Hematology Times

Lab mice
Photo by Aaron Logan

Preclinical research suggests that targeting 2 kinases may provide an approach to treating graft-vs-host-disease (GVHD) that does not compromise the tumor-fighting capabilities of the immune system.

Researchers said that dual inhibition of Aurora kinase A and JAK2, attenuating CD28 costimulation and IL-6-mediated signal transduction, respectively, can fight GVHD without destroying potential antitumor cytotoxic T lymphocyte (CTL) responses.

The team detailed these findings in Science Translational Medicine.

“It is known that Aurora kinase A and JAK2 pathway activation contributes to GVHD,” said study author Brian C. Betts, MD, of H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

“However, drugs that inhibit either protein alone do not completely prevent GVHD. We hypothesized that co-treatment with drugs that target both Aurora kinase A and JAK2 could prevent GVHD better than either drug alone.”

In fact, Dr Betts and his colleagues engineered and tested 2 compounds that inhibit both Aurora kinase A and JAK2—AJI-100 and AJI-214.

The team then compared the AJI analogs to the Aurora kinase A inhibitor alisertib, the JAK2 inhibitor TG101348, the combination of alisertib and TG101348, and dimethyl sulfoxide (DMSO) control.

The researchers first found that AJI-214 and AJI-100 “exerted significant suppression of T cells” in vitro, suppressing alloreactive T-cell proliferation with a potency that was similar to that of alisertib and TG101348 in combination.

The team noted that inhibition of Aurora kinase A and JAK2—with either AJI analog or alisertib and TG101348 in combination—significantly reduced alloreactive conventional T cells (Tconv) and helper T cells (TH1 and TH17) but permitted the differentiation of inducible regulatory T cells (iTregs).

In fact, the researchers said that dual inhibition of Aurora kinase A and JAK2 supports potent CD39+ iTregs. They observed higher CD39 cell surface density among AJI-214–treated iTregs, which resulted in improved scavenging of extracellular adenosine triphosphate, when compared to DMSO-treated iTregs.

The team then tested AJI-100 in mouse models of GVHD, as this drug has better bioavailability than AJI-214.

AJI-100 significantly improved the overall survival of the mice and reduced the severity of GVHD, compared to vehicle control (P=0.003).

In comparison, alisertib and TG101348 in combination significantly delayed the onset and severity of GVHD when compared to vehicle or TG101348 alone (P<0.0001 and P=0.0001). But the combination did not significantly improve survival in the mice.

Next, the researchers tested the effects of AJI-100 on CTLs by generating human antitumor CTLs in xenotransplanted mice. The mice received AJI-100 or vehicle control, as well as irradiated U937 cells. Unvaccinated, xenotransplanted mice served as negative controls.

The team said AJI-100 did not inhibit CTL generation because CD8+ CTLs from AJI-100–treated and vehicle-treated mice demonstrated similarly enhanced killing capacity against U937 targets in vitro, when compared to unvaccinated controls.

Additional experiments in mice showed that AJI-100 significantly increases the ratio of Tregs to activated Tconv while eliminating TH17 and TH1 cells.

The researchers therefore concluded that inhibiting CD28 and IL-6 signal transduction pathways in donor T cells may increase the Treg/Tconv ratio, prevent GVHD, and preserve antitumor CTLs.

“This novel prevention strategy warrants further investigation because of its potential to reduce the risk of GVHD and possibly be more effective and selective than commonly used GVHD treatments currently available today,” Dr Betts said.

Lab mice
Photo by Aaron Logan

Preclinical research suggests that targeting 2 kinases may provide an approach to treating graft-vs-host-disease (GVHD) that does not compromise the tumor-fighting capabilities of the immune system.

Researchers said that dual inhibition of Aurora kinase A and JAK2, attenuating CD28 costimulation and IL-6-mediated signal transduction, respectively, can fight GVHD without destroying potential antitumor cytotoxic T lymphocyte (CTL) responses.

The team detailed these findings in Science Translational Medicine.

“It is known that Aurora kinase A and JAK2 pathway activation contributes to GVHD,” said study author Brian C. Betts, MD, of H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

“However, drugs that inhibit either protein alone do not completely prevent GVHD. We hypothesized that co-treatment with drugs that target both Aurora kinase A and JAK2 could prevent GVHD better than either drug alone.”

In fact, Dr Betts and his colleagues engineered and tested 2 compounds that inhibit both Aurora kinase A and JAK2—AJI-100 and AJI-214.

The team then compared the AJI analogs to the Aurora kinase A inhibitor alisertib, the JAK2 inhibitor TG101348, the combination of alisertib and TG101348, and dimethyl sulfoxide (DMSO) control.

The researchers first found that AJI-214 and AJI-100 “exerted significant suppression of T cells” in vitro, suppressing alloreactive T-cell proliferation with a potency that was similar to that of alisertib and TG101348 in combination.

The team noted that inhibition of Aurora kinase A and JAK2—with either AJI analog or alisertib and TG101348 in combination—significantly reduced alloreactive conventional T cells (Tconv) and helper T cells (TH1 and TH17) but permitted the differentiation of inducible regulatory T cells (iTregs).

In fact, the researchers said that dual inhibition of Aurora kinase A and JAK2 supports potent CD39+ iTregs. They observed higher CD39 cell surface density among AJI-214–treated iTregs, which resulted in improved scavenging of extracellular adenosine triphosphate, when compared to DMSO-treated iTregs.

The team then tested AJI-100 in mouse models of GVHD, as this drug has better bioavailability than AJI-214.

AJI-100 significantly improved the overall survival of the mice and reduced the severity of GVHD, compared to vehicle control (P=0.003).

In comparison, alisertib and TG101348 in combination significantly delayed the onset and severity of GVHD when compared to vehicle or TG101348 alone (P<0.0001 and P=0.0001). But the combination did not significantly improve survival in the mice.

Next, the researchers tested the effects of AJI-100 on CTLs by generating human antitumor CTLs in xenotransplanted mice. The mice received AJI-100 or vehicle control, as well as irradiated U937 cells. Unvaccinated, xenotransplanted mice served as negative controls.

The team said AJI-100 did not inhibit CTL generation because CD8+ CTLs from AJI-100–treated and vehicle-treated mice demonstrated similarly enhanced killing capacity against U937 targets in vitro, when compared to unvaccinated controls.

Additional experiments in mice showed that AJI-100 significantly increases the ratio of Tregs to activated Tconv while eliminating TH17 and TH1 cells.

The researchers therefore concluded that inhibiting CD28 and IL-6 signal transduction pathways in donor T cells may increase the Treg/Tconv ratio, prevent GVHD, and preserve antitumor CTLs.

“This novel prevention strategy warrants further investigation because of its potential to reduce the risk of GVHD and possibly be more effective and selective than commonly used GVHD treatments currently available today,” Dr Betts said.

Lab mice
Photo by Aaron Logan

Preclinical research suggests that targeting 2 kinases may provide an approach to treating graft-vs-host-disease (GVHD) that does not compromise the tumor-fighting capabilities of the immune system.

Researchers said that dual inhibition of Aurora kinase A and JAK2, attenuating CD28 costimulation and IL-6-mediated signal transduction, respectively, can fight GVHD without destroying potential antitumor cytotoxic T lymphocyte (CTL) responses.

The team detailed these findings in Science Translational Medicine.

“It is known that Aurora kinase A and JAK2 pathway activation contributes to GVHD,” said study author Brian C. Betts, MD, of H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

“However, drugs that inhibit either protein alone do not completely prevent GVHD. We hypothesized that co-treatment with drugs that target both Aurora kinase A and JAK2 could prevent GVHD better than either drug alone.”

In fact, Dr Betts and his colleagues engineered and tested 2 compounds that inhibit both Aurora kinase A and JAK2—AJI-100 and AJI-214.

The team then compared the AJI analogs to the Aurora kinase A inhibitor alisertib, the JAK2 inhibitor TG101348, the combination of alisertib and TG101348, and dimethyl sulfoxide (DMSO) control.

The researchers first found that AJI-214 and AJI-100 “exerted significant suppression of T cells” in vitro, suppressing alloreactive T-cell proliferation with a potency that was similar to that of alisertib and TG101348 in combination.

The team noted that inhibition of Aurora kinase A and JAK2—with either AJI analog or alisertib and TG101348 in combination—significantly reduced alloreactive conventional T cells (Tconv) and helper T cells (TH1 and TH17) but permitted the differentiation of inducible regulatory T cells (iTregs).

In fact, the researchers said that dual inhibition of Aurora kinase A and JAK2 supports potent CD39+ iTregs. They observed higher CD39 cell surface density among AJI-214–treated iTregs, which resulted in improved scavenging of extracellular adenosine triphosphate, when compared to DMSO-treated iTregs.

The team then tested AJI-100 in mouse models of GVHD, as this drug has better bioavailability than AJI-214.

AJI-100 significantly improved the overall survival of the mice and reduced the severity of GVHD, compared to vehicle control (P=0.003).

In comparison, alisertib and TG101348 in combination significantly delayed the onset and severity of GVHD when compared to vehicle or TG101348 alone (P<0.0001 and P=0.0001). But the combination did not significantly improve survival in the mice.

Next, the researchers tested the effects of AJI-100 on CTLs by generating human antitumor CTLs in xenotransplanted mice. The mice received AJI-100 or vehicle control, as well as irradiated U937 cells. Unvaccinated, xenotransplanted mice served as negative controls.

The team said AJI-100 did not inhibit CTL generation because CD8+ CTLs from AJI-100–treated and vehicle-treated mice demonstrated similarly enhanced killing capacity against U937 targets in vitro, when compared to unvaccinated controls.

Additional experiments in mice showed that AJI-100 significantly increases the ratio of Tregs to activated Tconv while eliminating TH17 and TH1 cells.

The researchers therefore concluded that inhibiting CD28 and IL-6 signal transduction pathways in donor T cells may increase the Treg/Tconv ratio, prevent GVHD, and preserve antitumor CTLs.

“This novel prevention strategy warrants further investigation because of its potential to reduce the risk of GVHD and possibly be more effective and selective than commonly used GVHD treatments currently available today,” Dr Betts said.

Malaria-carrying mosquito
Photo by James Gathany

Mosquitoes carrying a greater number of malaria-causing parasites may be more likely to cause infection, according to a study published in PLOS Pathogens.

More than 100 years have passed since scientists first discovered that infectious mosquitoes inject malaria parasites when they bite people.

However, it hasn’t been clear whether injecting more parasites with each bite increases a person’s chances of infection or if all infectious bites are equally dangerous.

In the new study, researchers set out to determine whether the number of parasites found in the salivary glands of malaria-carrying mosquitos impacts disease transmission.

Via experiments in mice, the team determined that the more parasites present in a mosquito’s salivary glands, the more likely it was to be infectious and the faster an infection would develop.

“It is surprising that the relationship between parasite density and infectiousness has not been properly investigated before, but the studies are quite complex to carry out,” noted Andrew Blagborough, PhD, of Imperial College London in the UK.

For this study, he and his colleagues set up repeated cycles of infection so that groups of infected mosquitoes containing variable numbers of parasites repeatedly bit sedated mice, transmitting malaria to them under a range of transmission settings.

This allowed the researchers to track how many individual parasites different mosquitoes harbored, how many mice were infected as a result of exposure to them, and how long it took the mice to develop malaria.

The team also analyzed data from human volunteers who were exposed to bites from infectious mosquitoes.

Dissection of these mosquitoes revealed that infection was significantly more likely—and occurred sooner—after bites from mosquitoes with more than 1000 individual parasites in their salivary glands.

By conducting further studies with mice and human volunteers, the researchers were able to provide an explanation for why the malaria vaccine RTS,S is effective only some of the time and why any protection rapidly drops off after 3 years.

The vaccine was less effective when mice or humans were bitten by mosquitoes carrying a greater number of parasites. The researchers think this is because the vaccine can only kill a certain proportion of the parasites and is overwhelmed when the parasite population is too large.

“Vaccine development has come a long way, and this new insight should help future vaccine studies to be tested more rigorously,” said study author Thomas Churcher, PhD, of Imperial College London.

“However, in the end, it is unlikely that one magic bullet will eradicate malaria, and we should continue to seek and apply combinations of strategies for reducing the burden of this disease.”

Malaria-carrying mosquito
Photo by James Gathany

Mosquitoes carrying a greater number of malaria-causing parasites may be more likely to cause infection, according to a study published in PLOS Pathogens.

More than 100 years have passed since scientists first discovered that infectious mosquitoes inject malaria parasites when they bite people.

However, it hasn’t been clear whether injecting more parasites with each bite increases a person’s chances of infection or if all infectious bites are equally dangerous.

In the new study, researchers set out to determine whether the number of parasites found in the salivary glands of malaria-carrying mosquitos impacts disease transmission.

Via experiments in mice, the team determined that the more parasites present in a mosquito’s salivary glands, the more likely it was to be infectious and the faster an infection would develop.

“It is surprising that the relationship between parasite density and infectiousness has not been properly investigated before, but the studies are quite complex to carry out,” noted Andrew Blagborough, PhD, of Imperial College London in the UK.

For this study, he and his colleagues set up repeated cycles of infection so that groups of infected mosquitoes containing variable numbers of parasites repeatedly bit sedated mice, transmitting malaria to them under a range of transmission settings.

This allowed the researchers to track how many individual parasites different mosquitoes harbored, how many mice were infected as a result of exposure to them, and how long it took the mice to develop malaria.

The team also analyzed data from human volunteers who were exposed to bites from infectious mosquitoes.

Dissection of these mosquitoes revealed that infection was significantly more likely—and occurred sooner—after bites from mosquitoes with more than 1000 individual parasites in their salivary glands.

By conducting further studies with mice and human volunteers, the researchers were able to provide an explanation for why the malaria vaccine RTS,S is effective only some of the time and why any protection rapidly drops off after 3 years.

The vaccine was less effective when mice or humans were bitten by mosquitoes carrying a greater number of parasites. The researchers think this is because the vaccine can only kill a certain proportion of the parasites and is overwhelmed when the parasite population is too large.

“Vaccine development has come a long way, and this new insight should help future vaccine studies to be tested more rigorously,” said study author Thomas Churcher, PhD, of Imperial College London.

“However, in the end, it is unlikely that one magic bullet will eradicate malaria, and we should continue to seek and apply combinations of strategies for reducing the burden of this disease.”

Malaria-carrying mosquito
Photo by James Gathany

Mosquitoes carrying a greater number of malaria-causing parasites may be more likely to cause infection, according to a study published in PLOS Pathogens.

More than 100 years have passed since scientists first discovered that infectious mosquitoes inject malaria parasites when they bite people.

However, it hasn’t been clear whether injecting more parasites with each bite increases a person’s chances of infection or if all infectious bites are equally dangerous.

In the new study, researchers set out to determine whether the number of parasites found in the salivary glands of malaria-carrying mosquitos impacts disease transmission.

Via experiments in mice, the team determined that the more parasites present in a mosquito’s salivary glands, the more likely it was to be infectious and the faster an infection would develop.

“It is surprising that the relationship between parasite density and infectiousness has not been properly investigated before, but the studies are quite complex to carry out,” noted Andrew Blagborough, PhD, of Imperial College London in the UK.

For this study, he and his colleagues set up repeated cycles of infection so that groups of infected mosquitoes containing variable numbers of parasites repeatedly bit sedated mice, transmitting malaria to them under a range of transmission settings.

This allowed the researchers to track how many individual parasites different mosquitoes harbored, how many mice were infected as a result of exposure to them, and how long it took the mice to develop malaria.

The team also analyzed data from human volunteers who were exposed to bites from infectious mosquitoes.

Dissection of these mosquitoes revealed that infection was significantly more likely—and occurred sooner—after bites from mosquitoes with more than 1000 individual parasites in their salivary glands.

By conducting further studies with mice and human volunteers, the researchers were able to provide an explanation for why the malaria vaccine RTS,S is effective only some of the time and why any protection rapidly drops off after 3 years.

The vaccine was less effective when mice or humans were bitten by mosquitoes carrying a greater number of parasites. The researchers think this is because the vaccine can only kill a certain proportion of the parasites and is overwhelmed when the parasite population is too large.

“Vaccine development has come a long way, and this new insight should help future vaccine studies to be tested more rigorously,” said study author Thomas Churcher, PhD, of Imperial College London.

“However, in the end, it is unlikely that one magic bullet will eradicate malaria, and we should continue to seek and apply combinations of strategies for reducing the burden of this disease.”

Woman wearing nebulizer mask
Photo by James Heilman

The US Food and Drug Administration (FDA) is warning consumers not to purchase or use PNC-27, a product being promoted and sold through PNC27.com as a treatment for all cancers.

The FDA has not evaluated or approved PNC-27 as safe and effective to treat any disease, including any form of cancer.

In addition, an FDA laboratory discovered the bacteria Variovorax paradoxus in a PNC-27 solution sample for inhalation.

The FDA has not received reports of illnesses or serious adverse events related to PNC-27.

However, the agency said consumers who use a contaminated product are at risk for serious, potentially life-threatening infections.

Individuals at higher risk include vulnerable populations, such as young children, elderly people, pregnant women, and individuals with weakened immune systems.

PNC-27 may be available in various dosage forms, such as a nebulized solution, intravenous solution, vaginal suppository, or rectal suppository.

The FDA recommends that patients who have used any PNC-27 product and have concerns contact their healthcare provider as soon as possible.

The agency is also encouraging healthcare professionals and consumers to report any adverse events possibly related to the use of a PNC-27 product to the FDA’s MedWatch Adverse Event Reporting Program.

Woman wearing nebulizer mask
Photo by James Heilman

The US Food and Drug Administration (FDA) is warning consumers not to purchase or use PNC-27, a product being promoted and sold through PNC27.com as a treatment for all cancers.

The FDA has not evaluated or approved PNC-27 as safe and effective to treat any disease, including any form of cancer.

In addition, an FDA laboratory discovered the bacteria Variovorax paradoxus in a PNC-27 solution sample for inhalation.

The FDA has not received reports of illnesses or serious adverse events related to PNC-27.

However, the agency said consumers who use a contaminated product are at risk for serious, potentially life-threatening infections.

Individuals at higher risk include vulnerable populations, such as young children, elderly people, pregnant women, and individuals with weakened immune systems.

PNC-27 may be available in various dosage forms, such as a nebulized solution, intravenous solution, vaginal suppository, or rectal suppository.

The FDA recommends that patients who have used any PNC-27 product and have concerns contact their healthcare provider as soon as possible.

The agency is also encouraging healthcare professionals and consumers to report any adverse events possibly related to the use of a PNC-27 product to the FDA’s MedWatch Adverse Event Reporting Program.

Woman wearing nebulizer mask
Photo by James Heilman

The US Food and Drug Administration (FDA) is warning consumers not to purchase or use PNC-27, a product being promoted and sold through PNC27.com as a treatment for all cancers.

The FDA has not evaluated or approved PNC-27 as safe and effective to treat any disease, including any form of cancer.

In addition, an FDA laboratory discovered the bacteria Variovorax paradoxus in a PNC-27 solution sample for inhalation.

The FDA has not received reports of illnesses or serious adverse events related to PNC-27.

However, the agency said consumers who use a contaminated product are at risk for serious, potentially life-threatening infections.

Individuals at higher risk include vulnerable populations, such as young children, elderly people, pregnant women, and individuals with weakened immune systems.

PNC-27 may be available in various dosage forms, such as a nebulized solution, intravenous solution, vaginal suppository, or rectal suppository.

The FDA recommends that patients who have used any PNC-27 product and have concerns contact their healthcare provider as soon as possible.

The agency is also encouraging healthcare professionals and consumers to report any adverse events possibly related to the use of a PNC-27 product to the FDA’s MedWatch Adverse Event Reporting Program.

Blood in bags and vials
Photo by Daniel Gay

Abbott’s Alinity s System for blood and plasma screening has received the CE mark and is now available for use in countries that recognize the mark.

The Alinity s System is designed to screen blood and plasma faster and more efficiently than Abbott’s current systems.

The company said the additional automation and flexibility of the Alinity s System helps blood and plasma centers improve productivity and maintain accuracy without expanding the instrument footprint.

According to Abbott, the Alinity s System offers a number of new features. It expands capacity to run up to 600 tests per hour, and it increases walk-away time to a minimum of 3 hours.

The system also gives laboratory professionals the ability to continuously load and

unload samples and supplies without pausing or stopping the system.

The Alinity s System improves centers’ ability to track all activities and actions associated with the testing and processing of each donation in accordance with relevant legislation and requirements.

And the system features an intuitive software interface, menu design, and sample loading layout (shared with other Alinity instruments), making it easy for lab technicians to learn and use.

“When Abbott developed the Alinity s System, we considered the challenges that blood and plasma centers face today as well as in the future, such as adequate space, easier training, and more time for lab professionals to work away from the instrument,” said Daman Kowalski, divisional vice president of new product development in diagnostics at Abbott.

“In addressing these challenges, the Alinity s System has the potential to transform how quickly and accurately these centers can screen blood and plasma, which means we can deliver life-saving blood components to the people who need it the most.”

Blood in bags and vials
Photo by Daniel Gay

Abbott’s Alinity s System for blood and plasma screening has received the CE mark and is now available for use in countries that recognize the mark.

The Alinity s System is designed to screen blood and plasma faster and more efficiently than Abbott’s current systems.

The company said the additional automation and flexibility of the Alinity s System helps blood and plasma centers improve productivity and maintain accuracy without expanding the instrument footprint.

According to Abbott, the Alinity s System offers a number of new features. It expands capacity to run up to 600 tests per hour, and it increases walk-away time to a minimum of 3 hours.

The system also gives laboratory professionals the ability to continuously load and

unload samples and supplies without pausing or stopping the system.

The Alinity s System improves centers’ ability to track all activities and actions associated with the testing and processing of each donation in accordance with relevant legislation and requirements.

And the system features an intuitive software interface, menu design, and sample loading layout (shared with other Alinity instruments), making it easy for lab technicians to learn and use.

“When Abbott developed the Alinity s System, we considered the challenges that blood and plasma centers face today as well as in the future, such as adequate space, easier training, and more time for lab professionals to work away from the instrument,” said Daman Kowalski, divisional vice president of new product development in diagnostics at Abbott.

“In addressing these challenges, the Alinity s System has the potential to transform how quickly and accurately these centers can screen blood and plasma, which means we can deliver life-saving blood components to the people who need it the most.”

Blood in bags and vials
Photo by Daniel Gay

Abbott’s Alinity s System for blood and plasma screening has received the CE mark and is now available for use in countries that recognize the mark.

The Alinity s System is designed to screen blood and plasma faster and more efficiently than Abbott’s current systems.

The company said the additional automation and flexibility of the Alinity s System helps blood and plasma centers improve productivity and maintain accuracy without expanding the instrument footprint.

According to Abbott, the Alinity s System offers a number of new features. It expands capacity to run up to 600 tests per hour, and it increases walk-away time to a minimum of 3 hours.

The system also gives laboratory professionals the ability to continuously load and

unload samples and supplies without pausing or stopping the system.

The Alinity s System improves centers’ ability to track all activities and actions associated with the testing and processing of each donation in accordance with relevant legislation and requirements.

And the system features an intuitive software interface, menu design, and sample loading layout (shared with other Alinity instruments), making it easy for lab technicians to learn and use.

“When Abbott developed the Alinity s System, we considered the challenges that blood and plasma centers face today as well as in the future, such as adequate space, easier training, and more time for lab professionals to work away from the instrument,” said Daman Kowalski, divisional vice president of new product development in diagnostics at Abbott.

“In addressing these challenges, the Alinity s System has the potential to transform how quickly and accurately these centers can screen blood and plasma, which means we can deliver life-saving blood components to the people who need it the most.”

Micrograph showing AML

New research suggests the protein SAMHD1 could be used to predict which

patients with acute myeloid leukemia (AML) will respond to treatment

with cytarabine.

Researchers found that response to cytarabine

was inversely correlated with SAMHD1 expression in AML cell lines, mouse

models of the disease, and adult patients with AML.

Jindrich Cinatl, PhD, of the University of Frankfurt in Germany, and his colleagues reported these findings in Nature Medicine.

The researchers first analyzed 13 AML cell lines and found that SAMHD1 reduces the cytotoxic effect of cytarabine. When the team depleted SAMHD1 in these cell lines, they were “markedly sensitized” to cytarabine.

The researchers also cultivated cytarabine-resistant AML cell lines and found that SAMHD1 levels increased along with cytarabine resistance. However, depleting SAMHD1 resensitized the cells to cytarabine. 

Investigation revealed that SAMHD1 removes the phosphate residues from the active form of cytarabine, Ara-CTP, and converts the drug to its inactive form, Ara-C.

The researchers then evaluated the role of SAMHD1 in AML in vivo. They transplanted SAMHD1-knockout AML cells and wild-type SAMHD1 AML cells into mice and treated the mice with cytarabine or phosphate-buffered saline.

Mice that received SAMHD1-knockout AML cells and cytarabine had significantly longer survival than mice that received wild-type SAMHD1 AML cells and cytarabine or either AML cell type plus phosphate-buffered saline.

Next, the researchers tested blasts isolated from the bone marrow of patients with therapy-naive AML.

The team found that basal SAMHD1 expression was significantly correlated with cytarabine IC₅₀ values. And depleting SAMHD1 diminished cytarabine IC₅₀ values by 3- to 15-fold.

Lastly, the researchers assessed whether SAMHD1 expression might be used to predict response to cytarabine-based therapy in patients with AML.

The team analyzed a cohort of 150 adult AML patients who had received 1 to 2 courses of induction therapy including cytarabine—either 2 cycles of 7+3 or 7+3 plus high-dose cytarabine in combination with mitoxantrone.

Analysis revealed that SAMHD1 expression was “markedly increased” among patients who did not achieve a complete remission (CR) at the end of induction.

Of the 112 patients who achieved a CR, 90 were scored as “SAMHD1 low,” and 22 were scored as “SAMHD1 high.” The CR rate was 44% in the SAMHD1-high cohort and 90% in the SAMHD1-low cohort.

In addition, the researchers found the level of SAMHD1 expression in blasts at patients’ initial diagnosis was predictive of event-free survival, relapse-free survival, and overall survival.

The team said these results suggest SAMHD1 could be used to guide treatment with cytarabine-based therapies in patients with AML.

Micrograph showing AML

New research suggests the protein SAMHD1 could be used to predict which

patients with acute myeloid leukemia (AML) will respond to treatment

with cytarabine.

Researchers found that response to cytarabine

was inversely correlated with SAMHD1 expression in AML cell lines, mouse

models of the disease, and adult patients with AML.

Jindrich Cinatl, PhD, of the University of Frankfurt in Germany, and his colleagues reported these findings in Nature Medicine.

The researchers first analyzed 13 AML cell lines and found that SAMHD1 reduces the cytotoxic effect of cytarabine. When the team depleted SAMHD1 in these cell lines, they were “markedly sensitized” to cytarabine.

The researchers also cultivated cytarabine-resistant AML cell lines and found that SAMHD1 levels increased along with cytarabine resistance. However, depleting SAMHD1 resensitized the cells to cytarabine. 

Investigation revealed that SAMHD1 removes the phosphate residues from the active form of cytarabine, Ara-CTP, and converts the drug to its inactive form, Ara-C.

The researchers then evaluated the role of SAMHD1 in AML in vivo. They transplanted SAMHD1-knockout AML cells and wild-type SAMHD1 AML cells into mice and treated the mice with cytarabine or phosphate-buffered saline.

Mice that received SAMHD1-knockout AML cells and cytarabine had significantly longer survival than mice that received wild-type SAMHD1 AML cells and cytarabine or either AML cell type plus phosphate-buffered saline.

Next, the researchers tested blasts isolated from the bone marrow of patients with therapy-naive AML.

The team found that basal SAMHD1 expression was significantly correlated with cytarabine IC₅₀ values. And depleting SAMHD1 diminished cytarabine IC₅₀ values by 3- to 15-fold.

Lastly, the researchers assessed whether SAMHD1 expression might be used to predict response to cytarabine-based therapy in patients with AML.

The team analyzed a cohort of 150 adult AML patients who had received 1 to 2 courses of induction therapy including cytarabine—either 2 cycles of 7+3 or 7+3 plus high-dose cytarabine in combination with mitoxantrone.

Analysis revealed that SAMHD1 expression was “markedly increased” among patients who did not achieve a complete remission (CR) at the end of induction.

Of the 112 patients who achieved a CR, 90 were scored as “SAMHD1 low,” and 22 were scored as “SAMHD1 high.” The CR rate was 44% in the SAMHD1-high cohort and 90% in the SAMHD1-low cohort.

In addition, the researchers found the level of SAMHD1 expression in blasts at patients’ initial diagnosis was predictive of event-free survival, relapse-free survival, and overall survival.

The team said these results suggest SAMHD1 could be used to guide treatment with cytarabine-based therapies in patients with AML.

Micrograph showing AML

New research suggests the protein SAMHD1 could be used to predict which

patients with acute myeloid leukemia (AML) will respond to treatment

with cytarabine.

Researchers found that response to cytarabine

was inversely correlated with SAMHD1 expression in AML cell lines, mouse

models of the disease, and adult patients with AML.

Jindrich Cinatl, PhD, of the University of Frankfurt in Germany, and his colleagues reported these findings in Nature Medicine.

The researchers first analyzed 13 AML cell lines and found that SAMHD1 reduces the cytotoxic effect of cytarabine. When the team depleted SAMHD1 in these cell lines, they were “markedly sensitized” to cytarabine.

The researchers also cultivated cytarabine-resistant AML cell lines and found that SAMHD1 levels increased along with cytarabine resistance. However, depleting SAMHD1 resensitized the cells to cytarabine. 

Investigation revealed that SAMHD1 removes the phosphate residues from the active form of cytarabine, Ara-CTP, and converts the drug to its inactive form, Ara-C.

The researchers then evaluated the role of SAMHD1 in AML in vivo. They transplanted SAMHD1-knockout AML cells and wild-type SAMHD1 AML cells into mice and treated the mice with cytarabine or phosphate-buffered saline.

Mice that received SAMHD1-knockout AML cells and cytarabine had significantly longer survival than mice that received wild-type SAMHD1 AML cells and cytarabine or either AML cell type plus phosphate-buffered saline.

Next, the researchers tested blasts isolated from the bone marrow of patients with therapy-naive AML.

The team found that basal SAMHD1 expression was significantly correlated with cytarabine IC₅₀ values. And depleting SAMHD1 diminished cytarabine IC₅₀ values by 3- to 15-fold.

Lastly, the researchers assessed whether SAMHD1 expression might be used to predict response to cytarabine-based therapy in patients with AML.

The team analyzed a cohort of 150 adult AML patients who had received 1 to 2 courses of induction therapy including cytarabine—either 2 cycles of 7+3 or 7+3 plus high-dose cytarabine in combination with mitoxantrone.

Analysis revealed that SAMHD1 expression was “markedly increased” among patients who did not achieve a complete remission (CR) at the end of induction.

Of the 112 patients who achieved a CR, 90 were scored as “SAMHD1 low,” and 22 were scored as “SAMHD1 high.” The CR rate was 44% in the SAMHD1-high cohort and 90% in the SAMHD1-low cohort.

In addition, the researchers found the level of SAMHD1 expression in blasts at patients’ initial diagnosis was predictive of event-free survival, relapse-free survival, and overall survival.

The team said these results suggest SAMHD1 could be used to guide treatment with cytarabine-based therapies in patients with AML.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Vials of injectable drugs
Photo by Bill Branson

The National Cancer Institute (NCI) has launched a new drug formulary designed to provide investigators at NCI-designated cancer centers with quicker access to approved and investigational agents for use in preclinical studies and clinical trials.

The formulary will enable NCI to act as an intermediary between investigators and participating pharmaceutical companies, facilitating the arrangements for access to and use of pharmaceutical agents.

Following company approval, investigators will be able to obtain agents from the formulary and test them in preclinical or clinical studies, including studies combining formulary agents from different companies.

The NCI says having agents available through the formulary will expedite the start of clinical trials by alleviating the lengthy negotiation process—sometimes up to 18 months—that has been required for investigators to access such agents on their own.

“The NCI Formulary will help researchers begin testing promising drug combinations more quickly, potentially helping patients much sooner,” said NCI Acting Director Douglas Lowy, MD.

“Rather than spending time negotiating agreements, investigators will be able to focus on the important research that can ultimately lead to improved cancer care.”

The NCI Formulary includes 15 targeted agents:

• Alectinib (ALK inhibitor, tyrosine kinase inhibitor)
• Atezolizumab (PD-L1 blocking monoclonal antibody)
• Bevacizumab (anti-angiogenesis inhibitor, monoclonal antibody)
• Cobimetinib (MEK1/2 inhibitor)
• Ensartinib (ALK inhibitor)
• Ipilimumab (anti-CTLA-4 monoclonal antibody)
• Larotrectinib (tyrosine kinase inhibitor)
• LY3039478 (Notch inhibitor)
• Nivolumab (PD-1 blocking monoclonal antibody)
• Obinutuzumab (anti-CD20 monoclonal antibody)
• Pertuzumab (anti-HER2 monoclonal antibody)
• Prexasertib (checkpoint kinase 1 inhibitor)
• Trastuzumab (anti-HER2 monoclonal antibody)
• Vemurafenib (BRAF mutant v600 inhibitor)
• Vismodegib (Hedgehog inhibitor)

The agents are products of 6 different pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery Holding Company LLC.

“The agreements with these companies demonstrate our shared commitment to expedite cancer clinical trials and improve outcomes for patients,” said James Doroshow, MD, NCI deputy director for clinical and translational research.

“We are very pleased that several additional pharmaceutical companies have already pledged a willingness to participate and are in various stages of negotiation with NCI. By the end of 2017, we expect to have doubled the number of partnerships and drugs available in the NCI Formulary.”

Vials of injectable drugs
Photo by Bill Branson

The National Cancer Institute (NCI) has launched a new drug formulary designed to provide investigators at NCI-designated cancer centers with quicker access to approved and investigational agents for use in preclinical studies and clinical trials.

The formulary will enable NCI to act as an intermediary between investigators and participating pharmaceutical companies, facilitating the arrangements for access to and use of pharmaceutical agents.

Following company approval, investigators will be able to obtain agents from the formulary and test them in preclinical or clinical studies, including studies combining formulary agents from different companies.

The NCI says having agents available through the formulary will expedite the start of clinical trials by alleviating the lengthy negotiation process—sometimes up to 18 months—that has been required for investigators to access such agents on their own.

“The NCI Formulary will help researchers begin testing promising drug combinations more quickly, potentially helping patients much sooner,” said NCI Acting Director Douglas Lowy, MD.

“Rather than spending time negotiating agreements, investigators will be able to focus on the important research that can ultimately lead to improved cancer care.”

The NCI Formulary includes 15 targeted agents:

• Alectinib (ALK inhibitor, tyrosine kinase inhibitor)
• Atezolizumab (PD-L1 blocking monoclonal antibody)
• Bevacizumab (anti-angiogenesis inhibitor, monoclonal antibody)
• Cobimetinib (MEK1/2 inhibitor)
• Ensartinib (ALK inhibitor)
• Ipilimumab (anti-CTLA-4 monoclonal antibody)
• Larotrectinib (tyrosine kinase inhibitor)
• LY3039478 (Notch inhibitor)
• Nivolumab (PD-1 blocking monoclonal antibody)
• Obinutuzumab (anti-CD20 monoclonal antibody)
• Pertuzumab (anti-HER2 monoclonal antibody)
• Prexasertib (checkpoint kinase 1 inhibitor)
• Trastuzumab (anti-HER2 monoclonal antibody)
• Vemurafenib (BRAF mutant v600 inhibitor)
• Vismodegib (Hedgehog inhibitor)

The agents are products of 6 different pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery Holding Company LLC.

“The agreements with these companies demonstrate our shared commitment to expedite cancer clinical trials and improve outcomes for patients,” said James Doroshow, MD, NCI deputy director for clinical and translational research.

“We are very pleased that several additional pharmaceutical companies have already pledged a willingness to participate and are in various stages of negotiation with NCI. By the end of 2017, we expect to have doubled the number of partnerships and drugs available in the NCI Formulary.”

Vials of injectable drugs
Photo by Bill Branson

The National Cancer Institute (NCI) has launched a new drug formulary designed to provide investigators at NCI-designated cancer centers with quicker access to approved and investigational agents for use in preclinical studies and clinical trials.

The formulary will enable NCI to act as an intermediary between investigators and participating pharmaceutical companies, facilitating the arrangements for access to and use of pharmaceutical agents.

Following company approval, investigators will be able to obtain agents from the formulary and test them in preclinical or clinical studies, including studies combining formulary agents from different companies.

The NCI says having agents available through the formulary will expedite the start of clinical trials by alleviating the lengthy negotiation process—sometimes up to 18 months—that has been required for investigators to access such agents on their own.

“The NCI Formulary will help researchers begin testing promising drug combinations more quickly, potentially helping patients much sooner,” said NCI Acting Director Douglas Lowy, MD.

“Rather than spending time negotiating agreements, investigators will be able to focus on the important research that can ultimately lead to improved cancer care.”

The NCI Formulary includes 15 targeted agents:

• Alectinib (ALK inhibitor, tyrosine kinase inhibitor)
• Atezolizumab (PD-L1 blocking monoclonal antibody)
• Bevacizumab (anti-angiogenesis inhibitor, monoclonal antibody)
• Cobimetinib (MEK1/2 inhibitor)
• Ensartinib (ALK inhibitor)
• Ipilimumab (anti-CTLA-4 monoclonal antibody)
• Larotrectinib (tyrosine kinase inhibitor)
• LY3039478 (Notch inhibitor)
• Nivolumab (PD-1 blocking monoclonal antibody)
• Obinutuzumab (anti-CD20 monoclonal antibody)
• Pertuzumab (anti-HER2 monoclonal antibody)
• Prexasertib (checkpoint kinase 1 inhibitor)
• Trastuzumab (anti-HER2 monoclonal antibody)
• Vemurafenib (BRAF mutant v600 inhibitor)
• Vismodegib (Hedgehog inhibitor)

The agents are products of 6 different pharmaceutical companies: Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery Holding Company LLC.

“The agreements with these companies demonstrate our shared commitment to expedite cancer clinical trials and improve outcomes for patients,” said James Doroshow, MD, NCI deputy director for clinical and translational research.

“We are very pleased that several additional pharmaceutical companies have already pledged a willingness to participate and are in various stages of negotiation with NCI. By the end of 2017, we expect to have doubled the number of partnerships and drugs available in the NCI Formulary.”

Bottles of warfarin
Photo courtesy of NIGMS

Researchers have developed an intervention intended to help hospitals and clinicians improve the management of patients on warfarin.

The team implemented the intervention at 8 medical centers in the New England region of the Veterans Health Administration (VA).

These

centers saw an improvement in time in the therapeutic range

(TTR) that was significantly better than the improvement seen in medical

centers without the intervention.

“Insufficient attention has been given in the past to how we can improve the management of warfarin,” said Adam Rose, MD, of Boston University School of Medicine in Massachusetts.

“This study demonstrates that a relatively simple approach can have a large impact.”

Dr Rose and his colleagues described this study in the Annals of Pharmacotherapy.

Intervention

The researchers implemented the intervention at 8 VA sites in New England known as Veterans Integrated Service Network 1 (VISN 1).

The team described the intervention as performance measurement augmented by targeted audit and feedback. Performance was measured via an online reporting system—known as a dashboard—that provided real-time data to clinicians.

The dashboard reported TTR at the patient and site level. The dashboard also reported processes of care that have been linked to TTR, including timely follow-up when the international normalized ratio (INR) is very low or very high, gaps in monitoring, and the proportion of patients with a mean INR value between 2.3 and 2.7.

The dashboard allowed clinicians to call patients who had been lost to follow-up, had low TTR, or were in need of urgent follow-up as a result of extreme INR values.

Results

The researchers examined changes in anticoagulation control, measured as TTR, after the intervention was implemented. They compared changes at VISN 1 sites with 116 other VA sites.

A total of 11,794 patients within VISN 1 and 1,248,782 patients outside of VISN 1 received warfarin for at least part of the study period.

At VISN 1 sites, TTR improved from 66.4% to 69.2%. At the other sites, TTR improved from 65.9% to 66.4% (P<0.001 for the between-group difference).

The researchers said improvement in TTR correlated strongly with the extent of improvement on process-of-care measures, which varied widely across VISN 1 sites.

“Patients who used these measures did better clinically than those in the control group,” Dr Rose said. “This study serves as a model for how other sites and health networks could feasibly approach improving the management of warfarin in their systems.”

“If all anticoagulation clinics in the VA were to achieve this level of improvement, it would prevent 48 strokes and 68 major bleeding events each year, with a savings to the VA system of more than $4 million annually.”

Bottles of warfarin
Photo courtesy of NIGMS

Researchers have developed an intervention intended to help hospitals and clinicians improve the management of patients on warfarin.

The team implemented the intervention at 8 medical centers in the New England region of the Veterans Health Administration (VA).

These

centers saw an improvement in time in the therapeutic range

(TTR) that was significantly better than the improvement seen in medical

centers without the intervention.

“Insufficient attention has been given in the past to how we can improve the management of warfarin,” said Adam Rose, MD, of Boston University School of Medicine in Massachusetts.

“This study demonstrates that a relatively simple approach can have a large impact.”

Dr Rose and his colleagues described this study in the Annals of Pharmacotherapy.

Intervention

The researchers implemented the intervention at 8 VA sites in New England known as Veterans Integrated Service Network 1 (VISN 1).

The team described the intervention as performance measurement augmented by targeted audit and feedback. Performance was measured via an online reporting system—known as a dashboard—that provided real-time data to clinicians.

The dashboard reported TTR at the patient and site level. The dashboard also reported processes of care that have been linked to TTR, including timely follow-up when the international normalized ratio (INR) is very low or very high, gaps in monitoring, and the proportion of patients with a mean INR value between 2.3 and 2.7.

The dashboard allowed clinicians to call patients who had been lost to follow-up, had low TTR, or were in need of urgent follow-up as a result of extreme INR values.

Results

The researchers examined changes in anticoagulation control, measured as TTR, after the intervention was implemented. They compared changes at VISN 1 sites with 116 other VA sites.

A total of 11,794 patients within VISN 1 and 1,248,782 patients outside of VISN 1 received warfarin for at least part of the study period.

At VISN 1 sites, TTR improved from 66.4% to 69.2%. At the other sites, TTR improved from 65.9% to 66.4% (P<0.001 for the between-group difference).

The researchers said improvement in TTR correlated strongly with the extent of improvement on process-of-care measures, which varied widely across VISN 1 sites.

“Patients who used these measures did better clinically than those in the control group,” Dr Rose said. “This study serves as a model for how other sites and health networks could feasibly approach improving the management of warfarin in their systems.”

“If all anticoagulation clinics in the VA were to achieve this level of improvement, it would prevent 48 strokes and 68 major bleeding events each year, with a savings to the VA system of more than $4 million annually.”

Bottles of warfarin
Photo courtesy of NIGMS

Researchers have developed an intervention intended to help hospitals and clinicians improve the management of patients on warfarin.

The team implemented the intervention at 8 medical centers in the New England region of the Veterans Health Administration (VA).

These

centers saw an improvement in time in the therapeutic range

(TTR) that was significantly better than the improvement seen in medical

centers without the intervention.

“Insufficient attention has been given in the past to how we can improve the management of warfarin,” said Adam Rose, MD, of Boston University School of Medicine in Massachusetts.

“This study demonstrates that a relatively simple approach can have a large impact.”

Dr Rose and his colleagues described this study in the Annals of Pharmacotherapy.

Intervention

The researchers implemented the intervention at 8 VA sites in New England known as Veterans Integrated Service Network 1 (VISN 1).

The team described the intervention as performance measurement augmented by targeted audit and feedback. Performance was measured via an online reporting system—known as a dashboard—that provided real-time data to clinicians.

The dashboard reported TTR at the patient and site level. The dashboard also reported processes of care that have been linked to TTR, including timely follow-up when the international normalized ratio (INR) is very low or very high, gaps in monitoring, and the proportion of patients with a mean INR value between 2.3 and 2.7.

The dashboard allowed clinicians to call patients who had been lost to follow-up, had low TTR, or were in need of urgent follow-up as a result of extreme INR values.

Results

The researchers examined changes in anticoagulation control, measured as TTR, after the intervention was implemented. They compared changes at VISN 1 sites with 116 other VA sites.

A total of 11,794 patients within VISN 1 and 1,248,782 patients outside of VISN 1 received warfarin for at least part of the study period.

At VISN 1 sites, TTR improved from 66.4% to 69.2%. At the other sites, TTR improved from 65.9% to 66.4% (P<0.001 for the between-group difference).

The researchers said improvement in TTR correlated strongly with the extent of improvement on process-of-care measures, which varied widely across VISN 1 sites.

“Patients who used these measures did better clinically than those in the control group,” Dr Rose said. “This study serves as a model for how other sites and health networks could feasibly approach improving the management of warfarin in their systems.”

“If all anticoagulation clinics in the VA were to achieve this level of improvement, it would prevent 48 strokes and 68 major bleeding events each year, with a savings to the VA system of more than $4 million annually.”

Lab mouse

Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.

The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
 
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.

The investigators are now attempting to translate these findings to the clinic.

“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“Now, we’ve made a fundamentally important breakthrough.”

The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.

The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).

The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.

The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).

To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.

The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.

The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.

The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.

The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.

Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.

However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.

The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.

Lab mouse

Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.

The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
 
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.

The investigators are now attempting to translate these findings to the clinic.

“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“Now, we’ve made a fundamentally important breakthrough.”

The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.

The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).

The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.

The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).

To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.

The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.

The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.

The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.

The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.

Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.

However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.

The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.

Lab mouse

Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.

The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
 
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.

The investigators are now attempting to translate these findings to the clinic.

“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.

“Now, we’ve made a fundamentally important breakthrough.”

The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.

The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).

The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.

The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).

To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.

The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.

The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.

The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.

The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.

Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.

However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.

The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.

Warfarin tablets

The American College of Cardiology (ACC) has published a guidance document for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation (NVAF).

The document includes recommendations on how and when to stop anticoagulants in NVAF patients undergoing surgery, deciding if a substitute medication should be used, and determining when it is safe for patients to resume anticoagulants after surgery.

The document was published in the Journal of the American College of Cardiology.

“With this new decision pathway [document], physicians will be able to make better-informed decisions, and this will contribute to improved patient outcomes,” said John U. Doherty, MD, chair of the document writing committee.

“In North America alone, more than 250,000 nonvalvular atrial fibrillation patients undergo surgery annually, so this document will impact many people.”

The document provides guidance on:

• The overall decision to keep a patient chronically on an anticoagulant by examining whether anticoagulation is warranted based on overall thrombotic risk.
• The decision to take the patient off an anticoagulant temporarily.
• How to temporarily stop the use of vitamin K antagonists and direct-acting oral anticoagulants.
• Deciding if bridging a patient—temporarily discontinuing an oral anticoagulant and replacing it with a subcutaneous or intravenous anticoagulant—before, during, and after surgery is the best choice. 
• Deciding how to bridge before, during, and after surgery.
• Deciding how and when to restart the patient’s regular anticoagulant after surgery.

Warfarin tablets

The American College of Cardiology (ACC) has published a guidance document for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation (NVAF).

The document includes recommendations on how and when to stop anticoagulants in NVAF patients undergoing surgery, deciding if a substitute medication should be used, and determining when it is safe for patients to resume anticoagulants after surgery.

The document was published in the Journal of the American College of Cardiology.

“With this new decision pathway [document], physicians will be able to make better-informed decisions, and this will contribute to improved patient outcomes,” said John U. Doherty, MD, chair of the document writing committee.

“In North America alone, more than 250,000 nonvalvular atrial fibrillation patients undergo surgery annually, so this document will impact many people.”

The document provides guidance on:

• The overall decision to keep a patient chronically on an anticoagulant by examining whether anticoagulation is warranted based on overall thrombotic risk.
• The decision to take the patient off an anticoagulant temporarily.
• How to temporarily stop the use of vitamin K antagonists and direct-acting oral anticoagulants.
• Deciding if bridging a patient—temporarily discontinuing an oral anticoagulant and replacing it with a subcutaneous or intravenous anticoagulant—before, during, and after surgery is the best choice. 
• Deciding how to bridge before, during, and after surgery.
• Deciding how and when to restart the patient’s regular anticoagulant after surgery.

Warfarin tablets

The American College of Cardiology (ACC) has published a guidance document for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation (NVAF).

The document includes recommendations on how and when to stop anticoagulants in NVAF patients undergoing surgery, deciding if a substitute medication should be used, and determining when it is safe for patients to resume anticoagulants after surgery.

The document was published in the Journal of the American College of Cardiology.

“With this new decision pathway [document], physicians will be able to make better-informed decisions, and this will contribute to improved patient outcomes,” said John U. Doherty, MD, chair of the document writing committee.

“In North America alone, more than 250,000 nonvalvular atrial fibrillation patients undergo surgery annually, so this document will impact many people.”

The document provides guidance on:

• The overall decision to keep a patient chronically on an anticoagulant by examining whether anticoagulation is warranted based on overall thrombotic risk.
• The decision to take the patient off an anticoagulant temporarily.
• How to temporarily stop the use of vitamin K antagonists and direct-acting oral anticoagulants.
• Deciding if bridging a patient—temporarily discontinuing an oral anticoagulant and replacing it with a subcutaneous or intravenous anticoagulant—before, during, and after surgery is the best choice. 
• Deciding how to bridge before, during, and after surgery.
• Deciding how and when to restart the patient’s regular anticoagulant after surgery.