg/m2, there were 2 dose-limiting toxicities. There were no such toxicities at a dose of 2940 mg/m2 over 2 hours, so this was considered the maximum-tolerated dose.
The following grade 2 or higher toxicities were probably or definitely related to treatment: nausea (1 grade 2), vomiting (1 grade 3), diarrhea (3 grade 2), proteinuria (1 grade 2), renal failure (4 grade 3), hypotension (1 grade 2), hypocalcemia (1 grade 2), hypoalbuminemia (1 grade 2), and hyperkalemia (1 grade 3).
Renal failure was resolved in 3 of the 4 patients. The remaining patient chose hospice care.
Response data
Five patients discontinued treatment—1 refused therapy, 1 acquired an infection, and 3 developed acute kidney failure.
Of the 21 patients evaluable for response, 4 had an objective response following CPI-613 treatment, and 2 had prolonged stable disease.
One patient with MDS achieved a complete response that has been maintained for more than 3 years. A patient with acute myeloid leukemia achieved a morphologically leukemia-free state, went on to transplant, and is still alive and leukemia-free.
A patient with Burkitt lymphoma achieved a partial response after 3 cycles of therapy that was maintained for 17 cycles. She discontinued CPI-613 to have her residual disease resected, and has not received any treatment since. She is now disease-free more than 12 months later.
A patient with cutaneous T-cell lymphoma achieved a partial response that has been sustained for more than 2 years. At her request, she started to receive continuous therapy (no 1-week rest period), and she remains on treatment without significant toxicities and no evidence of marrow suppression.
The 2 patients with prolonged stable disease had MDS. Their disease was stable for 8 and 12 cycles, respectively. Two patients with multiple myeloma also initially had stable disease, but they progressed after 2 and 4 cycles, respectively.
Two patients died from disease progression while on study.
The researchers said these results suggest that agents targeting mitochondrial metabolism can be safe and active in hematologic malignancies. A phase 2 trial of CPI-613 is now underway.
Support for the phase 1 trial was provided by National Cancer Institute grants P30CA012197 and 1K08CA169809, the Doug Coley Foundation for Leukemia Research, the Frances P. Tutwiler Fund, The MacKay Foundation for Cancer Research, and Cornerstone Pharmaceuticals, which manufactured and provided CPI-613.
A drug that targets mitochondrial function is largely safe and can be active in heavily pretreated patients with hematologic malignancies, a phase 1 trial indicates.
The drug, CPI-613, prompted responses in only 4 of 21 evaluable patients. However, 2 of those responses lasted more than 2 years.
CPI-613 was generally well-tolerated and did not induce bone marrow suppression. Four patients experienced renal failure, but it was reversed in 3 of them.
These results appear in Clinical Cancer Research.
“This drug is selectively taken up by cancer cells and then shuts down the production of energy in the mitochondria,” said study author Timothy Pardee, MD, PhD, of the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, North Carolina.
“This is the first drug to inhibit mitochondria in this way, and, if it proves effective in further clinical trials, it will open up a whole new approach to fighting cancer.”
Dr Pardee and his colleagues evaluated CPI-613 in 26 patients with relapsed or refractory hematologic malignancies—11 with acute myeloid leukemia, 6 with non-Hodgkin lymphoma, 4 with multiple myeloma, 4 with myelodysplastic syndrome (MDS), and 1 with Hodgkin lymphoma.
The median patient age was 65 years (range, 19-81), and the median number of prior therapies was 3 (range, 1-9).
Treatment dosing and toxicity
Patients received CPI-613 as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.
When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3780 mg/m2, there were 2 dose-limiting toxicities. There were no such toxicities at a dose of 2940 mg/m2 over 2 hours, so this was considered the maximum-tolerated dose.
The following grade 2 or higher toxicities were probably or definitely related to treatment: nausea (1 grade 2), vomiting (1 grade 3), diarrhea (3 grade 2), proteinuria (1 grade 2), renal failure (4 grade 3), hypotension (1 grade 2), hypocalcemia (1 grade 2), hypoalbuminemia (1 grade 2), and hyperkalemia (1 grade 3).
Renal failure was resolved in 3 of the 4 patients. The remaining patient chose hospice care.
Response data
Five patients discontinued treatment—1 refused therapy, 1 acquired an infection, and 3 developed acute kidney failure.
Of the 21 patients evaluable for response, 4 had an objective response following CPI-613 treatment, and 2 had prolonged stable disease.
One patient with MDS achieved a complete response that has been maintained for more than 3 years. A patient with acute myeloid leukemia achieved a morphologically leukemia-free state, went on to transplant, and is still alive and leukemia-free.
A patient with Burkitt lymphoma achieved a partial response after 3 cycles of therapy that was maintained for 17 cycles. She discontinued CPI-613 to have her residual disease resected, and has not received any treatment since. She is now disease-free more than 12 months later.
A patient with cutaneous T-cell lymphoma achieved a partial response that has been sustained for more than 2 years. At her request, she started to receive continuous therapy (no 1-week rest period), and she remains on treatment without significant toxicities and no evidence of marrow suppression.
The 2 patients with prolonged stable disease had MDS. Their disease was stable for 8 and 12 cycles, respectively. Two patients with multiple myeloma also initially had stable disease, but they progressed after 2 and 4 cycles, respectively.
Two patients died from disease progression while on study.
The researchers said these results suggest that agents targeting mitochondrial metabolism can be safe and active in hematologic malignancies. A phase 2 trial of CPI-613 is now underway.
Support for the phase 1 trial was provided by National Cancer Institute grants P30CA012197 and 1K08CA169809, the Doug Coley Foundation for Leukemia Research, the Frances P. Tutwiler Fund, The MacKay Foundation for Cancer Research, and Cornerstone Pharmaceuticals, which manufactured and provided CPI-613.
A drug that targets mitochondrial function is largely safe and can be active in heavily pretreated patients with hematologic malignancies, a phase 1 trial indicates.
The drug, CPI-613, prompted responses in only 4 of 21 evaluable patients. However, 2 of those responses lasted more than 2 years.
CPI-613 was generally well-tolerated and did not induce bone marrow suppression. Four patients experienced renal failure, but it was reversed in 3 of them.
These results appear in Clinical Cancer Research.
“This drug is selectively taken up by cancer cells and then shuts down the production of energy in the mitochondria,” said study author Timothy Pardee, MD, PhD, of the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, North Carolina.
“This is the first drug to inhibit mitochondria in this way, and, if it proves effective in further clinical trials, it will open up a whole new approach to fighting cancer.”
Dr Pardee and his colleagues evaluated CPI-613 in 26 patients with relapsed or refractory hematologic malignancies—11 with acute myeloid leukemia, 6 with non-Hodgkin lymphoma, 4 with multiple myeloma, 4 with myelodysplastic syndrome (MDS), and 1 with Hodgkin lymphoma.
The median patient age was 65 years (range, 19-81), and the median number of prior therapies was 3 (range, 1-9).
Treatment dosing and toxicity
Patients received CPI-613 as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.
When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3780 mg/m2, there were 2 dose-limiting toxicities. There were no such toxicities at a dose of 2940 mg/m2 over 2 hours, so this was considered the maximum-tolerated dose.
The following grade 2 or higher toxicities were probably or definitely related to treatment: nausea (1 grade 2), vomiting (1 grade 3), diarrhea (3 grade 2), proteinuria (1 grade 2), renal failure (4 grade 3), hypotension (1 grade 2), hypocalcemia (1 grade 2), hypoalbuminemia (1 grade 2), and hyperkalemia (1 grade 3).
Renal failure was resolved in 3 of the 4 patients. The remaining patient chose hospice care.
Response data
Five patients discontinued treatment—1 refused therapy, 1 acquired an infection, and 3 developed acute kidney failure.
Of the 21 patients evaluable for response, 4 had an objective response following CPI-613 treatment, and 2 had prolonged stable disease.
One patient with MDS achieved a complete response that has been maintained for more than 3 years. A patient with acute myeloid leukemia achieved a morphologically leukemia-free state, went on to transplant, and is still alive and leukemia-free.
A patient with Burkitt lymphoma achieved a partial response after 3 cycles of therapy that was maintained for 17 cycles. She discontinued CPI-613 to have her residual disease resected, and has not received any treatment since. She is now disease-free more than 12 months later.
A patient with cutaneous T-cell lymphoma achieved a partial response that has been sustained for more than 2 years. At her request, she started to receive continuous therapy (no 1-week rest period), and she remains on treatment without significant toxicities and no evidence of marrow suppression.
The 2 patients with prolonged stable disease had MDS. Their disease was stable for 8 and 12 cycles, respectively. Two patients with multiple myeloma also initially had stable disease, but they progressed after 2 and 4 cycles, respectively.
Two patients died from disease progression while on study.
The researchers said these results suggest that agents targeting mitochondrial metabolism can be safe and active in hematologic malignancies. A phase 2 trial of CPI-613 is now underway.
Support for the phase 1 trial was provided by National Cancer Institute grants P30CA012197 and 1K08CA169809, the Doug Coley Foundation for Leukemia Research, the Frances P. Tutwiler Fund, The MacKay Foundation for Cancer Research, and Cornerstone Pharmaceuticals, which manufactured and provided CPI-613.
Method may fight inhibitor formation in hemophilia A
A new strategy may one day prevent hemophilia patients from developing antibodies that inhibit clotting factors.
With this method, plant cells “teach” the immune system to tolerate the clotting factor protein.
In mice with hemophilia A, the strategy prevented and reversed the formation of factor VIII (FVIII) inhibitors.
Henry Daniell, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia, and his colleagues described the approach in Blood. The work was supported by the National Institutes of Health and Bayer.
“The only current treatments for inhibitor formation cost $1 million and are risky for patients,” Dr Daniell said. “Our technique, which uses plant-based capsules, has the potential to be a cost-effective and safe alternative.”
Developing the technique
Previous studies had shown that exposing the immune system to individual components of the clotting factor protein could induce tolerance to the whole protein.
FVIII is composed of a heavy chain and a light chain, with each containing 3 domains. For their study, the researchers used the whole heavy chain and the C2 domain of the light chain.
Dr Daniell and his colleagues developed a platform for delivering drugs and biotherapeutics that relies on genetically modifying plants so they express the protein of interest.
Trying that same method with the components of the FVIII molecule, the team first fused the heavy chain DNA with DNA encoding a cholera toxin subunit, a protein that can cross the intestinal wall and enter the bloodstream, and did the same with the C2 DNA.
They introduced the fused genes into tobacco chloroplasts, so that some plants expressed the heavy chain and cholera toxin proteins and others expressed the C2 and cholera toxin proteins. They then ground up the plant leaves and suspended them in a solution, mixing the heavy chain and C2 solutions together.
Testing in mice
The researchers fed the mixed solution to mice with hemophilia A twice a week for 2 months and compared them to mice that consumed unmodified plant material. The team then gave the mice infusions of FVIII.
As expected, the control mice formed high levels of inhibitors. But the mice fed the experimental plant material formed much lower levels of inhibitors—on average, 7 times lower.
Mice that consumed the experimental plants exhibited upregulation of cytokines associated with suppressing or regulating immune responses, while control mice showed upregulation of cytokines associated with triggering an immune response.
By transferring subsets of regulatory T cells taken from the mice that received the experimental plants into normal mice, the researchers were able to suppress inhibitor formation. This suggests the T cells were able to carry tolerance-inducing characteristics to the new population of animals.
“This gives us an explanation for the mechanism of how this tolerance is being created,” Dr Daniell said.
Finally, the researchers tried to reverse inhibitor formation. They fed the experimental plant material to mice that had already developed inhibitors.
Compared to a control group, the mice given the FVIII-containing plant material had their inhibitor formation slow and then reverse, decreasing 3- to 7-fold over 2 or 3 months of feeding.
This strategy holds promise for preventing and even reversing inhibitor formation in hemophiliacs receiving FVIII infusions. However, the researchers’ experiments showed that inhibitor levels could rise again as time passes.
“After some time, antibodies do develop if you stop giving them the plant material,” Dr Daniell said. “This is not a one-time treatment. You need to do it repetitively to maintain the tolerance.”
Dr Daniell and the Penn Center for Innovation are now working with a pharmaceutical company to test this oral tolerance strategy in other animal species, with plans to begin human trials shortly thereafter. For human use, the goal would be to use lettuce plants instead of tobacco plants.
A new strategy may one day prevent hemophilia patients from developing antibodies that inhibit clotting factors.
With this method, plant cells “teach” the immune system to tolerate the clotting factor protein.
In mice with hemophilia A, the strategy prevented and reversed the formation of factor VIII (FVIII) inhibitors.
Henry Daniell, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia, and his colleagues described the approach in Blood. The work was supported by the National Institutes of Health and Bayer.
“The only current treatments for inhibitor formation cost $1 million and are risky for patients,” Dr Daniell said. “Our technique, which uses plant-based capsules, has the potential to be a cost-effective and safe alternative.”
Developing the technique
Previous studies had shown that exposing the immune system to individual components of the clotting factor protein could induce tolerance to the whole protein.
FVIII is composed of a heavy chain and a light chain, with each containing 3 domains. For their study, the researchers used the whole heavy chain and the C2 domain of the light chain.
Dr Daniell and his colleagues developed a platform for delivering drugs and biotherapeutics that relies on genetically modifying plants so they express the protein of interest.
Trying that same method with the components of the FVIII molecule, the team first fused the heavy chain DNA with DNA encoding a cholera toxin subunit, a protein that can cross the intestinal wall and enter the bloodstream, and did the same with the C2 DNA.
They introduced the fused genes into tobacco chloroplasts, so that some plants expressed the heavy chain and cholera toxin proteins and others expressed the C2 and cholera toxin proteins. They then ground up the plant leaves and suspended them in a solution, mixing the heavy chain and C2 solutions together.
Testing in mice
The researchers fed the mixed solution to mice with hemophilia A twice a week for 2 months and compared them to mice that consumed unmodified plant material. The team then gave the mice infusions of FVIII.
As expected, the control mice formed high levels of inhibitors. But the mice fed the experimental plant material formed much lower levels of inhibitors—on average, 7 times lower.
Mice that consumed the experimental plants exhibited upregulation of cytokines associated with suppressing or regulating immune responses, while control mice showed upregulation of cytokines associated with triggering an immune response.
By transferring subsets of regulatory T cells taken from the mice that received the experimental plants into normal mice, the researchers were able to suppress inhibitor formation. This suggests the T cells were able to carry tolerance-inducing characteristics to the new population of animals.
“This gives us an explanation for the mechanism of how this tolerance is being created,” Dr Daniell said.
Finally, the researchers tried to reverse inhibitor formation. They fed the experimental plant material to mice that had already developed inhibitors.
Compared to a control group, the mice given the FVIII-containing plant material had their inhibitor formation slow and then reverse, decreasing 3- to 7-fold over 2 or 3 months of feeding.
This strategy holds promise for preventing and even reversing inhibitor formation in hemophiliacs receiving FVIII infusions. However, the researchers’ experiments showed that inhibitor levels could rise again as time passes.
“After some time, antibodies do develop if you stop giving them the plant material,” Dr Daniell said. “This is not a one-time treatment. You need to do it repetitively to maintain the tolerance.”
Dr Daniell and the Penn Center for Innovation are now working with a pharmaceutical company to test this oral tolerance strategy in other animal species, with plans to begin human trials shortly thereafter. For human use, the goal would be to use lettuce plants instead of tobacco plants.
A new strategy may one day prevent hemophilia patients from developing antibodies that inhibit clotting factors.
With this method, plant cells “teach” the immune system to tolerate the clotting factor protein.
In mice with hemophilia A, the strategy prevented and reversed the formation of factor VIII (FVIII) inhibitors.
Henry Daniell, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia, and his colleagues described the approach in Blood. The work was supported by the National Institutes of Health and Bayer.
“The only current treatments for inhibitor formation cost $1 million and are risky for patients,” Dr Daniell said. “Our technique, which uses plant-based capsules, has the potential to be a cost-effective and safe alternative.”
Developing the technique
Previous studies had shown that exposing the immune system to individual components of the clotting factor protein could induce tolerance to the whole protein.
FVIII is composed of a heavy chain and a light chain, with each containing 3 domains. For their study, the researchers used the whole heavy chain and the C2 domain of the light chain.
Dr Daniell and his colleagues developed a platform for delivering drugs and biotherapeutics that relies on genetically modifying plants so they express the protein of interest.
Trying that same method with the components of the FVIII molecule, the team first fused the heavy chain DNA with DNA encoding a cholera toxin subunit, a protein that can cross the intestinal wall and enter the bloodstream, and did the same with the C2 DNA.
They introduced the fused genes into tobacco chloroplasts, so that some plants expressed the heavy chain and cholera toxin proteins and others expressed the C2 and cholera toxin proteins. They then ground up the plant leaves and suspended them in a solution, mixing the heavy chain and C2 solutions together.
Testing in mice
The researchers fed the mixed solution to mice with hemophilia A twice a week for 2 months and compared them to mice that consumed unmodified plant material. The team then gave the mice infusions of FVIII.
As expected, the control mice formed high levels of inhibitors. But the mice fed the experimental plant material formed much lower levels of inhibitors—on average, 7 times lower.
Mice that consumed the experimental plants exhibited upregulation of cytokines associated with suppressing or regulating immune responses, while control mice showed upregulation of cytokines associated with triggering an immune response.
By transferring subsets of regulatory T cells taken from the mice that received the experimental plants into normal mice, the researchers were able to suppress inhibitor formation. This suggests the T cells were able to carry tolerance-inducing characteristics to the new population of animals.
“This gives us an explanation for the mechanism of how this tolerance is being created,” Dr Daniell said.
Finally, the researchers tried to reverse inhibitor formation. They fed the experimental plant material to mice that had already developed inhibitors.
Compared to a control group, the mice given the FVIII-containing plant material had their inhibitor formation slow and then reverse, decreasing 3- to 7-fold over 2 or 3 months of feeding.
This strategy holds promise for preventing and even reversing inhibitor formation in hemophiliacs receiving FVIII infusions. However, the researchers’ experiments showed that inhibitor levels could rise again as time passes.
“After some time, antibodies do develop if you stop giving them the plant material,” Dr Daniell said. “This is not a one-time treatment. You need to do it repetitively to maintain the tolerance.”
Dr Daniell and the Penn Center for Innovation are now working with a pharmaceutical company to test this oral tolerance strategy in other animal species, with plans to begin human trials shortly thereafter. For human use, the goal would be to use lettuce plants instead of tobacco plants.
Banked blood grows stiffer with age, study shows
Credit: Daniel Gay
The longer blood is stored, the less it is able to carry oxygen into the tiny microcapillaries of the body, according to a study published in Scientific Reports.
Using advanced optical techniques, researchers measured the stiffness of the membrane surrounding red blood cells.
They found that, even though the cells retain their shape and hemoglobin content, the membranes get stiffer over time, which steadily decreases the cells’ functionality.
“Our results show some surprising facts: Even though the blood looks good on the surface, its functionality is degrading steadily with time,” said study author Gabriel Popescu, PhD, of the University of Illinois at Urbana-Champaign.
Dr Popescu and his colleagues wanted to measure changes in red blood cells over time to help determine what effect older blood could have on a patient.
They used an optical technique called spatial light interference microscopy (SLIM), which was developed in Dr Popescu’s lab in 2011. It uses light to noninvasively measure cell mass and topology with nanoscale accuracy. Through software and hardware advances, the SLIM system today acquires images almost 100 times faster than it did 3 years ago.
The researchers took time-lapse images of red blood cells, measuring and charting their properties. In particular, the team was able to measure nanometer-scale motions of the cell membrane, which are indicative of the cell’s stiffness and function. The fainter the membrane motion, the less functional the cell.
The measurements revealed that a lot of characteristics stay the same over time. The cells retain their shape, mass, and hemoglobin content, for example.
However, the membranes become stiffer and less elastic as time passes. This is important because the cells need to be flexible enough to travel through tiny capillaries and permeable enough for oxygen to pass through.
“In microcirculation, such as that in the brain, cells need to squeeze though very narrow capillaries to carry oxygen,” said study author Basanta Bhaduri, PhD, of the University of Illinois at Urbana-Champaign.
“If they are not deformable enough, the oxygen transport is impeded to that particular organ, and major clinical problems may arise. This is the reason why new red blood cells are produced continuously by the bone marrow, such that no cells older than 100 days or so exist in our circulation.”
The researchers hope the SLIM imaging method will be used clinically to monitor stored blood before it is given to patients, since conventional white-light microscopes can be easily adapted for SLIM with a few extra components.
“These results can have a wide variety of clinical applications,” said author Krishna Tangella, MD, of the University of Illinois at Urbana-Champaign.
“Functional data from red blood cells would help physicians determine when to give red cell transfusions for patients with anemia. This study may help better utilization of red cell transfusions, which will not only decrease healthcare costs but also increase the quality of care.”
Credit: Daniel Gay
The longer blood is stored, the less it is able to carry oxygen into the tiny microcapillaries of the body, according to a study published in Scientific Reports.
Using advanced optical techniques, researchers measured the stiffness of the membrane surrounding red blood cells.
They found that, even though the cells retain their shape and hemoglobin content, the membranes get stiffer over time, which steadily decreases the cells’ functionality.
“Our results show some surprising facts: Even though the blood looks good on the surface, its functionality is degrading steadily with time,” said study author Gabriel Popescu, PhD, of the University of Illinois at Urbana-Champaign.
Dr Popescu and his colleagues wanted to measure changes in red blood cells over time to help determine what effect older blood could have on a patient.
They used an optical technique called spatial light interference microscopy (SLIM), which was developed in Dr Popescu’s lab in 2011. It uses light to noninvasively measure cell mass and topology with nanoscale accuracy. Through software and hardware advances, the SLIM system today acquires images almost 100 times faster than it did 3 years ago.
The researchers took time-lapse images of red blood cells, measuring and charting their properties. In particular, the team was able to measure nanometer-scale motions of the cell membrane, which are indicative of the cell’s stiffness and function. The fainter the membrane motion, the less functional the cell.
The measurements revealed that a lot of characteristics stay the same over time. The cells retain their shape, mass, and hemoglobin content, for example.
However, the membranes become stiffer and less elastic as time passes. This is important because the cells need to be flexible enough to travel through tiny capillaries and permeable enough for oxygen to pass through.
“In microcirculation, such as that in the brain, cells need to squeeze though very narrow capillaries to carry oxygen,” said study author Basanta Bhaduri, PhD, of the University of Illinois at Urbana-Champaign.
“If they are not deformable enough, the oxygen transport is impeded to that particular organ, and major clinical problems may arise. This is the reason why new red blood cells are produced continuously by the bone marrow, such that no cells older than 100 days or so exist in our circulation.”
The researchers hope the SLIM imaging method will be used clinically to monitor stored blood before it is given to patients, since conventional white-light microscopes can be easily adapted for SLIM with a few extra components.
“These results can have a wide variety of clinical applications,” said author Krishna Tangella, MD, of the University of Illinois at Urbana-Champaign.
“Functional data from red blood cells would help physicians determine when to give red cell transfusions for patients with anemia. This study may help better utilization of red cell transfusions, which will not only decrease healthcare costs but also increase the quality of care.”
Credit: Daniel Gay
The longer blood is stored, the less it is able to carry oxygen into the tiny microcapillaries of the body, according to a study published in Scientific Reports.
Using advanced optical techniques, researchers measured the stiffness of the membrane surrounding red blood cells.
They found that, even though the cells retain their shape and hemoglobin content, the membranes get stiffer over time, which steadily decreases the cells’ functionality.
“Our results show some surprising facts: Even though the blood looks good on the surface, its functionality is degrading steadily with time,” said study author Gabriel Popescu, PhD, of the University of Illinois at Urbana-Champaign.
Dr Popescu and his colleagues wanted to measure changes in red blood cells over time to help determine what effect older blood could have on a patient.
They used an optical technique called spatial light interference microscopy (SLIM), which was developed in Dr Popescu’s lab in 2011. It uses light to noninvasively measure cell mass and topology with nanoscale accuracy. Through software and hardware advances, the SLIM system today acquires images almost 100 times faster than it did 3 years ago.
The researchers took time-lapse images of red blood cells, measuring and charting their properties. In particular, the team was able to measure nanometer-scale motions of the cell membrane, which are indicative of the cell’s stiffness and function. The fainter the membrane motion, the less functional the cell.
The measurements revealed that a lot of characteristics stay the same over time. The cells retain their shape, mass, and hemoglobin content, for example.
However, the membranes become stiffer and less elastic as time passes. This is important because the cells need to be flexible enough to travel through tiny capillaries and permeable enough for oxygen to pass through.
“In microcirculation, such as that in the brain, cells need to squeeze though very narrow capillaries to carry oxygen,” said study author Basanta Bhaduri, PhD, of the University of Illinois at Urbana-Champaign.
“If they are not deformable enough, the oxygen transport is impeded to that particular organ, and major clinical problems may arise. This is the reason why new red blood cells are produced continuously by the bone marrow, such that no cells older than 100 days or so exist in our circulation.”
The researchers hope the SLIM imaging method will be used clinically to monitor stored blood before it is given to patients, since conventional white-light microscopes can be easily adapted for SLIM with a few extra components.
“These results can have a wide variety of clinical applications,” said author Krishna Tangella, MD, of the University of Illinois at Urbana-Champaign.
“Functional data from red blood cells would help physicians determine when to give red cell transfusions for patients with anemia. This study may help better utilization of red cell transfusions, which will not only decrease healthcare costs but also increase the quality of care.”
Overcoming an obstacle to RBC development
Researchers have discovered a natural barrier to hematopoiesis and a way to circumvent it, according to a paper published in Blood.
The group found that components of the exosome complex—exosc8 and exosc9—suppress red blood cell (RBC) maturation.
“From a fundamental perspective, this is very important because this mechanism counteracts the development of precursor cells into red blood cells, thereby establishing a balance between developed cells and the progenitor population,” said study author Emery Bresnick, PhD, of the UW School of Medicine and Public Health in Madison, Wisconsin.
“In the context of translation, if you want to maximize the output of end-stage red blood cells, which we’re not able to do at this time, our study provides a rational approach involving lowering the levels of these subunits.”
Specifically, the researchers found that GATA-1 and Foxo3 can repress the exosome components, thereby allowing for RBC maturation.
The barrier explained
Dr Bresnick and his colleagues noted that the primary obstacle in converting hematopoietic stem cells into RBCs involves late-stage maturation.
“The problem isn’t simply getting erythroid precursors produced by the bucket, but understanding how these cells systematically lose their nuclei and organelles to become a red blood cell, the final product,” Dr Bresnick said.
“This is the bottleneck, even in the stem cell world of embryonic and induced pluripotent stem cells. We know little about how the cell orchestrates the intricate processes that constitute late-stage maturation.”
At the end of RBC development, the erythroid precursor must eject its own genetic material via enucleation. Although it’s clear why enucleation is important (making the cell more flexible and allowing it to carry more oxygen), exactly how the cell does it has been unclear.
Besides ejecting the nucleus, the cell must be cleared of other organelles, such as the endoplasmic reticulum and mitochondria. This process (autophagy) is linked to a pair of transcription factors—GATA1 and Foxo3—that control gene expression important in RBC development.
Because they knew GATA1 and Foxo3 promote autophagy, Dr Bresnick and his colleagues wondered if the proteins these transcription factors repress play an important role in cell maturation.
This led them to identify exosc8 and exosc9, two units of the exosome that ultimately established the development barrier.
The researchers plan to continue studying the exosome because many RNAs in the cell are not degraded by the exosome. Determining exactly how the exosome decides what RNA to dispose of may provide an even better understanding of the newly discovered barrier.
“One goal we have is to establish the specific RNA targets the exosome is regulating that are responsible for the blockade,” Dr Bresnick said. “In doing so, we might even uncover targets that are easier to manipulate than the exosome itself.”
Researchers have discovered a natural barrier to hematopoiesis and a way to circumvent it, according to a paper published in Blood.
The group found that components of the exosome complex—exosc8 and exosc9—suppress red blood cell (RBC) maturation.
“From a fundamental perspective, this is very important because this mechanism counteracts the development of precursor cells into red blood cells, thereby establishing a balance between developed cells and the progenitor population,” said study author Emery Bresnick, PhD, of the UW School of Medicine and Public Health in Madison, Wisconsin.
“In the context of translation, if you want to maximize the output of end-stage red blood cells, which we’re not able to do at this time, our study provides a rational approach involving lowering the levels of these subunits.”
Specifically, the researchers found that GATA-1 and Foxo3 can repress the exosome components, thereby allowing for RBC maturation.
The barrier explained
Dr Bresnick and his colleagues noted that the primary obstacle in converting hematopoietic stem cells into RBCs involves late-stage maturation.
“The problem isn’t simply getting erythroid precursors produced by the bucket, but understanding how these cells systematically lose their nuclei and organelles to become a red blood cell, the final product,” Dr Bresnick said.
“This is the bottleneck, even in the stem cell world of embryonic and induced pluripotent stem cells. We know little about how the cell orchestrates the intricate processes that constitute late-stage maturation.”
At the end of RBC development, the erythroid precursor must eject its own genetic material via enucleation. Although it’s clear why enucleation is important (making the cell more flexible and allowing it to carry more oxygen), exactly how the cell does it has been unclear.
Besides ejecting the nucleus, the cell must be cleared of other organelles, such as the endoplasmic reticulum and mitochondria. This process (autophagy) is linked to a pair of transcription factors—GATA1 and Foxo3—that control gene expression important in RBC development.
Because they knew GATA1 and Foxo3 promote autophagy, Dr Bresnick and his colleagues wondered if the proteins these transcription factors repress play an important role in cell maturation.
This led them to identify exosc8 and exosc9, two units of the exosome that ultimately established the development barrier.
The researchers plan to continue studying the exosome because many RNAs in the cell are not degraded by the exosome. Determining exactly how the exosome decides what RNA to dispose of may provide an even better understanding of the newly discovered barrier.
“One goal we have is to establish the specific RNA targets the exosome is regulating that are responsible for the blockade,” Dr Bresnick said. “In doing so, we might even uncover targets that are easier to manipulate than the exosome itself.”
Researchers have discovered a natural barrier to hematopoiesis and a way to circumvent it, according to a paper published in Blood.
The group found that components of the exosome complex—exosc8 and exosc9—suppress red blood cell (RBC) maturation.
“From a fundamental perspective, this is very important because this mechanism counteracts the development of precursor cells into red blood cells, thereby establishing a balance between developed cells and the progenitor population,” said study author Emery Bresnick, PhD, of the UW School of Medicine and Public Health in Madison, Wisconsin.
“In the context of translation, if you want to maximize the output of end-stage red blood cells, which we’re not able to do at this time, our study provides a rational approach involving lowering the levels of these subunits.”
Specifically, the researchers found that GATA-1 and Foxo3 can repress the exosome components, thereby allowing for RBC maturation.
The barrier explained
Dr Bresnick and his colleagues noted that the primary obstacle in converting hematopoietic stem cells into RBCs involves late-stage maturation.
“The problem isn’t simply getting erythroid precursors produced by the bucket, but understanding how these cells systematically lose their nuclei and organelles to become a red blood cell, the final product,” Dr Bresnick said.
“This is the bottleneck, even in the stem cell world of embryonic and induced pluripotent stem cells. We know little about how the cell orchestrates the intricate processes that constitute late-stage maturation.”
At the end of RBC development, the erythroid precursor must eject its own genetic material via enucleation. Although it’s clear why enucleation is important (making the cell more flexible and allowing it to carry more oxygen), exactly how the cell does it has been unclear.
Besides ejecting the nucleus, the cell must be cleared of other organelles, such as the endoplasmic reticulum and mitochondria. This process (autophagy) is linked to a pair of transcription factors—GATA1 and Foxo3—that control gene expression important in RBC development.
Because they knew GATA1 and Foxo3 promote autophagy, Dr Bresnick and his colleagues wondered if the proteins these transcription factors repress play an important role in cell maturation.
This led them to identify exosc8 and exosc9, two units of the exosome that ultimately established the development barrier.
The researchers plan to continue studying the exosome because many RNAs in the cell are not degraded by the exosome. Determining exactly how the exosome decides what RNA to dispose of may provide an even better understanding of the newly discovered barrier.
“One goal we have is to establish the specific RNA targets the exosome is regulating that are responsible for the blockade,” Dr Bresnick said. “In doing so, we might even uncover targets that are easier to manipulate than the exosome itself.”
Health Canada approves dabigatran for VTE
Credit: Kevin MacKenzie
Health Canada has approved dabigatran etexilate (Pradaxa) for the treatment and prevention of venous thromboembolism (VTE).
Dabigatran is a novel, reversible, oral direct thrombin inhibitor that has been on the market for more than 5 years and is approved in more than 100 countries.
Health Canada’s latest approval of dabigatran is based on results from four phase 3 trials—RE-MEDY, RE-SONATE, and RE-COVER I and II.
The trials suggested that dabigatran given at 150 mg twice daily can treat and prevent a recurrence of deep vein thrombosis or pulmonary embolism.
RE-COVER I
In the first RE-COVER trial, dabigatran proved noninferior to warfarin for preventing VTE recurrence, and rates of major bleeding were similar between the treatment arms. However, patients were more likely to discontinue dabigatran due to adverse events.
VTE recurred in 2.4% of patients treated with dabigatran and 2.1% of patients who received warfarin (P<0.001 for noninferiority).
Bleeding events occurred in 16.1% of patients who received dabigatran and 21.9% of warfarin-treated patients (P<0.001). Major bleeding occurred in 1.6% and 1.9% of patients, respectively (P=0.38).
The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar between the treatment arms. But adverse events leading to treatment discontinuation occurred in 9.0% of dabigatran-treated patients and 6.8% of patients in the warfarin arm (P=0.05).
Results from RE-COVER were presented at ASH 2009 and published in NEJM.
RE-COVER II
The RE-COVER II trial suggested that dabigatran was noninferior to warfarin for preventing VTE recurrence and related deaths. This outcome occurred in 2.3% of dabigatran-treated patients and 2.2% of warfarin-treated patients (P<0.001 for noninferiority).
Major bleeding occurred 1.2% of patients who received dabigatran and 1.7% of patients who received warfarin. Any bleeding occurred in 15.6% and 22.1% of patients, respectively.
Overall, rates of death, adverse events, and acute coronary syndromes were similar between the treatment arms.
Results from RE-COVER II were published in Circulation in 2013.
RE-MEDY and RE-SONATE
The RE-MEDY and RE-SONATE trials were designed to evaluate dabigatran as extended VTE prophylaxis. Results of both trials were reported in a single NEJM article published in 2013.
The RE-MEDY trial showed that dabigatran was noninferior to warfarin as extended prophylaxis for recurrent VTE, and warfarin presented a significantly higher risk of bleeding.
VTE recurred in 1.8% of patients in the dabigatran arm and 1.3% of patients in the warfarin arm (P=0.01 for noninferiority). And the rate of clinically relevant or major bleeding was lower with dabigatran than with warfarin—at 5.6% and 10.2%, respectively (P<0.001).
Results of the RE-SONATE trial showed that dabigatran was superior to placebo for preventing recurrent VTE, although the drug significantly increased the risk of major or clinically relevant bleeding.
VTE recurred in 0.4% of patients in the dabigatran arm and 5.6% of patients in the placebo arm (P<0.001). Clinically relevant or major bleeding occurred in 5.3% of patients in the dabigatran and 1.8% of patients in the placebo arm (P=0.001).
Safety concerns with dabigatran
Over the years, the safety of dabigatran has been called into question, as serious bleeding events have been reported in patients taking the drug.
However, results of two investigations by the US Food and Drug Administration—one reported in 2012 and one reported this year—have suggested the benefits of dabigatran outweigh the risks.
Recently, a series of papers published in The BMJ raised concerns about dabigatran, claiming the drug’s developer underreported adverse events and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy. The developer, Boehringer Ingelheim, denied these allegations.
For more information on dabigatran, see its product monograph.
Credit: Kevin MacKenzie
Health Canada has approved dabigatran etexilate (Pradaxa) for the treatment and prevention of venous thromboembolism (VTE).
Dabigatran is a novel, reversible, oral direct thrombin inhibitor that has been on the market for more than 5 years and is approved in more than 100 countries.
Health Canada’s latest approval of dabigatran is based on results from four phase 3 trials—RE-MEDY, RE-SONATE, and RE-COVER I and II.
The trials suggested that dabigatran given at 150 mg twice daily can treat and prevent a recurrence of deep vein thrombosis or pulmonary embolism.
RE-COVER I
In the first RE-COVER trial, dabigatran proved noninferior to warfarin for preventing VTE recurrence, and rates of major bleeding were similar between the treatment arms. However, patients were more likely to discontinue dabigatran due to adverse events.
VTE recurred in 2.4% of patients treated with dabigatran and 2.1% of patients who received warfarin (P<0.001 for noninferiority).
Bleeding events occurred in 16.1% of patients who received dabigatran and 21.9% of warfarin-treated patients (P<0.001). Major bleeding occurred in 1.6% and 1.9% of patients, respectively (P=0.38).
The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar between the treatment arms. But adverse events leading to treatment discontinuation occurred in 9.0% of dabigatran-treated patients and 6.8% of patients in the warfarin arm (P=0.05).
Results from RE-COVER were presented at ASH 2009 and published in NEJM.
RE-COVER II
The RE-COVER II trial suggested that dabigatran was noninferior to warfarin for preventing VTE recurrence and related deaths. This outcome occurred in 2.3% of dabigatran-treated patients and 2.2% of warfarin-treated patients (P<0.001 for noninferiority).
Major bleeding occurred 1.2% of patients who received dabigatran and 1.7% of patients who received warfarin. Any bleeding occurred in 15.6% and 22.1% of patients, respectively.
Overall, rates of death, adverse events, and acute coronary syndromes were similar between the treatment arms.
Results from RE-COVER II were published in Circulation in 2013.
RE-MEDY and RE-SONATE
The RE-MEDY and RE-SONATE trials were designed to evaluate dabigatran as extended VTE prophylaxis. Results of both trials were reported in a single NEJM article published in 2013.
The RE-MEDY trial showed that dabigatran was noninferior to warfarin as extended prophylaxis for recurrent VTE, and warfarin presented a significantly higher risk of bleeding.
VTE recurred in 1.8% of patients in the dabigatran arm and 1.3% of patients in the warfarin arm (P=0.01 for noninferiority). And the rate of clinically relevant or major bleeding was lower with dabigatran than with warfarin—at 5.6% and 10.2%, respectively (P<0.001).
Results of the RE-SONATE trial showed that dabigatran was superior to placebo for preventing recurrent VTE, although the drug significantly increased the risk of major or clinically relevant bleeding.
VTE recurred in 0.4% of patients in the dabigatran arm and 5.6% of patients in the placebo arm (P<0.001). Clinically relevant or major bleeding occurred in 5.3% of patients in the dabigatran and 1.8% of patients in the placebo arm (P=0.001).
Safety concerns with dabigatran
Over the years, the safety of dabigatran has been called into question, as serious bleeding events have been reported in patients taking the drug.
However, results of two investigations by the US Food and Drug Administration—one reported in 2012 and one reported this year—have suggested the benefits of dabigatran outweigh the risks.
Recently, a series of papers published in The BMJ raised concerns about dabigatran, claiming the drug’s developer underreported adverse events and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy. The developer, Boehringer Ingelheim, denied these allegations.
For more information on dabigatran, see its product monograph.
Credit: Kevin MacKenzie
Health Canada has approved dabigatran etexilate (Pradaxa) for the treatment and prevention of venous thromboembolism (VTE).
Dabigatran is a novel, reversible, oral direct thrombin inhibitor that has been on the market for more than 5 years and is approved in more than 100 countries.
Health Canada’s latest approval of dabigatran is based on results from four phase 3 trials—RE-MEDY, RE-SONATE, and RE-COVER I and II.
The trials suggested that dabigatran given at 150 mg twice daily can treat and prevent a recurrence of deep vein thrombosis or pulmonary embolism.
RE-COVER I
In the first RE-COVER trial, dabigatran proved noninferior to warfarin for preventing VTE recurrence, and rates of major bleeding were similar between the treatment arms. However, patients were more likely to discontinue dabigatran due to adverse events.
VTE recurred in 2.4% of patients treated with dabigatran and 2.1% of patients who received warfarin (P<0.001 for noninferiority).
Bleeding events occurred in 16.1% of patients who received dabigatran and 21.9% of warfarin-treated patients (P<0.001). Major bleeding occurred in 1.6% and 1.9% of patients, respectively (P=0.38).
The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar between the treatment arms. But adverse events leading to treatment discontinuation occurred in 9.0% of dabigatran-treated patients and 6.8% of patients in the warfarin arm (P=0.05).
Results from RE-COVER were presented at ASH 2009 and published in NEJM.
RE-COVER II
The RE-COVER II trial suggested that dabigatran was noninferior to warfarin for preventing VTE recurrence and related deaths. This outcome occurred in 2.3% of dabigatran-treated patients and 2.2% of warfarin-treated patients (P<0.001 for noninferiority).
Major bleeding occurred 1.2% of patients who received dabigatran and 1.7% of patients who received warfarin. Any bleeding occurred in 15.6% and 22.1% of patients, respectively.
Overall, rates of death, adverse events, and acute coronary syndromes were similar between the treatment arms.
Results from RE-COVER II were published in Circulation in 2013.
RE-MEDY and RE-SONATE
The RE-MEDY and RE-SONATE trials were designed to evaluate dabigatran as extended VTE prophylaxis. Results of both trials were reported in a single NEJM article published in 2013.
The RE-MEDY trial showed that dabigatran was noninferior to warfarin as extended prophylaxis for recurrent VTE, and warfarin presented a significantly higher risk of bleeding.
VTE recurred in 1.8% of patients in the dabigatran arm and 1.3% of patients in the warfarin arm (P=0.01 for noninferiority). And the rate of clinically relevant or major bleeding was lower with dabigatran than with warfarin—at 5.6% and 10.2%, respectively (P<0.001).
Results of the RE-SONATE trial showed that dabigatran was superior to placebo for preventing recurrent VTE, although the drug significantly increased the risk of major or clinically relevant bleeding.
VTE recurred in 0.4% of patients in the dabigatran arm and 5.6% of patients in the placebo arm (P<0.001). Clinically relevant or major bleeding occurred in 5.3% of patients in the dabigatran and 1.8% of patients in the placebo arm (P=0.001).
Safety concerns with dabigatran
Over the years, the safety of dabigatran has been called into question, as serious bleeding events have been reported in patients taking the drug.
However, results of two investigations by the US Food and Drug Administration—one reported in 2012 and one reported this year—have suggested the benefits of dabigatran outweigh the risks.
Recently, a series of papers published in The BMJ raised concerns about dabigatran, claiming the drug’s developer underreported adverse events and withheld data showing that monitoring and dose adjustment could improve the safety of dabigatran without compromising its efficacy. The developer, Boehringer Ingelheim, denied these allegations.
For more information on dabigatran, see its product monograph.