Hematology Times

Micrograph showing T-cell

acute lymphoblastic leukemia

Image by Hind Medyouf

Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.

These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.

In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.

“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.

These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.

By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.

All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.

The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.

Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.

By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.

The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.

“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”

The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.

“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.

“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”

In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.

The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.

“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.

Micrograph showing T-cell

acute lymphoblastic leukemia

Image by Hind Medyouf

Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.

These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.

In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.

“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.

These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.

By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.

All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.

The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.

Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.

By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.

The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.

“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”

The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.

“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.

“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”

In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.

The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.

“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.

Micrograph showing T-cell

acute lymphoblastic leukemia

Image by Hind Medyouf

Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.

These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.

In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.

“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.

These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.

By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.

All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.

The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.

Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.

By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.

The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.

“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”

The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.

“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.

“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”

In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.

The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.

“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted orphan designation to BMN 270, an investigational gene therapy, for the treatment of patients with hemophilia A.

BMN 270 is an adeno-associated virus-factor VIII (FVIII) vector designed to restore FVIII plasma concentrations in these patients.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

BMN 270 is under development by BioMarin Pharmaceutical Inc.

BioMarin is conducting a phase 1/2 study to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.

Researchers are assessing the safety of a single infusion of BMN 270 and the change in FVIII expression level from baseline to 16 weeks after infusion.

The group is also assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses.

Patients will be monitored for safety and durability of effect for 5 years. BioMarin plans to provide an update on this trial in April.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted orphan designation to BMN 270, an investigational gene therapy, for the treatment of patients with hemophilia A.

BMN 270 is an adeno-associated virus-factor VIII (FVIII) vector designed to restore FVIII plasma concentrations in these patients.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

BMN 270 is under development by BioMarin Pharmaceutical Inc.

BioMarin is conducting a phase 1/2 study to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.

Researchers are assessing the safety of a single infusion of BMN 270 and the change in FVIII expression level from baseline to 16 weeks after infusion.

The group is also assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses.

Patients will be monitored for safety and durability of effect for 5 years. BioMarin plans to provide an update on this trial in April.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted orphan designation to BMN 270, an investigational gene therapy, for the treatment of patients with hemophilia A.

BMN 270 is an adeno-associated virus-factor VIII (FVIII) vector designed to restore FVIII plasma concentrations in these patients.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

BMN 270 is under development by BioMarin Pharmaceutical Inc.

BioMarin is conducting a phase 1/2 study to evaluate the safety and efficacy of BMN 270 in up to 12 patients with severe hemophilia A.

Researchers are assessing the safety of a single infusion of BMN 270 and the change in FVIII expression level from baseline to 16 weeks after infusion.

The group is also assessing the impact of BMN 270 on the frequency of FVIII replacement therapy, the number of bleeding episodes requiring treatment, and any potential immune responses.

Patients will be monitored for safety and durability of effect for 5 years. BioMarin plans to provide an update on this trial in April.

Red blood cell culture showing

Staphylococcus infection

Photo by Bill Branson

A central catheter maintenance bundle can decrease the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in the American Journal of Critical Care.

A team from the healthcare company Select Medical developed and implemented the bundle at 30 long-term acute care hospitals.

The team used infection prevention guidelines from the Centers for Disease Control and Prevention as the core of the bundle, with mandatory use of alcohol-based central catheter caps and chlorhexidine gluconate dressings.

Ongoing education of clinical staff about the protocol and a checklist to track compliance were also key elements of the initiative.

At each hospital, staff nurses who demonstrated competency in the care of central catheters monitored implementation of the bundle for the initial 6 months of the study.

Researchers reviewed the medical records of 6660 patients discharged during the 14 months prior to the study and 6559 patients discharged after implementation of the bundle. Patient days and central catheter days before and after the bundle was implemented were comparable.

Six months after the bundle was implemented, the CLABSI standardized infection rate had dropped 29%. The rate was 1.28 in the 6 months before the bundle was implemented and 0.96 six months after implementation.

There was a mean reduction of 4.5 CLABSIs per hospital for 14 months after the bundle was implemented.

“Our results encourage the development and implementation of similar bundles as effective infection reduction strategies in [long-term acute care hospitals],” said study author Antony Grigonis, PhD, vice-president of quality and healthcare analytics at Select Medical.

“Preventing these infections can help reduce complications and the length of stay for other patients. This infection reduction could also translate to a savings of approximately $3.7 million annually for the 30 long-term acute care hospitals studied.”

Select Medical, which is based in Mechanicsburg, Pennsylvania, owns long-term acute care and inpatient rehabilitation hospitals, as well as occupational health and physical therapy clinics.

Red blood cell culture showing

Staphylococcus infection

Photo by Bill Branson

A central catheter maintenance bundle can decrease the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in the American Journal of Critical Care.

A team from the healthcare company Select Medical developed and implemented the bundle at 30 long-term acute care hospitals.

The team used infection prevention guidelines from the Centers for Disease Control and Prevention as the core of the bundle, with mandatory use of alcohol-based central catheter caps and chlorhexidine gluconate dressings.

Ongoing education of clinical staff about the protocol and a checklist to track compliance were also key elements of the initiative.

At each hospital, staff nurses who demonstrated competency in the care of central catheters monitored implementation of the bundle for the initial 6 months of the study.

Researchers reviewed the medical records of 6660 patients discharged during the 14 months prior to the study and 6559 patients discharged after implementation of the bundle. Patient days and central catheter days before and after the bundle was implemented were comparable.

Six months after the bundle was implemented, the CLABSI standardized infection rate had dropped 29%. The rate was 1.28 in the 6 months before the bundle was implemented and 0.96 six months after implementation.

There was a mean reduction of 4.5 CLABSIs per hospital for 14 months after the bundle was implemented.

“Our results encourage the development and implementation of similar bundles as effective infection reduction strategies in [long-term acute care hospitals],” said study author Antony Grigonis, PhD, vice-president of quality and healthcare analytics at Select Medical.

“Preventing these infections can help reduce complications and the length of stay for other patients. This infection reduction could also translate to a savings of approximately $3.7 million annually for the 30 long-term acute care hospitals studied.”

Select Medical, which is based in Mechanicsburg, Pennsylvania, owns long-term acute care and inpatient rehabilitation hospitals, as well as occupational health and physical therapy clinics.

Red blood cell culture showing

Staphylococcus infection

Photo by Bill Branson

A central catheter maintenance bundle can decrease the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in the American Journal of Critical Care.

A team from the healthcare company Select Medical developed and implemented the bundle at 30 long-term acute care hospitals.

The team used infection prevention guidelines from the Centers for Disease Control and Prevention as the core of the bundle, with mandatory use of alcohol-based central catheter caps and chlorhexidine gluconate dressings.

Ongoing education of clinical staff about the protocol and a checklist to track compliance were also key elements of the initiative.

At each hospital, staff nurses who demonstrated competency in the care of central catheters monitored implementation of the bundle for the initial 6 months of the study.

Researchers reviewed the medical records of 6660 patients discharged during the 14 months prior to the study and 6559 patients discharged after implementation of the bundle. Patient days and central catheter days before and after the bundle was implemented were comparable.

Six months after the bundle was implemented, the CLABSI standardized infection rate had dropped 29%. The rate was 1.28 in the 6 months before the bundle was implemented and 0.96 six months after implementation.

There was a mean reduction of 4.5 CLABSIs per hospital for 14 months after the bundle was implemented.

“Our results encourage the development and implementation of similar bundles as effective infection reduction strategies in [long-term acute care hospitals],” said study author Antony Grigonis, PhD, vice-president of quality and healthcare analytics at Select Medical.

“Preventing these infections can help reduce complications and the length of stay for other patients. This infection reduction could also translate to a savings of approximately $3.7 million annually for the 30 long-term acute care hospitals studied.”

Select Medical, which is based in Mechanicsburg, Pennsylvania, owns long-term acute care and inpatient rehabilitation hospitals, as well as occupational health and physical therapy clinics.

Cord blood donation

Photo courtesy of NHS

The US Food and Drug Administration (FDA) has issued a guidance document intended to help reduce the risk of Zika virus transmission via human cells, tissues, and cellular and tissue-based products (HCT/Ps).

The guidance addresses donation of HCT/Ps from both living and deceased donors, including donors of umbilical cord blood and hematopoietic stem/progenitor cells.

In this document, the FDA recommends a 6-month deferral period for most HCT/P donors who may have been exposed to the Zika virus.

The exception is donors of gestational tissues, who should be considered ineligible if they were at risk of contracting the virus at any time during their pregnancy.

The new guidance is a part of the FDA’s ongoing efforts to protect HCT/Ps and blood products from Zika virus transmission. Last month, the agency issued recommendations for reducing the risk of Zika virus transmission via blood transfusion.

There is a potential risk that Zika virus can be transmitted by HCT/Ps used as part of a medical, surgical, or reproductive procedure. HCT/Ps include products such as corneas, bone, skin, heart valves, hematopoietic stem/progenitor cells, gestational tissues such as amniotic membrane, and reproductive tissues such as semen and oocytes.

According to the Centers for Disease Control and Prevention, Zika virus can be spread by a man to his sexual partners. To date, there have been several cases of sexual transmission in the US.

Current information about Zika virus detection in semen suggests the period of deferral for HCT/P donors should be longer than the period recommended for donors of whole blood and blood components.

Therefore, the FDA has recommended that living donors of HCT/Ps be considered ineligible if they were diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had sex with a male with either of those risk factors within the past 6 months.

Donors of umbilical cord blood, placenta, or other gestational tissues should be considered ineligible if they have had any of the above risk factors at any point during their pregnancy.

Deceased donors should be considered ineligible if they were diagnosed with Zika virus infection in the past 6 months.

A deferral period of 6 months was chosen because of the limited data available on the length of time the virus can persist in all tissues. Zika virus has been detected in tissues and body fluids after the virus is no longer detectable in the blood stream and has been detected in semen possibly up to 10 weeks after the onset of symptoms.

Less evidence exists regarding the potential for transmission of Zika virus by HCT/Ps typically recovered from deceased donors. As more information becomes available, the understanding of the risks to recipients of HCT/Ps, including HCT/Ps recovered from deceased donors, may evolve.

The FDA said it will continue to monitor the situation and evaluate new information regarding the associated risks as it becomes available.

In addition, the FDA said it is prioritizing the development of blood donor screening and diagnostic tests that may be useful for identifying the presence of or recent infection with the Zika virus. The agency is prepared to evaluate investigational vaccines and therapeutics that might be developed and review technology that may help suppress populations of the mosquitoes that can spread the virus.

Cord blood donation

Photo courtesy of NHS

The US Food and Drug Administration (FDA) has issued a guidance document intended to help reduce the risk of Zika virus transmission via human cells, tissues, and cellular and tissue-based products (HCT/Ps).

The guidance addresses donation of HCT/Ps from both living and deceased donors, including donors of umbilical cord blood and hematopoietic stem/progenitor cells.

In this document, the FDA recommends a 6-month deferral period for most HCT/P donors who may have been exposed to the Zika virus.

The exception is donors of gestational tissues, who should be considered ineligible if they were at risk of contracting the virus at any time during their pregnancy.

The new guidance is a part of the FDA’s ongoing efforts to protect HCT/Ps and blood products from Zika virus transmission. Last month, the agency issued recommendations for reducing the risk of Zika virus transmission via blood transfusion.

There is a potential risk that Zika virus can be transmitted by HCT/Ps used as part of a medical, surgical, or reproductive procedure. HCT/Ps include products such as corneas, bone, skin, heart valves, hematopoietic stem/progenitor cells, gestational tissues such as amniotic membrane, and reproductive tissues such as semen and oocytes.

According to the Centers for Disease Control and Prevention, Zika virus can be spread by a man to his sexual partners. To date, there have been several cases of sexual transmission in the US.

Current information about Zika virus detection in semen suggests the period of deferral for HCT/P donors should be longer than the period recommended for donors of whole blood and blood components.

Therefore, the FDA has recommended that living donors of HCT/Ps be considered ineligible if they were diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had sex with a male with either of those risk factors within the past 6 months.

Donors of umbilical cord blood, placenta, or other gestational tissues should be considered ineligible if they have had any of the above risk factors at any point during their pregnancy.

Deceased donors should be considered ineligible if they were diagnosed with Zika virus infection in the past 6 months.

A deferral period of 6 months was chosen because of the limited data available on the length of time the virus can persist in all tissues. Zika virus has been detected in tissues and body fluids after the virus is no longer detectable in the blood stream and has been detected in semen possibly up to 10 weeks after the onset of symptoms.

Less evidence exists regarding the potential for transmission of Zika virus by HCT/Ps typically recovered from deceased donors. As more information becomes available, the understanding of the risks to recipients of HCT/Ps, including HCT/Ps recovered from deceased donors, may evolve.

The FDA said it will continue to monitor the situation and evaluate new information regarding the associated risks as it becomes available.

In addition, the FDA said it is prioritizing the development of blood donor screening and diagnostic tests that may be useful for identifying the presence of or recent infection with the Zika virus. The agency is prepared to evaluate investigational vaccines and therapeutics that might be developed and review technology that may help suppress populations of the mosquitoes that can spread the virus.

Cord blood donation

Photo courtesy of NHS

The US Food and Drug Administration (FDA) has issued a guidance document intended to help reduce the risk of Zika virus transmission via human cells, tissues, and cellular and tissue-based products (HCT/Ps).

The guidance addresses donation of HCT/Ps from both living and deceased donors, including donors of umbilical cord blood and hematopoietic stem/progenitor cells.

In this document, the FDA recommends a 6-month deferral period for most HCT/P donors who may have been exposed to the Zika virus.

The exception is donors of gestational tissues, who should be considered ineligible if they were at risk of contracting the virus at any time during their pregnancy.

The new guidance is a part of the FDA’s ongoing efforts to protect HCT/Ps and blood products from Zika virus transmission. Last month, the agency issued recommendations for reducing the risk of Zika virus transmission via blood transfusion.

There is a potential risk that Zika virus can be transmitted by HCT/Ps used as part of a medical, surgical, or reproductive procedure. HCT/Ps include products such as corneas, bone, skin, heart valves, hematopoietic stem/progenitor cells, gestational tissues such as amniotic membrane, and reproductive tissues such as semen and oocytes.

According to the Centers for Disease Control and Prevention, Zika virus can be spread by a man to his sexual partners. To date, there have been several cases of sexual transmission in the US.

Current information about Zika virus detection in semen suggests the period of deferral for HCT/P donors should be longer than the period recommended for donors of whole blood and blood components.

Therefore, the FDA has recommended that living donors of HCT/Ps be considered ineligible if they were diagnosed with Zika virus infection, were in an area with active Zika virus transmission, or had sex with a male with either of those risk factors within the past 6 months.

Donors of umbilical cord blood, placenta, or other gestational tissues should be considered ineligible if they have had any of the above risk factors at any point during their pregnancy.

Deceased donors should be considered ineligible if they were diagnosed with Zika virus infection in the past 6 months.

A deferral period of 6 months was chosen because of the limited data available on the length of time the virus can persist in all tissues. Zika virus has been detected in tissues and body fluids after the virus is no longer detectable in the blood stream and has been detected in semen possibly up to 10 weeks after the onset of symptoms.

Less evidence exists regarding the potential for transmission of Zika virus by HCT/Ps typically recovered from deceased donors. As more information becomes available, the understanding of the risks to recipients of HCT/Ps, including HCT/Ps recovered from deceased donors, may evolve.

The FDA said it will continue to monitor the situation and evaluate new information regarding the associated risks as it becomes available.

In addition, the FDA said it is prioritizing the development of blood donor screening and diagnostic tests that may be useful for identifying the presence of or recent infection with the Zika virus. The agency is prepared to evaluate investigational vaccines and therapeutics that might be developed and review technology that may help suppress populations of the mosquitoes that can spread the virus.

Embryonic stem cells

Researchers believe they have identified key factors that drive hematopoietic specification and differentiation.

The team performed detailed analyses on cells at 6 consecutive stages of development—starting with embryonic stem cells and ending with macrophages.

They said this revealed the complete set of regulatory elements driving differential gene expression during these stages of development.

The researchers described this work in Developmental Cell.

The team studied hematopoietic specification and differentiation by looking at 6 stages of cell development—embryonic stem cells, mesoderm cells, hemangioblasts, hemogenic endothelium, hematopoietic precursors, and macrophages.

“We examined how embryonic cells develop towards blood cells by collecting multi-omics data from measuring gene activity, changes in chromosome structure, and the interaction of regulatory factors with the genes themselves,” explained study author Constanze Bonifer, PhD, of the University of Birmingham in the UK.

“Our research shows, in unprecedented detail, how a vast network of interacting genes control blood cell development. It also shows how we can use such data to enhance our knowledge of this process.”

The researchers said their findings help explain how regulatory elements in the DNA work together, driving gene expression and the switch from one developmental stage to another.

The team believes the work also revealed the minimum requirements for generating blood cells from an unrelated, cultured cell type.

The researchers have made their findings available to the public on the following website: http://www.haemopoiesis.leeds.ac.uk/data_analysis/.

Embryonic stem cells

Researchers believe they have identified key factors that drive hematopoietic specification and differentiation.

The team performed detailed analyses on cells at 6 consecutive stages of development—starting with embryonic stem cells and ending with macrophages.

They said this revealed the complete set of regulatory elements driving differential gene expression during these stages of development.

The researchers described this work in Developmental Cell.

The team studied hematopoietic specification and differentiation by looking at 6 stages of cell development—embryonic stem cells, mesoderm cells, hemangioblasts, hemogenic endothelium, hematopoietic precursors, and macrophages.

“We examined how embryonic cells develop towards blood cells by collecting multi-omics data from measuring gene activity, changes in chromosome structure, and the interaction of regulatory factors with the genes themselves,” explained study author Constanze Bonifer, PhD, of the University of Birmingham in the UK.

“Our research shows, in unprecedented detail, how a vast network of interacting genes control blood cell development. It also shows how we can use such data to enhance our knowledge of this process.”

The researchers said their findings help explain how regulatory elements in the DNA work together, driving gene expression and the switch from one developmental stage to another.

The team believes the work also revealed the minimum requirements for generating blood cells from an unrelated, cultured cell type.

The researchers have made their findings available to the public on the following website: http://www.haemopoiesis.leeds.ac.uk/data_analysis/.

Embryonic stem cells

Researchers believe they have identified key factors that drive hematopoietic specification and differentiation.

The team performed detailed analyses on cells at 6 consecutive stages of development—starting with embryonic stem cells and ending with macrophages.

They said this revealed the complete set of regulatory elements driving differential gene expression during these stages of development.

The researchers described this work in Developmental Cell.

The team studied hematopoietic specification and differentiation by looking at 6 stages of cell development—embryonic stem cells, mesoderm cells, hemangioblasts, hemogenic endothelium, hematopoietic precursors, and macrophages.

“We examined how embryonic cells develop towards blood cells by collecting multi-omics data from measuring gene activity, changes in chromosome structure, and the interaction of regulatory factors with the genes themselves,” explained study author Constanze Bonifer, PhD, of the University of Birmingham in the UK.

“Our research shows, in unprecedented detail, how a vast network of interacting genes control blood cell development. It also shows how we can use such data to enhance our knowledge of this process.”

The researchers said their findings help explain how regulatory elements in the DNA work together, driving gene expression and the switch from one developmental stage to another.

The team believes the work also revealed the minimum requirements for generating blood cells from an unrelated, cultured cell type.

The researchers have made their findings available to the public on the following website: http://www.haemopoiesis.leeds.ac.uk/data_analysis/.

MRI scanner

A new study indicates that early screening can reduce the risk of death from breast cancer among female survivors of childhood Hodgkin lymphoma (HL) who received chest radiation.

Researchers found evidence to suggest that starting mammograms at age 25 can reduce the risk of breast cancer death among these patients, but using MRI can reduce the risk further.

Unfortunately, both methods come with a risk of false-positive results.

David Hodgson, MD, of the University of Toronto in Canada, and his colleagues reported these findings in the Journal of the National Cancer Institute.

Dr Hodgson estimates there are thousands of HL survivors in North America treated throughout the 1990s and later who received chest radiation and are unaware they are at risk of breast cancer and eligible for early screening.

“Many of these are women who received radiotherapy to more normal tissue or at higher doses than are used currently,” he said. “But even for more recently treated patients, screening should reduce the risk of breast cancer death.”

For this study, Dr Hodgson and his colleagues gathered published information from dozens of studies about the risk of developing breast cancer in childhood HL survivors, the accuracy of different forms of breast cancer screening, and the rates at which women agree to be screened when asked.

Using mathematical models, the researchers used these data to quantify the effectiveness of starting screening early—at age 25.

The team found that, using mammography, about 260 survivors of childhood HL would need to be invited to have early breast cancer screening to prevent 1 breast cancer death.

However, the use of MRI for screening improved the effectiveness considerably. It reduced the number of women needing screening to prevent 1 breast cancer death to less than 80.

For HL survivors treated at age 15, the absolute risk of breast cancer mortality by age 75 was predicted to decrease from 16.65% with no early screening to 16.28% with annual mammography, 15.40% with annual MRI, 15.38% with same-day annual mammography and MRI, and 15.37% with alternating mammography and MRI every 6 months.

Dr Hodgson cautioned that there is a risk of false-positive screening results, particuarly with MRI, given that the method can detect many changes in breast tissue, most of which are not cancer.

The data suggested that, from age 25 to 75, at least one false-positive result would occur in 48% of women screened with mammography, 74% screened with MRI alone, and 79% screened with both methods.

The number of false-positives per 1000 screens would be 29.98 with mammography, 71.71 with MRI, and 99.52 with either same-day mammography and MRI or alternating mammography and MRI.

“So this is important for patients to know and for physicians to counsel patients about because it’s stressful for a patient to be called back about suspicious findings,” Dr Hodgson said.

MRI scanner

A new study indicates that early screening can reduce the risk of death from breast cancer among female survivors of childhood Hodgkin lymphoma (HL) who received chest radiation.

Researchers found evidence to suggest that starting mammograms at age 25 can reduce the risk of breast cancer death among these patients, but using MRI can reduce the risk further.

Unfortunately, both methods come with a risk of false-positive results.

David Hodgson, MD, of the University of Toronto in Canada, and his colleagues reported these findings in the Journal of the National Cancer Institute.

Dr Hodgson estimates there are thousands of HL survivors in North America treated throughout the 1990s and later who received chest radiation and are unaware they are at risk of breast cancer and eligible for early screening.

“Many of these are women who received radiotherapy to more normal tissue or at higher doses than are used currently,” he said. “But even for more recently treated patients, screening should reduce the risk of breast cancer death.”

For this study, Dr Hodgson and his colleagues gathered published information from dozens of studies about the risk of developing breast cancer in childhood HL survivors, the accuracy of different forms of breast cancer screening, and the rates at which women agree to be screened when asked.

Using mathematical models, the researchers used these data to quantify the effectiveness of starting screening early—at age 25.

The team found that, using mammography, about 260 survivors of childhood HL would need to be invited to have early breast cancer screening to prevent 1 breast cancer death.

However, the use of MRI for screening improved the effectiveness considerably. It reduced the number of women needing screening to prevent 1 breast cancer death to less than 80.

For HL survivors treated at age 15, the absolute risk of breast cancer mortality by age 75 was predicted to decrease from 16.65% with no early screening to 16.28% with annual mammography, 15.40% with annual MRI, 15.38% with same-day annual mammography and MRI, and 15.37% with alternating mammography and MRI every 6 months.

Dr Hodgson cautioned that there is a risk of false-positive screening results, particuarly with MRI, given that the method can detect many changes in breast tissue, most of which are not cancer.

The data suggested that, from age 25 to 75, at least one false-positive result would occur in 48% of women screened with mammography, 74% screened with MRI alone, and 79% screened with both methods.

The number of false-positives per 1000 screens would be 29.98 with mammography, 71.71 with MRI, and 99.52 with either same-day mammography and MRI or alternating mammography and MRI.

“So this is important for patients to know and for physicians to counsel patients about because it’s stressful for a patient to be called back about suspicious findings,” Dr Hodgson said.

MRI scanner

A new study indicates that early screening can reduce the risk of death from breast cancer among female survivors of childhood Hodgkin lymphoma (HL) who received chest radiation.

Researchers found evidence to suggest that starting mammograms at age 25 can reduce the risk of breast cancer death among these patients, but using MRI can reduce the risk further.

Unfortunately, both methods come with a risk of false-positive results.

David Hodgson, MD, of the University of Toronto in Canada, and his colleagues reported these findings in the Journal of the National Cancer Institute.

Dr Hodgson estimates there are thousands of HL survivors in North America treated throughout the 1990s and later who received chest radiation and are unaware they are at risk of breast cancer and eligible for early screening.

“Many of these are women who received radiotherapy to more normal tissue or at higher doses than are used currently,” he said. “But even for more recently treated patients, screening should reduce the risk of breast cancer death.”

For this study, Dr Hodgson and his colleagues gathered published information from dozens of studies about the risk of developing breast cancer in childhood HL survivors, the accuracy of different forms of breast cancer screening, and the rates at which women agree to be screened when asked.

Using mathematical models, the researchers used these data to quantify the effectiveness of starting screening early—at age 25.

The team found that, using mammography, about 260 survivors of childhood HL would need to be invited to have early breast cancer screening to prevent 1 breast cancer death.

However, the use of MRI for screening improved the effectiveness considerably. It reduced the number of women needing screening to prevent 1 breast cancer death to less than 80.

For HL survivors treated at age 15, the absolute risk of breast cancer mortality by age 75 was predicted to decrease from 16.65% with no early screening to 16.28% with annual mammography, 15.40% with annual MRI, 15.38% with same-day annual mammography and MRI, and 15.37% with alternating mammography and MRI every 6 months.

Dr Hodgson cautioned that there is a risk of false-positive screening results, particuarly with MRI, given that the method can detect many changes in breast tissue, most of which are not cancer.

The data suggested that, from age 25 to 75, at least one false-positive result would occur in 48% of women screened with mammography, 74% screened with MRI alone, and 79% screened with both methods.

The number of false-positives per 1000 screens would be 29.98 with mammography, 71.71 with MRI, and 99.52 with either same-day mammography and MRI or alternating mammography and MRI.

“So this is important for patients to know and for physicians to counsel patients about because it’s stressful for a patient to be called back about suspicious findings,” Dr Hodgson said.

Spectra Optia Apheresis System

Image courtesy of Terumo BCT

The National Institute for Health and Care Excellence (NICE) has issued a guidance recommending a new device for managing sickle cell disease (SCD).

The device is the Spectra Optia Apheresis System for automated red blood cell (RBC) exchange in patients with SCD who need regular blood transfusions.

The Spectra Optia Apheresis System automatically replaces sickled RBCs with healthy RBCs.

The system is made up of 3 components: an apheresis machine, embedded software, and a single-use, disposable blood tubing set.

NICE said the Spectra Optia system is faster than manual RBC exchange, and patients need RBC exchange less often with this device. In addition, the system could provide considerable savings to the National Health Service (NHS) in England.

“The device could save the NHS in England an estimated £13 million each year—around £18,000 per patient—with the size of the saving depending on the patient’s condition and the equipment already owned by the NHS,” said Carole Longson, director of the NICE Centre for Health Technology Evaluation.

“We also recommend that specialists collaborate to collect and publish data on some outcomes of treatment with Spectra Optia to provide further clinical evidence. It would be particularly helpful to have long-term data on how automated and manual exchange affects the amount of iron in the body and the need to treat this complication.”

Treatment with the Spectra Optia system is intended to be iron-neutral, meaning that patients who are already iron-overloaded can have their condition managed effectively.

The Spectra Optia Apheresis System is manufactured by Terumo BCT.

Costs and savings

The list prices (excluding tax) for the components of the Spectra Optia Apheresis System are as follows:

• Spectra Optia device: £45,350
• RBC exchange software: £6700
• Spectra Optia exchange set: £1007 per 6
• Astotube with injection port: £218 per 50
• ACD-A anticoagulant (750 ml): £57 per 12
• Service charge: £4572 per year.

Bulk order discounts are available.

Based on current evidence and expert advice on the anticipated benefits of the technology when used in patients with iron overload, cost modelling shows that, in most cases, using Spectra Optia is cost-saving compared with manual RBC exchange or top-up transfusion.

The savings depend on the iron overload status of the patient and are more likely to be achieved if devices already owned by the NHS can be used to treat SCD.

The estimated cost saving for adopting Spectra Optia is £18,100 per patient per year, which has the potential to save the NHS £12.9 million each year.

Spectra Optia Apheresis System

Image courtesy of Terumo BCT

The National Institute for Health and Care Excellence (NICE) has issued a guidance recommending a new device for managing sickle cell disease (SCD).

The device is the Spectra Optia Apheresis System for automated red blood cell (RBC) exchange in patients with SCD who need regular blood transfusions.

The Spectra Optia Apheresis System automatically replaces sickled RBCs with healthy RBCs.

The system is made up of 3 components: an apheresis machine, embedded software, and a single-use, disposable blood tubing set.

NICE said the Spectra Optia system is faster than manual RBC exchange, and patients need RBC exchange less often with this device. In addition, the system could provide considerable savings to the National Health Service (NHS) in England.

“The device could save the NHS in England an estimated £13 million each year—around £18,000 per patient—with the size of the saving depending on the patient’s condition and the equipment already owned by the NHS,” said Carole Longson, director of the NICE Centre for Health Technology Evaluation.

“We also recommend that specialists collaborate to collect and publish data on some outcomes of treatment with Spectra Optia to provide further clinical evidence. It would be particularly helpful to have long-term data on how automated and manual exchange affects the amount of iron in the body and the need to treat this complication.”

Treatment with the Spectra Optia system is intended to be iron-neutral, meaning that patients who are already iron-overloaded can have their condition managed effectively.

The Spectra Optia Apheresis System is manufactured by Terumo BCT.

Costs and savings

The list prices (excluding tax) for the components of the Spectra Optia Apheresis System are as follows:

• Spectra Optia device: £45,350
• RBC exchange software: £6700
• Spectra Optia exchange set: £1007 per 6
• Astotube with injection port: £218 per 50
• ACD-A anticoagulant (750 ml): £57 per 12
• Service charge: £4572 per year.

Bulk order discounts are available.

Based on current evidence and expert advice on the anticipated benefits of the technology when used in patients with iron overload, cost modelling shows that, in most cases, using Spectra Optia is cost-saving compared with manual RBC exchange or top-up transfusion.

The savings depend on the iron overload status of the patient and are more likely to be achieved if devices already owned by the NHS can be used to treat SCD.

The estimated cost saving for adopting Spectra Optia is £18,100 per patient per year, which has the potential to save the NHS £12.9 million each year.

Spectra Optia Apheresis System

Image courtesy of Terumo BCT

The National Institute for Health and Care Excellence (NICE) has issued a guidance recommending a new device for managing sickle cell disease (SCD).

The device is the Spectra Optia Apheresis System for automated red blood cell (RBC) exchange in patients with SCD who need regular blood transfusions.

The Spectra Optia Apheresis System automatically replaces sickled RBCs with healthy RBCs.

The system is made up of 3 components: an apheresis machine, embedded software, and a single-use, disposable blood tubing set.

NICE said the Spectra Optia system is faster than manual RBC exchange, and patients need RBC exchange less often with this device. In addition, the system could provide considerable savings to the National Health Service (NHS) in England.

“The device could save the NHS in England an estimated £13 million each year—around £18,000 per patient—with the size of the saving depending on the patient’s condition and the equipment already owned by the NHS,” said Carole Longson, director of the NICE Centre for Health Technology Evaluation.

“We also recommend that specialists collaborate to collect and publish data on some outcomes of treatment with Spectra Optia to provide further clinical evidence. It would be particularly helpful to have long-term data on how automated and manual exchange affects the amount of iron in the body and the need to treat this complication.”

Treatment with the Spectra Optia system is intended to be iron-neutral, meaning that patients who are already iron-overloaded can have their condition managed effectively.

The Spectra Optia Apheresis System is manufactured by Terumo BCT.

Costs and savings

The list prices (excluding tax) for the components of the Spectra Optia Apheresis System are as follows:

• Spectra Optia device: £45,350
• RBC exchange software: £6700
• Spectra Optia exchange set: £1007 per 6
• Astotube with injection port: £218 per 50
• ACD-A anticoagulant (750 ml): £57 per 12
• Service charge: £4572 per year.

Bulk order discounts are available.

Based on current evidence and expert advice on the anticipated benefits of the technology when used in patients with iron overload, cost modelling shows that, in most cases, using Spectra Optia is cost-saving compared with manual RBC exchange or top-up transfusion.

The savings depend on the iron overload status of the patient and are more likely to be achieved if devices already owned by the NHS can be used to treat SCD.

The estimated cost saving for adopting Spectra Optia is £18,100 per patient per year, which has the potential to save the NHS £12.9 million each year.

Blood in bags and vials

Photo by Daniel Gay

Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.

Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.

But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.

So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.

To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.

The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).

Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).

The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.

However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).

On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).

The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.

However, such a strategy might impact other important neonatal outcomes, so further study is needed.

Blood in bags and vials

Photo by Daniel Gay

Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.

Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.

But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.

So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.

To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.

The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).

Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).

The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.

However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).

On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).

The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.

However, such a strategy might impact other important neonatal outcomes, so further study is needed.

Blood in bags and vials

Photo by Daniel Gay

Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.

Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.

But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.

So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.

To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.

The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).

Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).

The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.

However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).

On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).

The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.

However, such a strategy might impact other important neonatal outcomes, so further study is needed.

Researchers in the lab

Photo by Rhoda Baer

Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).

Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.

The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.

And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.

To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.

HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.

“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.

“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”

The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.

Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).

“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”

Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.

“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”

Researchers in the lab

Photo by Rhoda Baer

Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).

Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.

The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.

And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.

To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.

HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.

“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.

“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”

The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.

Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).

“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”

Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.

“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”

Researchers in the lab

Photo by Rhoda Baer

Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).

Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.

The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.

And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.

To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.

HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.

“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.

“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”

The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.

Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).

“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”

Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.

“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”

Red blood cells

The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).

The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.

Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.

The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.

Phase 3 trials

The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.

Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.

The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).

The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.

The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.

AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.

“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.

“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’

Red blood cells

The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).

The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.

Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.

The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.

Phase 3 trials

The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.

Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.

The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).

The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.

The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.

AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.

“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.

“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’

Red blood cells

The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).

The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.

Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.

The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.

Phase 3 trials

The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.

Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.

The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).

The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.

The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.

AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.

“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.

“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’