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Drug receives orphan designation for ocular GVHD
The US Food and Drug Administration (FDA) has granted orphan drug designation to OCU300 (brimonidine tartrate) for the treatment of ocular graft-versus-host disease (oGVHD) occurring after allogeneic hematopoietic stem cell transplant.
Brimonidine tartrate is an alpha adrenergic agonist that is already FDA-approved to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Ocugen Inc. is repurposing the drug as OCU300 for the treatment of oGVHD under the FDA’s 505(b)(2) regulatory pathway.
“We are very excited to receive the first-ever orphan drug designation by the FDA for oGVHD, emphasizing the unmet medical need for patients with this disease,” said Shankar Musunuri, PhD, chairman, chief executive officer, and co-founder of Ocugen Inc.
“This is a significant milestone that will allow us to further advance the clinical development of OCU300, with a proprietary nanoemulsion, into a phase 3 clinical trial in the near future.”
According to Ocugen, OCU300 produced a beneficial effect in 90% of patients with oGVHD in an observational study, and the drug did not produce significant side effects.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved. 
The US Food and Drug Administration (FDA) has granted orphan drug designation to OCU300 (brimonidine tartrate) for the treatment of ocular graft-versus-host disease (oGVHD) occurring after allogeneic hematopoietic stem cell transplant.
Brimonidine tartrate is an alpha adrenergic agonist that is already FDA-approved to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Ocugen Inc. is repurposing the drug as OCU300 for the treatment of oGVHD under the FDA’s 505(b)(2) regulatory pathway.
“We are very excited to receive the first-ever orphan drug designation by the FDA for oGVHD, emphasizing the unmet medical need for patients with this disease,” said Shankar Musunuri, PhD, chairman, chief executive officer, and co-founder of Ocugen Inc.
“This is a significant milestone that will allow us to further advance the clinical development of OCU300, with a proprietary nanoemulsion, into a phase 3 clinical trial in the near future.”
According to Ocugen, OCU300 produced a beneficial effect in 90% of patients with oGVHD in an observational study, and the drug did not produce significant side effects.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to OCU300 (brimonidine tartrate) for the treatment of ocular graft-versus-host disease (oGVHD) occurring after allogeneic hematopoietic stem cell transplant.
Brimonidine tartrate is an alpha adrenergic agonist that is already FDA-approved to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Ocugen Inc. is repurposing the drug as OCU300 for the treatment of oGVHD under the FDA’s 505(b)(2) regulatory pathway.
“We are very excited to receive the first-ever orphan drug designation by the FDA for oGVHD, emphasizing the unmet medical need for patients with this disease,” said Shankar Musunuri, PhD, chairman, chief executive officer, and co-founder of Ocugen Inc.
“This is a significant milestone that will allow us to further advance the clinical development of OCU300, with a proprietary nanoemulsion, into a phase 3 clinical trial in the near future.”
According to Ocugen, OCU300 produced a beneficial effect in 90% of patients with oGVHD in an observational study, and the drug did not produce significant side effects.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
Targeting heme synthesis to treat AML
Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.
The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.
Previous research had suggested that heme production was affected in leukemia.
However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”
The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.
They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.
Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.
The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.
The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.
Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.
In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.
What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.
“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”
“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”
Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.
He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.
The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.
Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.
The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.
Previous research had suggested that heme production was affected in leukemia.
However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”
The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.
They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.
Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.
The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.
The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.
Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.
In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.
What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.
“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”
“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”
Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.
He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.
The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.
Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.
The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.
Previous research had suggested that heme production was affected in leukemia.
However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”
The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.
They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.
Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.
The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.
The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.
Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.
In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.
What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.
“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”
“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”
Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.
He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.
The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.
Advanced cancer patients have lower survival after cardiac arrest
A new study suggests patients with advanced cancer who suffer cardiac arrest in the hospital have a survival rate of less than 10%, which is about half the rate of patients without cancer who suffer cardiac arrest.
This finding helps to clear up some myths about cardiac arrest survival and can be used as a guidepost when hospitalized cancer patients and their families consider do-not-resuscitate (DNR) orders, said Jeffrey T. Bruckel, MD, of the University of Rochester Medical Center in New York.
“We’re hopeful that our study, in some way, will help doctors and cancer patients make more informed decisions about the end of life,” Dr Bruckel said. “It’s very important to have early, frank discussions around the goals of care.”
Dr Bruckel and his colleagues published their study in the Journal of Oncology Practice.
The researchers used a US-wide resuscitation registry to evaluate survival after cardiac arrest in patients treated at 369 hospitals.
The study excluded patients with implantable defibrillators and those who were admitted for surgery, emergency room treatment, rehabilitation, or treatment from cardiac catheterization labs or interventional radiology.
Of the 47,157 eligible patients who experienced cardiac arrest, 14% (n=6585) had advanced cancer, including hematologic malignancies.
After cardiac arrest, 57.5% of the advanced cancer patients were resuscitated successfully, as were 63% of non-cancer patients (P<0.001).
After resuscitation, 9.6% of the cancer patients survived to be discharged, compared to 19.2% of non-cancer patients (P<0.001).
When the researchers adjusted their analysis for potential confounders, results were similar. The rate of successful resuscitation was 52.3% in advanced cancer patients and 56.6% in non-cancer patients (P<0.001). The rate of survival to discharge was 7.4% and 13.4%, respectively (P<0.001).
Dr Bruckel said there was no evidence to suggest that patients with advanced cancer received less aggressive resuscitation care.
However, there was a significant difference in the mean duration of resuscitation time among non-survivors with cancer—22.5 minutes—and non-survivors without cancer—24.2 minutes (P<0.001). After adjustment, the mean duration of resuscitation was 22.5 minutes and 24.1 minutes, respectively (P<0.001).
Cancer patients were more likely than those without cancer to sign DNR orders after resuscitation—55.6% and 43%, respectively (P<0.001). Results were similar after adjustment—50.4% and 41.6%, respectively (P<0.001).
Dr Bruckel and his colleagues said there were several limitations to this study, including a lack of detailed data on the types of advanced cancer and cancer treatments being given at the time of cardiac arrest.
Therefore, the next step in advancing this work is to gather data on the types of cancer diagnosis and treatment plans of patients who undergo in-hospital cardiac arrest.
Dr Bruckel also believes it is important to know how patients feel about this data and how both patients and physicians are using this data in decision-making.
“A large component of end-of-life care involves patient and family care decision-making, and a lot of that is driven by the routine discussions that we have,” Dr Bruckel said. “Not every patient is going to want detailed information, but for those that do, it’s important to have it. It’s important to tell them what we know.”
A new study suggests patients with advanced cancer who suffer cardiac arrest in the hospital have a survival rate of less than 10%, which is about half the rate of patients without cancer who suffer cardiac arrest.
This finding helps to clear up some myths about cardiac arrest survival and can be used as a guidepost when hospitalized cancer patients and their families consider do-not-resuscitate (DNR) orders, said Jeffrey T. Bruckel, MD, of the University of Rochester Medical Center in New York.
“We’re hopeful that our study, in some way, will help doctors and cancer patients make more informed decisions about the end of life,” Dr Bruckel said. “It’s very important to have early, frank discussions around the goals of care.”
Dr Bruckel and his colleagues published their study in the Journal of Oncology Practice.
The researchers used a US-wide resuscitation registry to evaluate survival after cardiac arrest in patients treated at 369 hospitals.
The study excluded patients with implantable defibrillators and those who were admitted for surgery, emergency room treatment, rehabilitation, or treatment from cardiac catheterization labs or interventional radiology.
Of the 47,157 eligible patients who experienced cardiac arrest, 14% (n=6585) had advanced cancer, including hematologic malignancies.
After cardiac arrest, 57.5% of the advanced cancer patients were resuscitated successfully, as were 63% of non-cancer patients (P<0.001).
After resuscitation, 9.6% of the cancer patients survived to be discharged, compared to 19.2% of non-cancer patients (P<0.001).
When the researchers adjusted their analysis for potential confounders, results were similar. The rate of successful resuscitation was 52.3% in advanced cancer patients and 56.6% in non-cancer patients (P<0.001). The rate of survival to discharge was 7.4% and 13.4%, respectively (P<0.001).
Dr Bruckel said there was no evidence to suggest that patients with advanced cancer received less aggressive resuscitation care.
However, there was a significant difference in the mean duration of resuscitation time among non-survivors with cancer—22.5 minutes—and non-survivors without cancer—24.2 minutes (P<0.001). After adjustment, the mean duration of resuscitation was 22.5 minutes and 24.1 minutes, respectively (P<0.001).
Cancer patients were more likely than those without cancer to sign DNR orders after resuscitation—55.6% and 43%, respectively (P<0.001). Results were similar after adjustment—50.4% and 41.6%, respectively (P<0.001).
Dr Bruckel and his colleagues said there were several limitations to this study, including a lack of detailed data on the types of advanced cancer and cancer treatments being given at the time of cardiac arrest.
Therefore, the next step in advancing this work is to gather data on the types of cancer diagnosis and treatment plans of patients who undergo in-hospital cardiac arrest.
Dr Bruckel also believes it is important to know how patients feel about this data and how both patients and physicians are using this data in decision-making.
“A large component of end-of-life care involves patient and family care decision-making, and a lot of that is driven by the routine discussions that we have,” Dr Bruckel said. “Not every patient is going to want detailed information, but for those that do, it’s important to have it. It’s important to tell them what we know.”
A new study suggests patients with advanced cancer who suffer cardiac arrest in the hospital have a survival rate of less than 10%, which is about half the rate of patients without cancer who suffer cardiac arrest.
This finding helps to clear up some myths about cardiac arrest survival and can be used as a guidepost when hospitalized cancer patients and their families consider do-not-resuscitate (DNR) orders, said Jeffrey T. Bruckel, MD, of the University of Rochester Medical Center in New York.
“We’re hopeful that our study, in some way, will help doctors and cancer patients make more informed decisions about the end of life,” Dr Bruckel said. “It’s very important to have early, frank discussions around the goals of care.”
Dr Bruckel and his colleagues published their study in the Journal of Oncology Practice.
The researchers used a US-wide resuscitation registry to evaluate survival after cardiac arrest in patients treated at 369 hospitals.
The study excluded patients with implantable defibrillators and those who were admitted for surgery, emergency room treatment, rehabilitation, or treatment from cardiac catheterization labs or interventional radiology.
Of the 47,157 eligible patients who experienced cardiac arrest, 14% (n=6585) had advanced cancer, including hematologic malignancies.
After cardiac arrest, 57.5% of the advanced cancer patients were resuscitated successfully, as were 63% of non-cancer patients (P<0.001).
After resuscitation, 9.6% of the cancer patients survived to be discharged, compared to 19.2% of non-cancer patients (P<0.001).
When the researchers adjusted their analysis for potential confounders, results were similar. The rate of successful resuscitation was 52.3% in advanced cancer patients and 56.6% in non-cancer patients (P<0.001). The rate of survival to discharge was 7.4% and 13.4%, respectively (P<0.001).
Dr Bruckel said there was no evidence to suggest that patients with advanced cancer received less aggressive resuscitation care.
However, there was a significant difference in the mean duration of resuscitation time among non-survivors with cancer—22.5 minutes—and non-survivors without cancer—24.2 minutes (P<0.001). After adjustment, the mean duration of resuscitation was 22.5 minutes and 24.1 minutes, respectively (P<0.001).
Cancer patients were more likely than those without cancer to sign DNR orders after resuscitation—55.6% and 43%, respectively (P<0.001). Results were similar after adjustment—50.4% and 41.6%, respectively (P<0.001).
Dr Bruckel and his colleagues said there were several limitations to this study, including a lack of detailed data on the types of advanced cancer and cancer treatments being given at the time of cardiac arrest.
Therefore, the next step in advancing this work is to gather data on the types of cancer diagnosis and treatment plans of patients who undergo in-hospital cardiac arrest.
Dr Bruckel also believes it is important to know how patients feel about this data and how both patients and physicians are using this data in decision-making.
“A large component of end-of-life care involves patient and family care decision-making, and a lot of that is driven by the routine discussions that we have,” Dr Bruckel said. “Not every patient is going to want detailed information, but for those that do, it’s important to have it. It’s important to tell them what we know.”
Database may provide insight into childhood cancers
A database containing information on more than 11,000 tumors is now available to researchers studying pediatric cancers.
The database was created as part of UC Santa Cruz Genomics Institute’s Treehouse Childhood Cancer Initiative.
The goal of this initiative is to allow researchers to analyze their patients’ data alongside data from thousands of patients with pediatric and adult cancers, including leukemias and lymphomas.
The intention is to help researchers find hidden causes of cancer that may be missed when they analyze a patient’s data in isolation.
The database, which is available at https://treehouse.xenahubs.net, contains RNA-sequencing gene expression data, as well as information on patients’ age, sex, and disease.
A database containing information on more than 11,000 tumors is now available to researchers studying pediatric cancers.
The database was created as part of UC Santa Cruz Genomics Institute’s Treehouse Childhood Cancer Initiative.
The goal of this initiative is to allow researchers to analyze their patients’ data alongside data from thousands of patients with pediatric and adult cancers, including leukemias and lymphomas.
The intention is to help researchers find hidden causes of cancer that may be missed when they analyze a patient’s data in isolation.
The database, which is available at https://treehouse.xenahubs.net, contains RNA-sequencing gene expression data, as well as information on patients’ age, sex, and disease.
A database containing information on more than 11,000 tumors is now available to researchers studying pediatric cancers.
The database was created as part of UC Santa Cruz Genomics Institute’s Treehouse Childhood Cancer Initiative.
The goal of this initiative is to allow researchers to analyze their patients’ data alongside data from thousands of patients with pediatric and adult cancers, including leukemias and lymphomas.
The intention is to help researchers find hidden causes of cancer that may be missed when they analyze a patient’s data in isolation.
The database, which is available at https://treehouse.xenahubs.net, contains RNA-sequencing gene expression data, as well as information on patients’ age, sex, and disease.
Glucose metabolism deemed key to platelet survival
New research published in Cell Reports suggests platelets are highly reliant on their ability to metabolize glucose.
Researchers studied mice lacking proteins that platelets use to import glucose—glucose transporter (GLUT) 1 and GLUT3.
These mice had lower platelet counts and their platelets had shorter life spans than platelets in wild-type mice.
“We found that glucose metabolism is very critical across the entire life cycle of platelets—from production, to what they do in the body, to how they get cleared from the body,” said E. Dale Abel, MBBS, PhD, of the University of Iowa in Iowa City.
For this study, Dr Abel and his colleagues studied genetically engineered mouse models that were missing GLUT1 and GLUT3 or GLUT3 alone and observed how platelet formation, function, and clearance were affected.
Mice missing glucose transporter proteins did produce platelets, and the platelets’ mitochondria metabolized other substances in place of glucose. However, the mice had platelet counts that were lower than normal.
The researchers were able to pinpoint 2 causes for the low platelet count in mice lacking GLUT1 and GLUT3—fewer platelets being produced and increased clearance of platelets.
The team tested megakaryocytes’ ability to generate new platelets by depleting the blood of platelets and observing the subsequent recovery, which was lower than normal.
They also tested the megakaryocytes in culture, stimulating them to create new platelets, and found the generation of new platelets was defective.
“Clearly, we show that there’s an obligate need for glucose to bud platelets off from the bone marrow,” Dr Abel said.
In addition, the team observed that young platelets functioned normally, even in the absence of glucose. But as they aged, the platelets were cleared from the circulation earlier than normal because they were being destroyed.
“We identified a new mechanism of necrosis by which the absence of glucose leads to the cleavage of a protein called calpain, which marks them for this necrotic pathway,” Dr Abel said. “If we treated the animals with a calpain inhibitor, we could reduce the increased platelet clearance.”
The team also sought to determine whether platelets could exist and function when mitochondria metabolism is halted.
They injected the mice with oligomycin, which inhibits mitochondrial metabolism. In the mice deficient in GLUT1 and GLUT3, platelet counts dropped to 0 within about 30 minutes. The same effect did not occur in wild-type mice.
“This work defined a very important role for metabolism in how platelets leave the bone marrow, how they come into circulation, and how they stay in circulation,” Dr Abel said. “It could even have implications for why platelets have to be used within a certain period of time when they’re donated at the blood bank—the fresher the better.”
New research published in Cell Reports suggests platelets are highly reliant on their ability to metabolize glucose.
Researchers studied mice lacking proteins that platelets use to import glucose—glucose transporter (GLUT) 1 and GLUT3.
These mice had lower platelet counts and their platelets had shorter life spans than platelets in wild-type mice.
“We found that glucose metabolism is very critical across the entire life cycle of platelets—from production, to what they do in the body, to how they get cleared from the body,” said E. Dale Abel, MBBS, PhD, of the University of Iowa in Iowa City.
For this study, Dr Abel and his colleagues studied genetically engineered mouse models that were missing GLUT1 and GLUT3 or GLUT3 alone and observed how platelet formation, function, and clearance were affected.
Mice missing glucose transporter proteins did produce platelets, and the platelets’ mitochondria metabolized other substances in place of glucose. However, the mice had platelet counts that were lower than normal.
The researchers were able to pinpoint 2 causes for the low platelet count in mice lacking GLUT1 and GLUT3—fewer platelets being produced and increased clearance of platelets.
The team tested megakaryocytes’ ability to generate new platelets by depleting the blood of platelets and observing the subsequent recovery, which was lower than normal.
They also tested the megakaryocytes in culture, stimulating them to create new platelets, and found the generation of new platelets was defective.
“Clearly, we show that there’s an obligate need for glucose to bud platelets off from the bone marrow,” Dr Abel said.
In addition, the team observed that young platelets functioned normally, even in the absence of glucose. But as they aged, the platelets were cleared from the circulation earlier than normal because they were being destroyed.
“We identified a new mechanism of necrosis by which the absence of glucose leads to the cleavage of a protein called calpain, which marks them for this necrotic pathway,” Dr Abel said. “If we treated the animals with a calpain inhibitor, we could reduce the increased platelet clearance.”
The team also sought to determine whether platelets could exist and function when mitochondria metabolism is halted.
They injected the mice with oligomycin, which inhibits mitochondrial metabolism. In the mice deficient in GLUT1 and GLUT3, platelet counts dropped to 0 within about 30 minutes. The same effect did not occur in wild-type mice.
“This work defined a very important role for metabolism in how platelets leave the bone marrow, how they come into circulation, and how they stay in circulation,” Dr Abel said. “It could even have implications for why platelets have to be used within a certain period of time when they’re donated at the blood bank—the fresher the better.”
New research published in Cell Reports suggests platelets are highly reliant on their ability to metabolize glucose.
Researchers studied mice lacking proteins that platelets use to import glucose—glucose transporter (GLUT) 1 and GLUT3.
These mice had lower platelet counts and their platelets had shorter life spans than platelets in wild-type mice.
“We found that glucose metabolism is very critical across the entire life cycle of platelets—from production, to what they do in the body, to how they get cleared from the body,” said E. Dale Abel, MBBS, PhD, of the University of Iowa in Iowa City.
For this study, Dr Abel and his colleagues studied genetically engineered mouse models that were missing GLUT1 and GLUT3 or GLUT3 alone and observed how platelet formation, function, and clearance were affected.
Mice missing glucose transporter proteins did produce platelets, and the platelets’ mitochondria metabolized other substances in place of glucose. However, the mice had platelet counts that were lower than normal.
The researchers were able to pinpoint 2 causes for the low platelet count in mice lacking GLUT1 and GLUT3—fewer platelets being produced and increased clearance of platelets.
The team tested megakaryocytes’ ability to generate new platelets by depleting the blood of platelets and observing the subsequent recovery, which was lower than normal.
They also tested the megakaryocytes in culture, stimulating them to create new platelets, and found the generation of new platelets was defective.
“Clearly, we show that there’s an obligate need for glucose to bud platelets off from the bone marrow,” Dr Abel said.
In addition, the team observed that young platelets functioned normally, even in the absence of glucose. But as they aged, the platelets were cleared from the circulation earlier than normal because they were being destroyed.
“We identified a new mechanism of necrosis by which the absence of glucose leads to the cleavage of a protein called calpain, which marks them for this necrotic pathway,” Dr Abel said. “If we treated the animals with a calpain inhibitor, we could reduce the increased platelet clearance.”
The team also sought to determine whether platelets could exist and function when mitochondria metabolism is halted.
They injected the mice with oligomycin, which inhibits mitochondrial metabolism. In the mice deficient in GLUT1 and GLUT3, platelet counts dropped to 0 within about 30 minutes. The same effect did not occur in wild-type mice.
“This work defined a very important role for metabolism in how platelets leave the bone marrow, how they come into circulation, and how they stay in circulation,” Dr Abel said. “It could even have implications for why platelets have to be used within a certain period of time when they’re donated at the blood bank—the fresher the better.”
Team characterizes RIMs in childhood cancer survivors
Neuroscientists say they have uncovered genetic differences between radiation-induced meningiomas (RIMs) and sporadic meningiomas (SMs).
Their work suggests RIMs have a different “mutational landscape” from SMs, a finding that may have “significant therapeutic implications” for childhood cancer survivors who undergo cranial radiation.
Gelareh Zadeh, MD, PhD, of the University of Toronto in Ontario, Canada, and her colleagues reported these findings in Nature Communications.
“Radiation-induced meningiomas appear the same [as SMs] on MRI and pathology, feel the same during surgery, and look the same under the operating microscope,” Dr Zadeh said.
“What’s different is they are more aggressive, tend to recur in multiples, and invade the brain, causing significant morbidity and limitations (or impairments) for individuals who survive following childhood radiation. By understanding the biology, the goal is to identify a therapeutic strategy that could be implemented early on after childhood radiation to prevent the formation of these tumors in the first place.”
To better understand the biology, Dr Zadeh and her colleagues analyzed 31 RIMs. This included 18 tumors from 16 patients with childhood cancers, 9 with leukemia.
The researchers found NF2 gene rearrangements in 12 of the RIMs and noted that such rearrangements have not been observed in SMs.
On the other hand, recurrent mutations characteristic of SMs—AKT1, KLF4, TRAF7, and SMO—were not found in the RIMs.
The researchers also noted that, overall, chromosomal aberrations in RIMs were more complex than those observed in SMs. And combined loss of chromosomes 1p and 22q was common in RIMs (16/18).
“Our research identified a specific rearrangement involving the NF2 gene that causes radiation-induced meningiomas,” said Kenneth Aldape, MD, of University Health Network in Toronto.
“But there are likely other genetic rearrangements that are occurring as a result of that radiation-induced DNA damage. So one of the next steps is to identify what the radiation is doing to the DNA of the meninges.”
“In addition, identifying the subset of childhood cancer patients who are at highest risk to develop meningioma is critical so that they could be followed closely for early detection and management.”
Neuroscientists say they have uncovered genetic differences between radiation-induced meningiomas (RIMs) and sporadic meningiomas (SMs).
Their work suggests RIMs have a different “mutational landscape” from SMs, a finding that may have “significant therapeutic implications” for childhood cancer survivors who undergo cranial radiation.
Gelareh Zadeh, MD, PhD, of the University of Toronto in Ontario, Canada, and her colleagues reported these findings in Nature Communications.
“Radiation-induced meningiomas appear the same [as SMs] on MRI and pathology, feel the same during surgery, and look the same under the operating microscope,” Dr Zadeh said.
“What’s different is they are more aggressive, tend to recur in multiples, and invade the brain, causing significant morbidity and limitations (or impairments) for individuals who survive following childhood radiation. By understanding the biology, the goal is to identify a therapeutic strategy that could be implemented early on after childhood radiation to prevent the formation of these tumors in the first place.”
To better understand the biology, Dr Zadeh and her colleagues analyzed 31 RIMs. This included 18 tumors from 16 patients with childhood cancers, 9 with leukemia.
The researchers found NF2 gene rearrangements in 12 of the RIMs and noted that such rearrangements have not been observed in SMs.
On the other hand, recurrent mutations characteristic of SMs—AKT1, KLF4, TRAF7, and SMO—were not found in the RIMs.
The researchers also noted that, overall, chromosomal aberrations in RIMs were more complex than those observed in SMs. And combined loss of chromosomes 1p and 22q was common in RIMs (16/18).
“Our research identified a specific rearrangement involving the NF2 gene that causes radiation-induced meningiomas,” said Kenneth Aldape, MD, of University Health Network in Toronto.
“But there are likely other genetic rearrangements that are occurring as a result of that radiation-induced DNA damage. So one of the next steps is to identify what the radiation is doing to the DNA of the meninges.”
“In addition, identifying the subset of childhood cancer patients who are at highest risk to develop meningioma is critical so that they could be followed closely for early detection and management.”
Neuroscientists say they have uncovered genetic differences between radiation-induced meningiomas (RIMs) and sporadic meningiomas (SMs).
Their work suggests RIMs have a different “mutational landscape” from SMs, a finding that may have “significant therapeutic implications” for childhood cancer survivors who undergo cranial radiation.
Gelareh Zadeh, MD, PhD, of the University of Toronto in Ontario, Canada, and her colleagues reported these findings in Nature Communications.
“Radiation-induced meningiomas appear the same [as SMs] on MRI and pathology, feel the same during surgery, and look the same under the operating microscope,” Dr Zadeh said.
“What’s different is they are more aggressive, tend to recur in multiples, and invade the brain, causing significant morbidity and limitations (or impairments) for individuals who survive following childhood radiation. By understanding the biology, the goal is to identify a therapeutic strategy that could be implemented early on after childhood radiation to prevent the formation of these tumors in the first place.”
To better understand the biology, Dr Zadeh and her colleagues analyzed 31 RIMs. This included 18 tumors from 16 patients with childhood cancers, 9 with leukemia.
The researchers found NF2 gene rearrangements in 12 of the RIMs and noted that such rearrangements have not been observed in SMs.
On the other hand, recurrent mutations characteristic of SMs—AKT1, KLF4, TRAF7, and SMO—were not found in the RIMs.
The researchers also noted that, overall, chromosomal aberrations in RIMs were more complex than those observed in SMs. And combined loss of chromosomes 1p and 22q was common in RIMs (16/18).
“Our research identified a specific rearrangement involving the NF2 gene that causes radiation-induced meningiomas,” said Kenneth Aldape, MD, of University Health Network in Toronto.
“But there are likely other genetic rearrangements that are occurring as a result of that radiation-induced DNA damage. So one of the next steps is to identify what the radiation is doing to the DNA of the meninges.”
“In addition, identifying the subset of childhood cancer patients who are at highest risk to develop meningioma is critical so that they could be followed closely for early detection and management.”
Drug granted priority review, breakthrough designation for ECD
The US Food and Drug Administration (FDA) has granted priority review and breakthrough therapy designation to vemurafenib (Zelboraf®) as a treatment for Erdheim-Chester disease (ECD) with BRAF V600 mutation.
Vemurafenib is a kinase inhibitor designed to inhibit some mutated forms of BRAF.
The drug is already FDA-approved to treat patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.
The FDA is expected to make a decision on the approval of vemurafenib in ECD by December 7, 2017.
The supplemental new drug application for vemurafenib in this indication is supported by data from the phase 2 VE-BASKET study.
VE-BASKET was designed to investigate the use of vemurafenib in patients with BRAF V600 mutation-positive diseases, including ECD.
Final results for the 22 people with ECD showed a best overall response rate of 54.5%. The median duration of response, progression-free survival, and overall survival were not reached at a median follow-up of 26.6 months.
The most common adverse events were joint pain, rash, hair loss, change in heart rhythm, fatigue, skin tags, diarrhea, and thickening of the skin. The most common grade 3 or higher adverse events were new skin cancers, high blood pressure, rash, and joint pain.
Initial results from this study were published in NEJM in August 2015.
About priority review
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted priority review and breakthrough therapy designation to vemurafenib (Zelboraf®) as a treatment for Erdheim-Chester disease (ECD) with BRAF V600 mutation.
Vemurafenib is a kinase inhibitor designed to inhibit some mutated forms of BRAF.
The drug is already FDA-approved to treat patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.
The FDA is expected to make a decision on the approval of vemurafenib in ECD by December 7, 2017.
The supplemental new drug application for vemurafenib in this indication is supported by data from the phase 2 VE-BASKET study.
VE-BASKET was designed to investigate the use of vemurafenib in patients with BRAF V600 mutation-positive diseases, including ECD.
Final results for the 22 people with ECD showed a best overall response rate of 54.5%. The median duration of response, progression-free survival, and overall survival were not reached at a median follow-up of 26.6 months.
The most common adverse events were joint pain, rash, hair loss, change in heart rhythm, fatigue, skin tags, diarrhea, and thickening of the skin. The most common grade 3 or higher adverse events were new skin cancers, high blood pressure, rash, and joint pain.
Initial results from this study were published in NEJM in August 2015.
About priority review
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted priority review and breakthrough therapy designation to vemurafenib (Zelboraf®) as a treatment for Erdheim-Chester disease (ECD) with BRAF V600 mutation.
Vemurafenib is a kinase inhibitor designed to inhibit some mutated forms of BRAF.
The drug is already FDA-approved to treat patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.
The FDA is expected to make a decision on the approval of vemurafenib in ECD by December 7, 2017.
The supplemental new drug application for vemurafenib in this indication is supported by data from the phase 2 VE-BASKET study.
VE-BASKET was designed to investigate the use of vemurafenib in patients with BRAF V600 mutation-positive diseases, including ECD.
Final results for the 22 people with ECD showed a best overall response rate of 54.5%. The median duration of response, progression-free survival, and overall survival were not reached at a median follow-up of 26.6 months.
The most common adverse events were joint pain, rash, hair loss, change in heart rhythm, fatigue, skin tags, diarrhea, and thickening of the skin. The most common grade 3 or higher adverse events were new skin cancers, high blood pressure, rash, and joint pain.
Initial results from this study were published in NEJM in August 2015.
About priority review
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
About breakthrough designation
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
FDA issues EUA for Zika virus test
The US Food and Drug Administration (FDA) has issued an emergency use authorization (EUA) for Thermo Fisher Scientific’s TaqPath Zika Virus Kit.
This means the TaqPath Zika Virus Kit is authorized for the qualitative detection of RNA from Zika virus and diagnosis of Zika virus infection in human serum and urine (collected alongside a patient-matched serum specimen) from individuals meeting the US Centers for Disease Control and Prevention’s criteria for testing.
The EUA does not mean the TaqPath Zika Virus Kit is FDA cleared or approved.
An EUA allows for the use of unapproved medical products or unapproved uses of approved medical products in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the TaqPath Zika Virus Kit means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
Testing using the TaqPath Zika Virus Kit is authorized to be conducted by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
More information on the TaqPath Zika Virus Kit and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has issued an emergency use authorization (EUA) for Thermo Fisher Scientific’s TaqPath Zika Virus Kit.
This means the TaqPath Zika Virus Kit is authorized for the qualitative detection of RNA from Zika virus and diagnosis of Zika virus infection in human serum and urine (collected alongside a patient-matched serum specimen) from individuals meeting the US Centers for Disease Control and Prevention’s criteria for testing.
The EUA does not mean the TaqPath Zika Virus Kit is FDA cleared or approved.
An EUA allows for the use of unapproved medical products or unapproved uses of approved medical products in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the TaqPath Zika Virus Kit means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
Testing using the TaqPath Zika Virus Kit is authorized to be conducted by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
More information on the TaqPath Zika Virus Kit and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has issued an emergency use authorization (EUA) for Thermo Fisher Scientific’s TaqPath Zika Virus Kit.
This means the TaqPath Zika Virus Kit is authorized for the qualitative detection of RNA from Zika virus and diagnosis of Zika virus infection in human serum and urine (collected alongside a patient-matched serum specimen) from individuals meeting the US Centers for Disease Control and Prevention’s criteria for testing.
The EUA does not mean the TaqPath Zika Virus Kit is FDA cleared or approved.
An EUA allows for the use of unapproved medical products or unapproved uses of approved medical products in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the TaqPath Zika Virus Kit means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
Testing using the TaqPath Zika Virus Kit is authorized to be conducted by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
More information on the TaqPath Zika Virus Kit and other Zika tests granted EUAs can be found on the FDA’s EUA page.
ATO enables anthracycline reduction in pediatric APL
Consolidation therapy that includes arsenic trioxide (ATO) can decrease anthracycline dosing by about 40% in children and young adults with acute promyelocytic leukemia (APL), according to new research.
And it can accomplish this without compromising survival in standard-risk patients.
Outcomes for high-risk patients compared favorably to other pediatric APL trials, the research indicated.
Investigators compared ATO consolidation in the AAML0631 trial to the historic control trial AIDA0493 and reported the results in the Journal of Clinical Oncology.
The AAML0631 phase 3 trial, conducted by the Children’s Oncology Group, compared newly diagnosed pediatric APL patients receiving ATO consolidation to the benchmark of event-free survival (EFS) in standard-risk (SR) patients established by the AIDA0493 trial.
AIDA0493 enrolled patients between January 1993 and June 2000. The protocol involved treatment with all-trans retinoic acid (ATRA), anthracyclines, and high-dose cytarabine. The trial resulted in overall survival (OS) of approximately 90%.
AAML0631
AAML063 investigators defined SR as a white blood cell count (WBC) at presentation less than 10,000 cells/μL. They defined high risk (HR) as a WBC count of 10,000 cells/μL or more.
AAML0631 patients had to be at least 2 years old and younger than 22, and their de novo APL had to be confirmed by PML-RARα polymerase chain reaction.
The patients could have had no prior leukemia treatment, except for steroids, hydroxyurea, or leukapheresis.
AAML0631 did not exclude patients based on organ function or performance status. AIDA0493, however, excluded patients with performance status of 4 or liver function tests greater than 3 times the upper limit of normal.
Patients were excluded from AAML0631 if they had preexisting prolonged QT syndrome because of the risk of QT interval prolongation with ATO.
AAML0631 treatment protocol
All patients received ATRA during induction, each consolidation course, and maintenance.
Induction therapy consisted of ATRA and idarubicin.
All patients received 2 cycles of ATO during the first consolidation. SR patients received an additional 2 consolidation courses, and HR patients received 3 consolidation courses that included high-dose cytarabine and anthracycline.
Maintenance therapy consisted of ATRA, oral methotrexate, and 6-mercaptopurine for 2 years.
Patients also received prophylactic treatment with intrathecal cytarabine.
Patient demographics
Investigators enrolled 108 patients between March 2009 and November 2012, of which 101 (66 SR and 35 HR) were evaluable.
Patients were a median age of 15.04 years (range, 2.01 – 21.34), 56% were female, 80% were white, 10% black, 2% Native American, 3% Asian, and 5% unknown.
Three quarters of the patients had an ECOG score of 0 or 1, median WBC counts of 3.8 x 1000 cells/uL (range, 0.4 – 173.8), and median platelet counts of 21.5 x 1000/uL (range, 3 – 198).
Almost two-thirds of patients (63%) had the classic translocation (15;17), and 37% had an additional 1 or more cytogenetic abnormalities.
The SR patients in AAML0631 had similar characteristics to the patients in AIDA0493 except for the distribution of performance status scores and differences in racial/ethnic diversity.
Efficacy
After a median follow-up of 3.73 years (range, 0.003 – 5.97), the 3-year overall survival (OS) was 94% ± 5% and the 3-year EFS was 91% ± 6%.
For SR patients, the OS was 98% ± 3% and the EFS 95% ± 5%.
For HR patients, the OS was 86% ± 12% and the EFS was 83% ± 13%.
SR patients had a 2-year EFS of 97%. This compared with 91% for patients in the AIDA0493 trial, which means that therapy with ATO was not inferior to therapy in the historic comparator trial (P=0.93).
And these results were achieved with a cumulative anthracycline dosing of idarubicin at 51 mg/m2 (SR) and 61 mg/m2 (HR) and mitoxantrone at 20 mg/m2.
This compared with the AIDA0493 cumulative anthracycline dosing of 80 mg/m2 of idarubicin and 50 mg/m2 of mitoxantrone.
The cumulative daunorubicin equivalent in the AAML0631 trial was 335 mg/m2 (SR) and 385 mg/m2 (HR) compared with 600 mg/m2 in the AIDA 0493 trial.
Toxicity
The percentage of patients with adverse events varied according to treatment cycle and was highest during induction and high-dose cytarabine-containing courses.
The most common adverse events were fever/neutropenia and infection.
Differentiation syndrome occurred in 20% of patients during induction, 31% in HR patients and 13% in SR patients. ATRA was held for 15 of these patients during induction. It was subsequently re-started at a lower dose and increased to the full dose.
QTc interval prolongation of grade 1 or 2 occurred in 16% (n=15) and 12% (n=11) during the ATO cycles.
One patient experienced grade 3 QTc interval prolongation during ATO consolidation. There were no grade 4 or 5 events for this toxicity.
One event of grade 1 ventricular arrhythmia and 1 event of grade 1 left ventricular systolic dysfunction occurred during ATO consolidation.
Two off-therapy cardiac events have been reported: a grade 1 QTc interval prolongation and a grade 2 ventricular arrhythmia.
No cardiac deaths have occurred, and liver toxicity was minimal during ATO cycles.
The investigators believe the favorable results of this study provide a new benchmark for outcomes in pediatric APL.
The Children’s Oncology Group is currently accruing pediatric APL patients to further investigate similar treatment approaches.
Consolidation therapy that includes arsenic trioxide (ATO) can decrease anthracycline dosing by about 40% in children and young adults with acute promyelocytic leukemia (APL), according to new research.
And it can accomplish this without compromising survival in standard-risk patients.
Outcomes for high-risk patients compared favorably to other pediatric APL trials, the research indicated.
Investigators compared ATO consolidation in the AAML0631 trial to the historic control trial AIDA0493 and reported the results in the Journal of Clinical Oncology.
The AAML0631 phase 3 trial, conducted by the Children’s Oncology Group, compared newly diagnosed pediatric APL patients receiving ATO consolidation to the benchmark of event-free survival (EFS) in standard-risk (SR) patients established by the AIDA0493 trial.
AIDA0493 enrolled patients between January 1993 and June 2000. The protocol involved treatment with all-trans retinoic acid (ATRA), anthracyclines, and high-dose cytarabine. The trial resulted in overall survival (OS) of approximately 90%.
AAML0631
AAML063 investigators defined SR as a white blood cell count (WBC) at presentation less than 10,000 cells/μL. They defined high risk (HR) as a WBC count of 10,000 cells/μL or more.
AAML0631 patients had to be at least 2 years old and younger than 22, and their de novo APL had to be confirmed by PML-RARα polymerase chain reaction.
The patients could have had no prior leukemia treatment, except for steroids, hydroxyurea, or leukapheresis.
AAML0631 did not exclude patients based on organ function or performance status. AIDA0493, however, excluded patients with performance status of 4 or liver function tests greater than 3 times the upper limit of normal.
Patients were excluded from AAML0631 if they had preexisting prolonged QT syndrome because of the risk of QT interval prolongation with ATO.
AAML0631 treatment protocol
All patients received ATRA during induction, each consolidation course, and maintenance.
Induction therapy consisted of ATRA and idarubicin.
All patients received 2 cycles of ATO during the first consolidation. SR patients received an additional 2 consolidation courses, and HR patients received 3 consolidation courses that included high-dose cytarabine and anthracycline.
Maintenance therapy consisted of ATRA, oral methotrexate, and 6-mercaptopurine for 2 years.
Patients also received prophylactic treatment with intrathecal cytarabine.
Patient demographics
Investigators enrolled 108 patients between March 2009 and November 2012, of which 101 (66 SR and 35 HR) were evaluable.
Patients were a median age of 15.04 years (range, 2.01 – 21.34), 56% were female, 80% were white, 10% black, 2% Native American, 3% Asian, and 5% unknown.
Three quarters of the patients had an ECOG score of 0 or 1, median WBC counts of 3.8 x 1000 cells/uL (range, 0.4 – 173.8), and median platelet counts of 21.5 x 1000/uL (range, 3 – 198).
Almost two-thirds of patients (63%) had the classic translocation (15;17), and 37% had an additional 1 or more cytogenetic abnormalities.
The SR patients in AAML0631 had similar characteristics to the patients in AIDA0493 except for the distribution of performance status scores and differences in racial/ethnic diversity.
Efficacy
After a median follow-up of 3.73 years (range, 0.003 – 5.97), the 3-year overall survival (OS) was 94% ± 5% and the 3-year EFS was 91% ± 6%.
For SR patients, the OS was 98% ± 3% and the EFS 95% ± 5%.
For HR patients, the OS was 86% ± 12% and the EFS was 83% ± 13%.
SR patients had a 2-year EFS of 97%. This compared with 91% for patients in the AIDA0493 trial, which means that therapy with ATO was not inferior to therapy in the historic comparator trial (P=0.93).
And these results were achieved with a cumulative anthracycline dosing of idarubicin at 51 mg/m2 (SR) and 61 mg/m2 (HR) and mitoxantrone at 20 mg/m2.
This compared with the AIDA0493 cumulative anthracycline dosing of 80 mg/m2 of idarubicin and 50 mg/m2 of mitoxantrone.
The cumulative daunorubicin equivalent in the AAML0631 trial was 335 mg/m2 (SR) and 385 mg/m2 (HR) compared with 600 mg/m2 in the AIDA 0493 trial.
Toxicity
The percentage of patients with adverse events varied according to treatment cycle and was highest during induction and high-dose cytarabine-containing courses.
The most common adverse events were fever/neutropenia and infection.
Differentiation syndrome occurred in 20% of patients during induction, 31% in HR patients and 13% in SR patients. ATRA was held for 15 of these patients during induction. It was subsequently re-started at a lower dose and increased to the full dose.
QTc interval prolongation of grade 1 or 2 occurred in 16% (n=15) and 12% (n=11) during the ATO cycles.
One patient experienced grade 3 QTc interval prolongation during ATO consolidation. There were no grade 4 or 5 events for this toxicity.
One event of grade 1 ventricular arrhythmia and 1 event of grade 1 left ventricular systolic dysfunction occurred during ATO consolidation.
Two off-therapy cardiac events have been reported: a grade 1 QTc interval prolongation and a grade 2 ventricular arrhythmia.
No cardiac deaths have occurred, and liver toxicity was minimal during ATO cycles.
The investigators believe the favorable results of this study provide a new benchmark for outcomes in pediatric APL.
The Children’s Oncology Group is currently accruing pediatric APL patients to further investigate similar treatment approaches.
Consolidation therapy that includes arsenic trioxide (ATO) can decrease anthracycline dosing by about 40% in children and young adults with acute promyelocytic leukemia (APL), according to new research.
And it can accomplish this without compromising survival in standard-risk patients.
Outcomes for high-risk patients compared favorably to other pediatric APL trials, the research indicated.
Investigators compared ATO consolidation in the AAML0631 trial to the historic control trial AIDA0493 and reported the results in the Journal of Clinical Oncology.
The AAML0631 phase 3 trial, conducted by the Children’s Oncology Group, compared newly diagnosed pediatric APL patients receiving ATO consolidation to the benchmark of event-free survival (EFS) in standard-risk (SR) patients established by the AIDA0493 trial.
AIDA0493 enrolled patients between January 1993 and June 2000. The protocol involved treatment with all-trans retinoic acid (ATRA), anthracyclines, and high-dose cytarabine. The trial resulted in overall survival (OS) of approximately 90%.
AAML0631
AAML063 investigators defined SR as a white blood cell count (WBC) at presentation less than 10,000 cells/μL. They defined high risk (HR) as a WBC count of 10,000 cells/μL or more.
AAML0631 patients had to be at least 2 years old and younger than 22, and their de novo APL had to be confirmed by PML-RARα polymerase chain reaction.
The patients could have had no prior leukemia treatment, except for steroids, hydroxyurea, or leukapheresis.
AAML0631 did not exclude patients based on organ function or performance status. AIDA0493, however, excluded patients with performance status of 4 or liver function tests greater than 3 times the upper limit of normal.
Patients were excluded from AAML0631 if they had preexisting prolonged QT syndrome because of the risk of QT interval prolongation with ATO.
AAML0631 treatment protocol
All patients received ATRA during induction, each consolidation course, and maintenance.
Induction therapy consisted of ATRA and idarubicin.
All patients received 2 cycles of ATO during the first consolidation. SR patients received an additional 2 consolidation courses, and HR patients received 3 consolidation courses that included high-dose cytarabine and anthracycline.
Maintenance therapy consisted of ATRA, oral methotrexate, and 6-mercaptopurine for 2 years.
Patients also received prophylactic treatment with intrathecal cytarabine.
Patient demographics
Investigators enrolled 108 patients between March 2009 and November 2012, of which 101 (66 SR and 35 HR) were evaluable.
Patients were a median age of 15.04 years (range, 2.01 – 21.34), 56% were female, 80% were white, 10% black, 2% Native American, 3% Asian, and 5% unknown.
Three quarters of the patients had an ECOG score of 0 or 1, median WBC counts of 3.8 x 1000 cells/uL (range, 0.4 – 173.8), and median platelet counts of 21.5 x 1000/uL (range, 3 – 198).
Almost two-thirds of patients (63%) had the classic translocation (15;17), and 37% had an additional 1 or more cytogenetic abnormalities.
The SR patients in AAML0631 had similar characteristics to the patients in AIDA0493 except for the distribution of performance status scores and differences in racial/ethnic diversity.
Efficacy
After a median follow-up of 3.73 years (range, 0.003 – 5.97), the 3-year overall survival (OS) was 94% ± 5% and the 3-year EFS was 91% ± 6%.
For SR patients, the OS was 98% ± 3% and the EFS 95% ± 5%.
For HR patients, the OS was 86% ± 12% and the EFS was 83% ± 13%.
SR patients had a 2-year EFS of 97%. This compared with 91% for patients in the AIDA0493 trial, which means that therapy with ATO was not inferior to therapy in the historic comparator trial (P=0.93).
And these results were achieved with a cumulative anthracycline dosing of idarubicin at 51 mg/m2 (SR) and 61 mg/m2 (HR) and mitoxantrone at 20 mg/m2.
This compared with the AIDA0493 cumulative anthracycline dosing of 80 mg/m2 of idarubicin and 50 mg/m2 of mitoxantrone.
The cumulative daunorubicin equivalent in the AAML0631 trial was 335 mg/m2 (SR) and 385 mg/m2 (HR) compared with 600 mg/m2 in the AIDA 0493 trial.
Toxicity
The percentage of patients with adverse events varied according to treatment cycle and was highest during induction and high-dose cytarabine-containing courses.
The most common adverse events were fever/neutropenia and infection.
Differentiation syndrome occurred in 20% of patients during induction, 31% in HR patients and 13% in SR patients. ATRA was held for 15 of these patients during induction. It was subsequently re-started at a lower dose and increased to the full dose.
QTc interval prolongation of grade 1 or 2 occurred in 16% (n=15) and 12% (n=11) during the ATO cycles.
One patient experienced grade 3 QTc interval prolongation during ATO consolidation. There were no grade 4 or 5 events for this toxicity.
One event of grade 1 ventricular arrhythmia and 1 event of grade 1 left ventricular systolic dysfunction occurred during ATO consolidation.
Two off-therapy cardiac events have been reported: a grade 1 QTc interval prolongation and a grade 2 ventricular arrhythmia.
No cardiac deaths have occurred, and liver toxicity was minimal during ATO cycles.
The investigators believe the favorable results of this study provide a new benchmark for outcomes in pediatric APL.
The Children’s Oncology Group is currently accruing pediatric APL patients to further investigate similar treatment approaches.
Program reduces transfusions in leukemia, HSCT patients
New research suggests a patient blood management (PBM) program can safely reduce transfusion use in patients with acute leukemia and those undergoing hematopoietic stem cell transplant (HSCT).
The program significantly reduced the use of red blood cell (RBC) and platelet transfusions without increasing morbidity or mortality in patients who were receiving intensive chemotherapy to treat acute leukemia and in patients receiving an allogeneic or autologous HSCT.
“There has been a long-standing belief among hematologists that patients with leukemia undergoing chemotherapy should have a transfusion of red blood cells if their hemoglobin level drops below about 9 g/dL to help avoid adverse outcomes,” said study author Michael Leahy, MB ChB, a consultant hematologist at the University of Western Australia in Perth.
“Findings in this real-world, non-clinical trial setting challenge that belief.”
Dr Leahy and his colleagues published their findings in Transfusion.
The researchers said the PBM program used in this study was built around the “3 pillars” concept of PBM, which are:
- Optimize the patient’s RBC mass
- Minimize blood loss
- Harness and optimize the patient’s physiologic anemia reserve.
No specific transfusion thresholds were established. However, the hospitals did adopt a single-unit RBC transfusion policy for symptomatic anemic patients who were not actively bleeding.
Results
The study included 695 admissions to 2 major hospitals in Western Australia. Patients were admitted between July 2010 and December 2014 for treatment of acute leukemia or for autologous or allogeneic HSCT.
During this time, the patients received 3384 RBC units and 3639 units of platelets.
The mean number of platelet units transfused per hospital admission decreased 35% from baseline to the end of the study period, from 6.3 to 4.1 units (P<0.001).
The mean number of RBC units transfused decreased 39%, from 6.1 to 3.7 (P<0.001). Meanwhile, the use of single-unit RBC transfusions increased from 39% to 67% (P<0.001).
And the mean hemoglobin level prior to RBC transfusion decreased from 8.0 g/dL to 6.8 g/dL (P<0.001).
“This study suggests that patients undergoing chemotherapy with hematological disease may tolerate much lower levels of hemoglobin than previously thought,” said Shannon Farmer, an adjunct research fellow at the University of Western Australia.
“The transfusion threshold, the hemoglobin value at which a transfusion is given, dropped significantly from 8.0 g/dL at the beginning of the study to 6.8 g/dL at the end. This was associated with significant reductions in transfusion and substantial costs savings without evidence of harm to the patients. In fact, it was associated with a trend toward improved survival.”
The reduction in blood products over the study period resulted in a cost savings of AU$694,886 (US$654,007)—AU$389,537 (US$364,177) for RBCs and AU$305,349 (US$289,830) for platelets.
There were no significant changes over the study period in length of hospital stay, serious bleeding events, or in-hospital mortality.
There was a non-significant reduction in the mean length of hospital stay, from 24.5 days to 22.6 days (P=0.338). The difference was still not significant after the researchers adjusted for patient age, patient group, and comorbidities (incident rate ratio=0.88; 95% CI, 0.75-1.04).
The rate of serious bleeding increased over the study period, from 5.3% to 7.0% (P=0.582). After adjustment, the odds ratio was 1.14 (95% CI, 0.38-3.44; P=0.811).
There was a non-significant decrease in in-hospital mortality, from 5.3% to 2.0% (P=0.218). After adjustment, the odds ratio was 0.31 (95% CI, 0.06-1.56; P=0.154).
Based on these results, the researchers concluded that PBM programs could have a substantial impact in this patient population, reducing blood utilization and healthcare costs.
New research suggests a patient blood management (PBM) program can safely reduce transfusion use in patients with acute leukemia and those undergoing hematopoietic stem cell transplant (HSCT).
The program significantly reduced the use of red blood cell (RBC) and platelet transfusions without increasing morbidity or mortality in patients who were receiving intensive chemotherapy to treat acute leukemia and in patients receiving an allogeneic or autologous HSCT.
“There has been a long-standing belief among hematologists that patients with leukemia undergoing chemotherapy should have a transfusion of red blood cells if their hemoglobin level drops below about 9 g/dL to help avoid adverse outcomes,” said study author Michael Leahy, MB ChB, a consultant hematologist at the University of Western Australia in Perth.
“Findings in this real-world, non-clinical trial setting challenge that belief.”
Dr Leahy and his colleagues published their findings in Transfusion.
The researchers said the PBM program used in this study was built around the “3 pillars” concept of PBM, which are:
- Optimize the patient’s RBC mass
- Minimize blood loss
- Harness and optimize the patient’s physiologic anemia reserve.
No specific transfusion thresholds were established. However, the hospitals did adopt a single-unit RBC transfusion policy for symptomatic anemic patients who were not actively bleeding.
Results
The study included 695 admissions to 2 major hospitals in Western Australia. Patients were admitted between July 2010 and December 2014 for treatment of acute leukemia or for autologous or allogeneic HSCT.
During this time, the patients received 3384 RBC units and 3639 units of platelets.
The mean number of platelet units transfused per hospital admission decreased 35% from baseline to the end of the study period, from 6.3 to 4.1 units (P<0.001).
The mean number of RBC units transfused decreased 39%, from 6.1 to 3.7 (P<0.001). Meanwhile, the use of single-unit RBC transfusions increased from 39% to 67% (P<0.001).
And the mean hemoglobin level prior to RBC transfusion decreased from 8.0 g/dL to 6.8 g/dL (P<0.001).
“This study suggests that patients undergoing chemotherapy with hematological disease may tolerate much lower levels of hemoglobin than previously thought,” said Shannon Farmer, an adjunct research fellow at the University of Western Australia.
“The transfusion threshold, the hemoglobin value at which a transfusion is given, dropped significantly from 8.0 g/dL at the beginning of the study to 6.8 g/dL at the end. This was associated with significant reductions in transfusion and substantial costs savings without evidence of harm to the patients. In fact, it was associated with a trend toward improved survival.”
The reduction in blood products over the study period resulted in a cost savings of AU$694,886 (US$654,007)—AU$389,537 (US$364,177) for RBCs and AU$305,349 (US$289,830) for platelets.
There were no significant changes over the study period in length of hospital stay, serious bleeding events, or in-hospital mortality.
There was a non-significant reduction in the mean length of hospital stay, from 24.5 days to 22.6 days (P=0.338). The difference was still not significant after the researchers adjusted for patient age, patient group, and comorbidities (incident rate ratio=0.88; 95% CI, 0.75-1.04).
The rate of serious bleeding increased over the study period, from 5.3% to 7.0% (P=0.582). After adjustment, the odds ratio was 1.14 (95% CI, 0.38-3.44; P=0.811).
There was a non-significant decrease in in-hospital mortality, from 5.3% to 2.0% (P=0.218). After adjustment, the odds ratio was 0.31 (95% CI, 0.06-1.56; P=0.154).
Based on these results, the researchers concluded that PBM programs could have a substantial impact in this patient population, reducing blood utilization and healthcare costs.
New research suggests a patient blood management (PBM) program can safely reduce transfusion use in patients with acute leukemia and those undergoing hematopoietic stem cell transplant (HSCT).
The program significantly reduced the use of red blood cell (RBC) and platelet transfusions without increasing morbidity or mortality in patients who were receiving intensive chemotherapy to treat acute leukemia and in patients receiving an allogeneic or autologous HSCT.
“There has been a long-standing belief among hematologists that patients with leukemia undergoing chemotherapy should have a transfusion of red blood cells if their hemoglobin level drops below about 9 g/dL to help avoid adverse outcomes,” said study author Michael Leahy, MB ChB, a consultant hematologist at the University of Western Australia in Perth.
“Findings in this real-world, non-clinical trial setting challenge that belief.”
Dr Leahy and his colleagues published their findings in Transfusion.
The researchers said the PBM program used in this study was built around the “3 pillars” concept of PBM, which are:
- Optimize the patient’s RBC mass
- Minimize blood loss
- Harness and optimize the patient’s physiologic anemia reserve.
No specific transfusion thresholds were established. However, the hospitals did adopt a single-unit RBC transfusion policy for symptomatic anemic patients who were not actively bleeding.
Results
The study included 695 admissions to 2 major hospitals in Western Australia. Patients were admitted between July 2010 and December 2014 for treatment of acute leukemia or for autologous or allogeneic HSCT.
During this time, the patients received 3384 RBC units and 3639 units of platelets.
The mean number of platelet units transfused per hospital admission decreased 35% from baseline to the end of the study period, from 6.3 to 4.1 units (P<0.001).
The mean number of RBC units transfused decreased 39%, from 6.1 to 3.7 (P<0.001). Meanwhile, the use of single-unit RBC transfusions increased from 39% to 67% (P<0.001).
And the mean hemoglobin level prior to RBC transfusion decreased from 8.0 g/dL to 6.8 g/dL (P<0.001).
“This study suggests that patients undergoing chemotherapy with hematological disease may tolerate much lower levels of hemoglobin than previously thought,” said Shannon Farmer, an adjunct research fellow at the University of Western Australia.
“The transfusion threshold, the hemoglobin value at which a transfusion is given, dropped significantly from 8.0 g/dL at the beginning of the study to 6.8 g/dL at the end. This was associated with significant reductions in transfusion and substantial costs savings without evidence of harm to the patients. In fact, it was associated with a trend toward improved survival.”
The reduction in blood products over the study period resulted in a cost savings of AU$694,886 (US$654,007)—AU$389,537 (US$364,177) for RBCs and AU$305,349 (US$289,830) for platelets.
There were no significant changes over the study period in length of hospital stay, serious bleeding events, or in-hospital mortality.
There was a non-significant reduction in the mean length of hospital stay, from 24.5 days to 22.6 days (P=0.338). The difference was still not significant after the researchers adjusted for patient age, patient group, and comorbidities (incident rate ratio=0.88; 95% CI, 0.75-1.04).
The rate of serious bleeding increased over the study period, from 5.3% to 7.0% (P=0.582). After adjustment, the odds ratio was 1.14 (95% CI, 0.38-3.44; P=0.811).
There was a non-significant decrease in in-hospital mortality, from 5.3% to 2.0% (P=0.218). After adjustment, the odds ratio was 0.31 (95% CI, 0.06-1.56; P=0.154).
Based on these results, the researchers concluded that PBM programs could have a substantial impact in this patient population, reducing blood utilization and healthcare costs.