Anemia

Photo by Jon Christofersen

Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.

Evidence was strongest for the association between SCT and venous and renal complications.

There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.

Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.

Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.

The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.

The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.

The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.

There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.

Exertion-related injury/death

The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.

However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.

There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.

However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.

Venous and renal outcomes

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.

Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).

Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.

Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.

Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

Photo by Jon Christofersen

Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.

Evidence was strongest for the association between SCT and venous and renal complications.

There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.

Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.

Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.

The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.

The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.

The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.

There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.

Exertion-related injury/death

The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.

However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.

There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.

However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.

Venous and renal outcomes

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.

Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).

Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.

Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.

Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

Photo by Jon Christofersen

Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.

Evidence was strongest for the association between SCT and venous and renal complications.

There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.

Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.

Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.

The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.

The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.

The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.

There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.

Exertion-related injury/death

The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.

However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.

There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.

However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.

Venous and renal outcomes

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.

Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).

Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.

Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.

Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

Although sickle cell trait (SCT) has been linked to numerous adverse clinical outcomes in multiple studies, only a handful of those associations have strong supporting evidence, results of a systematic review suggest.

Venous and renal complications had the strongest evidence supporting an association with SCT, while exertion-related sudden death – perhaps the highest-profile potential complication of SCT – had moderate-strength evidence supporting a link, according to the review.

By contrast, most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link, according to Rakhi P. Naik, MD, of Johns Hopkins University, Baltimore, and coauthors of the review.

“Future rigorous studies are needed to address potential complications of SCT and to determine modifiers of risk,” they wrote. The report in the Annals of Internal Medicine.

The systematic review by Dr. Naik and colleagues focused on 41 studies, most of which were population-based cohort or case-control studies. They rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, renal, vascular, pediatric, surgery- and trauma-related outcomes, and mortality.

Exercise-related injury has received considerable attention, particularly in relation to the military and athletics.

The strength of evidence for a link between SCT and exertion-related death was low in their analysis, which included two studies evaluating the outcome. However, Dr. Naik and coauthors did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions such a highly strenuous athletic training or the military.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” they wrote.

Similarly, the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors, Dr. Naik and coauthors said, based on their analysis of two studies looking at this outcome.

Venous complications had a stronger body of evidence, including several studies showing high levels of procoagulants, which makes elevated venous thromboembolism risk plausible in individuals with SCT.

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was no increased risk of isolated deep-vein thrombosis in these individuals.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” Dr. Naik and colleagues wrote in a discussion of the results.

Renal outcomes were often attributed to SCT, and in this review, the authors said there was evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease.

Out of six studies looking at proteinuria, the one high-quality study found a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without, according to the review.

Out of four studies looking at chronic kidney disease, the two high-quality studies found 1.57- to 1.89-fold increased risk of those outcomes in African Americans with SCT.

Support for the study came in part from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

SOURCE: Naik RP et al. Ann Intern Med. 2018 Oct 30. doi:10.7326/M18-1161.

Although sickle cell trait (SCT) has been linked to numerous adverse clinical outcomes in multiple studies, only a handful of those associations have strong supporting evidence, results of a systematic review suggest.

Venous and renal complications had the strongest evidence supporting an association with SCT, while exertion-related sudden death – perhaps the highest-profile potential complication of SCT – had moderate-strength evidence supporting a link, according to the review.

By contrast, most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link, according to Rakhi P. Naik, MD, of Johns Hopkins University, Baltimore, and coauthors of the review.

“Future rigorous studies are needed to address potential complications of SCT and to determine modifiers of risk,” they wrote. The report in the Annals of Internal Medicine.

The systematic review by Dr. Naik and colleagues focused on 41 studies, most of which were population-based cohort or case-control studies. They rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, renal, vascular, pediatric, surgery- and trauma-related outcomes, and mortality.

Exercise-related injury has received considerable attention, particularly in relation to the military and athletics.

The strength of evidence for a link between SCT and exertion-related death was low in their analysis, which included two studies evaluating the outcome. However, Dr. Naik and coauthors did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions such a highly strenuous athletic training or the military.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” they wrote.

Similarly, the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors, Dr. Naik and coauthors said, based on their analysis of two studies looking at this outcome.

Venous complications had a stronger body of evidence, including several studies showing high levels of procoagulants, which makes elevated venous thromboembolism risk plausible in individuals with SCT.

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was no increased risk of isolated deep-vein thrombosis in these individuals.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” Dr. Naik and colleagues wrote in a discussion of the results.

Renal outcomes were often attributed to SCT, and in this review, the authors said there was evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease.

Out of six studies looking at proteinuria, the one high-quality study found a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without, according to the review.

Out of four studies looking at chronic kidney disease, the two high-quality studies found 1.57- to 1.89-fold increased risk of those outcomes in African Americans with SCT.

Support for the study came in part from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

SOURCE: Naik RP et al. Ann Intern Med. 2018 Oct 30. doi:10.7326/M18-1161.

Although sickle cell trait (SCT) has been linked to numerous adverse clinical outcomes in multiple studies, only a handful of those associations have strong supporting evidence, results of a systematic review suggest.

Venous and renal complications had the strongest evidence supporting an association with SCT, while exertion-related sudden death – perhaps the highest-profile potential complication of SCT – had moderate-strength evidence supporting a link, according to the review.

By contrast, most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link, according to Rakhi P. Naik, MD, of Johns Hopkins University, Baltimore, and coauthors of the review.

“Future rigorous studies are needed to address potential complications of SCT and to determine modifiers of risk,” they wrote. The report in the Annals of Internal Medicine.

The systematic review by Dr. Naik and colleagues focused on 41 studies, most of which were population-based cohort or case-control studies. They rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, renal, vascular, pediatric, surgery- and trauma-related outcomes, and mortality.

Exercise-related injury has received considerable attention, particularly in relation to the military and athletics.

The strength of evidence for a link between SCT and exertion-related death was low in their analysis, which included two studies evaluating the outcome. However, Dr. Naik and coauthors did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions such a highly strenuous athletic training or the military.

“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” they wrote.

Similarly, the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors, Dr. Naik and coauthors said, based on their analysis of two studies looking at this outcome.

Venous complications had a stronger body of evidence, including several studies showing high levels of procoagulants, which makes elevated venous thromboembolism risk plausible in individuals with SCT.

High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was no increased risk of isolated deep-vein thrombosis in these individuals.

“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” Dr. Naik and colleagues wrote in a discussion of the results.

Renal outcomes were often attributed to SCT, and in this review, the authors said there was evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease.

Out of six studies looking at proteinuria, the one high-quality study found a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without, according to the review.

Out of four studies looking at chronic kidney disease, the two high-quality studies found 1.57- to 1.89-fold increased risk of those outcomes in African Americans with SCT.

Support for the study came in part from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.

SOURCE: Naik RP et al. Ann Intern Med. 2018 Oct 30. doi:10.7326/M18-1161.

Hospital of Philadelphia

A novel approach can restore hematopoietic stem cell (HSC) function in Fanconi anemia (FA), according to preclinical research published in Nature Communications.

The investigators showed that Lnk (Sh2b3) deficiency restores HSC proliferation and survival in Fancd2-deficient mice.

And it does so, in part, by alleviating blocks to cytokine-mediated JAK2 signaling.

These findings, the researchers wrote, “highlight a new role for cytokine/JAK signaling” and have therapeutic implications for FA.

The investigators noted that FA is caused by mutations in genes that are essential for DNA interstrand crosslink repair and replication stress tolerance.

Allogeneic transplant can replace defective HSCs in patients with FA, the researchers said, but there are no interventions that mitigate defects in HSCs. So the investigators decided to test whether Lnk deficiency ameliorates HSC defects in FA.

Using a model of FA in which mice lacked Fancd2, the researchers inhibited the regulatory protein Sh2b3/Lnk.

The investigators said Lnk deficiency restored the proliferation and survival of Fancd2⁻/⁻ HSCs while also reducing replication stress and genomic instability. Lnk deficiency did not, however, affect DNA interstrand crosslink repair.

“We expected that inhibiting Lnk would restore the ability of FA cells to repair DNA damage, but this was not the case,” said study author Wei Tong, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Instead, inhibiting Lnk stabilized the stalled replication machinery, allowing affected cells to continue to copy DNA, and to prevent small errors from cascading into a catastrophic failure. The most exciting aspect of this discovery is that Lnk is part of a well-known growth pathway that can be manipulated by existing drugs in other diseases.”

That pathway is the TPO/MPL/JAK2 pathway, which is already targeted by eltrombopag and romiplostin for immune thrombocytopenia and eltrombopag for aplastic anemia.

The researchers plan to continue their work with animal models of FA and Lnk.

“Our ultimate goal is to translate our knowledge into treatments for both Fanconi anemia and for the broader problem of bone marrow failure,” Dr. Tong said.

This research was supported by the National Institutes of Health, the Fanconi Anemia Research Fund, the Department of Defense, the Basser Center for BRCA Team Science Grant, the Leukemia Lymphoma Society Scholar Award, and the Patel Family Award.

The researchers declared no competing interests.

Hospital of Philadelphia

A novel approach can restore hematopoietic stem cell (HSC) function in Fanconi anemia (FA), according to preclinical research published in Nature Communications.

The investigators showed that Lnk (Sh2b3) deficiency restores HSC proliferation and survival in Fancd2-deficient mice.

And it does so, in part, by alleviating blocks to cytokine-mediated JAK2 signaling.

These findings, the researchers wrote, “highlight a new role for cytokine/JAK signaling” and have therapeutic implications for FA.

The investigators noted that FA is caused by mutations in genes that are essential for DNA interstrand crosslink repair and replication stress tolerance.

Allogeneic transplant can replace defective HSCs in patients with FA, the researchers said, but there are no interventions that mitigate defects in HSCs. So the investigators decided to test whether Lnk deficiency ameliorates HSC defects in FA.

Using a model of FA in which mice lacked Fancd2, the researchers inhibited the regulatory protein Sh2b3/Lnk.

The investigators said Lnk deficiency restored the proliferation and survival of Fancd2⁻/⁻ HSCs while also reducing replication stress and genomic instability. Lnk deficiency did not, however, affect DNA interstrand crosslink repair.

“We expected that inhibiting Lnk would restore the ability of FA cells to repair DNA damage, but this was not the case,” said study author Wei Tong, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Instead, inhibiting Lnk stabilized the stalled replication machinery, allowing affected cells to continue to copy DNA, and to prevent small errors from cascading into a catastrophic failure. The most exciting aspect of this discovery is that Lnk is part of a well-known growth pathway that can be manipulated by existing drugs in other diseases.”

That pathway is the TPO/MPL/JAK2 pathway, which is already targeted by eltrombopag and romiplostin for immune thrombocytopenia and eltrombopag for aplastic anemia.

The researchers plan to continue their work with animal models of FA and Lnk.

“Our ultimate goal is to translate our knowledge into treatments for both Fanconi anemia and for the broader problem of bone marrow failure,” Dr. Tong said.

This research was supported by the National Institutes of Health, the Fanconi Anemia Research Fund, the Department of Defense, the Basser Center for BRCA Team Science Grant, the Leukemia Lymphoma Society Scholar Award, and the Patel Family Award.

The researchers declared no competing interests.

Hospital of Philadelphia

A novel approach can restore hematopoietic stem cell (HSC) function in Fanconi anemia (FA), according to preclinical research published in Nature Communications.

The investigators showed that Lnk (Sh2b3) deficiency restores HSC proliferation and survival in Fancd2-deficient mice.

And it does so, in part, by alleviating blocks to cytokine-mediated JAK2 signaling.

These findings, the researchers wrote, “highlight a new role for cytokine/JAK signaling” and have therapeutic implications for FA.

The investigators noted that FA is caused by mutations in genes that are essential for DNA interstrand crosslink repair and replication stress tolerance.

Allogeneic transplant can replace defective HSCs in patients with FA, the researchers said, but there are no interventions that mitigate defects in HSCs. So the investigators decided to test whether Lnk deficiency ameliorates HSC defects in FA.

Using a model of FA in which mice lacked Fancd2, the researchers inhibited the regulatory protein Sh2b3/Lnk.

The investigators said Lnk deficiency restored the proliferation and survival of Fancd2⁻/⁻ HSCs while also reducing replication stress and genomic instability. Lnk deficiency did not, however, affect DNA interstrand crosslink repair.

“We expected that inhibiting Lnk would restore the ability of FA cells to repair DNA damage, but this was not the case,” said study author Wei Tong, PhD, of Children’s Hospital of Philadelphia in Pennsylvania.

“Instead, inhibiting Lnk stabilized the stalled replication machinery, allowing affected cells to continue to copy DNA, and to prevent small errors from cascading into a catastrophic failure. The most exciting aspect of this discovery is that Lnk is part of a well-known growth pathway that can be manipulated by existing drugs in other diseases.”

That pathway is the TPO/MPL/JAK2 pathway, which is already targeted by eltrombopag and romiplostin for immune thrombocytopenia and eltrombopag for aplastic anemia.

The researchers plan to continue their work with animal models of FA and Lnk.

“Our ultimate goal is to translate our knowledge into treatments for both Fanconi anemia and for the broader problem of bone marrow failure,” Dr. Tong said.

This research was supported by the National Institutes of Health, the Fanconi Anemia Research Fund, the Department of Defense, the Basser Center for BRCA Team Science Grant, the Leukemia Lymphoma Society Scholar Award, and the Patel Family Award.

The researchers declared no competing interests.

Image from Graham Beards

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to PRN1008 for the treatment of patients with immune thrombocytopenia (ITP).

PRN1008 is an oral, reversible, covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed by Principia Biopharma, Inc.

Principia is conducting a phase 1/2 trial (NCT03395210) to evaluate the safety and efficacy of PRN1008 in patients with ITP.

Results of preclinical research with PRN1008 in ITP were presented at the 2017 ASH Annual Meeting.

There, researchers reported that PRN1008 significantly reduced platelet loss in a mouse model of ITP.

The team found the BTK inhibitor could diminish platelet loss in two ways:

• By reducing platelet destruction via inhibition of autoantibody/FcγR signaling in splenic macrophages
• By reducing autoantibody generation through inhibition of B-cell activation and maturation.

The researchers also assessed the effects of PRN1008 and ibrutinib on platelet function in samples from healthy volunteers and ITP patients.

Samples were treated with one of the two BTK inhibitors, and platelet aggregation was induced by platelet agonists.

Unlike ibrutinib, PRN1008 did not impact platelet aggregation in healthy volunteer or ITP patient samples.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image from Graham Beards

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to PRN1008 for the treatment of patients with immune thrombocytopenia (ITP).

PRN1008 is an oral, reversible, covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed by Principia Biopharma, Inc.

Principia is conducting a phase 1/2 trial (NCT03395210) to evaluate the safety and efficacy of PRN1008 in patients with ITP.

Results of preclinical research with PRN1008 in ITP were presented at the 2017 ASH Annual Meeting.

There, researchers reported that PRN1008 significantly reduced platelet loss in a mouse model of ITP.

The team found the BTK inhibitor could diminish platelet loss in two ways:

• By reducing platelet destruction via inhibition of autoantibody/FcγR signaling in splenic macrophages
• By reducing autoantibody generation through inhibition of B-cell activation and maturation.

The researchers also assessed the effects of PRN1008 and ibrutinib on platelet function in samples from healthy volunteers and ITP patients.

Samples were treated with one of the two BTK inhibitors, and platelet aggregation was induced by platelet agonists.

Unlike ibrutinib, PRN1008 did not impact platelet aggregation in healthy volunteer or ITP patient samples.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image from Graham Beards

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to PRN1008 for the treatment of patients with immune thrombocytopenia (ITP).

PRN1008 is an oral, reversible, covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed by Principia Biopharma, Inc.

Principia is conducting a phase 1/2 trial (NCT03395210) to evaluate the safety and efficacy of PRN1008 in patients with ITP.

Results of preclinical research with PRN1008 in ITP were presented at the 2017 ASH Annual Meeting.

There, researchers reported that PRN1008 significantly reduced platelet loss in a mouse model of ITP.

The team found the BTK inhibitor could diminish platelet loss in two ways:

• By reducing platelet destruction via inhibition of autoantibody/FcγR signaling in splenic macrophages
• By reducing autoantibody generation through inhibition of B-cell activation and maturation.

The researchers also assessed the effects of PRN1008 and ibrutinib on platelet function in samples from healthy volunteers and ITP patients.

Samples were treated with one of the two BTK inhibitors, and platelet aggregation was induced by platelet agonists.

Unlike ibrutinib, PRN1008 did not impact platelet aggregation in healthy volunteer or ITP patient samples.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Photo by Diane Reid

Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.

Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).

However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.

For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.

Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.

The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.

Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.

Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.

Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.

Factors associated with intense care

The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.

Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:

• Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
• Ages 30 to 39—OR=1.8 (P<0.01)
• Ages 40 to 49—OR=1.4 (P<0.05).

Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.

Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).

Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).

Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).

Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).

“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.

“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”

This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.

Photo by Diane Reid

Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.

Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).

However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.

For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.

Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.

The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.

Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.

Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.

Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.

Factors associated with intense care

The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.

Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:

• Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
• Ages 30 to 39—OR=1.8 (P<0.01)
• Ages 40 to 49—OR=1.4 (P<0.05).

Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.

Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).

Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).

Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).

Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).

“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.

“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”

This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.

Photo by Diane Reid

Patients who die within a year of allogeneic hematopoietic stem cell transplant (HSCT) tend to receive “medically intense” end-of-life care, an analysis suggests.

Researchers studied more than 2,000 patients who died within a year of allogeneic HSCT and found that a majority of the patients died in the hospital, and about half of them were admitted to the intensive care unit (ICU).

However, patient age, underlying diagnosis, and other factors influenced the likelihood of receiving intense end-of-life care.

For example, patients diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) were less likely than patients with acute lymphoblastic leukemia (ALL) to receive medically intense care.

Emily Johnston, MD, of the University of Alabama at Birmingham, and her colleagues reported these findings in the Journal of Clinical Oncology.

The researchers studied 2,135 patients in California who underwent inpatient HSCT and died within a year of the transplant (not as a result of peripartum events or trauma) between 2000 and 2013.

Fifty-three percent of the patients received some type of medically intense intervention, and 57% had at least two types of intense interventions.

Eighty-three percent of patients died in hospital, and 43% spent all of their last 30 days in the hospital.

Forty-nine percent of patients were admitted to the ICU, 45% were intubated, 22% underwent hemodialysis, and 8% received cardiopulmonary resuscitation.

Factors associated with intense care

The researchers said receipt of a medically intense intervention varied by age at death, underlying diagnosis, year of HSCT, location of care, and comorbidities. However, use of intense interventions did not vary according to sex, race/ethnicity, insurance type, or income.

Compared to patients age 60 and older, patients in the following age groups were more likely to receive medically intense interventions:

• Ages 15 to 21—odds ratio (OR)=2.6 (P<0.001)
• Ages 30 to 39—OR=1.8 (P<0.01)
• Ages 40 to 49—OR=1.4 (P<0.05).

Patients with comorbidities were more likely to receive intense interventions as well. The OR was 1.6 (P<0.01) for patients with one comorbidity and 2.5 (P<0.001) for patients with two or more comorbidities.

Patients with AML or MDS were less likely than patients with ALL to receive a medically intense intervention—OR=0.7 (P<0.05).

Patients who were transplanted between 2000 and 2004 were less likely to receive an intense intervention than patients transplanted between 2010 and 2013—OR=0.7 (P<0.01).

Patients who changed hospitals between HSCT and death were less likely to receive an intense intervention than patients who stayed at the same hospital. The OR was 0.3 if they transferred to a community hospital and 0.4 if they transferred to a specialty hospital (P<0.001 for both).

Patients living in rural areas were less likely than urban patients to receive a medically intense intervention—OR=0.6 (P<0.05).

“From our data, we understand there is a correlation with high-intensity end-of-life care in patients who die within one year after receiving a stem cell transplant, but we are still unsure if that was the care they wanted,” Dr. Johnston said.

“The findings suggest that, as oncologists, we need to start having end-of-life care conversations earlier with patients to determine if a high-intensity treatment plan is consistent with their goals or if a lower-intensity treatment plan is best. It’s not a one-size-fits-all approach in end-of-life care.”

This research was supported by Stanford University. One study author reported relationships with Corvus Pharmaceuticals, Shire Pharmaceuticals, and Adaptive Biotechnologies. All other authors reported no conflicts.

The Food and Drug Administration has approved ID CORE XT, a molecular-based assay that uses DNA to test for non-ABO red blood cell types for use in transfusion.

It’s the second molecular test for blood compatibility but the first to report genotype in its results, according to an announcement from the agency.

The test is important because it evaluates patients – especially those who receive repeated blood transfusions for conditions such as sickle cell anemia – for non-ABO antigens, but it does so without using antisera, which is sometimes unavailable.

A study found comparable performance between the ID CORE XT, licensed serologic reagents, and DNA sequencing tests, according to the FDA.

The ID CORE XT test is marketed by Progenika Biopharma, a Grifols company.

More information can be found in the full FDA press announcement.

[email protected]

The Food and Drug Administration has approved ID CORE XT, a molecular-based assay that uses DNA to test for non-ABO red blood cell types for use in transfusion.

It’s the second molecular test for blood compatibility but the first to report genotype in its results, according to an announcement from the agency.

The test is important because it evaluates patients – especially those who receive repeated blood transfusions for conditions such as sickle cell anemia – for non-ABO antigens, but it does so without using antisera, which is sometimes unavailable.

A study found comparable performance between the ID CORE XT, licensed serologic reagents, and DNA sequencing tests, according to the FDA.

The ID CORE XT test is marketed by Progenika Biopharma, a Grifols company.

More information can be found in the full FDA press announcement.

[email protected]

The Food and Drug Administration has approved ID CORE XT, a molecular-based assay that uses DNA to test for non-ABO red blood cell types for use in transfusion.

It’s the second molecular test for blood compatibility but the first to report genotype in its results, according to an announcement from the agency.

The test is important because it evaluates patients – especially those who receive repeated blood transfusions for conditions such as sickle cell anemia – for non-ABO antigens, but it does so without using antisera, which is sometimes unavailable.

A study found comparable performance between the ID CORE XT, licensed serologic reagents, and DNA sequencing tests, according to the FDA.

The ID CORE XT test is marketed by Progenika Biopharma, a Grifols company.

More information can be found in the full FDA press announcement.

[email protected]

Image by Betty Pace

Crizanlizumab can reduce vaso-occlusive crises (VOCs) across subgroups of patients with sickle cell disease (SCD), according to a post-hoc analysis of the phase 2 SUSTAIN trial.

Researchers found crizanlizumab was more effective than placebo at delaying time to first VOC and eliminating crises in patients who had numerous previous crises, exhibited the HbSS genotype, or were taking concomitant hydroxyurea.

Abdullah Kutlar, MD, of the Medical College of Georgia in Augusta, and his colleagues reported these findings in the American Journal of Hematology.

The phase 2 SUSTAIN trial previously showed that crizanlizumab—a humanized, anti–P-selectin monoclonal antibody—reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months.

Additionally, a subgroup analysis showed there was a lower frequency of VOCs with crizanlizumab at 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post-hoc analysis took a deeper look at these observations across the same subgroups. Specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events in 132 patients.

Crizanlizumab eliminated VOCs about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (5 to 10 VOCs in the year prior)—28.0% and 4.2%, respectively.

Crizanlizumab eliminated VOCs about twice as often as placebo in patients with the HbSS genotype—31.9% and 17.0%, respectively—and in patients who were using concomitant hydroxyurea—33.3% and 17.5%, respectively.

Further analysis showed that crizanlizumab delayed time to first VOC across all subgroups.

In patients with the HbSS genotype, the time to first VOC was 4.07 months with crizanlizumab and 1.12 months with placebo.

In patients with a higher frequency of previous VOCs, the time to first on-study VOC was 2.43 months with crizanlizumab and 1.03 months with placebo.

In patients taking hydroxyurea, the time to first VOC was 2.43 months with crizanlizumab and 1.45 months with placebo.

Safety was comparable across subgroups.

This study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

Image by Betty Pace

Crizanlizumab can reduce vaso-occlusive crises (VOCs) across subgroups of patients with sickle cell disease (SCD), according to a post-hoc analysis of the phase 2 SUSTAIN trial.

Researchers found crizanlizumab was more effective than placebo at delaying time to first VOC and eliminating crises in patients who had numerous previous crises, exhibited the HbSS genotype, or were taking concomitant hydroxyurea.

Abdullah Kutlar, MD, of the Medical College of Georgia in Augusta, and his colleagues reported these findings in the American Journal of Hematology.

The phase 2 SUSTAIN trial previously showed that crizanlizumab—a humanized, anti–P-selectin monoclonal antibody—reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months.

Additionally, a subgroup analysis showed there was a lower frequency of VOCs with crizanlizumab at 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post-hoc analysis took a deeper look at these observations across the same subgroups. Specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events in 132 patients.

Crizanlizumab eliminated VOCs about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (5 to 10 VOCs in the year prior)—28.0% and 4.2%, respectively.

Crizanlizumab eliminated VOCs about twice as often as placebo in patients with the HbSS genotype—31.9% and 17.0%, respectively—and in patients who were using concomitant hydroxyurea—33.3% and 17.5%, respectively.

Further analysis showed that crizanlizumab delayed time to first VOC across all subgroups.

In patients with the HbSS genotype, the time to first VOC was 4.07 months with crizanlizumab and 1.12 months with placebo.

In patients with a higher frequency of previous VOCs, the time to first on-study VOC was 2.43 months with crizanlizumab and 1.03 months with placebo.

In patients taking hydroxyurea, the time to first VOC was 2.43 months with crizanlizumab and 1.45 months with placebo.

Safety was comparable across subgroups.

This study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

Image by Betty Pace

Crizanlizumab can reduce vaso-occlusive crises (VOCs) across subgroups of patients with sickle cell disease (SCD), according to a post-hoc analysis of the phase 2 SUSTAIN trial.

Researchers found crizanlizumab was more effective than placebo at delaying time to first VOC and eliminating crises in patients who had numerous previous crises, exhibited the HbSS genotype, or were taking concomitant hydroxyurea.

Abdullah Kutlar, MD, of the Medical College of Georgia in Augusta, and his colleagues reported these findings in the American Journal of Hematology.

The phase 2 SUSTAIN trial previously showed that crizanlizumab—a humanized, anti–P-selectin monoclonal antibody—reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months.

Additionally, a subgroup analysis showed there was a lower frequency of VOCs with crizanlizumab at 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post-hoc analysis took a deeper look at these observations across the same subgroups. Specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events in 132 patients.

Crizanlizumab eliminated VOCs about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (5 to 10 VOCs in the year prior)—28.0% and 4.2%, respectively.

Crizanlizumab eliminated VOCs about twice as often as placebo in patients with the HbSS genotype—31.9% and 17.0%, respectively—and in patients who were using concomitant hydroxyurea—33.3% and 17.5%, respectively.

Further analysis showed that crizanlizumab delayed time to first VOC across all subgroups.

In patients with the HbSS genotype, the time to first VOC was 4.07 months with crizanlizumab and 1.12 months with placebo.

In patients with a higher frequency of previous VOCs, the time to first on-study VOC was 2.43 months with crizanlizumab and 1.03 months with placebo.

In patients taking hydroxyurea, the time to first VOC was 2.43 months with crizanlizumab and 1.45 months with placebo.

Safety was comparable across subgroups.

This study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

Crizanlizumab effectively reduced vaso-occlusive crises among patients with sickle cell disease (SCD) who have numerous crises, exhibit the HbSS genotype, and take concomitant hydroxyurea, according to investigators.

CDC/Janice Haney Carr

Across subgroups, crizanlizumab was safe and more effective than placebo at delaying time to first vaso-occlusive crisis (VOC) and eliminating crises, reported lead author Abdullah Kutlar, MD, of the Sickle Cell Center at the Medical College of Georgia, Augusta, and his colleagues.

The phase 2 SUSTAIN trial recently showed that crizanlizumab – a humanized, anti–P-selectin monoclonal antibody – reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months (N Engl J Med. 2017;376:429-39).

Additionally, a subgroup analysis showed that there was a lower frequency of pain crises with crizanlizumab 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post hoc analysis took a deeper look at these observations across the same subgroups; specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events. They reported the findings in the American Journal of Hematology.

Crizanlizumab eliminated pain crises about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (28.0% vs. 4.2%), and about twice as often in patients with the HbSS genotype (31.9% vs. 17.0%), and patients who were using concomitant hydroxyurea (33.3% vs. 17.5%).

Further analysis showed that crizanlizumab delayed time to first pain crisis across all subgroups, most dramatically in patients with the HbSS genotype (4.07 months for crizanlizumab vs. 1.12 months for placebo). Safety was comparable across subgroups.

“These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with hydroxyurea for the prevention of VOCs,” the investigators wrote.

An ongoing phase 2 pharmacokinetic/pharmacodynamic study is evaluating a higher dose of crizanlizumab (7.5 mg/kg), and another trial seeks to evaluate pediatric doses of the drug.

The study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

SOURCE: Kutlar A et al. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.

Crizanlizumab effectively reduced vaso-occlusive crises among patients with sickle cell disease (SCD) who have numerous crises, exhibit the HbSS genotype, and take concomitant hydroxyurea, according to investigators.

CDC/Janice Haney Carr

Across subgroups, crizanlizumab was safe and more effective than placebo at delaying time to first vaso-occlusive crisis (VOC) and eliminating crises, reported lead author Abdullah Kutlar, MD, of the Sickle Cell Center at the Medical College of Georgia, Augusta, and his colleagues.

The phase 2 SUSTAIN trial recently showed that crizanlizumab – a humanized, anti–P-selectin monoclonal antibody – reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months (N Engl J Med. 2017;376:429-39).

Additionally, a subgroup analysis showed that there was a lower frequency of pain crises with crizanlizumab 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post hoc analysis took a deeper look at these observations across the same subgroups; specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events. They reported the findings in the American Journal of Hematology.

Crizanlizumab eliminated pain crises about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (28.0% vs. 4.2%), and about twice as often in patients with the HbSS genotype (31.9% vs. 17.0%), and patients who were using concomitant hydroxyurea (33.3% vs. 17.5%).

Further analysis showed that crizanlizumab delayed time to first pain crisis across all subgroups, most dramatically in patients with the HbSS genotype (4.07 months for crizanlizumab vs. 1.12 months for placebo). Safety was comparable across subgroups.

“These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with hydroxyurea for the prevention of VOCs,” the investigators wrote.

An ongoing phase 2 pharmacokinetic/pharmacodynamic study is evaluating a higher dose of crizanlizumab (7.5 mg/kg), and another trial seeks to evaluate pediatric doses of the drug.

The study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

SOURCE: Kutlar A et al. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.

Crizanlizumab effectively reduced vaso-occlusive crises among patients with sickle cell disease (SCD) who have numerous crises, exhibit the HbSS genotype, and take concomitant hydroxyurea, according to investigators.

CDC/Janice Haney Carr

Across subgroups, crizanlizumab was safe and more effective than placebo at delaying time to first vaso-occlusive crisis (VOC) and eliminating crises, reported lead author Abdullah Kutlar, MD, of the Sickle Cell Center at the Medical College of Georgia, Augusta, and his colleagues.

The phase 2 SUSTAIN trial recently showed that crizanlizumab – a humanized, anti–P-selectin monoclonal antibody – reduced the frequency of VOCs by 45% and delayed time to first crisis by about 3 months (N Engl J Med. 2017;376:429-39).

Additionally, a subgroup analysis showed that there was a lower frequency of pain crises with crizanlizumab 5 mg/kg, compared with placebo, regardless of the number of prior VOCs, concomitant hydroxyurea use, or the SCD genotype.

The present post hoc analysis took a deeper look at these observations across the same subgroups; specifically, the investigators assessed elimination of VOCs, time to first crisis, and adverse events. They reported the findings in the American Journal of Hematology.

Crizanlizumab eliminated pain crises about seven times more frequently than did placebo in patients who had a high frequency of VOCs before the study (28.0% vs. 4.2%), and about twice as often in patients with the HbSS genotype (31.9% vs. 17.0%), and patients who were using concomitant hydroxyurea (33.3% vs. 17.5%).

Further analysis showed that crizanlizumab delayed time to first pain crisis across all subgroups, most dramatically in patients with the HbSS genotype (4.07 months for crizanlizumab vs. 1.12 months for placebo). Safety was comparable across subgroups.

“These findings provide supportive evidence that crizanlizumab provides a clinically meaningful treatment benefit when used alone or in combination with hydroxyurea for the prevention of VOCs,” the investigators wrote.

An ongoing phase 2 pharmacokinetic/pharmacodynamic study is evaluating a higher dose of crizanlizumab (7.5 mg/kg), and another trial seeks to evaluate pediatric doses of the drug.

The study was sponsored by Novartis. The authors reported financial relationships with Novartis, Bluebird Bio, AstraZeneca, and others.

SOURCE: Kutlar A et al. Am J Hematol. 2018 Oct 8. doi: 10.1002/ajh.25308.

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Micrograph showing MDS

Researchers have developed a new risk model for primary myelodysplastic syndromes (MDS) that integrates genetic and clinical information.

The research team considered the current standard for prognostication—the revised International Prognostic Scoring System (IPSS-R)—to be too complex, limited to newly diagnosed cases, and missing information on mutations and age.

So they devised a “simpler and more contemporary” prognostic system, the Mayo Alliance Prognostic Model for MDS.

The team, from the Mayo Clinic in Rochester, Minnesota, and the National Taiwan University Hospital (NTUH), described the new model in Mayo Clinic Proceedings.

Lead author Ayalew Tefferi, MD, of the Mayo Clinic, said the new model “is not an enhancement of the international prognostic scoring system tool, it's a complete makeover."

The team analyzed mutation information from 357 patients with primary MDS or leukemic transformation treated at the Mayo Clinic from the end of December 1994 through mid-December 2017.

The patients were a median age of 74 and 70% were males.

They compared the Mayo patients to 328 NTUH patients, who were a median age of 66 and 65% were males.

Multivariate analysis of the Mayo cohort identified the following as predictors of inferior overall survival:

• Monosomal karyotype (hazard ratio [HR], 5.2; 95% CI, 3.1-8.6)
• Non-monosomal karyotype abnormalities other than single/double del(5q) (HR, 1.8; 95% CI, 1.3-2.6)
• RUNX1 (HR, 2.0; 95% CI, 1.2-3.1)
• ASXL1 (HR, 1.7; 95% CI, 1.2-2.3) mutations
• Absence of SF3B1 mutations (HR, 1.6; 95% CI, 1.1-2.4)
• Age greater than 70 years (HR, 2.2; 95% CI, 1.6-3.1)
• Hemoglobin level less than 8 g/dL in women or less than 9 g/dL in men (HR, 2.3; 95% CI, 1.7-3.1)
• Platelet count less than 75 x 10⁹/L (HR, 1.5; 95% CI, 1.1-2.1)
• 10% or more bone marrow blasts (HR, 1.7; 95% CI, 1.1-2.8)

They then provided values to reflect the prognostic contribution of each of the above predictors and devised the new 4-tiered Mayo prognostic model.

Median 5-year overall survival rates in the 4 categories in the Mayo model were 73% (low risk), 34% (intermediate-1), 7% (intermediate-2), and 0% (high risk; 9-month median survival).

The team then validated the Mayo alliance model by using the NTUH cohort and compared it to the IPSS-R.

The investigators were able to confirm superior predictive accuracy of their model and a substantial discordance between the the Mayo model and the IPSS-R in terms of the pattern of risk distribution.

Examples of discordance included:

• More than 25% of patients belonging to the high-risk category according to the Mayo alliance model were classified as IPSS-R low or intermediate risk
• Almost 50% of patients with intermediate-2 risk category according to the Mayo alliance model were classified as IPSS-R very low or low risk
• Almost 50% of patients with IPSS-R very low risk were classified as intermediate-2 or intermediate-1 risk according to the Mayo alliance model

The authors wrote that this “suggests a fundamental and not incremental advantage for the new Mayo alliance model.” 

Micrograph showing MDS

Researchers have developed a new risk model for primary myelodysplastic syndromes (MDS) that integrates genetic and clinical information.

The research team considered the current standard for prognostication—the revised International Prognostic Scoring System (IPSS-R)—to be too complex, limited to newly diagnosed cases, and missing information on mutations and age.

So they devised a “simpler and more contemporary” prognostic system, the Mayo Alliance Prognostic Model for MDS.

The team, from the Mayo Clinic in Rochester, Minnesota, and the National Taiwan University Hospital (NTUH), described the new model in Mayo Clinic Proceedings.

Lead author Ayalew Tefferi, MD, of the Mayo Clinic, said the new model “is not an enhancement of the international prognostic scoring system tool, it's a complete makeover."

The team analyzed mutation information from 357 patients with primary MDS or leukemic transformation treated at the Mayo Clinic from the end of December 1994 through mid-December 2017.

The patients were a median age of 74 and 70% were males.

They compared the Mayo patients to 328 NTUH patients, who were a median age of 66 and 65% were males.

Multivariate analysis of the Mayo cohort identified the following as predictors of inferior overall survival:

• Monosomal karyotype (hazard ratio [HR], 5.2; 95% CI, 3.1-8.6)
• Non-monosomal karyotype abnormalities other than single/double del(5q) (HR, 1.8; 95% CI, 1.3-2.6)
• RUNX1 (HR, 2.0; 95% CI, 1.2-3.1)
• ASXL1 (HR, 1.7; 95% CI, 1.2-2.3) mutations
• Absence of SF3B1 mutations (HR, 1.6; 95% CI, 1.1-2.4)
• Age greater than 70 years (HR, 2.2; 95% CI, 1.6-3.1)
• Hemoglobin level less than 8 g/dL in women or less than 9 g/dL in men (HR, 2.3; 95% CI, 1.7-3.1)
• Platelet count less than 75 x 10⁹/L (HR, 1.5; 95% CI, 1.1-2.1)
• 10% or more bone marrow blasts (HR, 1.7; 95% CI, 1.1-2.8)

They then provided values to reflect the prognostic contribution of each of the above predictors and devised the new 4-tiered Mayo prognostic model.

Median 5-year overall survival rates in the 4 categories in the Mayo model were 73% (low risk), 34% (intermediate-1), 7% (intermediate-2), and 0% (high risk; 9-month median survival).

The team then validated the Mayo alliance model by using the NTUH cohort and compared it to the IPSS-R.

The investigators were able to confirm superior predictive accuracy of their model and a substantial discordance between the the Mayo model and the IPSS-R in terms of the pattern of risk distribution.

Examples of discordance included:

• More than 25% of patients belonging to the high-risk category according to the Mayo alliance model were classified as IPSS-R low or intermediate risk
• Almost 50% of patients with intermediate-2 risk category according to the Mayo alliance model were classified as IPSS-R very low or low risk
• Almost 50% of patients with IPSS-R very low risk were classified as intermediate-2 or intermediate-1 risk according to the Mayo alliance model

The authors wrote that this “suggests a fundamental and not incremental advantage for the new Mayo alliance model.” 

Micrograph showing MDS

Researchers have developed a new risk model for primary myelodysplastic syndromes (MDS) that integrates genetic and clinical information.

The research team considered the current standard for prognostication—the revised International Prognostic Scoring System (IPSS-R)—to be too complex, limited to newly diagnosed cases, and missing information on mutations and age.

So they devised a “simpler and more contemporary” prognostic system, the Mayo Alliance Prognostic Model for MDS.

The team, from the Mayo Clinic in Rochester, Minnesota, and the National Taiwan University Hospital (NTUH), described the new model in Mayo Clinic Proceedings.

Lead author Ayalew Tefferi, MD, of the Mayo Clinic, said the new model “is not an enhancement of the international prognostic scoring system tool, it's a complete makeover."

The team analyzed mutation information from 357 patients with primary MDS or leukemic transformation treated at the Mayo Clinic from the end of December 1994 through mid-December 2017.

The patients were a median age of 74 and 70% were males.

They compared the Mayo patients to 328 NTUH patients, who were a median age of 66 and 65% were males.

Multivariate analysis of the Mayo cohort identified the following as predictors of inferior overall survival:

• Monosomal karyotype (hazard ratio [HR], 5.2; 95% CI, 3.1-8.6)
• Non-monosomal karyotype abnormalities other than single/double del(5q) (HR, 1.8; 95% CI, 1.3-2.6)
• RUNX1 (HR, 2.0; 95% CI, 1.2-3.1)
• ASXL1 (HR, 1.7; 95% CI, 1.2-2.3) mutations
• Absence of SF3B1 mutations (HR, 1.6; 95% CI, 1.1-2.4)
• Age greater than 70 years (HR, 2.2; 95% CI, 1.6-3.1)
• Hemoglobin level less than 8 g/dL in women or less than 9 g/dL in men (HR, 2.3; 95% CI, 1.7-3.1)
• Platelet count less than 75 x 10⁹/L (HR, 1.5; 95% CI, 1.1-2.1)
• 10% or more bone marrow blasts (HR, 1.7; 95% CI, 1.1-2.8)

They then provided values to reflect the prognostic contribution of each of the above predictors and devised the new 4-tiered Mayo prognostic model.

Median 5-year overall survival rates in the 4 categories in the Mayo model were 73% (low risk), 34% (intermediate-1), 7% (intermediate-2), and 0% (high risk; 9-month median survival).

The team then validated the Mayo alliance model by using the NTUH cohort and compared it to the IPSS-R.

The investigators were able to confirm superior predictive accuracy of their model and a substantial discordance between the the Mayo model and the IPSS-R in terms of the pattern of risk distribution.

Examples of discordance included:

• More than 25% of patients belonging to the high-risk category according to the Mayo alliance model were classified as IPSS-R low or intermediate risk
• Almost 50% of patients with intermediate-2 risk category according to the Mayo alliance model were classified as IPSS-R very low or low risk
• Almost 50% of patients with IPSS-R very low risk were classified as intermediate-2 or intermediate-1 risk according to the Mayo alliance model

The authors wrote that this “suggests a fundamental and not incremental advantage for the new Mayo alliance model.”