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Compound could treat T-ALL subtype
Photo courtesy of
The Ottawa Hospital
An experimental compound is “highly promising” as a potential treatment for a subtype of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team found the histone demethylase UTX is important for the maintenance of TAL1-positive T-ALL.
Inhibiting UTX with a compound known as GSK-J4 proved toxic to TAL1-positive T-ALL cells in vitro and in vivo, but normal cells were spared.
The researchers reported these findings in Genes & Development.
“It’s very exciting because this is the first time anyone has found a potential personalized treatment for this aggressive disease,” said study author Marjorie Brand, PhD, of The Ottawa Hospital Research Institute in Ontario, Canada.
“Unlike current therapies, ours targets the offending gene without harming the rest of the body.”
Dr Brand and her colleagues decided the best way to find a better treatment for TAL1-positive T-ALL was to investigate exactly how it works at a molecular level. So they analyzed the TAL1 gene, which, in certain circumstances, can transform T-cell precursors into leukemic cells.
They found that TAL1 needs UTX to trigger leukemia production. This was surprising because UTX was previously described as a tumor suppressor in T-ALL.
The team said their work suggests UTX is actually a pro-oncogenic cofactor that is essential for leukemia maintenance in TAL1-positive—but not TAL1-negative—T-ALL.
The researchers found that targeting UTX with the H3K27 demethylase inhibitor GSK-J4 could completely halt the growth of TAL1-positive leukemia cells and induce apoptosis in these cells in vitro. But the compound did not have the same effect in TAL1-negative T-ALL.
The team also tested GSK-J4 in mouse models of T-ALL. After 3 weeks of treatment, there was a “dramatic decrease” in the percentage of leukemic blasts in the bone marrow of mice with TAL1-positive T-ALL. These mice also had a reduction in the infiltration of leukemic cells in the spleen.
However, mice with TAL1-negative T-ALL did not experience the same benefits.
The researchers said GSK-J4 appeared to be well-tolerated. None of the treated mice experienced weight loss or adverse effects in the intestine, spleen, liver, kidney, or hematopoietic system.
“While our study is a proof-of-concept, these promising results might one day lead to a similar targeted treatment for humans,” said study author Carmen Palii, PhD, also of The Ottawa Hospital Research Institute.
In the meantime, the researchers are conducting additional studies in mice, testing higher doses of GSK-J4 and evaluating long-term side effects of the compound. 
Photo courtesy of
The Ottawa Hospital
An experimental compound is “highly promising” as a potential treatment for a subtype of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team found the histone demethylase UTX is important for the maintenance of TAL1-positive T-ALL.
Inhibiting UTX with a compound known as GSK-J4 proved toxic to TAL1-positive T-ALL cells in vitro and in vivo, but normal cells were spared.
The researchers reported these findings in Genes & Development.
“It’s very exciting because this is the first time anyone has found a potential personalized treatment for this aggressive disease,” said study author Marjorie Brand, PhD, of The Ottawa Hospital Research Institute in Ontario, Canada.
“Unlike current therapies, ours targets the offending gene without harming the rest of the body.”
Dr Brand and her colleagues decided the best way to find a better treatment for TAL1-positive T-ALL was to investigate exactly how it works at a molecular level. So they analyzed the TAL1 gene, which, in certain circumstances, can transform T-cell precursors into leukemic cells.
They found that TAL1 needs UTX to trigger leukemia production. This was surprising because UTX was previously described as a tumor suppressor in T-ALL.
The team said their work suggests UTX is actually a pro-oncogenic cofactor that is essential for leukemia maintenance in TAL1-positive—but not TAL1-negative—T-ALL.
The researchers found that targeting UTX with the H3K27 demethylase inhibitor GSK-J4 could completely halt the growth of TAL1-positive leukemia cells and induce apoptosis in these cells in vitro. But the compound did not have the same effect in TAL1-negative T-ALL.
The team also tested GSK-J4 in mouse models of T-ALL. After 3 weeks of treatment, there was a “dramatic decrease” in the percentage of leukemic blasts in the bone marrow of mice with TAL1-positive T-ALL. These mice also had a reduction in the infiltration of leukemic cells in the spleen.
However, mice with TAL1-negative T-ALL did not experience the same benefits.
The researchers said GSK-J4 appeared to be well-tolerated. None of the treated mice experienced weight loss or adverse effects in the intestine, spleen, liver, kidney, or hematopoietic system.
“While our study is a proof-of-concept, these promising results might one day lead to a similar targeted treatment for humans,” said study author Carmen Palii, PhD, also of The Ottawa Hospital Research Institute.
In the meantime, the researchers are conducting additional studies in mice, testing higher doses of GSK-J4 and evaluating long-term side effects of the compound.
Photo courtesy of
The Ottawa Hospital
An experimental compound is “highly promising” as a potential treatment for a subtype of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team found the histone demethylase UTX is important for the maintenance of TAL1-positive T-ALL.
Inhibiting UTX with a compound known as GSK-J4 proved toxic to TAL1-positive T-ALL cells in vitro and in vivo, but normal cells were spared.
The researchers reported these findings in Genes & Development.
“It’s very exciting because this is the first time anyone has found a potential personalized treatment for this aggressive disease,” said study author Marjorie Brand, PhD, of The Ottawa Hospital Research Institute in Ontario, Canada.
“Unlike current therapies, ours targets the offending gene without harming the rest of the body.”
Dr Brand and her colleagues decided the best way to find a better treatment for TAL1-positive T-ALL was to investigate exactly how it works at a molecular level. So they analyzed the TAL1 gene, which, in certain circumstances, can transform T-cell precursors into leukemic cells.
They found that TAL1 needs UTX to trigger leukemia production. This was surprising because UTX was previously described as a tumor suppressor in T-ALL.
The team said their work suggests UTX is actually a pro-oncogenic cofactor that is essential for leukemia maintenance in TAL1-positive—but not TAL1-negative—T-ALL.
The researchers found that targeting UTX with the H3K27 demethylase inhibitor GSK-J4 could completely halt the growth of TAL1-positive leukemia cells and induce apoptosis in these cells in vitro. But the compound did not have the same effect in TAL1-negative T-ALL.
The team also tested GSK-J4 in mouse models of T-ALL. After 3 weeks of treatment, there was a “dramatic decrease” in the percentage of leukemic blasts in the bone marrow of mice with TAL1-positive T-ALL. These mice also had a reduction in the infiltration of leukemic cells in the spleen.
However, mice with TAL1-negative T-ALL did not experience the same benefits.
The researchers said GSK-J4 appeared to be well-tolerated. None of the treated mice experienced weight loss or adverse effects in the intestine, spleen, liver, kidney, or hematopoietic system.
“While our study is a proof-of-concept, these promising results might one day lead to a similar targeted treatment for humans,” said study author Carmen Palii, PhD, also of The Ottawa Hospital Research Institute.
In the meantime, the researchers are conducting additional studies in mice, testing higher doses of GSK-J4 and evaluating long-term side effects of the compound.
EMA initiative aims to accelerate drug development
Photo courtesy of the FDA
The European Medicines Agency (EMA) has launched PRIME (PRIority MEdicines), an initiative intended to accelerate the development of drugs that target unmet medical needs.
These “priority medicines” may offer a major therapeutic advantage over existing treatments or benefit patients who currently have no treatment options in the European Union (EU).
Through PRIME, the EMA will offer early support to drug developers to optimize the generation of robust data on a treatment’s benefits and risks and enable accelerated assessment of an application for marketing authorization.
By engaging with developers early, the EMA aims to strengthen the design of clinical trials to facilitate the generation of high quality data to support an application for marketing authorization.
PRIME builds on the existing regulatory framework and available tools such as scientific advice and accelerated assessment.
To be accepted for PRIME, a treatment has to show the potential to benefit patients with unmet medical needs based on early clinical data.
Once a candidate medicine has been selected for PRIME, the EMA:
- Appoints a rapporteur from the Committee for Medicinal Products for Human Use (CHMP), or from the Committee on Advanced Therapies (CAT) in the case of an advanced therapy, to provide continuous support and help to build knowledge before a company submits an application for marketing authorization
- Organizes a kick-off meeting with the CHMP/CAT rapporteur and a multidisciplinary group of experts from relevant EMA scientific committees and working parties, and provides guidance on the overall development plan and regulatory strategy
- Assigns a dedicated EMA contact point
- Provides scientific advice at key development milestones, involving additional stakeholders such as health technology assessment bodies to facilitate quicker access to the new drug
- Confirms potential for accelerated assessment when an application for marketing authorization is submitted.
PRIME is open to all drug companies on the basis of preliminary clinical evidence. However, micro-, small- and medium-sized enterprises and applicants from the academic sector can apply earlier on the basis of compelling non-clinical data and tolerability data from initial clinical trials. They may also request fee waivers for scientific advice.
The EMA has released guidance documents on PRIME as well as a comprehensive overview of the EU early access regulatory tools—ie, accelerated assessment, conditional marketing authorization, and compassionate use.
The agency has also published revised guidelines on the implementation of accelerated assessment and conditional marketing authorization. These tools are reserved for treatments addressing major public health needs, and the revised guidelines provide more detailed information based on past experience.
Although PRIME is specifically designed to promote accelerated assessment, the EMA said the initiative will also help drug developers make the best use of other EU early access tools and initiatives, which can be combined whenever a drug fulfills the respective criteria.
PRIME was developed in consultation with the EMA’s scientific committees, the European Commission and its expert group on Safe and Timely Access to Medicines for Patients, as well as the European medicines regulatory network.
The main principles of PRIME were released for a 2-month public consultation in 2015, and the comments received were taken into account in the final version.
Photo courtesy of the FDA
The European Medicines Agency (EMA) has launched PRIME (PRIority MEdicines), an initiative intended to accelerate the development of drugs that target unmet medical needs.
These “priority medicines” may offer a major therapeutic advantage over existing treatments or benefit patients who currently have no treatment options in the European Union (EU).
Through PRIME, the EMA will offer early support to drug developers to optimize the generation of robust data on a treatment’s benefits and risks and enable accelerated assessment of an application for marketing authorization.
By engaging with developers early, the EMA aims to strengthen the design of clinical trials to facilitate the generation of high quality data to support an application for marketing authorization.
PRIME builds on the existing regulatory framework and available tools such as scientific advice and accelerated assessment.
To be accepted for PRIME, a treatment has to show the potential to benefit patients with unmet medical needs based on early clinical data.
Once a candidate medicine has been selected for PRIME, the EMA:
- Appoints a rapporteur from the Committee for Medicinal Products for Human Use (CHMP), or from the Committee on Advanced Therapies (CAT) in the case of an advanced therapy, to provide continuous support and help to build knowledge before a company submits an application for marketing authorization
- Organizes a kick-off meeting with the CHMP/CAT rapporteur and a multidisciplinary group of experts from relevant EMA scientific committees and working parties, and provides guidance on the overall development plan and regulatory strategy
- Assigns a dedicated EMA contact point
- Provides scientific advice at key development milestones, involving additional stakeholders such as health technology assessment bodies to facilitate quicker access to the new drug
- Confirms potential for accelerated assessment when an application for marketing authorization is submitted.
PRIME is open to all drug companies on the basis of preliminary clinical evidence. However, micro-, small- and medium-sized enterprises and applicants from the academic sector can apply earlier on the basis of compelling non-clinical data and tolerability data from initial clinical trials. They may also request fee waivers for scientific advice.
The EMA has released guidance documents on PRIME as well as a comprehensive overview of the EU early access regulatory tools—ie, accelerated assessment, conditional marketing authorization, and compassionate use.
The agency has also published revised guidelines on the implementation of accelerated assessment and conditional marketing authorization. These tools are reserved for treatments addressing major public health needs, and the revised guidelines provide more detailed information based on past experience.
Although PRIME is specifically designed to promote accelerated assessment, the EMA said the initiative will also help drug developers make the best use of other EU early access tools and initiatives, which can be combined whenever a drug fulfills the respective criteria.
PRIME was developed in consultation with the EMA’s scientific committees, the European Commission and its expert group on Safe and Timely Access to Medicines for Patients, as well as the European medicines regulatory network.
The main principles of PRIME were released for a 2-month public consultation in 2015, and the comments received were taken into account in the final version.
Photo courtesy of the FDA
The European Medicines Agency (EMA) has launched PRIME (PRIority MEdicines), an initiative intended to accelerate the development of drugs that target unmet medical needs.
These “priority medicines” may offer a major therapeutic advantage over existing treatments or benefit patients who currently have no treatment options in the European Union (EU).
Through PRIME, the EMA will offer early support to drug developers to optimize the generation of robust data on a treatment’s benefits and risks and enable accelerated assessment of an application for marketing authorization.
By engaging with developers early, the EMA aims to strengthen the design of clinical trials to facilitate the generation of high quality data to support an application for marketing authorization.
PRIME builds on the existing regulatory framework and available tools such as scientific advice and accelerated assessment.
To be accepted for PRIME, a treatment has to show the potential to benefit patients with unmet medical needs based on early clinical data.
Once a candidate medicine has been selected for PRIME, the EMA:
- Appoints a rapporteur from the Committee for Medicinal Products for Human Use (CHMP), or from the Committee on Advanced Therapies (CAT) in the case of an advanced therapy, to provide continuous support and help to build knowledge before a company submits an application for marketing authorization
- Organizes a kick-off meeting with the CHMP/CAT rapporteur and a multidisciplinary group of experts from relevant EMA scientific committees and working parties, and provides guidance on the overall development plan and regulatory strategy
- Assigns a dedicated EMA contact point
- Provides scientific advice at key development milestones, involving additional stakeholders such as health technology assessment bodies to facilitate quicker access to the new drug
- Confirms potential for accelerated assessment when an application for marketing authorization is submitted.
PRIME is open to all drug companies on the basis of preliminary clinical evidence. However, micro-, small- and medium-sized enterprises and applicants from the academic sector can apply earlier on the basis of compelling non-clinical data and tolerability data from initial clinical trials. They may also request fee waivers for scientific advice.
The EMA has released guidance documents on PRIME as well as a comprehensive overview of the EU early access regulatory tools—ie, accelerated assessment, conditional marketing authorization, and compassionate use.
The agency has also published revised guidelines on the implementation of accelerated assessment and conditional marketing authorization. These tools are reserved for treatments addressing major public health needs, and the revised guidelines provide more detailed information based on past experience.
Although PRIME is specifically designed to promote accelerated assessment, the EMA said the initiative will also help drug developers make the best use of other EU early access tools and initiatives, which can be combined whenever a drug fulfills the respective criteria.
PRIME was developed in consultation with the EMA’s scientific committees, the European Commission and its expert group on Safe and Timely Access to Medicines for Patients, as well as the European medicines regulatory network.
The main principles of PRIME were released for a 2-month public consultation in 2015, and the comments received were taken into account in the final version.
CDC quantifies threat of resistant HAIs in US
in the intensive care unit
New data from the US Centers for Disease Control and Prevention (CDC) suggest the incidence of certain healthcare-associated infections (HAIs) has fallen in recent years, but antibiotic-resistant bacteria remain a threat.
Therefore, the CDC is advising healthcare workers to use a combination of infection control recommendations to better protect patients from these infections.
“New data show that far too many patients are getting infected with dangerous, drug-resistant bacteria in healthcare settings,” said CDC Director Tom Frieden, MD.
The facts and figures are available in the CDC’s latest Vital Signs report and the agency’s annual progress report on HAI prevention.
The data indicate that 1 in 7 catheter- and surgery-related HAIs in acute care hospitals can be caused by 6 types of antibiotic-resistant bacteria. That number increases to 1 in 4 infections in long-term acute care hospitals.
The 6 antibiotic-resistant threats are carbapenem-resistant Enterobacteriaceae (CRE), methicillin-resistant Staphylococcus aureus (MRSA), ESBL-producing Enterobacteriaceae (extended-spectrum β-lactamases), vancomycin-resistant Enterococcus (VRE), multidrug-resistant Pseudomonas aeruginosa, and multidrug-resistant Acinetobacter.
Prevention and resistance
According to the CDC’s data, acute care hospitals saw a 50% decrease in central line-associated bloodstream infections between 2008 and 2014. But 1 in 6 remaining central line-associated bloodstream infections is caused by urgent or serious antibiotic-resistant bacteria.
Between 2008 and 2014, acute care hospitals saw a 17% decrease in surgical site infections related to 10 procedures that were tracked in previous HAI progress reports. One in 7 remaining surgical site infections is caused by urgent or serious antibiotic-resistant bacteria.
Acute care hospitals saw no change in the incidence of catheter-associated urinary tract infections (CAUTIs) between 2009 and 2014. However, there was a reduction in CAUTIs between 2013 and 2014. One in 10 CAUTIs is caused by urgent or serious antibiotic-resistant bacteria.
The Vital Signs report also examines Clostridium difficile, which caused almost half a million infections in the US in 2011 alone. The CDC’s annual progress report shows that hospital-onset C difficile infections decreased by 8% between 2011 and 2014.
In addition to the reports, the CDC has released a web app with interactive data on HAIs caused by antibiotic-resistant bacteria.
The tool, known as the Antibiotic Resistance Patient Safety Atlas, provides national, regional, and state map views of superbug/drug combinations showing percent resistance over time. The Atlas uses data reported to the CDC’s National Healthcare Safety Network from 2011 to 2014 from more than 4000 healthcare facilities.
in the intensive care unit
New data from the US Centers for Disease Control and Prevention (CDC) suggest the incidence of certain healthcare-associated infections (HAIs) has fallen in recent years, but antibiotic-resistant bacteria remain a threat.
Therefore, the CDC is advising healthcare workers to use a combination of infection control recommendations to better protect patients from these infections.
“New data show that far too many patients are getting infected with dangerous, drug-resistant bacteria in healthcare settings,” said CDC Director Tom Frieden, MD.
The facts and figures are available in the CDC’s latest Vital Signs report and the agency’s annual progress report on HAI prevention.
The data indicate that 1 in 7 catheter- and surgery-related HAIs in acute care hospitals can be caused by 6 types of antibiotic-resistant bacteria. That number increases to 1 in 4 infections in long-term acute care hospitals.
The 6 antibiotic-resistant threats are carbapenem-resistant Enterobacteriaceae (CRE), methicillin-resistant Staphylococcus aureus (MRSA), ESBL-producing Enterobacteriaceae (extended-spectrum β-lactamases), vancomycin-resistant Enterococcus (VRE), multidrug-resistant Pseudomonas aeruginosa, and multidrug-resistant Acinetobacter.
Prevention and resistance
According to the CDC’s data, acute care hospitals saw a 50% decrease in central line-associated bloodstream infections between 2008 and 2014. But 1 in 6 remaining central line-associated bloodstream infections is caused by urgent or serious antibiotic-resistant bacteria.
Between 2008 and 2014, acute care hospitals saw a 17% decrease in surgical site infections related to 10 procedures that were tracked in previous HAI progress reports. One in 7 remaining surgical site infections is caused by urgent or serious antibiotic-resistant bacteria.
Acute care hospitals saw no change in the incidence of catheter-associated urinary tract infections (CAUTIs) between 2009 and 2014. However, there was a reduction in CAUTIs between 2013 and 2014. One in 10 CAUTIs is caused by urgent or serious antibiotic-resistant bacteria.
The Vital Signs report also examines Clostridium difficile, which caused almost half a million infections in the US in 2011 alone. The CDC’s annual progress report shows that hospital-onset C difficile infections decreased by 8% between 2011 and 2014.
In addition to the reports, the CDC has released a web app with interactive data on HAIs caused by antibiotic-resistant bacteria.
The tool, known as the Antibiotic Resistance Patient Safety Atlas, provides national, regional, and state map views of superbug/drug combinations showing percent resistance over time. The Atlas uses data reported to the CDC’s National Healthcare Safety Network from 2011 to 2014 from more than 4000 healthcare facilities.
in the intensive care unit
New data from the US Centers for Disease Control and Prevention (CDC) suggest the incidence of certain healthcare-associated infections (HAIs) has fallen in recent years, but antibiotic-resistant bacteria remain a threat.
Therefore, the CDC is advising healthcare workers to use a combination of infection control recommendations to better protect patients from these infections.
“New data show that far too many patients are getting infected with dangerous, drug-resistant bacteria in healthcare settings,” said CDC Director Tom Frieden, MD.
The facts and figures are available in the CDC’s latest Vital Signs report and the agency’s annual progress report on HAI prevention.
The data indicate that 1 in 7 catheter- and surgery-related HAIs in acute care hospitals can be caused by 6 types of antibiotic-resistant bacteria. That number increases to 1 in 4 infections in long-term acute care hospitals.
The 6 antibiotic-resistant threats are carbapenem-resistant Enterobacteriaceae (CRE), methicillin-resistant Staphylococcus aureus (MRSA), ESBL-producing Enterobacteriaceae (extended-spectrum β-lactamases), vancomycin-resistant Enterococcus (VRE), multidrug-resistant Pseudomonas aeruginosa, and multidrug-resistant Acinetobacter.
Prevention and resistance
According to the CDC’s data, acute care hospitals saw a 50% decrease in central line-associated bloodstream infections between 2008 and 2014. But 1 in 6 remaining central line-associated bloodstream infections is caused by urgent or serious antibiotic-resistant bacteria.
Between 2008 and 2014, acute care hospitals saw a 17% decrease in surgical site infections related to 10 procedures that were tracked in previous HAI progress reports. One in 7 remaining surgical site infections is caused by urgent or serious antibiotic-resistant bacteria.
Acute care hospitals saw no change in the incidence of catheter-associated urinary tract infections (CAUTIs) between 2009 and 2014. However, there was a reduction in CAUTIs between 2013 and 2014. One in 10 CAUTIs is caused by urgent or serious antibiotic-resistant bacteria.
The Vital Signs report also examines Clostridium difficile, which caused almost half a million infections in the US in 2011 alone. The CDC’s annual progress report shows that hospital-onset C difficile infections decreased by 8% between 2011 and 2014.
In addition to the reports, the CDC has released a web app with interactive data on HAIs caused by antibiotic-resistant bacteria.
The tool, known as the Antibiotic Resistance Patient Safety Atlas, provides national, regional, and state map views of superbug/drug combinations showing percent resistance over time. The Atlas uses data reported to the CDC’s National Healthcare Safety Network from 2011 to 2014 from more than 4000 healthcare facilities.
Inhibitor exhibits activity against myeloma
A dual kinase inhibitor has shown early promise as a potential treatment for multiple myeloma (MM), according to investigators.
The inhibitor, ON123300, targets both AMPK-related protein kinase 5 (ARK5) and cyclin-dependent kinase 4 (CDK4), proteins responsible for maintaining energy balance within the cell.
Investigators found that ON123300 can induce apoptosis in MM cells in vitro and halt tumor growth in mouse models of MM.
The team reported these findings in Cancer Research.
“ARK5 is critical for myeloma survival, and this study suggests a novel function for ARK5 in bridging the mTOR and MYC pathways,” said study author Deepak Perumal, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“Given that MYC is critically overexpressed in myeloma, we sought to determine whether selective inhibition of ARK5 and CDK4 could be an effective way to target MYC-driven proliferation in myeloma.”
The team at Mount Sinai developed ON123300 in collaboration with Onconova Therapeutics, Inc. And they tested the drug in MM cell lines and primary samples from patients with recurring MM, as well as human HS-5 bone marrow stromal cells.
ON123300 induced rapid cell-cycle arrest and apoptosis in MM cells but was not toxic to normal peripheral blood cells.
In mouse models of MM, ON123300 decreased tumor growth without causing significant toxicity.
The investigators also discovered that MM cells that are sensitive to ON123300 have a unique genomic signature, which could guide the clinical development of the drug.
“Our study results show that ON123300 induces cell death and negatively regulates key oncogenic pathways in multiple myeloma cells,” said Samir Parekh, MD, also of the Icahn School of Medicine at Mount Sinai.
“This is the first report showing potent cytotoxicity of CDK4/ARK5 inhibition in MM and provides the foundation for further clinical trials using CDK4/ARK5 inhibitors to improve outcomes for MM patients.”
A dual kinase inhibitor has shown early promise as a potential treatment for multiple myeloma (MM), according to investigators.
The inhibitor, ON123300, targets both AMPK-related protein kinase 5 (ARK5) and cyclin-dependent kinase 4 (CDK4), proteins responsible for maintaining energy balance within the cell.
Investigators found that ON123300 can induce apoptosis in MM cells in vitro and halt tumor growth in mouse models of MM.
The team reported these findings in Cancer Research.
“ARK5 is critical for myeloma survival, and this study suggests a novel function for ARK5 in bridging the mTOR and MYC pathways,” said study author Deepak Perumal, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“Given that MYC is critically overexpressed in myeloma, we sought to determine whether selective inhibition of ARK5 and CDK4 could be an effective way to target MYC-driven proliferation in myeloma.”
The team at Mount Sinai developed ON123300 in collaboration with Onconova Therapeutics, Inc. And they tested the drug in MM cell lines and primary samples from patients with recurring MM, as well as human HS-5 bone marrow stromal cells.
ON123300 induced rapid cell-cycle arrest and apoptosis in MM cells but was not toxic to normal peripheral blood cells.
In mouse models of MM, ON123300 decreased tumor growth without causing significant toxicity.
The investigators also discovered that MM cells that are sensitive to ON123300 have a unique genomic signature, which could guide the clinical development of the drug.
“Our study results show that ON123300 induces cell death and negatively regulates key oncogenic pathways in multiple myeloma cells,” said Samir Parekh, MD, also of the Icahn School of Medicine at Mount Sinai.
“This is the first report showing potent cytotoxicity of CDK4/ARK5 inhibition in MM and provides the foundation for further clinical trials using CDK4/ARK5 inhibitors to improve outcomes for MM patients.”
A dual kinase inhibitor has shown early promise as a potential treatment for multiple myeloma (MM), according to investigators.
The inhibitor, ON123300, targets both AMPK-related protein kinase 5 (ARK5) and cyclin-dependent kinase 4 (CDK4), proteins responsible for maintaining energy balance within the cell.
Investigators found that ON123300 can induce apoptosis in MM cells in vitro and halt tumor growth in mouse models of MM.
The team reported these findings in Cancer Research.
“ARK5 is critical for myeloma survival, and this study suggests a novel function for ARK5 in bridging the mTOR and MYC pathways,” said study author Deepak Perumal, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“Given that MYC is critically overexpressed in myeloma, we sought to determine whether selective inhibition of ARK5 and CDK4 could be an effective way to target MYC-driven proliferation in myeloma.”
The team at Mount Sinai developed ON123300 in collaboration with Onconova Therapeutics, Inc. And they tested the drug in MM cell lines and primary samples from patients with recurring MM, as well as human HS-5 bone marrow stromal cells.
ON123300 induced rapid cell-cycle arrest and apoptosis in MM cells but was not toxic to normal peripheral blood cells.
In mouse models of MM, ON123300 decreased tumor growth without causing significant toxicity.
The investigators also discovered that MM cells that are sensitive to ON123300 have a unique genomic signature, which could guide the clinical development of the drug.
“Our study results show that ON123300 induces cell death and negatively regulates key oncogenic pathways in multiple myeloma cells,” said Samir Parekh, MD, also of the Icahn School of Medicine at Mount Sinai.
“This is the first report showing potent cytotoxicity of CDK4/ARK5 inhibition in MM and provides the foundation for further clinical trials using CDK4/ARK5 inhibitors to improve outcomes for MM patients.”
System could aid assessment of sickle cell disease
and a normal one
Image by Betty Pace
A microfluidic system can measure the deformability and adhesion of red blood cells (RBCs) in samples from patients with sickle cell disease (SCD), according to research published in Technology.
The researchers noted that RBC deformability has been associated with vaso-occlusion in SCD, but we have limited knowledge on deformation characteristics of RBCs adhered to endothelium-associated proteins in microphysiological fluid flow conditions.
In the past, various approaches have been used to measure RBC deformability, including optical tweezers, micropipette aspiration, and atomic force microscopy. These methods have enabled sensitive and controlled measurement of RBC mechanical properties, but they are typically performed in open environments without fluid flow.
“Microfluidic techniques allow incorporation of physiological flow conditions, as well as biologically relevant adhesion surfaces in a closed setting, which better mimic the natural physiological environment of the RBCs in blood flow,” said study author Umut Gurkan, PhD, of the Case Western Reserve University in Cleveland, Ohio.
For their system, Dr Gurkan and his colleagues integrated a microfluidic approach with a cell-dimensioning algorithm.
They introduced a new parameter to assess the deformability of RBCs. It is known as the dynamic deformability index (DDI), which they defined as the time-dependent change of the cell’s aspect ratio in response to fluid flow shear stress.
The researchers assessed the deformability and adhesion of RBCs containing healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS). And they found the DDI of HbS-containing RBCs was significantly lower than the DDI of HbA-containing RBCs.
The team also found they could divide HbS-containing RBCs into 2 groups—deformable and non-deformable RBCs.
“We report, for the first time, on the subpopulations of RBCs in terms of dynamic deformation characteristics in SCD: deformable and non-deformable RBCs,” said Yunus Alapan, a PhD candidate at Case Western Reserve University.
“Furthermore, we analyzed adhesion of non-deformable RBCs, in comparison to deformable RBCs, quantitatively at physiological and above physiological flow shear stresses in blood samples obtained from SCD patients.”
“We observed significantly greater numbers of adhered non-deformable sickle RBCs than deformable sickle RBCs at flow shear stresses well above the physiological range, suggesting an interplay between dynamic deformability and increased adhesion of RBCs in vaso-occlusive events.”
Now, the researchers are working to further characterize deformability and adhesion of RBCs in a greater number of SCD patients to analyze their associations with clinical phenotypes and complications.
The team said their system may provide important biophysical insights into disease pathophysiology when widely applied in SCD.
They also believe the microfluidic platform has the potential to be used as an in vitro assay for monitoring disease activity at baseline, during clinical flux after treatment, during painful episodes, and in association with long-term complications.
and a normal one
Image by Betty Pace
A microfluidic system can measure the deformability and adhesion of red blood cells (RBCs) in samples from patients with sickle cell disease (SCD), according to research published in Technology.
The researchers noted that RBC deformability has been associated with vaso-occlusion in SCD, but we have limited knowledge on deformation characteristics of RBCs adhered to endothelium-associated proteins in microphysiological fluid flow conditions.
In the past, various approaches have been used to measure RBC deformability, including optical tweezers, micropipette aspiration, and atomic force microscopy. These methods have enabled sensitive and controlled measurement of RBC mechanical properties, but they are typically performed in open environments without fluid flow.
“Microfluidic techniques allow incorporation of physiological flow conditions, as well as biologically relevant adhesion surfaces in a closed setting, which better mimic the natural physiological environment of the RBCs in blood flow,” said study author Umut Gurkan, PhD, of the Case Western Reserve University in Cleveland, Ohio.
For their system, Dr Gurkan and his colleagues integrated a microfluidic approach with a cell-dimensioning algorithm.
They introduced a new parameter to assess the deformability of RBCs. It is known as the dynamic deformability index (DDI), which they defined as the time-dependent change of the cell’s aspect ratio in response to fluid flow shear stress.
The researchers assessed the deformability and adhesion of RBCs containing healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS). And they found the DDI of HbS-containing RBCs was significantly lower than the DDI of HbA-containing RBCs.
The team also found they could divide HbS-containing RBCs into 2 groups—deformable and non-deformable RBCs.
“We report, for the first time, on the subpopulations of RBCs in terms of dynamic deformation characteristics in SCD: deformable and non-deformable RBCs,” said Yunus Alapan, a PhD candidate at Case Western Reserve University.
“Furthermore, we analyzed adhesion of non-deformable RBCs, in comparison to deformable RBCs, quantitatively at physiological and above physiological flow shear stresses in blood samples obtained from SCD patients.”
“We observed significantly greater numbers of adhered non-deformable sickle RBCs than deformable sickle RBCs at flow shear stresses well above the physiological range, suggesting an interplay between dynamic deformability and increased adhesion of RBCs in vaso-occlusive events.”
Now, the researchers are working to further characterize deformability and adhesion of RBCs in a greater number of SCD patients to analyze their associations with clinical phenotypes and complications.
The team said their system may provide important biophysical insights into disease pathophysiology when widely applied in SCD.
They also believe the microfluidic platform has the potential to be used as an in vitro assay for monitoring disease activity at baseline, during clinical flux after treatment, during painful episodes, and in association with long-term complications.
and a normal one
Image by Betty Pace
A microfluidic system can measure the deformability and adhesion of red blood cells (RBCs) in samples from patients with sickle cell disease (SCD), according to research published in Technology.
The researchers noted that RBC deformability has been associated with vaso-occlusion in SCD, but we have limited knowledge on deformation characteristics of RBCs adhered to endothelium-associated proteins in microphysiological fluid flow conditions.
In the past, various approaches have been used to measure RBC deformability, including optical tweezers, micropipette aspiration, and atomic force microscopy. These methods have enabled sensitive and controlled measurement of RBC mechanical properties, but they are typically performed in open environments without fluid flow.
“Microfluidic techniques allow incorporation of physiological flow conditions, as well as biologically relevant adhesion surfaces in a closed setting, which better mimic the natural physiological environment of the RBCs in blood flow,” said study author Umut Gurkan, PhD, of the Case Western Reserve University in Cleveland, Ohio.
For their system, Dr Gurkan and his colleagues integrated a microfluidic approach with a cell-dimensioning algorithm.
They introduced a new parameter to assess the deformability of RBCs. It is known as the dynamic deformability index (DDI), which they defined as the time-dependent change of the cell’s aspect ratio in response to fluid flow shear stress.
The researchers assessed the deformability and adhesion of RBCs containing healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS). And they found the DDI of HbS-containing RBCs was significantly lower than the DDI of HbA-containing RBCs.
The team also found they could divide HbS-containing RBCs into 2 groups—deformable and non-deformable RBCs.
“We report, for the first time, on the subpopulations of RBCs in terms of dynamic deformation characteristics in SCD: deformable and non-deformable RBCs,” said Yunus Alapan, a PhD candidate at Case Western Reserve University.
“Furthermore, we analyzed adhesion of non-deformable RBCs, in comparison to deformable RBCs, quantitatively at physiological and above physiological flow shear stresses in blood samples obtained from SCD patients.”
“We observed significantly greater numbers of adhered non-deformable sickle RBCs than deformable sickle RBCs at flow shear stresses well above the physiological range, suggesting an interplay between dynamic deformability and increased adhesion of RBCs in vaso-occlusive events.”
Now, the researchers are working to further characterize deformability and adhesion of RBCs in a greater number of SCD patients to analyze their associations with clinical phenotypes and complications.
The team said their system may provide important biophysical insights into disease pathophysiology when widely applied in SCD.
They also believe the microfluidic platform has the potential to be used as an in vitro assay for monitoring disease activity at baseline, during clinical flux after treatment, during painful episodes, and in association with long-term complications.
Targeting a protein to prevent malignancy
Photo by Aaron Logan
New research suggests hematologic malignancies driven by MYC might be prevented by lowering levels of another protein, MCL-1.
“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers,” said Stephanie Grabow, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
“We have now shown that the same approach might be able to prevent those cancers from forming in the first place.”
Dr Grabow and her colleagues described this work in Cell Reports.
Previous research indicated that expression from both MCL-1 alleles is essential for the survival of hematopoietic stem and progenitor cells during stress-induced repopulation of the hematopoietic system.
So, with this study, Dr Grabow and her colleagues set out to determine whether reducing MCL-1 protein levels might hinder the development of hematologic malignancies.
In experiments with mice, the investigators found that loss of one MCL-1 allele significantly delayed the development of MYC-driven lymphoma and reduced MYC-driven accumulation of pre-leukemic cancer-initiating cells.
However, loss of one p53 allele accelerated MYC-driven lymphomagenesis even when one MCL-1 allele was deleted. Loss of PUMA accelerated lymphoma development as well, though to a much lesser extent.
Loss of BIM substantially accelerated lymphomagenesis when one MCL-1 allele was deleted, restoring lymphoma-initiating cells and the rate of tumor development.
And loss of one BIM allele overrode the survival defect observed in pre-leukemic Eμ-Myc B-cell progenitors when one MCL-1 allele was deleted.
The investigators noted that loss of one MCL-1 allele did not noticeably impair the survival of normal B lymphoid cells even though it greatly diminished the survival of MYC-overexpressing B-cell progenitors.
“No one had realized just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” Dr Grabow said.
“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anticancer drugs.”
Study investigator Brandon Aubrey, MBBS, also of the Walter and Eliza Hall Institute, said this research could inform future strategies to prevent cancer.
“Early treatment or even cancer prevention are likely to be a more effective way to fight cancer than treating an established cancer after it has already formed and made a person sick,” he said. ”Our research has suggested that dependency on MCL-1 could be a key vulnerability of many developing cancers.”
“In the future, MCL-1 inhibitors might have potential benefit for treating the very early stages of MYC-driven cancers, or we may even be able use these agents to prevent people from getting cancer in the first place.”
Photo by Aaron Logan
New research suggests hematologic malignancies driven by MYC might be prevented by lowering levels of another protein, MCL-1.
“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers,” said Stephanie Grabow, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
“We have now shown that the same approach might be able to prevent those cancers from forming in the first place.”
Dr Grabow and her colleagues described this work in Cell Reports.
Previous research indicated that expression from both MCL-1 alleles is essential for the survival of hematopoietic stem and progenitor cells during stress-induced repopulation of the hematopoietic system.
So, with this study, Dr Grabow and her colleagues set out to determine whether reducing MCL-1 protein levels might hinder the development of hematologic malignancies.
In experiments with mice, the investigators found that loss of one MCL-1 allele significantly delayed the development of MYC-driven lymphoma and reduced MYC-driven accumulation of pre-leukemic cancer-initiating cells.
However, loss of one p53 allele accelerated MYC-driven lymphomagenesis even when one MCL-1 allele was deleted. Loss of PUMA accelerated lymphoma development as well, though to a much lesser extent.
Loss of BIM substantially accelerated lymphomagenesis when one MCL-1 allele was deleted, restoring lymphoma-initiating cells and the rate of tumor development.
And loss of one BIM allele overrode the survival defect observed in pre-leukemic Eμ-Myc B-cell progenitors when one MCL-1 allele was deleted.
The investigators noted that loss of one MCL-1 allele did not noticeably impair the survival of normal B lymphoid cells even though it greatly diminished the survival of MYC-overexpressing B-cell progenitors.
“No one had realized just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” Dr Grabow said.
“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anticancer drugs.”
Study investigator Brandon Aubrey, MBBS, also of the Walter and Eliza Hall Institute, said this research could inform future strategies to prevent cancer.
“Early treatment or even cancer prevention are likely to be a more effective way to fight cancer than treating an established cancer after it has already formed and made a person sick,” he said. ”Our research has suggested that dependency on MCL-1 could be a key vulnerability of many developing cancers.”
“In the future, MCL-1 inhibitors might have potential benefit for treating the very early stages of MYC-driven cancers, or we may even be able use these agents to prevent people from getting cancer in the first place.”
Photo by Aaron Logan
New research suggests hematologic malignancies driven by MYC might be prevented by lowering levels of another protein, MCL-1.
“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers,” said Stephanie Grabow, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
“We have now shown that the same approach might be able to prevent those cancers from forming in the first place.”
Dr Grabow and her colleagues described this work in Cell Reports.
Previous research indicated that expression from both MCL-1 alleles is essential for the survival of hematopoietic stem and progenitor cells during stress-induced repopulation of the hematopoietic system.
So, with this study, Dr Grabow and her colleagues set out to determine whether reducing MCL-1 protein levels might hinder the development of hematologic malignancies.
In experiments with mice, the investigators found that loss of one MCL-1 allele significantly delayed the development of MYC-driven lymphoma and reduced MYC-driven accumulation of pre-leukemic cancer-initiating cells.
However, loss of one p53 allele accelerated MYC-driven lymphomagenesis even when one MCL-1 allele was deleted. Loss of PUMA accelerated lymphoma development as well, though to a much lesser extent.
Loss of BIM substantially accelerated lymphomagenesis when one MCL-1 allele was deleted, restoring lymphoma-initiating cells and the rate of tumor development.
And loss of one BIM allele overrode the survival defect observed in pre-leukemic Eμ-Myc B-cell progenitors when one MCL-1 allele was deleted.
The investigators noted that loss of one MCL-1 allele did not noticeably impair the survival of normal B lymphoid cells even though it greatly diminished the survival of MYC-overexpressing B-cell progenitors.
“No one had realized just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” Dr Grabow said.
“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anticancer drugs.”
Study investigator Brandon Aubrey, MBBS, also of the Walter and Eliza Hall Institute, said this research could inform future strategies to prevent cancer.
“Early treatment or even cancer prevention are likely to be a more effective way to fight cancer than treating an established cancer after it has already formed and made a person sick,” he said. ”Our research has suggested that dependency on MCL-1 could be a key vulnerability of many developing cancers.”
“In the future, MCL-1 inhibitors might have potential benefit for treating the very early stages of MYC-driven cancers, or we may even be able use these agents to prevent people from getting cancer in the first place.”
Study sheds new light on blood clot structure
Photo by Vera Kratochvil
Researchers say they have discovered significant differences between blood clot structure in adults and newborns, a finding that could help us better understand the challenges in addressing post-operative bleeding in neonatal patients.
The researchers also found evidence to suggest the current standard of care for treating post-operative bleeding may pose an increased risk of thrombosis in newborns as compared to adults.
The team reported these findings in Anesthesiology.
“We knew that neonates—infants less than 1 month old—are more likely than adults to suffer from severe bleeding after heart surgery, which poses a variety of health risks,” said study author Ashley Brown, PhD, of the University of North Carolina at Chapel Hill.
“The current standard of care is to give neonatal patients blood products . . . derived from adult blood, but neonatal blood and adult blood aren’t the same. Many of the components involved in clotting in newborns have differing levels of activity, or effectiveness, compared to the same components in adults. Our goal was to better understand how clotting in neonates differs from that in adults so that we can move closer to developing more effective treatment strategies for these infants.”
The researchers’ hypothesis was that fibrinogen from neonates would form clots that are different from those formed by adult fibrinogen, and this proved correct. However, the team was surprised to find that fibrinogen from adults did not integrate well with fibrinogen from neonates.
To test their hypothesis, the researchers took samples of neonate fibrinogen and adult fibrinogen and compared clot formation. The team looked at clots formed solely of adult fibrinogen, clots formed solely of neonate fibrinogen, and clots made from a mixture of the two.
Neonate fibrinogen formed less dense, more fragile clots than adult fibrinogen. Likewise, a mixture of adult and neonate fibrinogen formed clots that were fragile and less dense, even if there was relatively little neonate fibrinogen in the mixture.
The researchers also evaluated how long it took these clots to dissolve. Clots of neonate fibrinogen dissolved about twice as quickly as clots formed from adult fibrinogen.
Clots formed from an adult and neonate fibrinogen mixture dissolved at approximately the same rate as adult-only clots, regardless of the percentage of neonate fibrinogen in the mixture.
“This suggests that using adult fibrinogen in neonatal patients may pose an increased risk of embolism or other adverse thrombotic events,” said study author Nina Guzzetta, MD, of the Emory University School of Medicine in Atlanta, Georgia.
“This work drives home that newborns are not just small adults, and we still have much to learn about clotting in neonates. It also tells us that there is a great deal of room for improvement in the current standard of care for post-operative bleeding in neonates.”
“We are investigating several approaches that may help address this problem, evaluating various modes of action,” Dr Brown added. “It is possible that we can use various external factors that promote clotting to stimulate the fibrinogen in neonates to form a denser clot.”
“We are investigating possible alternatives to help neonates form a better clot after major surgery without having to use adult fibrinogen. For example, we are investigating the use of synthetic platelet-like particles developed by our team to augment hemostasis . . . in blood samples collected from these patients.”
Photo by Vera Kratochvil
Researchers say they have discovered significant differences between blood clot structure in adults and newborns, a finding that could help us better understand the challenges in addressing post-operative bleeding in neonatal patients.
The researchers also found evidence to suggest the current standard of care for treating post-operative bleeding may pose an increased risk of thrombosis in newborns as compared to adults.
The team reported these findings in Anesthesiology.
“We knew that neonates—infants less than 1 month old—are more likely than adults to suffer from severe bleeding after heart surgery, which poses a variety of health risks,” said study author Ashley Brown, PhD, of the University of North Carolina at Chapel Hill.
“The current standard of care is to give neonatal patients blood products . . . derived from adult blood, but neonatal blood and adult blood aren’t the same. Many of the components involved in clotting in newborns have differing levels of activity, or effectiveness, compared to the same components in adults. Our goal was to better understand how clotting in neonates differs from that in adults so that we can move closer to developing more effective treatment strategies for these infants.”
The researchers’ hypothesis was that fibrinogen from neonates would form clots that are different from those formed by adult fibrinogen, and this proved correct. However, the team was surprised to find that fibrinogen from adults did not integrate well with fibrinogen from neonates.
To test their hypothesis, the researchers took samples of neonate fibrinogen and adult fibrinogen and compared clot formation. The team looked at clots formed solely of adult fibrinogen, clots formed solely of neonate fibrinogen, and clots made from a mixture of the two.
Neonate fibrinogen formed less dense, more fragile clots than adult fibrinogen. Likewise, a mixture of adult and neonate fibrinogen formed clots that were fragile and less dense, even if there was relatively little neonate fibrinogen in the mixture.
The researchers also evaluated how long it took these clots to dissolve. Clots of neonate fibrinogen dissolved about twice as quickly as clots formed from adult fibrinogen.
Clots formed from an adult and neonate fibrinogen mixture dissolved at approximately the same rate as adult-only clots, regardless of the percentage of neonate fibrinogen in the mixture.
“This suggests that using adult fibrinogen in neonatal patients may pose an increased risk of embolism or other adverse thrombotic events,” said study author Nina Guzzetta, MD, of the Emory University School of Medicine in Atlanta, Georgia.
“This work drives home that newborns are not just small adults, and we still have much to learn about clotting in neonates. It also tells us that there is a great deal of room for improvement in the current standard of care for post-operative bleeding in neonates.”
“We are investigating several approaches that may help address this problem, evaluating various modes of action,” Dr Brown added. “It is possible that we can use various external factors that promote clotting to stimulate the fibrinogen in neonates to form a denser clot.”
“We are investigating possible alternatives to help neonates form a better clot after major surgery without having to use adult fibrinogen. For example, we are investigating the use of synthetic platelet-like particles developed by our team to augment hemostasis . . . in blood samples collected from these patients.”
Photo by Vera Kratochvil
Researchers say they have discovered significant differences between blood clot structure in adults and newborns, a finding that could help us better understand the challenges in addressing post-operative bleeding in neonatal patients.
The researchers also found evidence to suggest the current standard of care for treating post-operative bleeding may pose an increased risk of thrombosis in newborns as compared to adults.
The team reported these findings in Anesthesiology.
“We knew that neonates—infants less than 1 month old—are more likely than adults to suffer from severe bleeding after heart surgery, which poses a variety of health risks,” said study author Ashley Brown, PhD, of the University of North Carolina at Chapel Hill.
“The current standard of care is to give neonatal patients blood products . . . derived from adult blood, but neonatal blood and adult blood aren’t the same. Many of the components involved in clotting in newborns have differing levels of activity, or effectiveness, compared to the same components in adults. Our goal was to better understand how clotting in neonates differs from that in adults so that we can move closer to developing more effective treatment strategies for these infants.”
The researchers’ hypothesis was that fibrinogen from neonates would form clots that are different from those formed by adult fibrinogen, and this proved correct. However, the team was surprised to find that fibrinogen from adults did not integrate well with fibrinogen from neonates.
To test their hypothesis, the researchers took samples of neonate fibrinogen and adult fibrinogen and compared clot formation. The team looked at clots formed solely of adult fibrinogen, clots formed solely of neonate fibrinogen, and clots made from a mixture of the two.
Neonate fibrinogen formed less dense, more fragile clots than adult fibrinogen. Likewise, a mixture of adult and neonate fibrinogen formed clots that were fragile and less dense, even if there was relatively little neonate fibrinogen in the mixture.
The researchers also evaluated how long it took these clots to dissolve. Clots of neonate fibrinogen dissolved about twice as quickly as clots formed from adult fibrinogen.
Clots formed from an adult and neonate fibrinogen mixture dissolved at approximately the same rate as adult-only clots, regardless of the percentage of neonate fibrinogen in the mixture.
“This suggests that using adult fibrinogen in neonatal patients may pose an increased risk of embolism or other adverse thrombotic events,” said study author Nina Guzzetta, MD, of the Emory University School of Medicine in Atlanta, Georgia.
“This work drives home that newborns are not just small adults, and we still have much to learn about clotting in neonates. It also tells us that there is a great deal of room for improvement in the current standard of care for post-operative bleeding in neonates.”
“We are investigating several approaches that may help address this problem, evaluating various modes of action,” Dr Brown added. “It is possible that we can use various external factors that promote clotting to stimulate the fibrinogen in neonates to form a denser clot.”
“We are investigating possible alternatives to help neonates form a better clot after major surgery without having to use adult fibrinogen. For example, we are investigating the use of synthetic platelet-like particles developed by our team to augment hemostasis . . . in blood samples collected from these patients.”
FDA approves long-acting hemophilia B therapy
The US Food and Drug Administration (FDA) has approved Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) for the treatment of hemophilia B.
The product—a fusion protein linking recombinant coagulation factor IX with recombinant albumin—is intended for use in children and adults for routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.
Appropriate patients age 12 and older can go up to 14 days between Idelvion infusions. This dosing interval has been achieved while maintaining high levels of factor IX activity—above 5% over 14 days at 75 IU/kg.
Idelvion is the first FDA-approved recombinant factor IX therapy that can extend the dosing interval up to 14 days.
Idelvion is expected to be available in the US later this month. The product is being developed by CSL Behring. For more details on the drug, see the full prescribing information.
Phase 3 trial
The FDA approved Idelvion based on results of the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of Idelvion in adults and children (ages 1 to 61) with hemophilia B.
Data from the phase 3 study were recently published in Blood. This study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).
The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with Idelvion once every 7 days for 26 weeks, followed by a 7-, 10- or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.
Group 2 received on-demand treatment with Idelvion for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).
The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.
For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).
Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of Idelvion.
None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).
There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).
Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to Idelvion. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.
The US Food and Drug Administration (FDA) has approved Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) for the treatment of hemophilia B.
The product—a fusion protein linking recombinant coagulation factor IX with recombinant albumin—is intended for use in children and adults for routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.
Appropriate patients age 12 and older can go up to 14 days between Idelvion infusions. This dosing interval has been achieved while maintaining high levels of factor IX activity—above 5% over 14 days at 75 IU/kg.
Idelvion is the first FDA-approved recombinant factor IX therapy that can extend the dosing interval up to 14 days.
Idelvion is expected to be available in the US later this month. The product is being developed by CSL Behring. For more details on the drug, see the full prescribing information.
Phase 3 trial
The FDA approved Idelvion based on results of the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of Idelvion in adults and children (ages 1 to 61) with hemophilia B.
Data from the phase 3 study were recently published in Blood. This study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).
The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with Idelvion once every 7 days for 26 weeks, followed by a 7-, 10- or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.
Group 2 received on-demand treatment with Idelvion for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).
The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.
For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).
Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of Idelvion.
None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).
There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).
Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to Idelvion. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.
The US Food and Drug Administration (FDA) has approved Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) for the treatment of hemophilia B.
The product—a fusion protein linking recombinant coagulation factor IX with recombinant albumin—is intended for use in children and adults for routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.
Appropriate patients age 12 and older can go up to 14 days between Idelvion infusions. This dosing interval has been achieved while maintaining high levels of factor IX activity—above 5% over 14 days at 75 IU/kg.
Idelvion is the first FDA-approved recombinant factor IX therapy that can extend the dosing interval up to 14 days.
Idelvion is expected to be available in the US later this month. The product is being developed by CSL Behring. For more details on the drug, see the full prescribing information.
Phase 3 trial
The FDA approved Idelvion based on results of the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of Idelvion in adults and children (ages 1 to 61) with hemophilia B.
Data from the phase 3 study were recently published in Blood. This study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).
The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with Idelvion once every 7 days for 26 weeks, followed by a 7-, 10- or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.
Group 2 received on-demand treatment with Idelvion for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).
The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.
For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).
Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of Idelvion.
None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).
There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).
Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to Idelvion. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.
FDA approves ibrutinib as first-line CLL therapy
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has approved the BTK inhibitor ibrutinib (Imbruvica) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL).
This means ibrutinib is now FDA-approved to treat CLL patients regardless of their treatment history, including patients with 17p deletion.
Ibrutinib is also FDA-approved to treat Waldenström’s macroglobulinemia, and the drug was granted accelerated approval to treat patients with mantle cell lymphoma who have received at least 1 prior therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc. For more details on the drug, see the full prescribing information, available at imbruvica.com.
RESONATE-2 trial
The latest FDA approval for ibrutinib is based on results from the phase 3 RESONATE-2 trial (PCYC-1115), which were presented at the 2015 ASH Annual Meeting and simultaneously published in NEJM.
RESONATE-2 enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma who were 65 or older.
Patients were randomized to receive ibrutinib (n=136) at 420 mg once a day until progression or unacceptable toxicity, or chlorambucil (n=133) on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis.
Key secondary endpoints included overall response rate (based on the same iWCLL criteria), overall survival (OS), and safety.
Ibrutinib significantly prolonged PFS, as determined by the IRC, reducing the risk of progression or death by 84% compared to chlorambucil. The hazard ratio was 0.16 (P<0.001). The median PFS was not reached in the ibrutinib arm but was 18.9 months for the chlorambucil arm.
Ibrutinib significantly prolonged OS as well, although the median OS was not reached in either treatment arm. The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil. The relative risk of death with ibrutinib was 84% lower than that with chlorambucil. The hazard ratio was 0.16 (P=0.001).
Ibrutinib was associated with a significantly higher IRC-assessed overall response rate compared to chlorambucil—82% and 35%, respectively (P<0.0001). Five patients (4%) in the ibrutinib arm achieved a complete response, as did 2 patients (2%) in the chlorambucil arm.
The median duration of treatment was 17.4 months in the ibrutinib arm and 7.1 months in the chlorambucil arm.
The most common adverse events of any grade—in the ibrutinib and chlorambucil arms, respectively—were diarrhea (42% and 17%), fatigue (30% and 38%), cough (22% and 15%), nausea (22% and 39%), peripheral edema (19% and 9%), dry eye (17% and 5%), arthralgia (16% and 7%), neutropenia (16% and 23%), and vomiting (13% and 20%).
Adverse events of grade 3 or higher—in the ibrutinib and chlorambucil arms, respectively—were neutropenia (10% and 18%), anemia (6% and 8%), hypertension (4% and 0%), pneumonia (4% and 2%), diarrhea (4% and 0%), maculopapular rash (3% and 2%), decreased platelet count (3% and 1%), abdominal pain (3% and 1%), hyponatremia (3% and 0%), thrombocytopenia (2% and 6%), febrile neutropenia (2% and 2%), upper respiratory tract infection (2% and 2%), pleural effusion (2% and 1%), cellulitis (2% and 0%), fatigue (1% and 5%), syncope (1% and 2%), and hemolytic anemia (0% and 2%).
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has approved the BTK inhibitor ibrutinib (Imbruvica) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL).
This means ibrutinib is now FDA-approved to treat CLL patients regardless of their treatment history, including patients with 17p deletion.
Ibrutinib is also FDA-approved to treat Waldenström’s macroglobulinemia, and the drug was granted accelerated approval to treat patients with mantle cell lymphoma who have received at least 1 prior therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc. For more details on the drug, see the full prescribing information, available at imbruvica.com.
RESONATE-2 trial
The latest FDA approval for ibrutinib is based on results from the phase 3 RESONATE-2 trial (PCYC-1115), which were presented at the 2015 ASH Annual Meeting and simultaneously published in NEJM.
RESONATE-2 enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma who were 65 or older.
Patients were randomized to receive ibrutinib (n=136) at 420 mg once a day until progression or unacceptable toxicity, or chlorambucil (n=133) on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis.
Key secondary endpoints included overall response rate (based on the same iWCLL criteria), overall survival (OS), and safety.
Ibrutinib significantly prolonged PFS, as determined by the IRC, reducing the risk of progression or death by 84% compared to chlorambucil. The hazard ratio was 0.16 (P<0.001). The median PFS was not reached in the ibrutinib arm but was 18.9 months for the chlorambucil arm.
Ibrutinib significantly prolonged OS as well, although the median OS was not reached in either treatment arm. The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil. The relative risk of death with ibrutinib was 84% lower than that with chlorambucil. The hazard ratio was 0.16 (P=0.001).
Ibrutinib was associated with a significantly higher IRC-assessed overall response rate compared to chlorambucil—82% and 35%, respectively (P<0.0001). Five patients (4%) in the ibrutinib arm achieved a complete response, as did 2 patients (2%) in the chlorambucil arm.
The median duration of treatment was 17.4 months in the ibrutinib arm and 7.1 months in the chlorambucil arm.
The most common adverse events of any grade—in the ibrutinib and chlorambucil arms, respectively—were diarrhea (42% and 17%), fatigue (30% and 38%), cough (22% and 15%), nausea (22% and 39%), peripheral edema (19% and 9%), dry eye (17% and 5%), arthralgia (16% and 7%), neutropenia (16% and 23%), and vomiting (13% and 20%).
Adverse events of grade 3 or higher—in the ibrutinib and chlorambucil arms, respectively—were neutropenia (10% and 18%), anemia (6% and 8%), hypertension (4% and 0%), pneumonia (4% and 2%), diarrhea (4% and 0%), maculopapular rash (3% and 2%), decreased platelet count (3% and 1%), abdominal pain (3% and 1%), hyponatremia (3% and 0%), thrombocytopenia (2% and 6%), febrile neutropenia (2% and 2%), upper respiratory tract infection (2% and 2%), pleural effusion (2% and 1%), cellulitis (2% and 0%), fatigue (1% and 5%), syncope (1% and 2%), and hemolytic anemia (0% and 2%).
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has approved the BTK inhibitor ibrutinib (Imbruvica) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL).
This means ibrutinib is now FDA-approved to treat CLL patients regardless of their treatment history, including patients with 17p deletion.
Ibrutinib is also FDA-approved to treat Waldenström’s macroglobulinemia, and the drug was granted accelerated approval to treat patients with mantle cell lymphoma who have received at least 1 prior therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc. For more details on the drug, see the full prescribing information, available at imbruvica.com.
RESONATE-2 trial
The latest FDA approval for ibrutinib is based on results from the phase 3 RESONATE-2 trial (PCYC-1115), which were presented at the 2015 ASH Annual Meeting and simultaneously published in NEJM.
RESONATE-2 enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma who were 65 or older.
Patients were randomized to receive ibrutinib (n=136) at 420 mg once a day until progression or unacceptable toxicity, or chlorambucil (n=133) on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis.
Key secondary endpoints included overall response rate (based on the same iWCLL criteria), overall survival (OS), and safety.
Ibrutinib significantly prolonged PFS, as determined by the IRC, reducing the risk of progression or death by 84% compared to chlorambucil. The hazard ratio was 0.16 (P<0.001). The median PFS was not reached in the ibrutinib arm but was 18.9 months for the chlorambucil arm.
Ibrutinib significantly prolonged OS as well, although the median OS was not reached in either treatment arm. The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil. The relative risk of death with ibrutinib was 84% lower than that with chlorambucil. The hazard ratio was 0.16 (P=0.001).
Ibrutinib was associated with a significantly higher IRC-assessed overall response rate compared to chlorambucil—82% and 35%, respectively (P<0.0001). Five patients (4%) in the ibrutinib arm achieved a complete response, as did 2 patients (2%) in the chlorambucil arm.
The median duration of treatment was 17.4 months in the ibrutinib arm and 7.1 months in the chlorambucil arm.
The most common adverse events of any grade—in the ibrutinib and chlorambucil arms, respectively—were diarrhea (42% and 17%), fatigue (30% and 38%), cough (22% and 15%), nausea (22% and 39%), peripheral edema (19% and 9%), dry eye (17% and 5%), arthralgia (16% and 7%), neutropenia (16% and 23%), and vomiting (13% and 20%).
Adverse events of grade 3 or higher—in the ibrutinib and chlorambucil arms, respectively—were neutropenia (10% and 18%), anemia (6% and 8%), hypertension (4% and 0%), pneumonia (4% and 2%), diarrhea (4% and 0%), maculopapular rash (3% and 2%), decreased platelet count (3% and 1%), abdominal pain (3% and 1%), hyponatremia (3% and 0%), thrombocytopenia (2% and 6%), febrile neutropenia (2% and 2%), upper respiratory tract infection (2% and 2%), pleural effusion (2% and 1%), cellulitis (2% and 0%), fatigue (1% and 5%), syncope (1% and 2%), and hemolytic anemia (0% and 2%).
TXA may increase risk of DVT but not PE
Photo courtesy of NIH
ORLANDO, FL—Results of a large, retrospective study suggest tranexamic acid (TXA) can reduce the need for transfusion in patients undergoing hip and knee replacement surgery without increasing the overall risk of venous thromboembolism (VTE).
However, patients treated with TXA were significantly more likely to develop deep vein thrombosis (DVT) than patients who did not receive the drug.
There was no significant difference between the treatment groups with regard to pulmonary embolism (PE).
These results were presented at the American Academy of Orthopaedic Surgeons (AAOS) 2016 Annual Meeting (abstract P101).
“[C]onflicting results have been published regarding the use of TXA in patients undergoing hip and knee replacement,” said study investigator Geoffrey Westrich, MD, of the Hospital for Special Surgery in New York, New York.
To assess the safety and efficacy of TXA in this patient population, Dr Westrich and his colleagues retrospectively reviewed the records of 4449 patients who had hip or knee replacement over a 6-month period.
There were 720 patients who received TXA topically, 636 who received TXA intravenously, and 3093 patients who did not receive the drug.
The investigators found that 9.7% of patients treated with either type of TXA received a blood transfusion, as did 22.1% of patients who were not treated with TXA.
TXA-treated patients received an average of 0.13 units of blood, compared to 0.37 units for patients in the non-TXA group.
The investigators said there was no significant difference in efficacy between topical and intravenous TXA.
“At our institution, TXA in either intravenous or topical form was effective in decreasing the amount of blood transfusions, as well as the number of units of blood transfused in primary and revision hip and knee replacement,” Dr Westrich said.
“Furthermore, when safety was evaluated, there was no statistically significant difference in blood clots in patients who received IV or topical TXA, reconfirming its safety.”
The odds of developing a hospital-acquired VTE was 1.63 among patients treated with TXA, which was not significantly higher than the odds for patients who did not receive the drug (P=0.24).
When the investigators evaluated DVT and PE separately, they found the TXA group had a significant increase in DVT (P=0.03) but not PE (P=0.94).
Photo courtesy of NIH
ORLANDO, FL—Results of a large, retrospective study suggest tranexamic acid (TXA) can reduce the need for transfusion in patients undergoing hip and knee replacement surgery without increasing the overall risk of venous thromboembolism (VTE).
However, patients treated with TXA were significantly more likely to develop deep vein thrombosis (DVT) than patients who did not receive the drug.
There was no significant difference between the treatment groups with regard to pulmonary embolism (PE).
These results were presented at the American Academy of Orthopaedic Surgeons (AAOS) 2016 Annual Meeting (abstract P101).
“[C]onflicting results have been published regarding the use of TXA in patients undergoing hip and knee replacement,” said study investigator Geoffrey Westrich, MD, of the Hospital for Special Surgery in New York, New York.
To assess the safety and efficacy of TXA in this patient population, Dr Westrich and his colleagues retrospectively reviewed the records of 4449 patients who had hip or knee replacement over a 6-month period.
There were 720 patients who received TXA topically, 636 who received TXA intravenously, and 3093 patients who did not receive the drug.
The investigators found that 9.7% of patients treated with either type of TXA received a blood transfusion, as did 22.1% of patients who were not treated with TXA.
TXA-treated patients received an average of 0.13 units of blood, compared to 0.37 units for patients in the non-TXA group.
The investigators said there was no significant difference in efficacy between topical and intravenous TXA.
“At our institution, TXA in either intravenous or topical form was effective in decreasing the amount of blood transfusions, as well as the number of units of blood transfused in primary and revision hip and knee replacement,” Dr Westrich said.
“Furthermore, when safety was evaluated, there was no statistically significant difference in blood clots in patients who received IV or topical TXA, reconfirming its safety.”
The odds of developing a hospital-acquired VTE was 1.63 among patients treated with TXA, which was not significantly higher than the odds for patients who did not receive the drug (P=0.24).
When the investigators evaluated DVT and PE separately, they found the TXA group had a significant increase in DVT (P=0.03) but not PE (P=0.94).
Photo courtesy of NIH
ORLANDO, FL—Results of a large, retrospective study suggest tranexamic acid (TXA) can reduce the need for transfusion in patients undergoing hip and knee replacement surgery without increasing the overall risk of venous thromboembolism (VTE).
However, patients treated with TXA were significantly more likely to develop deep vein thrombosis (DVT) than patients who did not receive the drug.
There was no significant difference between the treatment groups with regard to pulmonary embolism (PE).
These results were presented at the American Academy of Orthopaedic Surgeons (AAOS) 2016 Annual Meeting (abstract P101).
“[C]onflicting results have been published regarding the use of TXA in patients undergoing hip and knee replacement,” said study investigator Geoffrey Westrich, MD, of the Hospital for Special Surgery in New York, New York.
To assess the safety and efficacy of TXA in this patient population, Dr Westrich and his colleagues retrospectively reviewed the records of 4449 patients who had hip or knee replacement over a 6-month period.
There were 720 patients who received TXA topically, 636 who received TXA intravenously, and 3093 patients who did not receive the drug.
The investigators found that 9.7% of patients treated with either type of TXA received a blood transfusion, as did 22.1% of patients who were not treated with TXA.
TXA-treated patients received an average of 0.13 units of blood, compared to 0.37 units for patients in the non-TXA group.
The investigators said there was no significant difference in efficacy between topical and intravenous TXA.
“At our institution, TXA in either intravenous or topical form was effective in decreasing the amount of blood transfusions, as well as the number of units of blood transfused in primary and revision hip and knee replacement,” Dr Westrich said.
“Furthermore, when safety was evaluated, there was no statistically significant difference in blood clots in patients who received IV or topical TXA, reconfirming its safety.”
The odds of developing a hospital-acquired VTE was 1.63 among patients treated with TXA, which was not significantly higher than the odds for patients who did not receive the drug (P=0.24).
When the investigators evaluated DVT and PE separately, they found the TXA group had a significant increase in DVT (P=0.03) but not PE (P=0.94).