Hematology

An international team of researchers have developed a “molecular map” of chronic lymphocytic leukemia (CLL) and used it to refine genetic subtypes and variations that appear to be linked to clinical outcomes.

Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.

“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.

According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.

For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.

“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”

In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”

The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.

The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”

Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”

While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”

In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”

The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
 

An international team of researchers have developed a “molecular map” of chronic lymphocytic leukemia (CLL) and used it to refine genetic subtypes and variations that appear to be linked to clinical outcomes.

Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.

“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.

According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.

For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.

“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”

In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”

The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.

The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”

Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”

While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”

In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”

The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
 

An international team of researchers have developed a “molecular map” of chronic lymphocytic leukemia (CLL) and used it to refine genetic subtypes and variations that appear to be linked to clinical outcomes.

Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.

“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.

According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.

For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.

“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”

In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”

The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.

The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”

Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”

While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”

In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”

The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
 

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

A version of this article first appeared on Medscape.com.

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

A version of this article first appeared on Medscape.com.

The new factor XI inhibitor antithrombotic, milvexian (Bristol-Myers Squibb/Janssen), has shown promising results in a dose-finding phase 2 trial in patients with acute ischemic stroke or transient ischemic attack (TIA), when given in addition to dual antiplatelet therapy.

Although there was no significant reduction in the primary composite endpoint of ischemic stroke or incident infarct on brain MRI at 90 days with milvexian versus placebo in the AXIOMATIC-SSP study, with no apparent dose response, the drug numerically reduced the risk for symptomatic ischemic stroke at most doses. And doses from 25 mg to 100 mg twice daily showed an approximately 30% relative risk reduction in symptomatic ischemic stroke versus placebo.

Milvexian at 25 mg once and twice daily was associated with a low incidence of major bleeding; a moderate increase in bleeding was seen with higher doses.

There was no increase in severe bleeding, compared with placebo, and no fatal bleeding occurred any study group.

“Based on the observed efficacy signal for ischemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population,” concluded lead investigator, Mukul Sharma, MD, associate professor of medicine at McMaster University, Hamilton, Ont.

Dr. Sharma presented the AXIOMATIC-SSP study results at the annual congress of the European Society of Cardiology.
 

New generation

Dr. Sharma explained that factor XI inhibitors represent the latest hope for a new generation of antithrombotic drugs with a low bleeding risk.

This has come about after observations that individuals born with factor XI deficiency have lower rates of ischemic stroke and thromboembolism than matched controls, without an offsetting increase in cerebral hemorrhage. In addition, spontaneous bleeding in these individuals is uncommon, and it is thought that factor XI is a strong driver of thrombus growth but plays a less important role in hemostasis, he noted.

“I think there is a tremendous niche for these drugs in stroke prevention,” Dr. Sharma said in an interview. “There is a huge unmet need in stroke patients for something other than aspirin over the long term which is effective but doesn’t cause hemorrhage.”

Dr. Sharma reported that antithrombotic efficacy of milvexian has already been demonstrated in a study of patients undergoing knee replacement in which the drug showed similar or increased efficacy in reducing thromboembolism, compared with enoxaparin, 40 mg, without an increase in major bleeding.

The aim of the current AXIOMATIC-SSP study was to find a dose suitable for use in the treatment of patients with acute stroke or TIA.

Patients with an acute ischemic stroke or TIA are at a high risk for another stroke in the first few months. Although antiplatelet drugs have reduced this event rate, there is still a significant residual risk for ischemic stroke, and the potential for major bleeding with additional antithrombotic therapies has limited the effectiveness of these options, Dr. Sharma explained. Currently, no anticoagulants are approved for noncardioembolic ischemic stroke prevention in the early phase.

The AXIOMATIC-SSP study included 2,366 patients within 48 hours of onset of a mild to moderate acute nonlacunar ischemic stroke. All patients had visible atherosclerotic plaque in a vessel supplying the affected brain region, and they all received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin alone from days 22 to 90.

They were randomly assigned to one of five doses of milvexian (25, 50, 100, or 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days.

The primary efficacy endpoint (symptomatic ischemic stroke or incident infarct on brain MRI) was numerically lower at the 50-mg and 100-mg twice-daily doses, and there was no apparent dose response (placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; 200 mg twice daily, 16.4%).

However, milvexian was associated with a numerically lower risk for clinical ischemic stroke at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; 200 mg twice daily, 7.7%).

The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium type 3 or 5 bleeding. This was similar to placebo for milvexian 25 mg once daily and twice daily (all 0.6%) but was moderately increased in the 50 mg twice daily (1.5%), 100 mg twice daily (1.6%), and 200 mg twice daily (1.5%) groups.

Most major bleeding episodes were gastrointestinal. There was no increase in severe bleeding or symptomatic intracranial hemorrhage versus placebo, and no fatal bleeding occurred in any arm of the study.
 

Incremental improvement

On the hope for a class of drugs that reduce ischemic events without increasing bleeding, Dr. Sharma said, “we keep hoping for a home run where there is no increase in bleeding with a new generation of antithrombotic, but what we seem to get is an incremental improvement with each new class.

“Factor Xa inhibitors have a lower rate of bleeding, compared to warfarin. I think we will see another incremental improvement in bleeding with these new factor XI inhibitors and hopefully less of the more serious bleeding,” he said in an interview.

He pointed out that, in this study, milvexian was given on top of dual antiplatelet therapy. “In stroke neurology that sounds very risky as we know that going from a single antiplatelet to two antiplatelet agents increases the risk of bleeding and now we are adding in a third antithrombotic, but we feel comfortable doing it because of what has been observed in patients who have a genetic deficiency of factor XI – very low rates of spontaneous bleeding and they don’t bleed intracranially largely,” he added.

In addition to milvexian, another oral factor XI inhibitor, asundexian (Bayer), is also in development, and similar results were reported in a phase 2 stroke trial (PACIFIC-STROKE) at the same ESC session.

Both drugs are now believed to be going forward into phase 3 trials.

Discussant of the study at the ESC Hotline session, Giovanna Liuzzo, MD, Catholic University of Rome, highlighted the large unmet need for stroke therapies, noting that patients with acute stroke or TIA have a stroke recurrence rate of 5% at 30 days and 17% at 2 years. Although antiplatelet agents are recommended, the use of anticoagulants has been limited by concerns over bleeding risk, and the factor XI inhibitors are promising in that they have the potential for a lower bleeding risk.

She suggested that results from the AXIOMATIC-SSP could point to a dose of milvexian of 25 mg twice daily as a balance between efficacy and bleeding to be taken into larger phase 3 trials

“The jury is still out on the safety and efficacy of milvexian as an adjunct to dual antiplatelet therapy for the prevention of recurrent noncardioembolic stroke,” Dr. Liuzzo concluded. “Only large-scale phase 3 trials will establish the safety and efficacy of factor XI inhibitors in the prevention of venous and arterial thrombosis.”

The AXIOMATIC-SSP study was funded by the Bristol-Myers Squibb/Janssen alliance. Dr. Sharma reported research contracts with Bristol-Myers Squibb, Bayer, and AstraZeneca, and consulting fees from Janssen, Bayer, HLS Therapeutics, and Alexion.

A version of this article first appeared on Medscape.com.

Ibrutinib (Imbruvica) is now available for use in children aged 1-12 years who have chronic graft-versus-host disease (cGVHD), which can develop after stem cell transplantation for treatment of a blood cancer.

Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.

Ibrutinib is already approved for use in adults with cGVHD.

The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.

This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”

These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.

“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”

The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.

The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.

The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).

The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.

The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.

Full prescribing information for ibrutinib is available here.

A version of this article first appeared on Medscape.com.

Ibrutinib (Imbruvica) is now available for use in children aged 1-12 years who have chronic graft-versus-host disease (cGVHD), which can develop after stem cell transplantation for treatment of a blood cancer.

Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.

Ibrutinib is already approved for use in adults with cGVHD.

The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.

This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”

These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.

“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”

The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.

The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.

The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).

The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.

The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.

Full prescribing information for ibrutinib is available here.

A version of this article first appeared on Medscape.com.

Ibrutinib (Imbruvica) is now available for use in children aged 1-12 years who have chronic graft-versus-host disease (cGVHD), which can develop after stem cell transplantation for treatment of a blood cancer.

Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.

Ibrutinib is already approved for use in adults with cGVHD.

The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.

This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”

These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.

“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”

The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.

The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.

The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).

The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.

The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.

Full prescribing information for ibrutinib is available here.

A version of this article first appeared on Medscape.com.

Two biomarkers present in blood measured on the day of traumatic brain injury (TBI) can accurately predict a patient’s risk for death or severe disability 6 months later, new research suggests.

In new data from the TRACK-TBI study group, high levels of glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) proteins found in glial cells and neurons, respectively, correlated with death and severe injury. Investigators note that measuring these biomarkers may give a more accurate assessment of a patient’s prognosis following TBI.

This study is the “first report of the accuracy of a blood test that can be obtained rapidly on the day of injury to predict neurological recovery at 6 months after injury,” lead author Frederick Korley, MD, PhD, associate professor of emergency medicine at the University of Michigan, Ann Arbor, said in a news release.

The findings were published online in the Lancet Neurology.
 

Added value

The researchers measured GFAP and UCH-L1 in blood samples taken from 1,696 patients with TBI on the day of their injury, and they assessed patient recovery 6 months later.

The markers were measured using the i-STAT TBI Plasma test (Abbott Labs). The test was approved in 2021 by the U.S. Food and Drug Administration to determine which patients with mild TBI should undergo computed tomography scans.

About two-thirds of the study population were men, and the average age was 39 years. All patients were evaluated at Level I trauma centers for injuries caused primarily by traffic accidents or falls.

Six months following injury, 7% of the patients had died and 14% had an unfavorable outcome, ranging from vegetative state to severe disability requiring daily support. In addition, 67% had incomplete recovery, ranging from moderate disabilities requiring assistance outside of the home to minor disabling neurological or psychological deficits.

Day-of-injury GFAP and UCH-L1 levels had a high probability of predicting death (87% for GFAP and 89% for UCH-L1) and severe disability (86% for both GFAP and UCH-L1) at 6 months, the investigators reported.

The biomarkers were less accurate in predicting incomplete recovery (62% for GFAP and 61% for UCH-L1).

The researchers also assessed the added value of combining the blood biomarkers to current TBI prognostic models that take into account variables such as age, motor score, pupil reactivity, and CT characteristics.

In patients with a Glasgow Coma Scale (GCS) score of 3-12, adding GFAP and UCH-L1 alone or combined to each of the three International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) models significantly increased their accuracy for predicting death (range, 90%-94%) and unfavorable outcome (range, 83%-89%).

In patients with milder TBI (GCS score, 13-15), adding GFAP and UCH-L1 to the UPFRONT prognostic model modestly increased accuracy for predicting incomplete recovery (69%).
 

‘Important’ findings

Commenting on the study, Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University, St. Louis, said this “critical” study shows that these biomarkers can “predict key outcomes,” including mortality and severe disability. “Thus, in conjunction with clinical evaluations and related data such as neuroimaging, these tests may warrant translation to broader clinical practice, particularly in acute settings,” said Dr. Raji, who was not involved in the research.

Also weighing in, Heidi Fusco, MD, assistant director of the traumatic brain injury program at NYU Langone Rusk Rehabilitation, said the findings are “important.”

“Prognosis after brain injury often is based on the initial presentation, ongoing clinical exams, and neuroimaging; and the addition of biomarkers would contribute to creating a more objective prognostic model,” Dr. Fusco said.

She noted “it’s unclear” whether clinical hospital laboratories would be able to accommodate this type of laboratory drawing.

“It is imperative that clinicians still use the patient history [and] clinical and radiological exam when making clinical decisions for a patient and not just lab values. It would be best to incorporate the GFAP and UCH-L1 into a preexisting prognostic model,” Dr. Fusco said.

The study was funded by the U.S. National Institutes of Health, the National Institute of Neurologic Disorders and Stroke, the U.S. Department of Defense, One Mind, and U.S. Army Medical Research and Development Command. Dr. Korley reported having previously consulted for Abbott Laboratories and has received research funding from Abbott Laboratories, which makes the assays used in the study. Dr. Raji is a consultant for Brainreader ApS and Neurevolution. Dr. Fusco has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Two biomarkers present in blood measured on the day of traumatic brain injury (TBI) can accurately predict a patient’s risk for death or severe disability 6 months later, new research suggests.

In new data from the TRACK-TBI study group, high levels of glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) proteins found in glial cells and neurons, respectively, correlated with death and severe injury. Investigators note that measuring these biomarkers may give a more accurate assessment of a patient’s prognosis following TBI.

This study is the “first report of the accuracy of a blood test that can be obtained rapidly on the day of injury to predict neurological recovery at 6 months after injury,” lead author Frederick Korley, MD, PhD, associate professor of emergency medicine at the University of Michigan, Ann Arbor, said in a news release.

The findings were published online in the Lancet Neurology.
 

Added value

The researchers measured GFAP and UCH-L1 in blood samples taken from 1,696 patients with TBI on the day of their injury, and they assessed patient recovery 6 months later.

The markers were measured using the i-STAT TBI Plasma test (Abbott Labs). The test was approved in 2021 by the U.S. Food and Drug Administration to determine which patients with mild TBI should undergo computed tomography scans.

About two-thirds of the study population were men, and the average age was 39 years. All patients were evaluated at Level I trauma centers for injuries caused primarily by traffic accidents or falls.

Six months following injury, 7% of the patients had died and 14% had an unfavorable outcome, ranging from vegetative state to severe disability requiring daily support. In addition, 67% had incomplete recovery, ranging from moderate disabilities requiring assistance outside of the home to minor disabling neurological or psychological deficits.

Day-of-injury GFAP and UCH-L1 levels had a high probability of predicting death (87% for GFAP and 89% for UCH-L1) and severe disability (86% for both GFAP and UCH-L1) at 6 months, the investigators reported.

The biomarkers were less accurate in predicting incomplete recovery (62% for GFAP and 61% for UCH-L1).

The researchers also assessed the added value of combining the blood biomarkers to current TBI prognostic models that take into account variables such as age, motor score, pupil reactivity, and CT characteristics.

In patients with a Glasgow Coma Scale (GCS) score of 3-12, adding GFAP and UCH-L1 alone or combined to each of the three International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) models significantly increased their accuracy for predicting death (range, 90%-94%) and unfavorable outcome (range, 83%-89%).

In patients with milder TBI (GCS score, 13-15), adding GFAP and UCH-L1 to the UPFRONT prognostic model modestly increased accuracy for predicting incomplete recovery (69%).
 

‘Important’ findings

Commenting on the study, Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University, St. Louis, said this “critical” study shows that these biomarkers can “predict key outcomes,” including mortality and severe disability. “Thus, in conjunction with clinical evaluations and related data such as neuroimaging, these tests may warrant translation to broader clinical practice, particularly in acute settings,” said Dr. Raji, who was not involved in the research.

Also weighing in, Heidi Fusco, MD, assistant director of the traumatic brain injury program at NYU Langone Rusk Rehabilitation, said the findings are “important.”

“Prognosis after brain injury often is based on the initial presentation, ongoing clinical exams, and neuroimaging; and the addition of biomarkers would contribute to creating a more objective prognostic model,” Dr. Fusco said.

She noted “it’s unclear” whether clinical hospital laboratories would be able to accommodate this type of laboratory drawing.

“It is imperative that clinicians still use the patient history [and] clinical and radiological exam when making clinical decisions for a patient and not just lab values. It would be best to incorporate the GFAP and UCH-L1 into a preexisting prognostic model,” Dr. Fusco said.

The study was funded by the U.S. National Institutes of Health, the National Institute of Neurologic Disorders and Stroke, the U.S. Department of Defense, One Mind, and U.S. Army Medical Research and Development Command. Dr. Korley reported having previously consulted for Abbott Laboratories and has received research funding from Abbott Laboratories, which makes the assays used in the study. Dr. Raji is a consultant for Brainreader ApS and Neurevolution. Dr. Fusco has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Two biomarkers present in blood measured on the day of traumatic brain injury (TBI) can accurately predict a patient’s risk for death or severe disability 6 months later, new research suggests.

In new data from the TRACK-TBI study group, high levels of glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) proteins found in glial cells and neurons, respectively, correlated with death and severe injury. Investigators note that measuring these biomarkers may give a more accurate assessment of a patient’s prognosis following TBI.

This study is the “first report of the accuracy of a blood test that can be obtained rapidly on the day of injury to predict neurological recovery at 6 months after injury,” lead author Frederick Korley, MD, PhD, associate professor of emergency medicine at the University of Michigan, Ann Arbor, said in a news release.

The findings were published online in the Lancet Neurology.
 

Added value

The researchers measured GFAP and UCH-L1 in blood samples taken from 1,696 patients with TBI on the day of their injury, and they assessed patient recovery 6 months later.

The markers were measured using the i-STAT TBI Plasma test (Abbott Labs). The test was approved in 2021 by the U.S. Food and Drug Administration to determine which patients with mild TBI should undergo computed tomography scans.

About two-thirds of the study population were men, and the average age was 39 years. All patients were evaluated at Level I trauma centers for injuries caused primarily by traffic accidents or falls.

Six months following injury, 7% of the patients had died and 14% had an unfavorable outcome, ranging from vegetative state to severe disability requiring daily support. In addition, 67% had incomplete recovery, ranging from moderate disabilities requiring assistance outside of the home to minor disabling neurological or psychological deficits.

Day-of-injury GFAP and UCH-L1 levels had a high probability of predicting death (87% for GFAP and 89% for UCH-L1) and severe disability (86% for both GFAP and UCH-L1) at 6 months, the investigators reported.

The biomarkers were less accurate in predicting incomplete recovery (62% for GFAP and 61% for UCH-L1).

The researchers also assessed the added value of combining the blood biomarkers to current TBI prognostic models that take into account variables such as age, motor score, pupil reactivity, and CT characteristics.

In patients with a Glasgow Coma Scale (GCS) score of 3-12, adding GFAP and UCH-L1 alone or combined to each of the three International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) models significantly increased their accuracy for predicting death (range, 90%-94%) and unfavorable outcome (range, 83%-89%).

In patients with milder TBI (GCS score, 13-15), adding GFAP and UCH-L1 to the UPFRONT prognostic model modestly increased accuracy for predicting incomplete recovery (69%).
 

‘Important’ findings

Commenting on the study, Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University, St. Louis, said this “critical” study shows that these biomarkers can “predict key outcomes,” including mortality and severe disability. “Thus, in conjunction with clinical evaluations and related data such as neuroimaging, these tests may warrant translation to broader clinical practice, particularly in acute settings,” said Dr. Raji, who was not involved in the research.

Also weighing in, Heidi Fusco, MD, assistant director of the traumatic brain injury program at NYU Langone Rusk Rehabilitation, said the findings are “important.”

“Prognosis after brain injury often is based on the initial presentation, ongoing clinical exams, and neuroimaging; and the addition of biomarkers would contribute to creating a more objective prognostic model,” Dr. Fusco said.

She noted “it’s unclear” whether clinical hospital laboratories would be able to accommodate this type of laboratory drawing.

“It is imperative that clinicians still use the patient history [and] clinical and radiological exam when making clinical decisions for a patient and not just lab values. It would be best to incorporate the GFAP and UCH-L1 into a preexisting prognostic model,” Dr. Fusco said.

The study was funded by the U.S. National Institutes of Health, the National Institute of Neurologic Disorders and Stroke, the U.S. Department of Defense, One Mind, and U.S. Army Medical Research and Development Command. Dr. Korley reported having previously consulted for Abbott Laboratories and has received research funding from Abbott Laboratories, which makes the assays used in the study. Dr. Raji is a consultant for Brainreader ApS and Neurevolution. Dr. Fusco has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Children born near fracking and other “unconventional” drilling sites are at two to three times greater risk of developing childhood leukemia, according to new research.

The study, published in the journal Environmental Health Perspectives, compared proximity of homes to unconventional oil and gas development (UOGD) sites and risk of the most common form of childhood leukemia, acute lymphoblastic leukemia (ALL).

Researchers looked at 405 children aged 2-7 diagnosed with ALL in Pennsylvania from 2009 to 2017. These children were compared to a control group of 2,080 without the disease matched on the year of birth.

“Unconventional oil and gas development can both use and release chemicals that have been linked to cancer,” study coauthor Nicole Deziel, PhD, of the Yale School of Public Health, New Haven, Conn., said in a  statement . She noted that the possibility that children living in close proximity to such sites are “exposed to these chemical carcinogens is a major public health concern.”

About 17 million Americans live within a half-mile of active oil and gas production, according to the Oil & Gas Threat Map, Common Dreams reports. That number includes 4 million children.

The Yale study also found that drinking water could be an important pathway of exposure to oil- and gas-related chemicals used in the UOGD methods of extraction.

Researchers used a new metric that measures exposure to contaminated drinking water and distance to a well. They were able to identify UOGD-affected wells that fell within watersheds where children and their families likely obtained their water.

“Previous health studies have found links between proximity to oil and gas drilling and various children’s health outcomes,” said Dr. Deziel. “This study is among the few to focus on drinking water specifically and the first to apply a novel metric designed to capture potential exposure through this pathway.”

A version of this article first appeared on WebMD.com.

Children born near fracking and other “unconventional” drilling sites are at two to three times greater risk of developing childhood leukemia, according to new research.

The study, published in the journal Environmental Health Perspectives, compared proximity of homes to unconventional oil and gas development (UOGD) sites and risk of the most common form of childhood leukemia, acute lymphoblastic leukemia (ALL).

Researchers looked at 405 children aged 2-7 diagnosed with ALL in Pennsylvania from 2009 to 2017. These children were compared to a control group of 2,080 without the disease matched on the year of birth.

“Unconventional oil and gas development can both use and release chemicals that have been linked to cancer,” study coauthor Nicole Deziel, PhD, of the Yale School of Public Health, New Haven, Conn., said in a  statement . She noted that the possibility that children living in close proximity to such sites are “exposed to these chemical carcinogens is a major public health concern.”

About 17 million Americans live within a half-mile of active oil and gas production, according to the Oil & Gas Threat Map, Common Dreams reports. That number includes 4 million children.

The Yale study also found that drinking water could be an important pathway of exposure to oil- and gas-related chemicals used in the UOGD methods of extraction.

Researchers used a new metric that measures exposure to contaminated drinking water and distance to a well. They were able to identify UOGD-affected wells that fell within watersheds where children and their families likely obtained their water.

“Previous health studies have found links between proximity to oil and gas drilling and various children’s health outcomes,” said Dr. Deziel. “This study is among the few to focus on drinking water specifically and the first to apply a novel metric designed to capture potential exposure through this pathway.”

A version of this article first appeared on WebMD.com.

Children born near fracking and other “unconventional” drilling sites are at two to three times greater risk of developing childhood leukemia, according to new research.

The study, published in the journal Environmental Health Perspectives, compared proximity of homes to unconventional oil and gas development (UOGD) sites and risk of the most common form of childhood leukemia, acute lymphoblastic leukemia (ALL).

Researchers looked at 405 children aged 2-7 diagnosed with ALL in Pennsylvania from 2009 to 2017. These children were compared to a control group of 2,080 without the disease matched on the year of birth.

“Unconventional oil and gas development can both use and release chemicals that have been linked to cancer,” study coauthor Nicole Deziel, PhD, of the Yale School of Public Health, New Haven, Conn., said in a  statement . She noted that the possibility that children living in close proximity to such sites are “exposed to these chemical carcinogens is a major public health concern.”

About 17 million Americans live within a half-mile of active oil and gas production, according to the Oil & Gas Threat Map, Common Dreams reports. That number includes 4 million children.

The Yale study also found that drinking water could be an important pathway of exposure to oil- and gas-related chemicals used in the UOGD methods of extraction.

Researchers used a new metric that measures exposure to contaminated drinking water and distance to a well. They were able to identify UOGD-affected wells that fell within watersheds where children and their families likely obtained their water.

“Previous health studies have found links between proximity to oil and gas drilling and various children’s health outcomes,” said Dr. Deziel. “This study is among the few to focus on drinking water specifically and the first to apply a novel metric designed to capture potential exposure through this pathway.”

A version of this article first appeared on WebMD.com.

Despite some gains, new research shows ongoing gender imbalances in hematology and oncology, as reflected in the predominantly male presenters at board review lecture series – where early career faculty are also underrepresented.

“Our study provides the first analysis of gender and early-career faculty disparities in speakers at hematology and medical oncology board review meetings,” the authors reported in research published in Blood Advances.

“We covered six major board reviews over the last 5 years that are either conducted yearly or every other year, [and] the general trend across all meetings showed skewness toward men speakers,” the authors reported.

Recent data from 2021 suggests a closing of the gender gap in oncology, with women making up 44.6% of oncologists in training. However, they still only represented 35.2% of practicing oncologists and are underrepresented in leadership positions in academic oncology, the authors reported.

With speaking roles at academic meetings potentially marking a key step in career advancement and improved opportunities, the authors sought to investigate the balance of gender, as well as early-career faculty among speakers at prominent hematology and/or oncology board review lecture series taking place in the United States between 2017 and 2021.

The five institutions and one society presenting the board review lecture series included Baylor College of Medicine/MD Anderson Cancer Center, both in Houston; Dana-Farber Brigham Cancer Center, Boston; George Washington University, Washington; Memorial Sloan Kettering Cancer Center, New York; Seattle Cancer Care Alliance; and the hematology board review series from the American Society of Hematology.

During the period in question, among 1,224 board review lectures presented, women constituted only 37.7% of the speakers. In lectures presented by American Board of Internal Medicine–certified speakers (n = 1,016, 83%), women were found to have made up fewer than 50% of speakers in five of six courses.

Men were also more likely to be recurrent speakers; across all courses, 13 men but only 2 women conducted 10 or more lectures. And while 35 men gave six or more lectures across all courses, only 12 women did so.

The lecture topics with the lowest rates of women presenters included malignant hematology (24.8%), solid tumors (38.9%), and benign hematology lectures (44.1%).

courtesy Dr. Al Hadidi

“We suspected [the imbalance in malignant hematology] since multiple recurrent roles were concentrated in the malignant hematology,” senior author Samer Al Hadidi, MD, of the Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AK, said in an interview.

He noted that “there are no regulations that such courses need to follow to ensure certain proportions of women and junior faculty are involved.”
 

Early-career faculty

In terms of early-career representation, more than 50% of lectures were given by faculty who had received their initial certifications more than 15 years earlier. The median time from initial certification was 12.5 years for hematology and 14 years for medical oncology.

The findings that more than half of the board review lectures were presented by faculty with more than 15 years’ experience since initial certification “reflects a lack of appropriate involvement of early-career faculty, who arguably may have more recent experience with board certification,” the authors wrote.

While being underrepresented in such roles is detrimental, there are no regulations that such courses follow to ensure certain proportions of women and junior faculty are involved, Dr. Al Hadidi noted.
 

Equal representation remains elusive

The study does suggest some notable gains. In a previous study of 181 academic conferences in the United States and Canada between 2007 and 2017, the rate of women speakers was only 15%, compared with 37.7% in the new study.

And an overall trend analysis in the study shows an approximately 10% increase in representation of women in all of the board reviews. However, only the ASH hematology board review achieved more than 50% women in their two courses.

“Overall, the proportion of women speakers is improving over the years, though it remains suboptimal,” Dr. Al Hadidi said.

The authors noted that oncology is clearly not the only specialty with gender disparities. They documented a lack of women speakers at conferences involving otolaryngology head and neck meetings, radiation oncology, emergency medicine, and research conferences.

They pointed to the work of ASH’s Women in Hematology Working Group as an important example of the needed effort to improve the balance of women hematologists.

courtesy Penn Medicine

Ariela Marshall, MD, director of women’s thrombosis and hemostasis at Penn Medicine in Philadelphia and a leader of ASH’s Women in Hematology Working Group, agreed that more efforts are needed to address both gender disparities as well as those of early career speakers. She asserted that the two disparities appear to be connected.

“If you broke down gender representation over time and the faculty/time since initial certification, the findings may mirror the percent of women in hematology-oncology at that given point in time,” Dr. Marshall said in an interview.

“If an institution is truly committed to taking action on gender equity, it needs to look at gender and experience equity of speakers,” she said. “Perhaps it’s the time to say ‘Dr. X has been doing this review course for 15 years. Let’s give someone else a chance.’

“This is not even just from a gender equity perspective but from a career development perspective overall,” she added. “Junior faculty need these speaking engagements a lot more than senior faculty.”

Meanwhile, the higher number of female trainees is a trend that ideally will be sustained as those trainees move into positions of leadership, Dr. Marshall noted.

“We do see that over time, we have achieved gender equity in the percent of women matriculating to medical school. And my hope is that, 20 years down the line, we will see the effects of this reflected in increased equity in leadership positions such as division/department chair, dean, and hospital CEO,” she said. “However, we have a lot of work to do because there are still huge inequities in the culture of medicine (institutional and more broadly), including gender-based discrimination, maternal discrimination, and high attrition rates for women physicians, compared to male physicians.

“It’s not enough to simply say ‘well, we have fixed the problem because our incoming medical student classes are now equitable in gender distribution,’ ”

The authors and Dr. Marshall had no disclosures to report.

Despite some gains, new research shows ongoing gender imbalances in hematology and oncology, as reflected in the predominantly male presenters at board review lecture series – where early career faculty are also underrepresented.

“Our study provides the first analysis of gender and early-career faculty disparities in speakers at hematology and medical oncology board review meetings,” the authors reported in research published in Blood Advances.

“We covered six major board reviews over the last 5 years that are either conducted yearly or every other year, [and] the general trend across all meetings showed skewness toward men speakers,” the authors reported.

Recent data from 2021 suggests a closing of the gender gap in oncology, with women making up 44.6% of oncologists in training. However, they still only represented 35.2% of practicing oncologists and are underrepresented in leadership positions in academic oncology, the authors reported.

With speaking roles at academic meetings potentially marking a key step in career advancement and improved opportunities, the authors sought to investigate the balance of gender, as well as early-career faculty among speakers at prominent hematology and/or oncology board review lecture series taking place in the United States between 2017 and 2021.

The five institutions and one society presenting the board review lecture series included Baylor College of Medicine/MD Anderson Cancer Center, both in Houston; Dana-Farber Brigham Cancer Center, Boston; George Washington University, Washington; Memorial Sloan Kettering Cancer Center, New York; Seattle Cancer Care Alliance; and the hematology board review series from the American Society of Hematology.

During the period in question, among 1,224 board review lectures presented, women constituted only 37.7% of the speakers. In lectures presented by American Board of Internal Medicine–certified speakers (n = 1,016, 83%), women were found to have made up fewer than 50% of speakers in five of six courses.

Men were also more likely to be recurrent speakers; across all courses, 13 men but only 2 women conducted 10 or more lectures. And while 35 men gave six or more lectures across all courses, only 12 women did so.

The lecture topics with the lowest rates of women presenters included malignant hematology (24.8%), solid tumors (38.9%), and benign hematology lectures (44.1%).

courtesy Dr. Al Hadidi

“We suspected [the imbalance in malignant hematology] since multiple recurrent roles were concentrated in the malignant hematology,” senior author Samer Al Hadidi, MD, of the Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AK, said in an interview.

He noted that “there are no regulations that such courses need to follow to ensure certain proportions of women and junior faculty are involved.”
 

Early-career faculty

In terms of early-career representation, more than 50% of lectures were given by faculty who had received their initial certifications more than 15 years earlier. The median time from initial certification was 12.5 years for hematology and 14 years for medical oncology.

The findings that more than half of the board review lectures were presented by faculty with more than 15 years’ experience since initial certification “reflects a lack of appropriate involvement of early-career faculty, who arguably may have more recent experience with board certification,” the authors wrote.

While being underrepresented in such roles is detrimental, there are no regulations that such courses follow to ensure certain proportions of women and junior faculty are involved, Dr. Al Hadidi noted.
 

Equal representation remains elusive

The study does suggest some notable gains. In a previous study of 181 academic conferences in the United States and Canada between 2007 and 2017, the rate of women speakers was only 15%, compared with 37.7% in the new study.

And an overall trend analysis in the study shows an approximately 10% increase in representation of women in all of the board reviews. However, only the ASH hematology board review achieved more than 50% women in their two courses.

“Overall, the proportion of women speakers is improving over the years, though it remains suboptimal,” Dr. Al Hadidi said.

The authors noted that oncology is clearly not the only specialty with gender disparities. They documented a lack of women speakers at conferences involving otolaryngology head and neck meetings, radiation oncology, emergency medicine, and research conferences.

They pointed to the work of ASH’s Women in Hematology Working Group as an important example of the needed effort to improve the balance of women hematologists.

courtesy Penn Medicine

Ariela Marshall, MD, director of women’s thrombosis and hemostasis at Penn Medicine in Philadelphia and a leader of ASH’s Women in Hematology Working Group, agreed that more efforts are needed to address both gender disparities as well as those of early career speakers. She asserted that the two disparities appear to be connected.

“If you broke down gender representation over time and the faculty/time since initial certification, the findings may mirror the percent of women in hematology-oncology at that given point in time,” Dr. Marshall said in an interview.

“If an institution is truly committed to taking action on gender equity, it needs to look at gender and experience equity of speakers,” she said. “Perhaps it’s the time to say ‘Dr. X has been doing this review course for 15 years. Let’s give someone else a chance.’

“This is not even just from a gender equity perspective but from a career development perspective overall,” she added. “Junior faculty need these speaking engagements a lot more than senior faculty.”

Meanwhile, the higher number of female trainees is a trend that ideally will be sustained as those trainees move into positions of leadership, Dr. Marshall noted.

“We do see that over time, we have achieved gender equity in the percent of women matriculating to medical school. And my hope is that, 20 years down the line, we will see the effects of this reflected in increased equity in leadership positions such as division/department chair, dean, and hospital CEO,” she said. “However, we have a lot of work to do because there are still huge inequities in the culture of medicine (institutional and more broadly), including gender-based discrimination, maternal discrimination, and high attrition rates for women physicians, compared to male physicians.

“It’s not enough to simply say ‘well, we have fixed the problem because our incoming medical student classes are now equitable in gender distribution,’ ”

The authors and Dr. Marshall had no disclosures to report.

Despite some gains, new research shows ongoing gender imbalances in hematology and oncology, as reflected in the predominantly male presenters at board review lecture series – where early career faculty are also underrepresented.

“Our study provides the first analysis of gender and early-career faculty disparities in speakers at hematology and medical oncology board review meetings,” the authors reported in research published in Blood Advances.

“We covered six major board reviews over the last 5 years that are either conducted yearly or every other year, [and] the general trend across all meetings showed skewness toward men speakers,” the authors reported.

Recent data from 2021 suggests a closing of the gender gap in oncology, with women making up 44.6% of oncologists in training. However, they still only represented 35.2% of practicing oncologists and are underrepresented in leadership positions in academic oncology, the authors reported.

With speaking roles at academic meetings potentially marking a key step in career advancement and improved opportunities, the authors sought to investigate the balance of gender, as well as early-career faculty among speakers at prominent hematology and/or oncology board review lecture series taking place in the United States between 2017 and 2021.

The five institutions and one society presenting the board review lecture series included Baylor College of Medicine/MD Anderson Cancer Center, both in Houston; Dana-Farber Brigham Cancer Center, Boston; George Washington University, Washington; Memorial Sloan Kettering Cancer Center, New York; Seattle Cancer Care Alliance; and the hematology board review series from the American Society of Hematology.

During the period in question, among 1,224 board review lectures presented, women constituted only 37.7% of the speakers. In lectures presented by American Board of Internal Medicine–certified speakers (n = 1,016, 83%), women were found to have made up fewer than 50% of speakers in five of six courses.

Men were also more likely to be recurrent speakers; across all courses, 13 men but only 2 women conducted 10 or more lectures. And while 35 men gave six or more lectures across all courses, only 12 women did so.

The lecture topics with the lowest rates of women presenters included malignant hematology (24.8%), solid tumors (38.9%), and benign hematology lectures (44.1%).

courtesy Dr. Al Hadidi

“We suspected [the imbalance in malignant hematology] since multiple recurrent roles were concentrated in the malignant hematology,” senior author Samer Al Hadidi, MD, of the Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AK, said in an interview.

He noted that “there are no regulations that such courses need to follow to ensure certain proportions of women and junior faculty are involved.”
 

Early-career faculty

In terms of early-career representation, more than 50% of lectures were given by faculty who had received their initial certifications more than 15 years earlier. The median time from initial certification was 12.5 years for hematology and 14 years for medical oncology.

The findings that more than half of the board review lectures were presented by faculty with more than 15 years’ experience since initial certification “reflects a lack of appropriate involvement of early-career faculty, who arguably may have more recent experience with board certification,” the authors wrote.

While being underrepresented in such roles is detrimental, there are no regulations that such courses follow to ensure certain proportions of women and junior faculty are involved, Dr. Al Hadidi noted.
 

Equal representation remains elusive

The study does suggest some notable gains. In a previous study of 181 academic conferences in the United States and Canada between 2007 and 2017, the rate of women speakers was only 15%, compared with 37.7% in the new study.

And an overall trend analysis in the study shows an approximately 10% increase in representation of women in all of the board reviews. However, only the ASH hematology board review achieved more than 50% women in their two courses.

“Overall, the proportion of women speakers is improving over the years, though it remains suboptimal,” Dr. Al Hadidi said.

The authors noted that oncology is clearly not the only specialty with gender disparities. They documented a lack of women speakers at conferences involving otolaryngology head and neck meetings, radiation oncology, emergency medicine, and research conferences.

They pointed to the work of ASH’s Women in Hematology Working Group as an important example of the needed effort to improve the balance of women hematologists.

courtesy Penn Medicine

Ariela Marshall, MD, director of women’s thrombosis and hemostasis at Penn Medicine in Philadelphia and a leader of ASH’s Women in Hematology Working Group, agreed that more efforts are needed to address both gender disparities as well as those of early career speakers. She asserted that the two disparities appear to be connected.

“If you broke down gender representation over time and the faculty/time since initial certification, the findings may mirror the percent of women in hematology-oncology at that given point in time,” Dr. Marshall said in an interview.

“If an institution is truly committed to taking action on gender equity, it needs to look at gender and experience equity of speakers,” she said. “Perhaps it’s the time to say ‘Dr. X has been doing this review course for 15 years. Let’s give someone else a chance.’

“This is not even just from a gender equity perspective but from a career development perspective overall,” she added. “Junior faculty need these speaking engagements a lot more than senior faculty.”

Meanwhile, the higher number of female trainees is a trend that ideally will be sustained as those trainees move into positions of leadership, Dr. Marshall noted.

“We do see that over time, we have achieved gender equity in the percent of women matriculating to medical school. And my hope is that, 20 years down the line, we will see the effects of this reflected in increased equity in leadership positions such as division/department chair, dean, and hospital CEO,” she said. “However, we have a lot of work to do because there are still huge inequities in the culture of medicine (institutional and more broadly), including gender-based discrimination, maternal discrimination, and high attrition rates for women physicians, compared to male physicians.

“It’s not enough to simply say ‘well, we have fixed the problem because our incoming medical student classes are now equitable in gender distribution,’ ”

The authors and Dr. Marshall had no disclosures to report.

The U.S. Food and Drug Administration has approved the gene therapy betibeglogene autotemcel (beti-cel) for adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved the gene therapy betibeglogene autotemcel (beti-cel) for adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved the gene therapy betibeglogene autotemcel (beti-cel) for adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions.

A version of this article first appeared on Medscape.com.