Despite the adoption of naloxone access laws, new findings suggest that naloxone availability without a prescription still varies between states.

Two research letters published Nov. 13 in JAMA examined pharmacy availability of naloxone in California and Texas 24 and 32 months, respectively, after implementation of expanded access laws.

In California, just 23.5% of retail pharmacies were dispensing naloxone without a prescription 2 years later. In Texas, however, 83.7% of chain pharmacies with expanded access via standing order reported that they would dispense naloxone without prescription 32 months later.

In the first study, investigators conducted an anonymous telephone survey of a 20% representative sample of California pharmacies. Posing as potential customers, interviewers asked pharmacy staff whether naloxone was available at their pharmacy without a prescription. They also inquired about what formulations were available, price, and whether naloxone could be billed to insurance, wrote Talia Puzantian, PharmD, and James J. Gasper, PharmD.

Naloxone was available at 23.5% (95% confidence interval, 21.0%-26.0%) of the 1,147 pharmacies that provided data. Chain pharmacies were more likely to dispense naloxone (31.6%; 95% CI, 28.3%-35.1%) than were independent pharmacies (7.5%; 95% CI, 5.1%-10.6%; P less than .001). Of pharmacies dispensing naloxone, 50.6% had nasal naloxone in stock, and 59.9% correctly said that naloxone could be billed to insurance, reported Dr. Puzantian, of the Keck Graduate Institute School of Pharmacy in Claremont, Calif., and Dr. Gasper, of the department of family and community medicine at the University of California, San Francisco.

Reasons for low availability in California pharmacies might include lack of knowledge and training, stigma about substance use, and time, Dr. Puzantian and Dr. Gasper said.

“Whether naloxone will become more available with training of additional pharmacists and implementation of standardized policies by pharmacy chains needs to be studied,” the authors concluded.

The second study examined naloxone availability among Texas chain pharmacies with public implementation of standing orders, for a survey of 2,317 CVS, Walgreens, HEB, and Walmart pharmacies. Interviewers posed as potential overdose responders, and inquired about purchasing naloxone without a prescription, reported Kirk E. Evoy, PharmD, of the College of Pharmacy at the University of Texas at Austin, and his coauthors.

Of the pharmacies surveyed, 83.7% (95% CI, 82.2%-85.2%) said they would dispense naloxone without a prescription, and 76.4% (95% CI, 74.7%-78.1%) currently stocked naloxone.

In addition, 79.9% (95% CI, 78.3%-81.6%) would allow purchase of naloxone for someone else, though only 49.7% (95% CI, 47.8%-51.9%) would allow the purchase to be billed to a third-party buyer’s insurance, the authors noted.

Although this study found that most pharmacies would dispense naloxone without a prescription, the findings cannot be applied to independent pharmacies, Dr. Evoy and his colleagues noted.

“Consistent naloxone supply in all pharmacies, improved pharmacist understanding of naloxone standing orders, and ubiquitous insurance coverage for third-party purchasers may further improve access,” they wrote.

Dr. Puzantian and Dr. Gasper reported no disclosures. Dr. Evoy disclosed receiving grant funding from the Institute for Integration of Medicine and Science at the UT Health in San Antonio, the Kleberg Foundation, and Texas Health and Human Services. Other authors disclosed previous receipt of donations of branded formulations of naloxone from Kaléo Pharma and Adapt Pharma.

SOURCE: Puzantian T et al. and Evoy KE et al. JAMA 2018 Nov 13.320(18):1933-7.

Despite the adoption of naloxone access laws, new findings suggest that naloxone availability without a prescription still varies between states.

Two research letters published Nov. 13 in JAMA examined pharmacy availability of naloxone in California and Texas 24 and 32 months, respectively, after implementation of expanded access laws.

In California, just 23.5% of retail pharmacies were dispensing naloxone without a prescription 2 years later. In Texas, however, 83.7% of chain pharmacies with expanded access via standing order reported that they would dispense naloxone without prescription 32 months later.

In the first study, investigators conducted an anonymous telephone survey of a 20% representative sample of California pharmacies. Posing as potential customers, interviewers asked pharmacy staff whether naloxone was available at their pharmacy without a prescription. They also inquired about what formulations were available, price, and whether naloxone could be billed to insurance, wrote Talia Puzantian, PharmD, and James J. Gasper, PharmD.

Naloxone was available at 23.5% (95% confidence interval, 21.0%-26.0%) of the 1,147 pharmacies that provided data. Chain pharmacies were more likely to dispense naloxone (31.6%; 95% CI, 28.3%-35.1%) than were independent pharmacies (7.5%; 95% CI, 5.1%-10.6%; P less than .001). Of pharmacies dispensing naloxone, 50.6% had nasal naloxone in stock, and 59.9% correctly said that naloxone could be billed to insurance, reported Dr. Puzantian, of the Keck Graduate Institute School of Pharmacy in Claremont, Calif., and Dr. Gasper, of the department of family and community medicine at the University of California, San Francisco.

Reasons for low availability in California pharmacies might include lack of knowledge and training, stigma about substance use, and time, Dr. Puzantian and Dr. Gasper said.

“Whether naloxone will become more available with training of additional pharmacists and implementation of standardized policies by pharmacy chains needs to be studied,” the authors concluded.

The second study examined naloxone availability among Texas chain pharmacies with public implementation of standing orders, for a survey of 2,317 CVS, Walgreens, HEB, and Walmart pharmacies. Interviewers posed as potential overdose responders, and inquired about purchasing naloxone without a prescription, reported Kirk E. Evoy, PharmD, of the College of Pharmacy at the University of Texas at Austin, and his coauthors.

Of the pharmacies surveyed, 83.7% (95% CI, 82.2%-85.2%) said they would dispense naloxone without a prescription, and 76.4% (95% CI, 74.7%-78.1%) currently stocked naloxone.

In addition, 79.9% (95% CI, 78.3%-81.6%) would allow purchase of naloxone for someone else, though only 49.7% (95% CI, 47.8%-51.9%) would allow the purchase to be billed to a third-party buyer’s insurance, the authors noted.

Although this study found that most pharmacies would dispense naloxone without a prescription, the findings cannot be applied to independent pharmacies, Dr. Evoy and his colleagues noted.

“Consistent naloxone supply in all pharmacies, improved pharmacist understanding of naloxone standing orders, and ubiquitous insurance coverage for third-party purchasers may further improve access,” they wrote.

Dr. Puzantian and Dr. Gasper reported no disclosures. Dr. Evoy disclosed receiving grant funding from the Institute for Integration of Medicine and Science at the UT Health in San Antonio, the Kleberg Foundation, and Texas Health and Human Services. Other authors disclosed previous receipt of donations of branded formulations of naloxone from Kaléo Pharma and Adapt Pharma.

SOURCE: Puzantian T et al. and Evoy KE et al. JAMA 2018 Nov 13.320(18):1933-7.

Despite the adoption of naloxone access laws, new findings suggest that naloxone availability without a prescription still varies between states.

Two research letters published Nov. 13 in JAMA examined pharmacy availability of naloxone in California and Texas 24 and 32 months, respectively, after implementation of expanded access laws.

In California, just 23.5% of retail pharmacies were dispensing naloxone without a prescription 2 years later. In Texas, however, 83.7% of chain pharmacies with expanded access via standing order reported that they would dispense naloxone without prescription 32 months later.

In the first study, investigators conducted an anonymous telephone survey of a 20% representative sample of California pharmacies. Posing as potential customers, interviewers asked pharmacy staff whether naloxone was available at their pharmacy without a prescription. They also inquired about what formulations were available, price, and whether naloxone could be billed to insurance, wrote Talia Puzantian, PharmD, and James J. Gasper, PharmD.

Naloxone was available at 23.5% (95% confidence interval, 21.0%-26.0%) of the 1,147 pharmacies that provided data. Chain pharmacies were more likely to dispense naloxone (31.6%; 95% CI, 28.3%-35.1%) than were independent pharmacies (7.5%; 95% CI, 5.1%-10.6%; P less than .001). Of pharmacies dispensing naloxone, 50.6% had nasal naloxone in stock, and 59.9% correctly said that naloxone could be billed to insurance, reported Dr. Puzantian, of the Keck Graduate Institute School of Pharmacy in Claremont, Calif., and Dr. Gasper, of the department of family and community medicine at the University of California, San Francisco.

Reasons for low availability in California pharmacies might include lack of knowledge and training, stigma about substance use, and time, Dr. Puzantian and Dr. Gasper said.

“Whether naloxone will become more available with training of additional pharmacists and implementation of standardized policies by pharmacy chains needs to be studied,” the authors concluded.

The second study examined naloxone availability among Texas chain pharmacies with public implementation of standing orders, for a survey of 2,317 CVS, Walgreens, HEB, and Walmart pharmacies. Interviewers posed as potential overdose responders, and inquired about purchasing naloxone without a prescription, reported Kirk E. Evoy, PharmD, of the College of Pharmacy at the University of Texas at Austin, and his coauthors.

Of the pharmacies surveyed, 83.7% (95% CI, 82.2%-85.2%) said they would dispense naloxone without a prescription, and 76.4% (95% CI, 74.7%-78.1%) currently stocked naloxone.

In addition, 79.9% (95% CI, 78.3%-81.6%) would allow purchase of naloxone for someone else, though only 49.7% (95% CI, 47.8%-51.9%) would allow the purchase to be billed to a third-party buyer’s insurance, the authors noted.

Although this study found that most pharmacies would dispense naloxone without a prescription, the findings cannot be applied to independent pharmacies, Dr. Evoy and his colleagues noted.

“Consistent naloxone supply in all pharmacies, improved pharmacist understanding of naloxone standing orders, and ubiquitous insurance coverage for third-party purchasers may further improve access,” they wrote.

Dr. Puzantian and Dr. Gasper reported no disclosures. Dr. Evoy disclosed receiving grant funding from the Institute for Integration of Medicine and Science at the UT Health in San Antonio, the Kleberg Foundation, and Texas Health and Human Services. Other authors disclosed previous receipt of donations of branded formulations of naloxone from Kaléo Pharma and Adapt Pharma.

SOURCE: Puzantian T et al. and Evoy KE et al. JAMA 2018 Nov 13.320(18):1933-7.

ORLANDO – “Expect the unexpected” when considering the health impacts of climate change on children, Susan Pacheo, MD, advised in her presentation at the annual meeting of the American Academy of Pediatrics.

Jeff Craven/MDedge News

“We don’t know what we’re going to see, and we need to be ready,” said Dr. Pacheo of the University of Texas, Houston.

Climate change is categorized by an increase in droughts, fires, storms, floods, mudslides, and extreme temperatures. According to the Centers for Disease Control and Prevention, the impacts of climate change on human health are multiple, but can include an increased rate of infectious disease, respiratory conditions, injury, cardiovascular-related health issues, malnutrition, and mental health problems.

These problems can especially target children, Dr. Pacheo noted. “Kids are vulnerable. You’ve heard this, you’ve experienced this, you see this every day in your pediatric population.”

Children are more vulnerable because of the increased exposure they have to the environment. They spend more time outdoors, they are closer to the ground, and they are likely to put objects in their mouth. Children also tend to swallow more water when swimming, compared with adults. A 2014 study by de Man et al. found that children exposed to storm sewers and combined sewers swallowed 1.7 mL of water per exposure event and that the risk of infection from pathogens such as noroviruses, enteroviruses, Campylobacter jejuni, Cryptosporidium, and Giardia was 23%-33% per event, compared with 0.016 mL of water per exposure in adults and a mean infection risk of 0.58%-3.90% per event (Water Research. 2014 Jan 1. doi: 10.1016/j.watres.2013.09.022).

In addition, socioeconomic status and built environment as well as a child’s immature lung development and higher respiratory rate can lead to children being impacted by factors such as air pollution. Poverty, access to medical care, and the structure and dynamics of family also can affect children.

“We need to do something because this is a problem of social justice and we, as pediatricians, are advocates of the vulnerable,” Dr. Pacheo said.

Cade Martin, Dawn Arlotta, USCDC

Expect to see an increase in the number of vector-borne, airborne, and pollution-related disease, as well as water- and food-borne diseases, as a result of climate change, in addition to other issues such as hand, foot, and mouth disease and antibiotic resistance, she noted. As historically colder parts of the world continue to have milder winters, disease-carrying insects such as ticks and mosquitoes will expand their habitats and transmission of diseases such as Zika virus, malaria, dengue fever, and chikungunya will increase.

Leptospirosis and Naegleria fowleri, the latter which can cause primary amebic meningoencephalitis, are also becoming more common. Food-borne illnesses like vibriosis are being seen in more northern areas of the world like Alaska, and ciguatera fish poisoning is expected to be more prevalent in the southeastern United States and Gulf of Mexico, Dr. Pacheo said.

Air pollution carries a risk of respiratory diseases, pneumonia, and bronchiolitis, with a 2017 systematic review by Nhung et al. finding increased exposure to ambient air pollution markers such as sulfur dioxide, ozone, nitrogen dioxide, and carbon monoxide was associated with pneumonia in children (Environ Pollut. 2017 Jul 25. doi: 10.1016/j.envpol.2017.07.063). Coccidioidomycosis, or valley fever, is caused by inhaling a fungus in the soil and is associated with dust storms primarily in the southwestern United States. Warmer temperatures also have caused toxic algae blooms that have killed marine life and caused respiratory distress; children should not go near or play in water when algae blooms are growing, she noted.

Recent studies have linked an increase in temperature with incidence of Escherichia coli, with a 2016 study by Philipsborn et al. showing a 1° Celsius increase in mean monthly temperature was associated with an 8% increase in incidence of diarrheagenic E. coli (J Infect Dis. 2016 Feb 29. doi: 10.1093/infdis/jiw081). The incidence of hand, foot, and mouth disease also is linked to temperature and humidity, with a 2018 study by Cheng et al. showing a 1° Celsius increase in temperature and humidity was significantly associated with hand, foot, and mouth disease (Sci Total Environ. 2018 Jan 12. doi: 10.1016/j.scitotenv.2018.01.006). Rates of influenza are controlled by the changing environment as well, and increasing the number of vaccinations will help lower the number of influenza cases.

“We need to be advocates, we need to educate ourselves like we’re doing now so that we can educate our patients and to create a plan for preparedness,” Dr. Pacheo said.

She reported no relevant conflicts of interest.

ORLANDO – “Expect the unexpected” when considering the health impacts of climate change on children, Susan Pacheo, MD, advised in her presentation at the annual meeting of the American Academy of Pediatrics.

Jeff Craven/MDedge News

“We don’t know what we’re going to see, and we need to be ready,” said Dr. Pacheo of the University of Texas, Houston.

Climate change is categorized by an increase in droughts, fires, storms, floods, mudslides, and extreme temperatures. According to the Centers for Disease Control and Prevention, the impacts of climate change on human health are multiple, but can include an increased rate of infectious disease, respiratory conditions, injury, cardiovascular-related health issues, malnutrition, and mental health problems.

These problems can especially target children, Dr. Pacheo noted. “Kids are vulnerable. You’ve heard this, you’ve experienced this, you see this every day in your pediatric population.”

Children are more vulnerable because of the increased exposure they have to the environment. They spend more time outdoors, they are closer to the ground, and they are likely to put objects in their mouth. Children also tend to swallow more water when swimming, compared with adults. A 2014 study by de Man et al. found that children exposed to storm sewers and combined sewers swallowed 1.7 mL of water per exposure event and that the risk of infection from pathogens such as noroviruses, enteroviruses, Campylobacter jejuni, Cryptosporidium, and Giardia was 23%-33% per event, compared with 0.016 mL of water per exposure in adults and a mean infection risk of 0.58%-3.90% per event (Water Research. 2014 Jan 1. doi: 10.1016/j.watres.2013.09.022).

In addition, socioeconomic status and built environment as well as a child’s immature lung development and higher respiratory rate can lead to children being impacted by factors such as air pollution. Poverty, access to medical care, and the structure and dynamics of family also can affect children.

“We need to do something because this is a problem of social justice and we, as pediatricians, are advocates of the vulnerable,” Dr. Pacheo said.

Cade Martin, Dawn Arlotta, USCDC

Expect to see an increase in the number of vector-borne, airborne, and pollution-related disease, as well as water- and food-borne diseases, as a result of climate change, in addition to other issues such as hand, foot, and mouth disease and antibiotic resistance, she noted. As historically colder parts of the world continue to have milder winters, disease-carrying insects such as ticks and mosquitoes will expand their habitats and transmission of diseases such as Zika virus, malaria, dengue fever, and chikungunya will increase.

Leptospirosis and Naegleria fowleri, the latter which can cause primary amebic meningoencephalitis, are also becoming more common. Food-borne illnesses like vibriosis are being seen in more northern areas of the world like Alaska, and ciguatera fish poisoning is expected to be more prevalent in the southeastern United States and Gulf of Mexico, Dr. Pacheo said.

Air pollution carries a risk of respiratory diseases, pneumonia, and bronchiolitis, with a 2017 systematic review by Nhung et al. finding increased exposure to ambient air pollution markers such as sulfur dioxide, ozone, nitrogen dioxide, and carbon monoxide was associated with pneumonia in children (Environ Pollut. 2017 Jul 25. doi: 10.1016/j.envpol.2017.07.063). Coccidioidomycosis, or valley fever, is caused by inhaling a fungus in the soil and is associated with dust storms primarily in the southwestern United States. Warmer temperatures also have caused toxic algae blooms that have killed marine life and caused respiratory distress; children should not go near or play in water when algae blooms are growing, she noted.

Recent studies have linked an increase in temperature with incidence of Escherichia coli, with a 2016 study by Philipsborn et al. showing a 1° Celsius increase in mean monthly temperature was associated with an 8% increase in incidence of diarrheagenic E. coli (J Infect Dis. 2016 Feb 29. doi: 10.1093/infdis/jiw081). The incidence of hand, foot, and mouth disease also is linked to temperature and humidity, with a 2018 study by Cheng et al. showing a 1° Celsius increase in temperature and humidity was significantly associated with hand, foot, and mouth disease (Sci Total Environ. 2018 Jan 12. doi: 10.1016/j.scitotenv.2018.01.006). Rates of influenza are controlled by the changing environment as well, and increasing the number of vaccinations will help lower the number of influenza cases.

“We need to be advocates, we need to educate ourselves like we’re doing now so that we can educate our patients and to create a plan for preparedness,” Dr. Pacheo said.

She reported no relevant conflicts of interest.

ORLANDO – “Expect the unexpected” when considering the health impacts of climate change on children, Susan Pacheo, MD, advised in her presentation at the annual meeting of the American Academy of Pediatrics.

Jeff Craven/MDedge News

“We don’t know what we’re going to see, and we need to be ready,” said Dr. Pacheo of the University of Texas, Houston.

Climate change is categorized by an increase in droughts, fires, storms, floods, mudslides, and extreme temperatures. According to the Centers for Disease Control and Prevention, the impacts of climate change on human health are multiple, but can include an increased rate of infectious disease, respiratory conditions, injury, cardiovascular-related health issues, malnutrition, and mental health problems.

These problems can especially target children, Dr. Pacheo noted. “Kids are vulnerable. You’ve heard this, you’ve experienced this, you see this every day in your pediatric population.”

Children are more vulnerable because of the increased exposure they have to the environment. They spend more time outdoors, they are closer to the ground, and they are likely to put objects in their mouth. Children also tend to swallow more water when swimming, compared with adults. A 2014 study by de Man et al. found that children exposed to storm sewers and combined sewers swallowed 1.7 mL of water per exposure event and that the risk of infection from pathogens such as noroviruses, enteroviruses, Campylobacter jejuni, Cryptosporidium, and Giardia was 23%-33% per event, compared with 0.016 mL of water per exposure in adults and a mean infection risk of 0.58%-3.90% per event (Water Research. 2014 Jan 1. doi: 10.1016/j.watres.2013.09.022).

In addition, socioeconomic status and built environment as well as a child’s immature lung development and higher respiratory rate can lead to children being impacted by factors such as air pollution. Poverty, access to medical care, and the structure and dynamics of family also can affect children.

“We need to do something because this is a problem of social justice and we, as pediatricians, are advocates of the vulnerable,” Dr. Pacheo said.

Cade Martin, Dawn Arlotta, USCDC

Expect to see an increase in the number of vector-borne, airborne, and pollution-related disease, as well as water- and food-borne diseases, as a result of climate change, in addition to other issues such as hand, foot, and mouth disease and antibiotic resistance, she noted. As historically colder parts of the world continue to have milder winters, disease-carrying insects such as ticks and mosquitoes will expand their habitats and transmission of diseases such as Zika virus, malaria, dengue fever, and chikungunya will increase.

Leptospirosis and Naegleria fowleri, the latter which can cause primary amebic meningoencephalitis, are also becoming more common. Food-borne illnesses like vibriosis are being seen in more northern areas of the world like Alaska, and ciguatera fish poisoning is expected to be more prevalent in the southeastern United States and Gulf of Mexico, Dr. Pacheo said.

Air pollution carries a risk of respiratory diseases, pneumonia, and bronchiolitis, with a 2017 systematic review by Nhung et al. finding increased exposure to ambient air pollution markers such as sulfur dioxide, ozone, nitrogen dioxide, and carbon monoxide was associated with pneumonia in children (Environ Pollut. 2017 Jul 25. doi: 10.1016/j.envpol.2017.07.063). Coccidioidomycosis, or valley fever, is caused by inhaling a fungus in the soil and is associated with dust storms primarily in the southwestern United States. Warmer temperatures also have caused toxic algae blooms that have killed marine life and caused respiratory distress; children should not go near or play in water when algae blooms are growing, she noted.

Recent studies have linked an increase in temperature with incidence of Escherichia coli, with a 2016 study by Philipsborn et al. showing a 1° Celsius increase in mean monthly temperature was associated with an 8% increase in incidence of diarrheagenic E. coli (J Infect Dis. 2016 Feb 29. doi: 10.1093/infdis/jiw081). The incidence of hand, foot, and mouth disease also is linked to temperature and humidity, with a 2018 study by Cheng et al. showing a 1° Celsius increase in temperature and humidity was significantly associated with hand, foot, and mouth disease (Sci Total Environ. 2018 Jan 12. doi: 10.1016/j.scitotenv.2018.01.006). Rates of influenza are controlled by the changing environment as well, and increasing the number of vaccinations will help lower the number of influenza cases.

“We need to be advocates, we need to educate ourselves like we’re doing now so that we can educate our patients and to create a plan for preparedness,” Dr. Pacheo said.

She reported no relevant conflicts of interest.

SAN DIEGO – Fewer than a quarter of patients with signs of stage 3 chronic kidney disease (CKD) underwent follow-up testing within 1 year, even though most of these patients underwent repeat cholesterol screening during the same time.

Considering that CKD can be asymptomatic until the late stages, “this is a lost opportunity to get a proper evaluation by a nephrologist,” study coauthor and nephrologist Barbara S. Gillespie, MD, MMS, of Covance, the drug development business of LabCorp, said in an interview. Dr. Gillespie and her colleagues presented their findings at Kidney Week 2018, sponsored by the American Society of Nephrology.

More than 90% of patients with stages 1-3 CKD didn’t know they had the condition, based on 2013-2016 data gathered by the United States Renal Data System . Just 57% of those with stage 4 CKD were aware of their disease.

For the retrospective study, the researchers identified 4.9 million patients (58% were women; mean age was 71) who had estimated glomerular filtration rate (eGFR) results below 60 mL/min per 1.73 m² from 2011 to 2018, based on serum creatinine tests performed at least twice and at least 3 months apart by LabCorp. The researchers tracked the patients for a median 26 months.

Based on the initial results, 92% of the patients had stage 3 CKD, 6% had stage 4, and 2% had stage 5. However, at 1 year, the percentages of overall patients who underwent urine albumin/creatinine ratio, serum phosphorus, and plasma parathyroid hormone were 24%, 12%, and 17%, respectively, lead author Jennifer Ennis, MD, of LabCorp, said in an interview.

Kidney Disease Improving Global Outcomes guidelines from 2012 recommend “assessments of GFR and albuminuria at least annually ... and more often for individuals at higher risk of progression, and/or where measurement will impact therapeutic decisions” (Ann Intern Med. 2013 Jun 4;158[11]:825-30).

Yet 76% of these patients also underwent annual LDL cholesterol screening. “This suggests that the patients were receiving evaluation and treatment for other common conditions, but that CKD may not have been specifically addressed,” Dr. Ennis said.

SOURCE: Ennis JL et al. Kidney Week 2018, Abstract PUB111.

SAN DIEGO – Fewer than a quarter of patients with signs of stage 3 chronic kidney disease (CKD) underwent follow-up testing within 1 year, even though most of these patients underwent repeat cholesterol screening during the same time.

Considering that CKD can be asymptomatic until the late stages, “this is a lost opportunity to get a proper evaluation by a nephrologist,” study coauthor and nephrologist Barbara S. Gillespie, MD, MMS, of Covance, the drug development business of LabCorp, said in an interview. Dr. Gillespie and her colleagues presented their findings at Kidney Week 2018, sponsored by the American Society of Nephrology.

More than 90% of patients with stages 1-3 CKD didn’t know they had the condition, based on 2013-2016 data gathered by the United States Renal Data System . Just 57% of those with stage 4 CKD were aware of their disease.

For the retrospective study, the researchers identified 4.9 million patients (58% were women; mean age was 71) who had estimated glomerular filtration rate (eGFR) results below 60 mL/min per 1.73 m² from 2011 to 2018, based on serum creatinine tests performed at least twice and at least 3 months apart by LabCorp. The researchers tracked the patients for a median 26 months.

Based on the initial results, 92% of the patients had stage 3 CKD, 6% had stage 4, and 2% had stage 5. However, at 1 year, the percentages of overall patients who underwent urine albumin/creatinine ratio, serum phosphorus, and plasma parathyroid hormone were 24%, 12%, and 17%, respectively, lead author Jennifer Ennis, MD, of LabCorp, said in an interview.

Kidney Disease Improving Global Outcomes guidelines from 2012 recommend “assessments of GFR and albuminuria at least annually ... and more often for individuals at higher risk of progression, and/or where measurement will impact therapeutic decisions” (Ann Intern Med. 2013 Jun 4;158[11]:825-30).

Yet 76% of these patients also underwent annual LDL cholesterol screening. “This suggests that the patients were receiving evaluation and treatment for other common conditions, but that CKD may not have been specifically addressed,” Dr. Ennis said.

SOURCE: Ennis JL et al. Kidney Week 2018, Abstract PUB111.

SAN DIEGO – Fewer than a quarter of patients with signs of stage 3 chronic kidney disease (CKD) underwent follow-up testing within 1 year, even though most of these patients underwent repeat cholesterol screening during the same time.

Considering that CKD can be asymptomatic until the late stages, “this is a lost opportunity to get a proper evaluation by a nephrologist,” study coauthor and nephrologist Barbara S. Gillespie, MD, MMS, of Covance, the drug development business of LabCorp, said in an interview. Dr. Gillespie and her colleagues presented their findings at Kidney Week 2018, sponsored by the American Society of Nephrology.

More than 90% of patients with stages 1-3 CKD didn’t know they had the condition, based on 2013-2016 data gathered by the United States Renal Data System . Just 57% of those with stage 4 CKD were aware of their disease.

For the retrospective study, the researchers identified 4.9 million patients (58% were women; mean age was 71) who had estimated glomerular filtration rate (eGFR) results below 60 mL/min per 1.73 m² from 2011 to 2018, based on serum creatinine tests performed at least twice and at least 3 months apart by LabCorp. The researchers tracked the patients for a median 26 months.

Based on the initial results, 92% of the patients had stage 3 CKD, 6% had stage 4, and 2% had stage 5. However, at 1 year, the percentages of overall patients who underwent urine albumin/creatinine ratio, serum phosphorus, and plasma parathyroid hormone were 24%, 12%, and 17%, respectively, lead author Jennifer Ennis, MD, of LabCorp, said in an interview.

Kidney Disease Improving Global Outcomes guidelines from 2012 recommend “assessments of GFR and albuminuria at least annually ... and more often for individuals at higher risk of progression, and/or where measurement will impact therapeutic decisions” (Ann Intern Med. 2013 Jun 4;158[11]:825-30).

Yet 76% of these patients also underwent annual LDL cholesterol screening. “This suggests that the patients were receiving evaluation and treatment for other common conditions, but that CKD may not have been specifically addressed,” Dr. Ennis said.

SOURCE: Ennis JL et al. Kidney Week 2018, Abstract PUB111.

The INPACT SFA trial demonstrated the long-term safety of the IN.PACT Admiral drug-coated balloon (DCB) through 5 years, with no device-, procedure-, or paclitaxel-related deaths seen, coupled with continued low thrombosis rates throughout 5 years, according to John R. Laird, MD, of the Adventist Heart & Vascular Institute, St. Helena, Calif.

Dr. Laird presented the final, 5-year results of the combined INPACT SFA I and II trials at the 2018 Vascular Interventional Vascular Advances meeting.

The combined studies compared 220 patients treated with DCB and 111 treated with standard percutaneous transluminal angioplasty (PTA) who were followed out to 5 years. The patient population was 65% men, had a mean age of about 68 years, and none of the baseline characteristics followed were statistically significant between the treatment groups. The mean total lesion length treated was 8.9 cm for the DCB group and 8.8 cm for the PTA group, also a nonsignificant difference.

The primary efficacy endpoint for the study was primary patency within 12 months, defined as freedom from clinically driven target lesion revascularization (CD-TLR) and duplex ultrasound–derived restenosis. The primary safety endpoint was freedom from device-and procedure-related death through 30 days, and freedom from target limb major amputation and CD-TLR within 12 months.

Although there were no significant differences seen between DCB and placebo for CD-TLR or any TLR, there was a significant difference seen in the time to CD-TLR over 1,800 days: 808 days for DCB versus 475 days for placebo (P less than .001).

There were no significant differences seen between the DCB and placebo for any of the safety endpoint components over 5 years.

INPACT SFA was the “first independently adjudicated, blinded, randomized trial to demonstrate superior effectiveness of a drug-coated balloon through 5 years,” and the “results support DCB as a first-line strategy for the treatment of femoropopliteal disease,” Dr. Laird concluded.

The trial was sponsored by Medtronic Endovascular. Dr. Laird reported that he is a consultant/advisory board member for Abbott Vascular, Bard, Boston Scientific, and Medtronic.

[email protected]

The INPACT SFA trial demonstrated the long-term safety of the IN.PACT Admiral drug-coated balloon (DCB) through 5 years, with no device-, procedure-, or paclitaxel-related deaths seen, coupled with continued low thrombosis rates throughout 5 years, according to John R. Laird, MD, of the Adventist Heart & Vascular Institute, St. Helena, Calif.

Dr. Laird presented the final, 5-year results of the combined INPACT SFA I and II trials at the 2018 Vascular Interventional Vascular Advances meeting.

The combined studies compared 220 patients treated with DCB and 111 treated with standard percutaneous transluminal angioplasty (PTA) who were followed out to 5 years. The patient population was 65% men, had a mean age of about 68 years, and none of the baseline characteristics followed were statistically significant between the treatment groups. The mean total lesion length treated was 8.9 cm for the DCB group and 8.8 cm for the PTA group, also a nonsignificant difference.

The primary efficacy endpoint for the study was primary patency within 12 months, defined as freedom from clinically driven target lesion revascularization (CD-TLR) and duplex ultrasound–derived restenosis. The primary safety endpoint was freedom from device-and procedure-related death through 30 days, and freedom from target limb major amputation and CD-TLR within 12 months.

Although there were no significant differences seen between DCB and placebo for CD-TLR or any TLR, there was a significant difference seen in the time to CD-TLR over 1,800 days: 808 days for DCB versus 475 days for placebo (P less than .001).

There were no significant differences seen between the DCB and placebo for any of the safety endpoint components over 5 years.

INPACT SFA was the “first independently adjudicated, blinded, randomized trial to demonstrate superior effectiveness of a drug-coated balloon through 5 years,” and the “results support DCB as a first-line strategy for the treatment of femoropopliteal disease,” Dr. Laird concluded.

The trial was sponsored by Medtronic Endovascular. Dr. Laird reported that he is a consultant/advisory board member for Abbott Vascular, Bard, Boston Scientific, and Medtronic.

[email protected]

The INPACT SFA trial demonstrated the long-term safety of the IN.PACT Admiral drug-coated balloon (DCB) through 5 years, with no device-, procedure-, or paclitaxel-related deaths seen, coupled with continued low thrombosis rates throughout 5 years, according to John R. Laird, MD, of the Adventist Heart & Vascular Institute, St. Helena, Calif.

Dr. Laird presented the final, 5-year results of the combined INPACT SFA I and II trials at the 2018 Vascular Interventional Vascular Advances meeting.

The combined studies compared 220 patients treated with DCB and 111 treated with standard percutaneous transluminal angioplasty (PTA) who were followed out to 5 years. The patient population was 65% men, had a mean age of about 68 years, and none of the baseline characteristics followed were statistically significant between the treatment groups. The mean total lesion length treated was 8.9 cm for the DCB group and 8.8 cm for the PTA group, also a nonsignificant difference.

The primary efficacy endpoint for the study was primary patency within 12 months, defined as freedom from clinically driven target lesion revascularization (CD-TLR) and duplex ultrasound–derived restenosis. The primary safety endpoint was freedom from device-and procedure-related death through 30 days, and freedom from target limb major amputation and CD-TLR within 12 months.

Although there were no significant differences seen between DCB and placebo for CD-TLR or any TLR, there was a significant difference seen in the time to CD-TLR over 1,800 days: 808 days for DCB versus 475 days for placebo (P less than .001).

There were no significant differences seen between the DCB and placebo for any of the safety endpoint components over 5 years.

INPACT SFA was the “first independently adjudicated, blinded, randomized trial to demonstrate superior effectiveness of a drug-coated balloon through 5 years,” and the “results support DCB as a first-line strategy for the treatment of femoropopliteal disease,” Dr. Laird concluded.

The trial was sponsored by Medtronic Endovascular. Dr. Laird reported that he is a consultant/advisory board member for Abbott Vascular, Bard, Boston Scientific, and Medtronic.

[email protected]

Clinical question: Can an opiate-prescribing standard that favors oral and subcutaneous over intravenous administration reduce exposure to intravenous opiates for hospitalized adults?

Background: IV opiates, while effective for analgesia, may have a higher addictive potential because of the rapid and intermittent rises of peak concentrations. Subcutaneous and/or oral administration is a proven method of opioid delivery with similar bioavailability and efficacy of intravenous administration with more favorable pharmacokinetics.

Study design: Intervention-based quality improvement project.

Dr. Chowdury is an assistant professor in the division of hospital medicine, University of Colorado, Denver.

Clinical question: Can an opiate-prescribing standard that favors oral and subcutaneous over intravenous administration reduce exposure to intravenous opiates for hospitalized adults?

Background: IV opiates, while effective for analgesia, may have a higher addictive potential because of the rapid and intermittent rises of peak concentrations. Subcutaneous and/or oral administration is a proven method of opioid delivery with similar bioavailability and efficacy of intravenous administration with more favorable pharmacokinetics.

Study design: Intervention-based quality improvement project.

Dr. Chowdury is an assistant professor in the division of hospital medicine, University of Colorado, Denver.

Clinical question: Can an opiate-prescribing standard that favors oral and subcutaneous over intravenous administration reduce exposure to intravenous opiates for hospitalized adults?

Background: IV opiates, while effective for analgesia, may have a higher addictive potential because of the rapid and intermittent rises of peak concentrations. Subcutaneous and/or oral administration is a proven method of opioid delivery with similar bioavailability and efficacy of intravenous administration with more favorable pharmacokinetics.

Study design: Intervention-based quality improvement project.

Dr. Chowdury is an assistant professor in the division of hospital medicine, University of Colorado, Denver.

SAN DIEGO – The wider picture of the patient’s health and prognosis, not just chronologic age, should enter into the clinical decision to initiate dialysis, according to Bjorg Thorsteinsdottir, MD, a palliative care physician at the Mayo Clinic in Rochester, Minn.

“People perceive they have no choice [but treatment], and we perceive we have to do things to them until everything is lost, then we expect them to do a 180 [degree turn],” she said in a presentation at the meeting sponsored by the American Society of Nephrology.

“A 90-year-old fit individual, with minimal comorbidity living independently, would absolutely be a good candidate for dialysis, while a 75-year-old patient with bad peripheral vascular disease and dementia, living in a nursing home, would be unlikely to live longer on dialysis than off dialysis,” she said. “We need to weigh the risks and benefits for each individual patient against their goals and values. We need to be honest about the lack of benefit for certain subgroups of patients and the heavy treatment burdens of dialysis. Age, comorbidity, and frailty all factor into these deliberations and prognosis.”

More than 107,000 people over age 75 in the United States received dialysis in 2015, according to statistics gathered by the National Kidney Foundation. Yet the survival advantage of dialysis is more limited in elderly patients with multiple comorbidities, Dr. Thorsteinsdottir said. “It becomes important to think about the harms of treatment.”

A 2016 study from the Netherlands found no survival advantage to dialysis, compared with conservative management among kidney failure patients aged 80 and older. The survival advantage was limited with dialysis in patients aged 70 and older who also had multiple comorbidities. (Clin J Am Soc Nephrol. 2016 Apr;11(4):633-40)

In an interview, Dr. Thorsteinsdottir acknowledged that “determining who is unlikely to benefit from dialysis is complicated.” However, she said, “we know that the following comorbidities are the worst: dementia and peripheral vascular disease.”

“No one that I know of currently has an age cutoff for dialysis,” Dr. Thorsteinsdottir said in the interview, “and I do not believe the U.S. is ready for any kind of explicit limit setting by the government on dialysis treatment.”

“We must respond to legitimate concerns raised by recent studies that suggest that strong moral imperatives – to treat anyone we can treat – have created a situation where we are not pausing and asking hard questions about whether the patient in front of us is likely to benefit from dialysis,” she said in the interview. “Patients sense this and do not feel that they are given any alternatives to dialysis treatment. This needs to change.”

Dr. Thorsteinsdottir reported no relevant financial disclosures.

SAN DIEGO – The wider picture of the patient’s health and prognosis, not just chronologic age, should enter into the clinical decision to initiate dialysis, according to Bjorg Thorsteinsdottir, MD, a palliative care physician at the Mayo Clinic in Rochester, Minn.

“People perceive they have no choice [but treatment], and we perceive we have to do things to them until everything is lost, then we expect them to do a 180 [degree turn],” she said in a presentation at the meeting sponsored by the American Society of Nephrology.

“A 90-year-old fit individual, with minimal comorbidity living independently, would absolutely be a good candidate for dialysis, while a 75-year-old patient with bad peripheral vascular disease and dementia, living in a nursing home, would be unlikely to live longer on dialysis than off dialysis,” she said. “We need to weigh the risks and benefits for each individual patient against their goals and values. We need to be honest about the lack of benefit for certain subgroups of patients and the heavy treatment burdens of dialysis. Age, comorbidity, and frailty all factor into these deliberations and prognosis.”

More than 107,000 people over age 75 in the United States received dialysis in 2015, according to statistics gathered by the National Kidney Foundation. Yet the survival advantage of dialysis is more limited in elderly patients with multiple comorbidities, Dr. Thorsteinsdottir said. “It becomes important to think about the harms of treatment.”

A 2016 study from the Netherlands found no survival advantage to dialysis, compared with conservative management among kidney failure patients aged 80 and older. The survival advantage was limited with dialysis in patients aged 70 and older who also had multiple comorbidities. (Clin J Am Soc Nephrol. 2016 Apr;11(4):633-40)

In an interview, Dr. Thorsteinsdottir acknowledged that “determining who is unlikely to benefit from dialysis is complicated.” However, she said, “we know that the following comorbidities are the worst: dementia and peripheral vascular disease.”

“No one that I know of currently has an age cutoff for dialysis,” Dr. Thorsteinsdottir said in the interview, “and I do not believe the U.S. is ready for any kind of explicit limit setting by the government on dialysis treatment.”

“We must respond to legitimate concerns raised by recent studies that suggest that strong moral imperatives – to treat anyone we can treat – have created a situation where we are not pausing and asking hard questions about whether the patient in front of us is likely to benefit from dialysis,” she said in the interview. “Patients sense this and do not feel that they are given any alternatives to dialysis treatment. This needs to change.”

Dr. Thorsteinsdottir reported no relevant financial disclosures.

SAN DIEGO – The wider picture of the patient’s health and prognosis, not just chronologic age, should enter into the clinical decision to initiate dialysis, according to Bjorg Thorsteinsdottir, MD, a palliative care physician at the Mayo Clinic in Rochester, Minn.

“People perceive they have no choice [but treatment], and we perceive we have to do things to them until everything is lost, then we expect them to do a 180 [degree turn],” she said in a presentation at the meeting sponsored by the American Society of Nephrology.

“A 90-year-old fit individual, with minimal comorbidity living independently, would absolutely be a good candidate for dialysis, while a 75-year-old patient with bad peripheral vascular disease and dementia, living in a nursing home, would be unlikely to live longer on dialysis than off dialysis,” she said. “We need to weigh the risks and benefits for each individual patient against their goals and values. We need to be honest about the lack of benefit for certain subgroups of patients and the heavy treatment burdens of dialysis. Age, comorbidity, and frailty all factor into these deliberations and prognosis.”

More than 107,000 people over age 75 in the United States received dialysis in 2015, according to statistics gathered by the National Kidney Foundation. Yet the survival advantage of dialysis is more limited in elderly patients with multiple comorbidities, Dr. Thorsteinsdottir said. “It becomes important to think about the harms of treatment.”

A 2016 study from the Netherlands found no survival advantage to dialysis, compared with conservative management among kidney failure patients aged 80 and older. The survival advantage was limited with dialysis in patients aged 70 and older who also had multiple comorbidities. (Clin J Am Soc Nephrol. 2016 Apr;11(4):633-40)

In an interview, Dr. Thorsteinsdottir acknowledged that “determining who is unlikely to benefit from dialysis is complicated.” However, she said, “we know that the following comorbidities are the worst: dementia and peripheral vascular disease.”

“No one that I know of currently has an age cutoff for dialysis,” Dr. Thorsteinsdottir said in the interview, “and I do not believe the U.S. is ready for any kind of explicit limit setting by the government on dialysis treatment.”

“We must respond to legitimate concerns raised by recent studies that suggest that strong moral imperatives – to treat anyone we can treat – have created a situation where we are not pausing and asking hard questions about whether the patient in front of us is likely to benefit from dialysis,” she said in the interview. “Patients sense this and do not feel that they are given any alternatives to dialysis treatment. This needs to change.”

Dr. Thorsteinsdottir reported no relevant financial disclosures.

CHICAGO – New recognition of the prognostic value of cytogenetic factors, minimal residual disease activity, and Philadelphia chromosome–like signature could improve the treatment and outcomes of acute lymphoblastic leukemia (ALL), according to Anjali Advani, MD.

CD20

About 80% of ALL is B-cell ALL and the majority of patients have pre–B-cell ALL, Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic, said at the American Society of Hematology Meeting on Hematologic Malignancies.

“And on the B lymphoblast, many antigens are expressed, including CD19, CD20, and CD52,” she said.

Rituximab, a drug often used for the treatment of lymphoma, is a chimeric monoclonal antibody against the protein CD20, which is expressed in 41% of ALL patients.

“Interestingly, CD20 expression in ALL has been associated with an adverse prognostic impact, which suggests that targeting this may potentially improve outcomes in these patients,” Dr. Advani said.

In fact, a recent randomized study by Sébastien Maury, MD, of the University of Paris-Est, and his colleagues, demonstrated that adding 16-18 doses of rituximab to a Berlin-Frankfurt-Münster (BFM)–based chemotherapy in Philadelphia chromosome (Ph)–negative patients aged 18-59 years with CD20-positive pre–B-cell ALL improved 2-year event-free survival from 52% to 65%. The data are consistent with those from prior studies, including a German study that showed a higher degree of minimal residual disease (MRD) negativity in patients treated with rituximab, she noted (N Engl J Med 2016;375:1044-53).

While the study by Dr. Maury and his colleagues didn’t look at MRD, that may offer an explanation for the improved event-free survival in their study, Dr. Advani suggested.
 

MRD

Minimal residual disease has become a standard part of practice in ALL, but pediatric ALL led the way in using early MRD measurement for risk-stratifying therapy, and it has taken a bit longer for it to be incorporated in the adult disease realm, Dr. Advani said.

Either flow cytometry or polymerase chain reaction (PCR) amplification can be used to measure MRD, she noted.


In one of the larger studies done in adults, researchers used PCR to look at MRD at two time points and stratified patients into three risk groups, including low, intermediate, and high risk (Blood. 2006 Feb 1;107:1116-23).

Measuring MRD at those two time points “clearly separated the prognosis of patients not only in terms of disease-free survival but [in] overall survival,” she said. “So that’s why, for ALL, this has really become very important.”

In the United States, where flow-based cytometry is used more, it is necessary to find a properly equipped laboratory that can provide reliable results, she added. “For example, at our center we actually send our MRD to Fred Hutchinson [Cancer Center in Seattle].”

Johns Hopkins [Baltimore] also has such a lab, and both can arrange to accept send-outs, she said.

The other “really exciting thing” in regard to MRD in ALL is the recent approval of blinatumomab for MRD-positive ALL, she said.

In a study of 113 evaluable patients who were treated with the monoclonal antibody, 78% achieved complete molecular response (Blood. 2018 Apr 5;131:1522-31).

“And probably most importantly, when they looked at those patients who responded to blinatumomab in terms of MRD, these patients had, again, not only improved relapse-free survival but also increased overall survival,” she said. “I think this really explains why in ALL, we are measuring MRD and how it can really impact these patients.”

One of the remaining questions that will be important to address going forward is whether patients with MRD-positive ALL should continue to be considered for transplant; some of these studies have shown “very, very good outcomes” in patients who have not been transplanted, she noted.

Ph-like signature

Another important new prognostic feature in ALL is the presence of the Ph-like signature, a gene expression signature that was initially described in children with poor-risk ALL, and which looks a lot like Ph-positive disease.

“When they delved in further, they identified that this signature actually correlated with multiple different [kinase] fusions ... and it turns out that 20%-25% of young adults have this signature,” she said.

Since event-free survival in young adults with ALL is usually in the 65%-70% range, most of the remaining 30%-35% likely have this signature, she explained.

The kinase fusions associated with the Ph-like signature retain intact tyrosine kinase domains, and the spectrum of the fusions changes across age groups.


Treatments targeting some of these – for example, dasatinib for patients with a Ph-like dasatinib-sensitive kinase mutation – are being investigated.

Additionally, the Children’s Oncology Group has developed a clinically adaptable screening assay to identify the signature, she noted.

“So I would say that, and there is probably some difference in opinion, it is now becoming fairly standard that at diagnosis in an adult with ALL we’re sending the Ph-like signature,” she said. “And again, usually you’re going to have to send this out, and at our center we send it out to [Nationwide Children’s Hospital] in Columbus [Ohio].”

As important as it is to identify the Ph-like signature, given its association with poor prognosis, a number of questions remain, including whether transplant improves outcomes.

“The hope is it probably does, and that’s something that’s being evaluated in studies,” she said, noting that clinical studies are also specifically targeting these patients.

“So these patients should probably be enrolled on a clinical trial, because their outcome is clearly inferior,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

[email protected]

CHICAGO – New recognition of the prognostic value of cytogenetic factors, minimal residual disease activity, and Philadelphia chromosome–like signature could improve the treatment and outcomes of acute lymphoblastic leukemia (ALL), according to Anjali Advani, MD.

CD20

About 80% of ALL is B-cell ALL and the majority of patients have pre–B-cell ALL, Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic, said at the American Society of Hematology Meeting on Hematologic Malignancies.

“And on the B lymphoblast, many antigens are expressed, including CD19, CD20, and CD52,” she said.

Rituximab, a drug often used for the treatment of lymphoma, is a chimeric monoclonal antibody against the protein CD20, which is expressed in 41% of ALL patients.

“Interestingly, CD20 expression in ALL has been associated with an adverse prognostic impact, which suggests that targeting this may potentially improve outcomes in these patients,” Dr. Advani said.

In fact, a recent randomized study by Sébastien Maury, MD, of the University of Paris-Est, and his colleagues, demonstrated that adding 16-18 doses of rituximab to a Berlin-Frankfurt-Münster (BFM)–based chemotherapy in Philadelphia chromosome (Ph)–negative patients aged 18-59 years with CD20-positive pre–B-cell ALL improved 2-year event-free survival from 52% to 65%. The data are consistent with those from prior studies, including a German study that showed a higher degree of minimal residual disease (MRD) negativity in patients treated with rituximab, she noted (N Engl J Med 2016;375:1044-53).

While the study by Dr. Maury and his colleagues didn’t look at MRD, that may offer an explanation for the improved event-free survival in their study, Dr. Advani suggested.
 

MRD

Minimal residual disease has become a standard part of practice in ALL, but pediatric ALL led the way in using early MRD measurement for risk-stratifying therapy, and it has taken a bit longer for it to be incorporated in the adult disease realm, Dr. Advani said.

Either flow cytometry or polymerase chain reaction (PCR) amplification can be used to measure MRD, she noted.


In one of the larger studies done in adults, researchers used PCR to look at MRD at two time points and stratified patients into three risk groups, including low, intermediate, and high risk (Blood. 2006 Feb 1;107:1116-23).

Measuring MRD at those two time points “clearly separated the prognosis of patients not only in terms of disease-free survival but [in] overall survival,” she said. “So that’s why, for ALL, this has really become very important.”

In the United States, where flow-based cytometry is used more, it is necessary to find a properly equipped laboratory that can provide reliable results, she added. “For example, at our center we actually send our MRD to Fred Hutchinson [Cancer Center in Seattle].”

Johns Hopkins [Baltimore] also has such a lab, and both can arrange to accept send-outs, she said.

The other “really exciting thing” in regard to MRD in ALL is the recent approval of blinatumomab for MRD-positive ALL, she said.

In a study of 113 evaluable patients who were treated with the monoclonal antibody, 78% achieved complete molecular response (Blood. 2018 Apr 5;131:1522-31).

“And probably most importantly, when they looked at those patients who responded to blinatumomab in terms of MRD, these patients had, again, not only improved relapse-free survival but also increased overall survival,” she said. “I think this really explains why in ALL, we are measuring MRD and how it can really impact these patients.”

One of the remaining questions that will be important to address going forward is whether patients with MRD-positive ALL should continue to be considered for transplant; some of these studies have shown “very, very good outcomes” in patients who have not been transplanted, she noted.

Ph-like signature

Another important new prognostic feature in ALL is the presence of the Ph-like signature, a gene expression signature that was initially described in children with poor-risk ALL, and which looks a lot like Ph-positive disease.

“When they delved in further, they identified that this signature actually correlated with multiple different [kinase] fusions ... and it turns out that 20%-25% of young adults have this signature,” she said.

Since event-free survival in young adults with ALL is usually in the 65%-70% range, most of the remaining 30%-35% likely have this signature, she explained.

The kinase fusions associated with the Ph-like signature retain intact tyrosine kinase domains, and the spectrum of the fusions changes across age groups.


Treatments targeting some of these – for example, dasatinib for patients with a Ph-like dasatinib-sensitive kinase mutation – are being investigated.

Additionally, the Children’s Oncology Group has developed a clinically adaptable screening assay to identify the signature, she noted.

“So I would say that, and there is probably some difference in opinion, it is now becoming fairly standard that at diagnosis in an adult with ALL we’re sending the Ph-like signature,” she said. “And again, usually you’re going to have to send this out, and at our center we send it out to [Nationwide Children’s Hospital] in Columbus [Ohio].”

As important as it is to identify the Ph-like signature, given its association with poor prognosis, a number of questions remain, including whether transplant improves outcomes.

“The hope is it probably does, and that’s something that’s being evaluated in studies,” she said, noting that clinical studies are also specifically targeting these patients.

“So these patients should probably be enrolled on a clinical trial, because their outcome is clearly inferior,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

[email protected]

CHICAGO – New recognition of the prognostic value of cytogenetic factors, minimal residual disease activity, and Philadelphia chromosome–like signature could improve the treatment and outcomes of acute lymphoblastic leukemia (ALL), according to Anjali Advani, MD.

CD20

About 80% of ALL is B-cell ALL and the majority of patients have pre–B-cell ALL, Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic, said at the American Society of Hematology Meeting on Hematologic Malignancies.

“And on the B lymphoblast, many antigens are expressed, including CD19, CD20, and CD52,” she said.

Rituximab, a drug often used for the treatment of lymphoma, is a chimeric monoclonal antibody against the protein CD20, which is expressed in 41% of ALL patients.

“Interestingly, CD20 expression in ALL has been associated with an adverse prognostic impact, which suggests that targeting this may potentially improve outcomes in these patients,” Dr. Advani said.

In fact, a recent randomized study by Sébastien Maury, MD, of the University of Paris-Est, and his colleagues, demonstrated that adding 16-18 doses of rituximab to a Berlin-Frankfurt-Münster (BFM)–based chemotherapy in Philadelphia chromosome (Ph)–negative patients aged 18-59 years with CD20-positive pre–B-cell ALL improved 2-year event-free survival from 52% to 65%. The data are consistent with those from prior studies, including a German study that showed a higher degree of minimal residual disease (MRD) negativity in patients treated with rituximab, she noted (N Engl J Med 2016;375:1044-53).

While the study by Dr. Maury and his colleagues didn’t look at MRD, that may offer an explanation for the improved event-free survival in their study, Dr. Advani suggested.
 

MRD

Minimal residual disease has become a standard part of practice in ALL, but pediatric ALL led the way in using early MRD measurement for risk-stratifying therapy, and it has taken a bit longer for it to be incorporated in the adult disease realm, Dr. Advani said.

Either flow cytometry or polymerase chain reaction (PCR) amplification can be used to measure MRD, she noted.


In one of the larger studies done in adults, researchers used PCR to look at MRD at two time points and stratified patients into three risk groups, including low, intermediate, and high risk (Blood. 2006 Feb 1;107:1116-23).

Measuring MRD at those two time points “clearly separated the prognosis of patients not only in terms of disease-free survival but [in] overall survival,” she said. “So that’s why, for ALL, this has really become very important.”

In the United States, where flow-based cytometry is used more, it is necessary to find a properly equipped laboratory that can provide reliable results, she added. “For example, at our center we actually send our MRD to Fred Hutchinson [Cancer Center in Seattle].”

Johns Hopkins [Baltimore] also has such a lab, and both can arrange to accept send-outs, she said.

The other “really exciting thing” in regard to MRD in ALL is the recent approval of blinatumomab for MRD-positive ALL, she said.

In a study of 113 evaluable patients who were treated with the monoclonal antibody, 78% achieved complete molecular response (Blood. 2018 Apr 5;131:1522-31).

“And probably most importantly, when they looked at those patients who responded to blinatumomab in terms of MRD, these patients had, again, not only improved relapse-free survival but also increased overall survival,” she said. “I think this really explains why in ALL, we are measuring MRD and how it can really impact these patients.”

One of the remaining questions that will be important to address going forward is whether patients with MRD-positive ALL should continue to be considered for transplant; some of these studies have shown “very, very good outcomes” in patients who have not been transplanted, she noted.

Ph-like signature

Another important new prognostic feature in ALL is the presence of the Ph-like signature, a gene expression signature that was initially described in children with poor-risk ALL, and which looks a lot like Ph-positive disease.

“When they delved in further, they identified that this signature actually correlated with multiple different [kinase] fusions ... and it turns out that 20%-25% of young adults have this signature,” she said.

Since event-free survival in young adults with ALL is usually in the 65%-70% range, most of the remaining 30%-35% likely have this signature, she explained.

The kinase fusions associated with the Ph-like signature retain intact tyrosine kinase domains, and the spectrum of the fusions changes across age groups.


Treatments targeting some of these – for example, dasatinib for patients with a Ph-like dasatinib-sensitive kinase mutation – are being investigated.

Additionally, the Children’s Oncology Group has developed a clinically adaptable screening assay to identify the signature, she noted.

“So I would say that, and there is probably some difference in opinion, it is now becoming fairly standard that at diagnosis in an adult with ALL we’re sending the Ph-like signature,” she said. “And again, usually you’re going to have to send this out, and at our center we send it out to [Nationwide Children’s Hospital] in Columbus [Ohio].”

As important as it is to identify the Ph-like signature, given its association with poor prognosis, a number of questions remain, including whether transplant improves outcomes.

“The hope is it probably does, and that’s something that’s being evaluated in studies,” she said, noting that clinical studies are also specifically targeting these patients.

“So these patients should probably be enrolled on a clinical trial, because their outcome is clearly inferior,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

[email protected]

A practice-changing study on in-hospital initiation of sacubitril-valartan finds that the practice is safe and effective in acute decompensated heart failure. Also today, concussion or TBI early in life is linked to suicide risk later, revised cholesterol guidelines veer toward personalized risk assessment, and sibling violence is the most common form of family violence.

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Spotify

A practice-changing study on in-hospital initiation of sacubitril-valartan finds that the practice is safe and effective in acute decompensated heart failure. Also today, concussion or TBI early in life is linked to suicide risk later, revised cholesterol guidelines veer toward personalized risk assessment, and sibling violence is the most common form of family violence.

Amazon Alexa
Apple Podcasts
Spotify

A practice-changing study on in-hospital initiation of sacubitril-valartan finds that the practice is safe and effective in acute decompensated heart failure. Also today, concussion or TBI early in life is linked to suicide risk later, revised cholesterol guidelines veer toward personalized risk assessment, and sibling violence is the most common form of family violence.

Amazon Alexa
Apple Podcasts
Spotify

Photo by Neil Osterweil

BOSTON—A blood management program for patients undergoing hematopoietic stem cell transplant (HSCT) can reduce inappropriate transfusions and costs without compromising patient outcomes, a new study suggests.

Researchers retrospectively compared outcomes before and after implementation of a patient blood management (PBM) program at a single institution.

After the program was implemented, the number of transfusions and the units transfused declined without affecting patient mortality, intensive care unit (ICU) admission rates, or other transfusion-related complications.

In addition, the program saved the hospital more than $600,000 over a year.

Nilesh Jambhekar, MD, of the Mayo Clinic in Rochester, Minnesota, reported these results in a presentation at AABB 2018 (abstract PBM3-ST4-22*).

Study design

Dr. Jambhekar and his colleagues looked at blood product use both before and after the Mayo Clinic started a PBM program that included emphasis on AABB best practice guidelines and electronic clinical-decision support for transfusion orders.

The researchers evaluated the frequency and proportion of red blood cell (RBC) and platelet transfusions, total transfusion quantities, transfusions that occurred outside of the clinical guidelines, and the activity-based costs of transfusions.

Dr. Jambhekar acknowledged that the study relied on rigid hemoglobin and platelet thresholds when considering transfusions conducted outside of the guidelines, defined as RBCs administered for hemoglobin values greater than 7 g/dL and platelet transfusions for platelet counts greater than 10 x 10⁹/L.

He noted, however, that the researchers conducted sensitivity analyses to account for exceptions such as patients with coronary disease or neutropenic fever.

The patient-centered outcomes the researchers evaluated included mortality, hospital and ICU admission rates, transfusion reactions, cerebrovascular and coronary ischemic events, and infections.

The study included data on 360 adults older than 18 who underwent HSCT in 2013, before the PBM program was implemented, and 368 transplanted in 2015, after implementation.

In each cohort, patients were followed out to 90 days after transplant.

Results

The total number of platelet units transfused dropped from 1,660 pre-PBM program to 1,417 post-PBM implementation. The total number of RBC units dropped from 1,158 to 826.

The researchers also saw changes in the proportions of inappropriate (outside guidelines) transfusions between the two time periods.

In 2013, 94.2% of RBC transfusions occurred outside the guidelines, compared with 35.4% in 2015 (P<0.0001). Similarly, the proportion of inappropriate platelet transfusions declined from 73.4% to 48.7% over the same time period (P<0.0001).

In addition, all-cause mortality at 3 months was significantly lower after the PBM program was introduced. The 3-month mortality rate was 30.7% for the 2013 cohort and 20.2% for the 2015 cohort (P=0.001).

Dr. Jambhekar noted that, in a multivariable analysis accounting for baseline differences between the groups, mortality for patients treated before the PBM program remained significantly higher, with an odds ratio of 1.85 (P=0.0008).

Neither hospital nor ICU admission within 30 days differed significantly between the groups, and there were no significant between-group differences in hospital or ICU lengths of stay.

Likewise, there were no significant between-group differences in myocardial infarctions, cerebrovascular events, sepsis, and febrile or allergic transfusion reactions.

Dr. Jambhekar noted that this study was retrospective in design and therefore could not fully account for potential confounders. It’s also unclear whether the results could be generalized for adoption by other institutions.

“In general, PBM implementation is probably helpful in reducing both platelet and PRBC [packed red blood cell] utilization, but it’s not an easy thing to do,” Dr. Jambhekar said.

“It requires institutional buy-in and key players to make it happen. Ongoing PBM-related activities like surveillance, education, and clinical decision feedback are critical to maintaining success that we’ve had.”

This study was internally funded. Dr. Jambhekar reported having nothing to disclose.

*Data presented differ from the abstract.

Photo by Neil Osterweil

BOSTON—A blood management program for patients undergoing hematopoietic stem cell transplant (HSCT) can reduce inappropriate transfusions and costs without compromising patient outcomes, a new study suggests.

Researchers retrospectively compared outcomes before and after implementation of a patient blood management (PBM) program at a single institution.

After the program was implemented, the number of transfusions and the units transfused declined without affecting patient mortality, intensive care unit (ICU) admission rates, or other transfusion-related complications.

In addition, the program saved the hospital more than $600,000 over a year.

Nilesh Jambhekar, MD, of the Mayo Clinic in Rochester, Minnesota, reported these results in a presentation at AABB 2018 (abstract PBM3-ST4-22*).

Study design

Dr. Jambhekar and his colleagues looked at blood product use both before and after the Mayo Clinic started a PBM program that included emphasis on AABB best practice guidelines and electronic clinical-decision support for transfusion orders.

The researchers evaluated the frequency and proportion of red blood cell (RBC) and platelet transfusions, total transfusion quantities, transfusions that occurred outside of the clinical guidelines, and the activity-based costs of transfusions.

Dr. Jambhekar acknowledged that the study relied on rigid hemoglobin and platelet thresholds when considering transfusions conducted outside of the guidelines, defined as RBCs administered for hemoglobin values greater than 7 g/dL and platelet transfusions for platelet counts greater than 10 x 10⁹/L.

He noted, however, that the researchers conducted sensitivity analyses to account for exceptions such as patients with coronary disease or neutropenic fever.

The patient-centered outcomes the researchers evaluated included mortality, hospital and ICU admission rates, transfusion reactions, cerebrovascular and coronary ischemic events, and infections.

The study included data on 360 adults older than 18 who underwent HSCT in 2013, before the PBM program was implemented, and 368 transplanted in 2015, after implementation.

In each cohort, patients were followed out to 90 days after transplant.

Results

The total number of platelet units transfused dropped from 1,660 pre-PBM program to 1,417 post-PBM implementation. The total number of RBC units dropped from 1,158 to 826.

The researchers also saw changes in the proportions of inappropriate (outside guidelines) transfusions between the two time periods.

In 2013, 94.2% of RBC transfusions occurred outside the guidelines, compared with 35.4% in 2015 (P<0.0001). Similarly, the proportion of inappropriate platelet transfusions declined from 73.4% to 48.7% over the same time period (P<0.0001).

In addition, all-cause mortality at 3 months was significantly lower after the PBM program was introduced. The 3-month mortality rate was 30.7% for the 2013 cohort and 20.2% for the 2015 cohort (P=0.001).

Dr. Jambhekar noted that, in a multivariable analysis accounting for baseline differences between the groups, mortality for patients treated before the PBM program remained significantly higher, with an odds ratio of 1.85 (P=0.0008).

Neither hospital nor ICU admission within 30 days differed significantly between the groups, and there were no significant between-group differences in hospital or ICU lengths of stay.

Likewise, there were no significant between-group differences in myocardial infarctions, cerebrovascular events, sepsis, and febrile or allergic transfusion reactions.

Dr. Jambhekar noted that this study was retrospective in design and therefore could not fully account for potential confounders. It’s also unclear whether the results could be generalized for adoption by other institutions.

“In general, PBM implementation is probably helpful in reducing both platelet and PRBC [packed red blood cell] utilization, but it’s not an easy thing to do,” Dr. Jambhekar said.

“It requires institutional buy-in and key players to make it happen. Ongoing PBM-related activities like surveillance, education, and clinical decision feedback are critical to maintaining success that we’ve had.”

This study was internally funded. Dr. Jambhekar reported having nothing to disclose.

*Data presented differ from the abstract.

Photo by Neil Osterweil

BOSTON—A blood management program for patients undergoing hematopoietic stem cell transplant (HSCT) can reduce inappropriate transfusions and costs without compromising patient outcomes, a new study suggests.

Researchers retrospectively compared outcomes before and after implementation of a patient blood management (PBM) program at a single institution.

After the program was implemented, the number of transfusions and the units transfused declined without affecting patient mortality, intensive care unit (ICU) admission rates, or other transfusion-related complications.

In addition, the program saved the hospital more than $600,000 over a year.

Nilesh Jambhekar, MD, of the Mayo Clinic in Rochester, Minnesota, reported these results in a presentation at AABB 2018 (abstract PBM3-ST4-22*).

Study design

Dr. Jambhekar and his colleagues looked at blood product use both before and after the Mayo Clinic started a PBM program that included emphasis on AABB best practice guidelines and electronic clinical-decision support for transfusion orders.

The researchers evaluated the frequency and proportion of red blood cell (RBC) and platelet transfusions, total transfusion quantities, transfusions that occurred outside of the clinical guidelines, and the activity-based costs of transfusions.

Dr. Jambhekar acknowledged that the study relied on rigid hemoglobin and platelet thresholds when considering transfusions conducted outside of the guidelines, defined as RBCs administered for hemoglobin values greater than 7 g/dL and platelet transfusions for platelet counts greater than 10 x 10⁹/L.

He noted, however, that the researchers conducted sensitivity analyses to account for exceptions such as patients with coronary disease or neutropenic fever.

The patient-centered outcomes the researchers evaluated included mortality, hospital and ICU admission rates, transfusion reactions, cerebrovascular and coronary ischemic events, and infections.

The study included data on 360 adults older than 18 who underwent HSCT in 2013, before the PBM program was implemented, and 368 transplanted in 2015, after implementation.

In each cohort, patients were followed out to 90 days after transplant.

Results

The total number of platelet units transfused dropped from 1,660 pre-PBM program to 1,417 post-PBM implementation. The total number of RBC units dropped from 1,158 to 826.

The researchers also saw changes in the proportions of inappropriate (outside guidelines) transfusions between the two time periods.

In 2013, 94.2% of RBC transfusions occurred outside the guidelines, compared with 35.4% in 2015 (P<0.0001). Similarly, the proportion of inappropriate platelet transfusions declined from 73.4% to 48.7% over the same time period (P<0.0001).

In addition, all-cause mortality at 3 months was significantly lower after the PBM program was introduced. The 3-month mortality rate was 30.7% for the 2013 cohort and 20.2% for the 2015 cohort (P=0.001).

Dr. Jambhekar noted that, in a multivariable analysis accounting for baseline differences between the groups, mortality for patients treated before the PBM program remained significantly higher, with an odds ratio of 1.85 (P=0.0008).

Neither hospital nor ICU admission within 30 days differed significantly between the groups, and there were no significant between-group differences in hospital or ICU lengths of stay.

Likewise, there were no significant between-group differences in myocardial infarctions, cerebrovascular events, sepsis, and febrile or allergic transfusion reactions.

Dr. Jambhekar noted that this study was retrospective in design and therefore could not fully account for potential confounders. It’s also unclear whether the results could be generalized for adoption by other institutions.

“In general, PBM implementation is probably helpful in reducing both platelet and PRBC [packed red blood cell] utilization, but it’s not an easy thing to do,” Dr. Jambhekar said.

“It requires institutional buy-in and key players to make it happen. Ongoing PBM-related activities like surveillance, education, and clinical decision feedback are critical to maintaining success that we’ve had.”

This study was internally funded. Dr. Jambhekar reported having nothing to disclose.

*Data presented differ from the abstract.

Image from Armed Forces Institute of Pathology

The AP-1 transcription factor family is of “major importance” in acute myeloid leukemia (AML), according to researchers.

The team said they identified transcription factor networks specific to AML subtypes, which showed that leukemic growth is dependent upon certain transcription factors, and “the global activation of signaling pathways parallels a growth dependence on AP-1 activity in multiple types of AML.”

Constanze Bonifer, PhD, of the University of Birmingham in the U.K., and her colleagues conducted this research and detailed their findings in Nature Genetics.

The researchers noted that previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA methylation patterns.

“Our work now defines these networks in detail and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” Dr. Bonifer and her colleagues wrote.

The researchers combined data obtained via several analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from AML patients with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.

The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the team reported.

Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.

In the in vitro study, the researchers transduced AML cells with a doxycycline-inducible version of a dominant-negative (dn) FOS protein.

“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB, and JDP families of transcription factors,” the researchers wrote. “[T]hus, it is challenging to target by defined RNA interference approaches.”

Results of the in vitro study showed that induction of dnFOS, mediated by doxycycline, inhibited proliferation of t(8;21)+ Kasumi-1 cells and FLT3-ITD-expressing MV4-11 cells.

Induction of dnFOS also inhibited the colony-forming ability of primary CD34+ FLT3-ITD cells but not CD34+ hematopoietic stem and progenitor cells.

To evaluate the relevance of AP-1 for leukemia propagation in vivo, the researchers transplanted either of two cell lines—Kasumi-1 or MV4-11—expressing inducible dnFOS in immunodeficient mice.

With Kasumi-1, granulosarcomas developed in six of seven untreated control mice and two mice treated with doxycycline, neither of which expressed the inducible protein.

With MV4-11, doxycycline inhibited leukemia development, and untreated mice rapidly developed tumors.

The researchers declared no competing interests related to this work, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship, and an MRC/Leuka Clinical Training Fellowship.

Image from Armed Forces Institute of Pathology

The AP-1 transcription factor family is of “major importance” in acute myeloid leukemia (AML), according to researchers.

The team said they identified transcription factor networks specific to AML subtypes, which showed that leukemic growth is dependent upon certain transcription factors, and “the global activation of signaling pathways parallels a growth dependence on AP-1 activity in multiple types of AML.”

Constanze Bonifer, PhD, of the University of Birmingham in the U.K., and her colleagues conducted this research and detailed their findings in Nature Genetics.

The researchers noted that previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA methylation patterns.

“Our work now defines these networks in detail and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” Dr. Bonifer and her colleagues wrote.

The researchers combined data obtained via several analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from AML patients with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.

The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the team reported.

Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.

In the in vitro study, the researchers transduced AML cells with a doxycycline-inducible version of a dominant-negative (dn) FOS protein.

“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB, and JDP families of transcription factors,” the researchers wrote. “[T]hus, it is challenging to target by defined RNA interference approaches.”

Results of the in vitro study showed that induction of dnFOS, mediated by doxycycline, inhibited proliferation of t(8;21)+ Kasumi-1 cells and FLT3-ITD-expressing MV4-11 cells.

Induction of dnFOS also inhibited the colony-forming ability of primary CD34+ FLT3-ITD cells but not CD34+ hematopoietic stem and progenitor cells.

To evaluate the relevance of AP-1 for leukemia propagation in vivo, the researchers transplanted either of two cell lines—Kasumi-1 or MV4-11—expressing inducible dnFOS in immunodeficient mice.

With Kasumi-1, granulosarcomas developed in six of seven untreated control mice and two mice treated with doxycycline, neither of which expressed the inducible protein.

With MV4-11, doxycycline inhibited leukemia development, and untreated mice rapidly developed tumors.

The researchers declared no competing interests related to this work, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship, and an MRC/Leuka Clinical Training Fellowship.

Image from Armed Forces Institute of Pathology

The AP-1 transcription factor family is of “major importance” in acute myeloid leukemia (AML), according to researchers.

The team said they identified transcription factor networks specific to AML subtypes, which showed that leukemic growth is dependent upon certain transcription factors, and “the global activation of signaling pathways parallels a growth dependence on AP-1 activity in multiple types of AML.”

Constanze Bonifer, PhD, of the University of Birmingham in the U.K., and her colleagues conducted this research and detailed their findings in Nature Genetics.

The researchers noted that previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA methylation patterns.

“Our work now defines these networks in detail and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” Dr. Bonifer and her colleagues wrote.

The researchers combined data obtained via several analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from AML patients with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.

The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the team reported.

Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.

In the in vitro study, the researchers transduced AML cells with a doxycycline-inducible version of a dominant-negative (dn) FOS protein.

“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB, and JDP families of transcription factors,” the researchers wrote. “[T]hus, it is challenging to target by defined RNA interference approaches.”

Results of the in vitro study showed that induction of dnFOS, mediated by doxycycline, inhibited proliferation of t(8;21)+ Kasumi-1 cells and FLT3-ITD-expressing MV4-11 cells.

Induction of dnFOS also inhibited the colony-forming ability of primary CD34+ FLT3-ITD cells but not CD34+ hematopoietic stem and progenitor cells.

To evaluate the relevance of AP-1 for leukemia propagation in vivo, the researchers transplanted either of two cell lines—Kasumi-1 or MV4-11—expressing inducible dnFOS in immunodeficient mice.

With Kasumi-1, granulosarcomas developed in six of seven untreated control mice and two mice treated with doxycycline, neither of which expressed the inducible protein.

With MV4-11, doxycycline inhibited leukemia development, and untreated mice rapidly developed tumors.

The researchers declared no competing interests related to this work, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship, and an MRC/Leuka Clinical Training Fellowship.