HT Staff

Warfarin tablets

Results of a large analysis suggest the latest guidelines for atrial fibrillation (AF) recommend anticoagulant therapy for nearly all women with AF and AF patients older than 65.

In 2014, the American Heart Association, American College of Cardiology, and Heart Rhythm Society issued broader guidelines for the use of anticoagulants in AF patients.

A group of researchers wanted to assess how these guidelines would change the use of anticoagulant therapy.

So they evaluated patients enrolled in the ORBIT-AF study, comparing how recommendations from the 2011 AF guidelines and the guidelines issued in 2014 would affect these patients.

Emily O’Brien, PhD, of the Duke Clinical Research Institute in Durham, North Carolina, and her colleagues conducted this research and described their findings in a letter to JAMA Internal Medicine.

The ORBIT-AF study included 10,132 AF patients from 176 sites across the US. Available data included patients’ age, gender, and risk factors such as prior congestive heart failure, high blood pressure, diabetes, and prior stroke.

The researchers found the overall proportion of AF patients recommended for anticoagulants increased from about 72% of patients with the 2011 guidelines to 91% with the newer guidelines.

A similar increase occurred for women with AF. Under the previous guidelines, anticoagulants would have been recommended for about 77% of female AF patients in the study population. Under the new guidelines, 98% of women in the sample population would have enough risk factors to qualify for treatment.

The 2014 guidelines also lower the age at which patients are considered at risk for stroke from 75 to 65.

In the study population, this meant that anticoagulant therapy would be recommended for almost 99% of patients with AF who were older than 65, compared to roughly 80% whose stroke risk was severe enough under the previous criteria.

“The full adoption of the guidelines could reclassify nearly 1 million people with AFib who previously weren’t recommended for treatment with blood thinners,” Dr O’Brien said.

“What we don’t know yet is the extent to which doctors in community practice will incorporate the guidelines into their clinical routines and what that will mean for the long-term outcomes for those patients. That will be the next step for our study.”

Warfarin tablets

Results of a large analysis suggest the latest guidelines for atrial fibrillation (AF) recommend anticoagulant therapy for nearly all women with AF and AF patients older than 65.

In 2014, the American Heart Association, American College of Cardiology, and Heart Rhythm Society issued broader guidelines for the use of anticoagulants in AF patients.

A group of researchers wanted to assess how these guidelines would change the use of anticoagulant therapy.

So they evaluated patients enrolled in the ORBIT-AF study, comparing how recommendations from the 2011 AF guidelines and the guidelines issued in 2014 would affect these patients.

Emily O’Brien, PhD, of the Duke Clinical Research Institute in Durham, North Carolina, and her colleagues conducted this research and described their findings in a letter to JAMA Internal Medicine.

The ORBIT-AF study included 10,132 AF patients from 176 sites across the US. Available data included patients’ age, gender, and risk factors such as prior congestive heart failure, high blood pressure, diabetes, and prior stroke.

The researchers found the overall proportion of AF patients recommended for anticoagulants increased from about 72% of patients with the 2011 guidelines to 91% with the newer guidelines.

A similar increase occurred for women with AF. Under the previous guidelines, anticoagulants would have been recommended for about 77% of female AF patients in the study population. Under the new guidelines, 98% of women in the sample population would have enough risk factors to qualify for treatment.

The 2014 guidelines also lower the age at which patients are considered at risk for stroke from 75 to 65.

In the study population, this meant that anticoagulant therapy would be recommended for almost 99% of patients with AF who were older than 65, compared to roughly 80% whose stroke risk was severe enough under the previous criteria.

“The full adoption of the guidelines could reclassify nearly 1 million people with AFib who previously weren’t recommended for treatment with blood thinners,” Dr O’Brien said.

“What we don’t know yet is the extent to which doctors in community practice will incorporate the guidelines into their clinical routines and what that will mean for the long-term outcomes for those patients. That will be the next step for our study.”

Warfarin tablets

Results of a large analysis suggest the latest guidelines for atrial fibrillation (AF) recommend anticoagulant therapy for nearly all women with AF and AF patients older than 65.

In 2014, the American Heart Association, American College of Cardiology, and Heart Rhythm Society issued broader guidelines for the use of anticoagulants in AF patients.

A group of researchers wanted to assess how these guidelines would change the use of anticoagulant therapy.

So they evaluated patients enrolled in the ORBIT-AF study, comparing how recommendations from the 2011 AF guidelines and the guidelines issued in 2014 would affect these patients.

Emily O’Brien, PhD, of the Duke Clinical Research Institute in Durham, North Carolina, and her colleagues conducted this research and described their findings in a letter to JAMA Internal Medicine.

The ORBIT-AF study included 10,132 AF patients from 176 sites across the US. Available data included patients’ age, gender, and risk factors such as prior congestive heart failure, high blood pressure, diabetes, and prior stroke.

The researchers found the overall proportion of AF patients recommended for anticoagulants increased from about 72% of patients with the 2011 guidelines to 91% with the newer guidelines.

A similar increase occurred for women with AF. Under the previous guidelines, anticoagulants would have been recommended for about 77% of female AF patients in the study population. Under the new guidelines, 98% of women in the sample population would have enough risk factors to qualify for treatment.

The 2014 guidelines also lower the age at which patients are considered at risk for stroke from 75 to 65.

In the study population, this meant that anticoagulant therapy would be recommended for almost 99% of patients with AF who were older than 65, compared to roughly 80% whose stroke risk was severe enough under the previous criteria.

“The full adoption of the guidelines could reclassify nearly 1 million people with AFib who previously weren’t recommended for treatment with blood thinners,” Dr O’Brien said.

“What we don’t know yet is the extent to which doctors in community practice will incorporate the guidelines into their clinical routines and what that will mean for the long-term outcomes for those patients. That will be the next step for our study.”

Cell culture

ATLANTA—Interventional radiologists say they’ve successfully used 3D printers to develop personalized medical devices that can deliver antibiotics and chemotherapy in a targeted manner in vitro.

Researchers and engineers collaborated to print catheters, stents, and filaments that were bioactive, giving these devices the ability to deliver antibiotics and chemotherapeutic medications to a targeted area in cell cultures.

Horacio R. D’Agostino, MD, of Louisiana State University Health Sciences Center in Shreveport, discussed this work at the 2015 Society of Interventional Radiology’s Annual Scientific Meeting (abstract 13).

“3D printing allows for tailor-made materials for personalized medicine,” Dr D’Agostino said. “It gives us the ability to construct devices that meet patients’ needs, from their unique anatomy to specific medicine requirements. And as tools in interventional radiology, these devices are part of treatment options that are less invasive than traditional surgery.”

Using 3D printing technology and resorbable bioplastics, Dr D’Agostino and his colleagues developed bioactive filaments, chemotherapy beads, and catheters and stents containing antibiotics or chemotherapeutic agents.

The team then tested these devices in cell cultures. They found the antibiotic-containing catheters inhibited E coli growth, and filaments carrying chemotherapeutic agents inhibited the growth of osteosarcoma cells.

“We treat a wide variety of patients and, with some patients, the current one-size-fits-all devices are not an option,” Dr D’Agostino noted. “3D printing gives us the ability to craft devices that are better suited for certain patient populations that are traditionally tough to treat, such as children and the obese, who have different anatomy. There’s limitless potential to be explored with this technology.”

The researchers were also able to print biodegradable filaments, catheters, and stents that contain antibiotics and chemotherapeutic agents. These devices might help patients avoid the need to undergo a second procedure or treatment to remove or destroy the delivery vehicle.

Dr D’Agostino said this early success with 3D-printed instruments in the lab warrants further studies, with the goal of receiving approval to use these devices in humans. He also sees an opportunity to collaborate with other medical specialties to deliver higher-quality, personalized care to all types of patients.

Cell culture

ATLANTA—Interventional radiologists say they’ve successfully used 3D printers to develop personalized medical devices that can deliver antibiotics and chemotherapy in a targeted manner in vitro.

Researchers and engineers collaborated to print catheters, stents, and filaments that were bioactive, giving these devices the ability to deliver antibiotics and chemotherapeutic medications to a targeted area in cell cultures.

Horacio R. D’Agostino, MD, of Louisiana State University Health Sciences Center in Shreveport, discussed this work at the 2015 Society of Interventional Radiology’s Annual Scientific Meeting (abstract 13).

“3D printing allows for tailor-made materials for personalized medicine,” Dr D’Agostino said. “It gives us the ability to construct devices that meet patients’ needs, from their unique anatomy to specific medicine requirements. And as tools in interventional radiology, these devices are part of treatment options that are less invasive than traditional surgery.”

Using 3D printing technology and resorbable bioplastics, Dr D’Agostino and his colleagues developed bioactive filaments, chemotherapy beads, and catheters and stents containing antibiotics or chemotherapeutic agents.

The team then tested these devices in cell cultures. They found the antibiotic-containing catheters inhibited E coli growth, and filaments carrying chemotherapeutic agents inhibited the growth of osteosarcoma cells.

“We treat a wide variety of patients and, with some patients, the current one-size-fits-all devices are not an option,” Dr D’Agostino noted. “3D printing gives us the ability to craft devices that are better suited for certain patient populations that are traditionally tough to treat, such as children and the obese, who have different anatomy. There’s limitless potential to be explored with this technology.”

The researchers were also able to print biodegradable filaments, catheters, and stents that contain antibiotics and chemotherapeutic agents. These devices might help patients avoid the need to undergo a second procedure or treatment to remove or destroy the delivery vehicle.

Dr D’Agostino said this early success with 3D-printed instruments in the lab warrants further studies, with the goal of receiving approval to use these devices in humans. He also sees an opportunity to collaborate with other medical specialties to deliver higher-quality, personalized care to all types of patients.

Cell culture

ATLANTA—Interventional radiologists say they’ve successfully used 3D printers to develop personalized medical devices that can deliver antibiotics and chemotherapy in a targeted manner in vitro.

Researchers and engineers collaborated to print catheters, stents, and filaments that were bioactive, giving these devices the ability to deliver antibiotics and chemotherapeutic medications to a targeted area in cell cultures.

Horacio R. D’Agostino, MD, of Louisiana State University Health Sciences Center in Shreveport, discussed this work at the 2015 Society of Interventional Radiology’s Annual Scientific Meeting (abstract 13).

“3D printing allows for tailor-made materials for personalized medicine,” Dr D’Agostino said. “It gives us the ability to construct devices that meet patients’ needs, from their unique anatomy to specific medicine requirements. And as tools in interventional radiology, these devices are part of treatment options that are less invasive than traditional surgery.”

Using 3D printing technology and resorbable bioplastics, Dr D’Agostino and his colleagues developed bioactive filaments, chemotherapy beads, and catheters and stents containing antibiotics or chemotherapeutic agents.

The team then tested these devices in cell cultures. They found the antibiotic-containing catheters inhibited E coli growth, and filaments carrying chemotherapeutic agents inhibited the growth of osteosarcoma cells.

“We treat a wide variety of patients and, with some patients, the current one-size-fits-all devices are not an option,” Dr D’Agostino noted. “3D printing gives us the ability to craft devices that are better suited for certain patient populations that are traditionally tough to treat, such as children and the obese, who have different anatomy. There’s limitless potential to be explored with this technology.”

The researchers were also able to print biodegradable filaments, catheters, and stents that contain antibiotics and chemotherapeutic agents. These devices might help patients avoid the need to undergo a second procedure or treatment to remove or destroy the delivery vehicle.

Dr D’Agostino said this early success with 3D-printed instruments in the lab warrants further studies, with the goal of receiving approval to use these devices in humans. He also sees an opportunity to collaborate with other medical specialties to deliver higher-quality, personalized care to all types of patients.

Cancer patient receives therapy

Photo by Rhoda Baer

Interim results of the phase 3 ENDEAVOR trial suggest that carfilzomib given in combination with low-dose dexamethasone may be more effective than bortezomib plus low-dose dexamethasone for certain patients with relapsed multiple myeloma (MM).

Patients who received the carfilzomib combination had a higher overall response rate and nearly twice the median progression-free survival (PFS) of patients who received the bortezomib combination.

Those who received carfilzomib had higher rates of cardiac and renal failure but lower rates of neuropathy. And rates of treatment discontinuation and on-study death were similar between the treatment arms.

Onyx Pharmaceuticals, the company developing carfilzomib (as Kyprolis), announced these results yesterday. The company plans to submit complete trial data for presentation at the 2015 ASCO Annual Meeting.

The ENDEAVOR trial included 929 MM patients who had relapsed after at least 1, but not more than 3, prior treatment regimens. They were randomized to receive carfilzomib or bortezomib, both in combination with low-dose dexamethasone.

Patients received carfilzomib as a 30-minute infusion, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was given at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m² in cycle 1 remained at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) received bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.

The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively (hazard ratio=0.53).

The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary endpoints of higher overall response rate and lower neuropathy events.

However, the rates for cardiac and renal failure were higher in the carfilzomib arm than the bortezomib arm. The same was true for hypertension and dyspnea.

Rates of cardiac and renal failure with carfilzomib in this trial were similar to those observed in the phase 3 ASPIRE trial, but rates of hypertension and dyspnea were higher in ENDEAVOR than ASPIRE.

Cancer patient receives therapy

Photo by Rhoda Baer

Interim results of the phase 3 ENDEAVOR trial suggest that carfilzomib given in combination with low-dose dexamethasone may be more effective than bortezomib plus low-dose dexamethasone for certain patients with relapsed multiple myeloma (MM).

Patients who received the carfilzomib combination had a higher overall response rate and nearly twice the median progression-free survival (PFS) of patients who received the bortezomib combination.

Those who received carfilzomib had higher rates of cardiac and renal failure but lower rates of neuropathy. And rates of treatment discontinuation and on-study death were similar between the treatment arms.

Onyx Pharmaceuticals, the company developing carfilzomib (as Kyprolis), announced these results yesterday. The company plans to submit complete trial data for presentation at the 2015 ASCO Annual Meeting.

The ENDEAVOR trial included 929 MM patients who had relapsed after at least 1, but not more than 3, prior treatment regimens. They were randomized to receive carfilzomib or bortezomib, both in combination with low-dose dexamethasone.

Patients received carfilzomib as a 30-minute infusion, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was given at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m² in cycle 1 remained at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) received bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.

The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively (hazard ratio=0.53).

The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary endpoints of higher overall response rate and lower neuropathy events.

However, the rates for cardiac and renal failure were higher in the carfilzomib arm than the bortezomib arm. The same was true for hypertension and dyspnea.

Rates of cardiac and renal failure with carfilzomib in this trial were similar to those observed in the phase 3 ASPIRE trial, but rates of hypertension and dyspnea were higher in ENDEAVOR than ASPIRE.

Cancer patient receives therapy

Photo by Rhoda Baer

Interim results of the phase 3 ENDEAVOR trial suggest that carfilzomib given in combination with low-dose dexamethasone may be more effective than bortezomib plus low-dose dexamethasone for certain patients with relapsed multiple myeloma (MM).

Patients who received the carfilzomib combination had a higher overall response rate and nearly twice the median progression-free survival (PFS) of patients who received the bortezomib combination.

Those who received carfilzomib had higher rates of cardiac and renal failure but lower rates of neuropathy. And rates of treatment discontinuation and on-study death were similar between the treatment arms.

Onyx Pharmaceuticals, the company developing carfilzomib (as Kyprolis), announced these results yesterday. The company plans to submit complete trial data for presentation at the 2015 ASCO Annual Meeting.

The ENDEAVOR trial included 929 MM patients who had relapsed after at least 1, but not more than 3, prior treatment regimens. They were randomized to receive carfilzomib or bortezomib, both in combination with low-dose dexamethasone.

Patients received carfilzomib as a 30-minute infusion, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was given at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² on days 8, 9, 15, and 16. Patients who tolerated 56 mg/m² in cycle 1 remained at this dose for subsequent cycles on days 1, 2, 8, 9, 15, and 16 on a 28-day cycle.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) received bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.

The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively (hazard ratio=0.53).

The carfilzomib combination also demonstrated superiority over the bortezomib combination for secondary endpoints of higher overall response rate and lower neuropathy events.

However, the rates for cardiac and renal failure were higher in the carfilzomib arm than the bortezomib arm. The same was true for hypertension and dyspnea.

Rates of cardiac and renal failure with carfilzomib in this trial were similar to those observed in the phase 3 ASPIRE trial, but rates of hypertension and dyspnea were higher in ENDEAVOR than ASPIRE.

Anopheles gambiae mosquito

Photo courtesy of CDC

Sexual biology may be the key to uncovering why Anopheles mosquitoes are unique in their ability to transmit malaria to humans, according to research published in Science.

By analyzing 16 Anopheles genomes, investigators found these mosquitoes’ reproductive traits evolved along with their capacity to transmit the Plasmodium parasite.

The team believes these findings may provide a new target for malaria control, particularly in regions hardest hit by the disease.

“Our study is the first to reveal the evolutionary dynamics between the sexes that are likely responsible for shaping the ability of Anopheles mosquitoes to transmit malaria to humans,” said study author Flaminia Catteruccia, PhD, of the University of Perugia in Italy.

She and her colleagues analyzed 9 globally dispersed Anopheles species, enabling reconstruction of the evolutionary history of the mosquitoes’ reproductive traits and capacity to transmit malaria.

Results showed that 2 key male reproductive traits in Anopheles are acquired and evolved together over time. The first is transferring ejaculate as a gelatinous, rod-shaped structure called the mating plug. And the second is the ability to synthesize a steroid hormone known as 20-hydroxyecdysone (20E), which is contained in the mating plug.

The investigators also demonstrated that the evolution of these male traits drove reciprocal adaptations in females that are strongly linked to the mosquitoes’ capacity to transmit malaria.

With prior research, the team had shown that sexual transfer of 20E induces a series of dramatic changes in the female mosquito, fundamentally altering her physiology and behavior. These changes affect a female’s reproductive output, longevity, and immune response to Plasmodium parasites, all key factors in malaria transmission.

All 4 species of Anopheles mosquitoes that transfer large levels of 20E are major malaria vectors originating from Africa and India, the regions of highest malaria burden.

The investigators believe that, by identifying factors important for malaria transmission, they have paved the way for the development of compounds to specifically target those factors. Such compounds could be incorporated into existing mosquito control technologies, boosting their overall effectiveness.

The team also thinks their findings might be applicable to Dengue and West Nile virus, which are transmitted by the Aedes and Culex mosquitoes, respectively. In these species, some aspects of reproductive biology are similar to Anopheles.

Anopheles gambiae mosquito

Photo courtesy of CDC

Sexual biology may be the key to uncovering why Anopheles mosquitoes are unique in their ability to transmit malaria to humans, according to research published in Science.

By analyzing 16 Anopheles genomes, investigators found these mosquitoes’ reproductive traits evolved along with their capacity to transmit the Plasmodium parasite.

The team believes these findings may provide a new target for malaria control, particularly in regions hardest hit by the disease.

“Our study is the first to reveal the evolutionary dynamics between the sexes that are likely responsible for shaping the ability of Anopheles mosquitoes to transmit malaria to humans,” said study author Flaminia Catteruccia, PhD, of the University of Perugia in Italy.

She and her colleagues analyzed 9 globally dispersed Anopheles species, enabling reconstruction of the evolutionary history of the mosquitoes’ reproductive traits and capacity to transmit malaria.

Results showed that 2 key male reproductive traits in Anopheles are acquired and evolved together over time. The first is transferring ejaculate as a gelatinous, rod-shaped structure called the mating plug. And the second is the ability to synthesize a steroid hormone known as 20-hydroxyecdysone (20E), which is contained in the mating plug.

The investigators also demonstrated that the evolution of these male traits drove reciprocal adaptations in females that are strongly linked to the mosquitoes’ capacity to transmit malaria.

With prior research, the team had shown that sexual transfer of 20E induces a series of dramatic changes in the female mosquito, fundamentally altering her physiology and behavior. These changes affect a female’s reproductive output, longevity, and immune response to Plasmodium parasites, all key factors in malaria transmission.

All 4 species of Anopheles mosquitoes that transfer large levels of 20E are major malaria vectors originating from Africa and India, the regions of highest malaria burden.

The investigators believe that, by identifying factors important for malaria transmission, they have paved the way for the development of compounds to specifically target those factors. Such compounds could be incorporated into existing mosquito control technologies, boosting their overall effectiveness.

The team also thinks their findings might be applicable to Dengue and West Nile virus, which are transmitted by the Aedes and Culex mosquitoes, respectively. In these species, some aspects of reproductive biology are similar to Anopheles.

Anopheles gambiae mosquito

Photo courtesy of CDC

Sexual biology may be the key to uncovering why Anopheles mosquitoes are unique in their ability to transmit malaria to humans, according to research published in Science.

By analyzing 16 Anopheles genomes, investigators found these mosquitoes’ reproductive traits evolved along with their capacity to transmit the Plasmodium parasite.

The team believes these findings may provide a new target for malaria control, particularly in regions hardest hit by the disease.

“Our study is the first to reveal the evolutionary dynamics between the sexes that are likely responsible for shaping the ability of Anopheles mosquitoes to transmit malaria to humans,” said study author Flaminia Catteruccia, PhD, of the University of Perugia in Italy.

She and her colleagues analyzed 9 globally dispersed Anopheles species, enabling reconstruction of the evolutionary history of the mosquitoes’ reproductive traits and capacity to transmit malaria.

Results showed that 2 key male reproductive traits in Anopheles are acquired and evolved together over time. The first is transferring ejaculate as a gelatinous, rod-shaped structure called the mating plug. And the second is the ability to synthesize a steroid hormone known as 20-hydroxyecdysone (20E), which is contained in the mating plug.

The investigators also demonstrated that the evolution of these male traits drove reciprocal adaptations in females that are strongly linked to the mosquitoes’ capacity to transmit malaria.

With prior research, the team had shown that sexual transfer of 20E induces a series of dramatic changes in the female mosquito, fundamentally altering her physiology and behavior. These changes affect a female’s reproductive output, longevity, and immune response to Plasmodium parasites, all key factors in malaria transmission.

All 4 species of Anopheles mosquitoes that transfer large levels of 20E are major malaria vectors originating from Africa and India, the regions of highest malaria burden.

The investigators believe that, by identifying factors important for malaria transmission, they have paved the way for the development of compounds to specifically target those factors. Such compounds could be incorporated into existing mosquito control technologies, boosting their overall effectiveness.

The team also thinks their findings might be applicable to Dengue and West Nile virus, which are transmitted by the Aedes and Culex mosquitoes, respectively. In these species, some aspects of reproductive biology are similar to Anopheles.

Results of a phase 3 study suggest a recombinant factor IX Fc fusion protein (rFIXFc, also known as eftrenonacog alfa and Alprolix) is a feasible treatment option for children with severe hemophilia B.

rFIXFc effectively prevented and treated bleeding episodes, patients did not develop inhibitors, and there were no serious adverse events related to treatment.

Sobi and Biogen Idec, the companies developing rFIXFc, recently announced these results from the now-complete Kids B-LONG study.

They said the successful completion of this study supports applications for pediatric indications in several regions and is an important step in seeking marketing authorization for rFIXFc in Europe.

Interim results of the Kids B-LONG study helped support the US approval of rFIXFc for use in children.

In Kids B-LONG, researchers tested rFIXFc in 30 previously treated children younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 participants received rFIXFc injections on at least 50 separate days.

Children who received rFIXFc prophylactically had an overall median annualized bleeding rate (ABR) of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of rFIXFc.

None of the patients developed inhibitors to rFIXFc. The terminal half-life of the product was 66.5 hours for children under 6 and 70.3 hours for children ages 6 to 11.

Researchers said there were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events. None of the patients discontinued the study due to an adverse event.

One adverse event—decreased appetite occurring in 1 patient—was considered related to rFIXFc treatment.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the phase 3 B-LONG study. Common adverse reactions in that study were headache and oral paresthesia.

Additional analyses of the Kids B-LONG study are ongoing, and detailed results will be presented at a future scientific meeting, according to Sobi and Biogen Idec.

Results of a phase 3 study suggest a recombinant factor IX Fc fusion protein (rFIXFc, also known as eftrenonacog alfa and Alprolix) is a feasible treatment option for children with severe hemophilia B.

rFIXFc effectively prevented and treated bleeding episodes, patients did not develop inhibitors, and there were no serious adverse events related to treatment.

Sobi and Biogen Idec, the companies developing rFIXFc, recently announced these results from the now-complete Kids B-LONG study.

They said the successful completion of this study supports applications for pediatric indications in several regions and is an important step in seeking marketing authorization for rFIXFc in Europe.

Interim results of the Kids B-LONG study helped support the US approval of rFIXFc for use in children.

In Kids B-LONG, researchers tested rFIXFc in 30 previously treated children younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 participants received rFIXFc injections on at least 50 separate days.

Children who received rFIXFc prophylactically had an overall median annualized bleeding rate (ABR) of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of rFIXFc.

None of the patients developed inhibitors to rFIXFc. The terminal half-life of the product was 66.5 hours for children under 6 and 70.3 hours for children ages 6 to 11.

Researchers said there were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events. None of the patients discontinued the study due to an adverse event.

One adverse event—decreased appetite occurring in 1 patient—was considered related to rFIXFc treatment.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the phase 3 B-LONG study. Common adverse reactions in that study were headache and oral paresthesia.

Additional analyses of the Kids B-LONG study are ongoing, and detailed results will be presented at a future scientific meeting, according to Sobi and Biogen Idec.

Results of a phase 3 study suggest a recombinant factor IX Fc fusion protein (rFIXFc, also known as eftrenonacog alfa and Alprolix) is a feasible treatment option for children with severe hemophilia B.

rFIXFc effectively prevented and treated bleeding episodes, patients did not develop inhibitors, and there were no serious adverse events related to treatment.

Sobi and Biogen Idec, the companies developing rFIXFc, recently announced these results from the now-complete Kids B-LONG study.

They said the successful completion of this study supports applications for pediatric indications in several regions and is an important step in seeking marketing authorization for rFIXFc in Europe.

Interim results of the Kids B-LONG study helped support the US approval of rFIXFc for use in children.

In Kids B-LONG, researchers tested rFIXFc in 30 previously treated children younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 participants received rFIXFc injections on at least 50 separate days.

Children who received rFIXFc prophylactically had an overall median annualized bleeding rate (ABR) of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of rFIXFc.

None of the patients developed inhibitors to rFIXFc. The terminal half-life of the product was 66.5 hours for children under 6 and 70.3 hours for children ages 6 to 11.

Researchers said there were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events. None of the patients discontinued the study due to an adverse event.

One adverse event—decreased appetite occurring in 1 patient—was considered related to rFIXFc treatment.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the phase 3 B-LONG study. Common adverse reactions in that study were headache and oral paresthesia.

Additional analyses of the Kids B-LONG study are ongoing, and detailed results will be presented at a future scientific meeting, according to Sobi and Biogen Idec.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has granted orphan designation to andexanet alfa for reversing the anticoagulant effect of factor Xa inhibitors in patients experiencing a serious, uncontrolled bleeding event and those who require urgent or emergent surgery.

At present, there is no approved antidote for these patients.

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

The drug is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

Andexanet alfa has the potential to address several clinical scenarios where a factor Xa antidote is needed by allowing for flexible and controlled reversal. This can be short-acting, through the administration of an intravenous (IV) bolus, or longer-acting with the addition of an extended infusion.

The FDA previously granted andexanet alfa breakthrough therapy designation, which is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

“Orphan drug designation for andexanet alfa recognizes its potential to address a significant unmet medical need and to advance the field by helping patients who currently have no treatment options,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, the company developing andexanet alfa.

The FDA’s orphan drug designation program provides orphan status to drugs and biologics that are intended for the treatment, diagnosis, or prevention of rare diseases/disorders that currently affect fewer than 200,000 people in the US.

Orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

Clinical development of andexanet alfa

Researchers are currently evaluating andexanet alfa in 2 randomized, placebo-controlled, phase 3 trials—ANNEXA-A and ANNEXA-R.

They previously reported promising results from the first part of the ANNEXA-A study, a test of andexanet alfa’s ability to reverse the effects of apixaban in healthy subjects when the antidote was given as a single IV bolus.

Researchers also reported favorable results from the first part of the ANNEXA-R study, in which they evaluated andexanet alfa’s ability to reverse the effects of rivaroxaban in healthy subjects when the antidote was given as a single IV bolus.

The second parts of the ANNEXA-A and ANNEXA-R studies are ongoing. The researchers are evaluating the use of andexanet alfa given as a bolus and a continuous infusion.

ANNEXA-4, a phase 4, single-arm, confirmatory study is also ongoing. Researchers are evaluating the drug in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has granted orphan designation to andexanet alfa for reversing the anticoagulant effect of factor Xa inhibitors in patients experiencing a serious, uncontrolled bleeding event and those who require urgent or emergent surgery.

At present, there is no approved antidote for these patients.

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

The drug is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

Andexanet alfa has the potential to address several clinical scenarios where a factor Xa antidote is needed by allowing for flexible and controlled reversal. This can be short-acting, through the administration of an intravenous (IV) bolus, or longer-acting with the addition of an extended infusion.

The FDA previously granted andexanet alfa breakthrough therapy designation, which is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

“Orphan drug designation for andexanet alfa recognizes its potential to address a significant unmet medical need and to advance the field by helping patients who currently have no treatment options,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, the company developing andexanet alfa.

The FDA’s orphan drug designation program provides orphan status to drugs and biologics that are intended for the treatment, diagnosis, or prevention of rare diseases/disorders that currently affect fewer than 200,000 people in the US.

Orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

Clinical development of andexanet alfa

Researchers are currently evaluating andexanet alfa in 2 randomized, placebo-controlled, phase 3 trials—ANNEXA-A and ANNEXA-R.

They previously reported promising results from the first part of the ANNEXA-A study, a test of andexanet alfa’s ability to reverse the effects of apixaban in healthy subjects when the antidote was given as a single IV bolus.

Researchers also reported favorable results from the first part of the ANNEXA-R study, in which they evaluated andexanet alfa’s ability to reverse the effects of rivaroxaban in healthy subjects when the antidote was given as a single IV bolus.

The second parts of the ANNEXA-A and ANNEXA-R studies are ongoing. The researchers are evaluating the use of andexanet alfa given as a bolus and a continuous infusion.

ANNEXA-4, a phase 4, single-arm, confirmatory study is also ongoing. Researchers are evaluating the drug in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.

Team performing surgery

Photo by Piotr Bodzek

The US Food and Drug Administration (FDA) has granted orphan designation to andexanet alfa for reversing the anticoagulant effect of factor Xa inhibitors in patients experiencing a serious, uncontrolled bleeding event and those who require urgent or emergent surgery.

At present, there is no approved antidote for these patients.

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

The drug is a modified human factor Xa molecule that acts as a decoy to target and sequester both oral and injectable factor Xa inhibitors in the blood. Once bound, the inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

Andexanet alfa has the potential to address several clinical scenarios where a factor Xa antidote is needed by allowing for flexible and controlled reversal. This can be short-acting, through the administration of an intravenous (IV) bolus, or longer-acting with the addition of an extended infusion.

The FDA previously granted andexanet alfa breakthrough therapy designation, which is intended to expedite the development and review of a drug candidate intended to treat a serious or life-threatening condition.

“Orphan drug designation for andexanet alfa recognizes its potential to address a significant unmet medical need and to advance the field by helping patients who currently have no treatment options,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, the company developing andexanet alfa.

The FDA’s orphan drug designation program provides orphan status to drugs and biologics that are intended for the treatment, diagnosis, or prevention of rare diseases/disorders that currently affect fewer than 200,000 people in the US.

Orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

Clinical development of andexanet alfa

Researchers are currently evaluating andexanet alfa in 2 randomized, placebo-controlled, phase 3 trials—ANNEXA-A and ANNEXA-R.

They previously reported promising results from the first part of the ANNEXA-A study, a test of andexanet alfa’s ability to reverse the effects of apixaban in healthy subjects when the antidote was given as a single IV bolus.

Researchers also reported favorable results from the first part of the ANNEXA-R study, in which they evaluated andexanet alfa’s ability to reverse the effects of rivaroxaban in healthy subjects when the antidote was given as a single IV bolus.

The second parts of the ANNEXA-A and ANNEXA-R studies are ongoing. The researchers are evaluating the use of andexanet alfa given as a bolus and a continuous infusion.

ANNEXA-4, a phase 4, single-arm, confirmatory study is also ongoing. Researchers are evaluating the drug in patients receiving apixaban, rivaroxaban, edoxaban, or enoxaparin who present with an acute major bleed.

Preparing for HSCT

Photo by Chad McNeeley

A retrospective study has shown that, since the 1980s, the world has seen a substantial increase in the use of hematopoietic stem cell transplants (HSCTs) and a significant rise in the number of donor registries.

Still, it seems many patients who would benefit from HSCT do not undergo the procedure due to a chronic shortage of resources and donors.

Dietger Niederwieser, MD, of the University Hospital Leipzig in Germany, and his colleagues recounted these findings in The Lancet Haematology.

Using data collected by the Worldwide Network for Blood and Marrow Transplantation (WBMT), the researchers systematically analyzed the growth of HSCT and changes in its use in 194 WHO member countries since the first HSCT was performed in 1957.

The team also examined the link between macroeconomic factors (eg, gross national income and healthcare expenditure) and transplant frequencies per 10 million inhabitants in each country.

The data showed that about 10,000 HSCTs had been performed by 1985, but that number rose to around 100,000 by 1995. By December 2012, nearly 1 million HSCTs—42% allogeneic and 58% autologous—had been performed at 1516 transplant centers across 75 countries.

Transplants were more common in countries with greater financial resources, more transplant teams, and an unrelated donor infrastructure. Most transplants were performed in Europe (53%), followed by the Americas (31%), South East Asia and the Western Pacific (15%), and the Eastern Mediterranean and Africa (2%).

The use of allogeneic HSCT has grown rapidly in all regions, without any signs of saturation. This likely reflects substantial underuse of this therapy, according to the researchers. And it suggests more patients would have received allogeneic transplants if they were accessible or suitable donors were available.

On the other hand, the researchers found that the number of countries with donor registries increased from 2 in 1987 to 57 in 2012. And the number of volunteer donors rose from 3072 in 1987 to over 22 million in 2012.

The international exchange of stem cell products also increased to more than 10,000 a year between 2006 and 2012, with substantial differences between countries in the amount of stem cells they import or export.

Despite these increases, the researchers noted that there are still too many patients who are unable to find a suitable donor. At any time, more than 37,000 people worldwide are waiting for an HSC donation.

“Patients, many of them children, are facing a life-and-death situation,” Dr Niederwieser said. “Ultimately, they will die if they cannot get the treatment they need. All countries need to provide adequate infrastructure for patients and donors to make sure that everyone who needs a transplant gets one, rather than the present situation in which access remains restricted to countries and people with sufficient resources.”

Preparing for HSCT

Photo by Chad McNeeley

A retrospective study has shown that, since the 1980s, the world has seen a substantial increase in the use of hematopoietic stem cell transplants (HSCTs) and a significant rise in the number of donor registries.

Still, it seems many patients who would benefit from HSCT do not undergo the procedure due to a chronic shortage of resources and donors.

Dietger Niederwieser, MD, of the University Hospital Leipzig in Germany, and his colleagues recounted these findings in The Lancet Haematology.

Using data collected by the Worldwide Network for Blood and Marrow Transplantation (WBMT), the researchers systematically analyzed the growth of HSCT and changes in its use in 194 WHO member countries since the first HSCT was performed in 1957.

The team also examined the link between macroeconomic factors (eg, gross national income and healthcare expenditure) and transplant frequencies per 10 million inhabitants in each country.

The data showed that about 10,000 HSCTs had been performed by 1985, but that number rose to around 100,000 by 1995. By December 2012, nearly 1 million HSCTs—42% allogeneic and 58% autologous—had been performed at 1516 transplant centers across 75 countries.

Transplants were more common in countries with greater financial resources, more transplant teams, and an unrelated donor infrastructure. Most transplants were performed in Europe (53%), followed by the Americas (31%), South East Asia and the Western Pacific (15%), and the Eastern Mediterranean and Africa (2%).

The use of allogeneic HSCT has grown rapidly in all regions, without any signs of saturation. This likely reflects substantial underuse of this therapy, according to the researchers. And it suggests more patients would have received allogeneic transplants if they were accessible or suitable donors were available.

On the other hand, the researchers found that the number of countries with donor registries increased from 2 in 1987 to 57 in 2012. And the number of volunteer donors rose from 3072 in 1987 to over 22 million in 2012.

The international exchange of stem cell products also increased to more than 10,000 a year between 2006 and 2012, with substantial differences between countries in the amount of stem cells they import or export.

Despite these increases, the researchers noted that there are still too many patients who are unable to find a suitable donor. At any time, more than 37,000 people worldwide are waiting for an HSC donation.

“Patients, many of them children, are facing a life-and-death situation,” Dr Niederwieser said. “Ultimately, they will die if they cannot get the treatment they need. All countries need to provide adequate infrastructure for patients and donors to make sure that everyone who needs a transplant gets one, rather than the present situation in which access remains restricted to countries and people with sufficient resources.”

Preparing for HSCT

Photo by Chad McNeeley

A retrospective study has shown that, since the 1980s, the world has seen a substantial increase in the use of hematopoietic stem cell transplants (HSCTs) and a significant rise in the number of donor registries.

Still, it seems many patients who would benefit from HSCT do not undergo the procedure due to a chronic shortage of resources and donors.

Dietger Niederwieser, MD, of the University Hospital Leipzig in Germany, and his colleagues recounted these findings in The Lancet Haematology.

Using data collected by the Worldwide Network for Blood and Marrow Transplantation (WBMT), the researchers systematically analyzed the growth of HSCT and changes in its use in 194 WHO member countries since the first HSCT was performed in 1957.

The team also examined the link between macroeconomic factors (eg, gross national income and healthcare expenditure) and transplant frequencies per 10 million inhabitants in each country.

The data showed that about 10,000 HSCTs had been performed by 1985, but that number rose to around 100,000 by 1995. By December 2012, nearly 1 million HSCTs—42% allogeneic and 58% autologous—had been performed at 1516 transplant centers across 75 countries.

Transplants were more common in countries with greater financial resources, more transplant teams, and an unrelated donor infrastructure. Most transplants were performed in Europe (53%), followed by the Americas (31%), South East Asia and the Western Pacific (15%), and the Eastern Mediterranean and Africa (2%).

The use of allogeneic HSCT has grown rapidly in all regions, without any signs of saturation. This likely reflects substantial underuse of this therapy, according to the researchers. And it suggests more patients would have received allogeneic transplants if they were accessible or suitable donors were available.

On the other hand, the researchers found that the number of countries with donor registries increased from 2 in 1987 to 57 in 2012. And the number of volunteer donors rose from 3072 in 1987 to over 22 million in 2012.

The international exchange of stem cell products also increased to more than 10,000 a year between 2006 and 2012, with substantial differences between countries in the amount of stem cells they import or export.

Despite these increases, the researchers noted that there are still too many patients who are unable to find a suitable donor. At any time, more than 37,000 people worldwide are waiting for an HSC donation.

“Patients, many of them children, are facing a life-and-death situation,” Dr Niederwieser said. “Ultimately, they will die if they cannot get the treatment they need. All countries need to provide adequate infrastructure for patients and donors to make sure that everyone who needs a transplant gets one, rather than the present situation in which access remains restricted to countries and people with sufficient resources.”

Hematopoietic stem cells

in the bone marrow

The incidence of clonal hematopoiesis in the general population may be higher than we thought and appears to increase dramatically with age, according to research published in Cell Reports.

Investigators used ultra-deep sequencing to search for evidence of clonal hematopoiesis driven by 15 recurrent leukemogenic mutations.

They sequenced DNA from more than 4000 subjects who had no evidence of hematologic malignancy.

And the incidence of clonal hematopoiesis was higher than has been observed in previous, exome-sequencing studies—0.8% in subjects under 60, rising to 19.5% in subjects ages 90 to 98.

“Ultra-deep sequencing has allowed us to see the very beginnings of cancer,” said study author George Vassiliou, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“These mutations will be harmless for the majority of people, but, for a few unlucky carriers, they will take the body on a journey towards leukemia. We are now beginning to understand the major landmarks on that journey.”

The investigators found that mutations affecting 2 genes, SF3B1 and SRSF2, appeared exclusively in 70-year-olds.

This suggests these mutations only confer a growth benefit for cells later in life, when there is less competition. And it explains why myelodysplastic syndromes, which are associated with these genes, appear almost exclusively in the elderly.

None of the 4219 subjects studied had mutations in the NPM1 gene, which is mutated in up to 40% of leukemia cases.

This unexpected result suggests that mutations in NPM1 behave as gatekeepers for leukemia, the investigators said. Once a mutation in this gene occurs in a cell with particular, previously accumulated, pre-leukemic mutations, leukemia will develop.

“The significance of mutations in this gene is astonishingly clear from these results: it simply doesn’t exist where there is no leukemia,” said study author Naomi Park, PhD, of the Wellcome Trust Sanger Institute.

“When it is mutated in the appropriate cell, the floodgates open, and leukemia is then very likely to develop. This fits with studies we’ve conducted in the past in which we found that the gene primes blood stem cells for leukemic transformation.”

Hematopoietic stem cells

in the bone marrow

The incidence of clonal hematopoiesis in the general population may be higher than we thought and appears to increase dramatically with age, according to research published in Cell Reports.

Investigators used ultra-deep sequencing to search for evidence of clonal hematopoiesis driven by 15 recurrent leukemogenic mutations.

They sequenced DNA from more than 4000 subjects who had no evidence of hematologic malignancy.

And the incidence of clonal hematopoiesis was higher than has been observed in previous, exome-sequencing studies—0.8% in subjects under 60, rising to 19.5% in subjects ages 90 to 98.

“Ultra-deep sequencing has allowed us to see the very beginnings of cancer,” said study author George Vassiliou, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“These mutations will be harmless for the majority of people, but, for a few unlucky carriers, they will take the body on a journey towards leukemia. We are now beginning to understand the major landmarks on that journey.”

The investigators found that mutations affecting 2 genes, SF3B1 and SRSF2, appeared exclusively in 70-year-olds.

This suggests these mutations only confer a growth benefit for cells later in life, when there is less competition. And it explains why myelodysplastic syndromes, which are associated with these genes, appear almost exclusively in the elderly.

None of the 4219 subjects studied had mutations in the NPM1 gene, which is mutated in up to 40% of leukemia cases.

This unexpected result suggests that mutations in NPM1 behave as gatekeepers for leukemia, the investigators said. Once a mutation in this gene occurs in a cell with particular, previously accumulated, pre-leukemic mutations, leukemia will develop.

“The significance of mutations in this gene is astonishingly clear from these results: it simply doesn’t exist where there is no leukemia,” said study author Naomi Park, PhD, of the Wellcome Trust Sanger Institute.

“When it is mutated in the appropriate cell, the floodgates open, and leukemia is then very likely to develop. This fits with studies we’ve conducted in the past in which we found that the gene primes blood stem cells for leukemic transformation.”

Hematopoietic stem cells

in the bone marrow

The incidence of clonal hematopoiesis in the general population may be higher than we thought and appears to increase dramatically with age, according to research published in Cell Reports.

Investigators used ultra-deep sequencing to search for evidence of clonal hematopoiesis driven by 15 recurrent leukemogenic mutations.

They sequenced DNA from more than 4000 subjects who had no evidence of hematologic malignancy.

And the incidence of clonal hematopoiesis was higher than has been observed in previous, exome-sequencing studies—0.8% in subjects under 60, rising to 19.5% in subjects ages 90 to 98.

“Ultra-deep sequencing has allowed us to see the very beginnings of cancer,” said study author George Vassiliou, MD, PhD, of the Wellcome Trust Sanger Institute in Cambridge, UK.

“These mutations will be harmless for the majority of people, but, for a few unlucky carriers, they will take the body on a journey towards leukemia. We are now beginning to understand the major landmarks on that journey.”

The investigators found that mutations affecting 2 genes, SF3B1 and SRSF2, appeared exclusively in 70-year-olds.

This suggests these mutations only confer a growth benefit for cells later in life, when there is less competition. And it explains why myelodysplastic syndromes, which are associated with these genes, appear almost exclusively in the elderly.

None of the 4219 subjects studied had mutations in the NPM1 gene, which is mutated in up to 40% of leukemia cases.

This unexpected result suggests that mutations in NPM1 behave as gatekeepers for leukemia, the investigators said. Once a mutation in this gene occurs in a cell with particular, previously accumulated, pre-leukemic mutations, leukemia will develop.

“The significance of mutations in this gene is astonishingly clear from these results: it simply doesn’t exist where there is no leukemia,” said study author Naomi Park, PhD, of the Wellcome Trust Sanger Institute.

“When it is mutated in the appropriate cell, the floodgates open, and leukemia is then very likely to develop. This fits with studies we’ve conducted in the past in which we found that the gene primes blood stem cells for leukemic transformation.”

Lab mouse

The use of animals in experimental research conducted at leading US laboratories has risen by more than 70% in recent years, according to a study published in the Journal of Medical Ethics.

The data contradict industry claims of reduced animal use and are at odds with government policies designed to curb and replace the use of animals in experiments, according to researchers.

The US is the world’s largest user of animals in experiments. And government data show declines in the use of cats, dogs, primates, rabbits, hamsters, and other larger mammals.

But the exclusion of the species most commonly used in laboratory research—mice, rats, birds, and all cold-blooded animals—from federal regulations has resulted in an absence of published data on how many of these animals are used in experiments.

To fill this gap, researchers at People for the Ethical Treatment of Animals (PETA) analyzed previously unpublished data collected by the National Institutes of Health (NIH) on the use of all vertebrate species at the top 25 institutions in receipt of NIH grants.

This includes such institutions as Harvard University, Yale University, Columbia University, the University of California-San Francisco, the University of Wisconsin-Madison, and Johns Hopkins University. Together, these institutions account for 27% of all NIH grants disbursed.

PETA’s analysis showed that the use of animals in laboratory research at these facilities rose by 72.7% between 1997 and 2012. This increase was largely driven by an increase in the use of mice. The use of other species remained mostly unchanged.

This study is the first ever to document figures on the use of mice, rats, birds, fish, reptiles, and amphibians in US laboratories. These species are not protected under the federal law governing the treatment of animals used in experiments—the Animal Welfare Act—and therefore are excluded from the law’s reporting requirements.

PETA’s study showed that these unregulated species comprise 98.8% of animals in laboratories.

The researchers said possible explanations for these results include personal and legal biases toward certain animal species. But the figures highlight a need for greater efforts to curb the use of animals in scientific research and more transparency in reporting on whether such efforts are succeeding.

A linked viewpoint article acknowledges the ongoing tensions between scientists and animal rights advocates but suggests that people on both sides of the divide do want to better understand one another.

It recommends that institutional policies be updated to better inform the public about the use of animals in scientific research, as well as opening up dialogue between a broad base of players to replace the often poorly informed and emotionally charged debate.

Lab mouse

The use of animals in experimental research conducted at leading US laboratories has risen by more than 70% in recent years, according to a study published in the Journal of Medical Ethics.

The data contradict industry claims of reduced animal use and are at odds with government policies designed to curb and replace the use of animals in experiments, according to researchers.

The US is the world’s largest user of animals in experiments. And government data show declines in the use of cats, dogs, primates, rabbits, hamsters, and other larger mammals.

But the exclusion of the species most commonly used in laboratory research—mice, rats, birds, and all cold-blooded animals—from federal regulations has resulted in an absence of published data on how many of these animals are used in experiments.

To fill this gap, researchers at People for the Ethical Treatment of Animals (PETA) analyzed previously unpublished data collected by the National Institutes of Health (NIH) on the use of all vertebrate species at the top 25 institutions in receipt of NIH grants.

This includes such institutions as Harvard University, Yale University, Columbia University, the University of California-San Francisco, the University of Wisconsin-Madison, and Johns Hopkins University. Together, these institutions account for 27% of all NIH grants disbursed.

PETA’s analysis showed that the use of animals in laboratory research at these facilities rose by 72.7% between 1997 and 2012. This increase was largely driven by an increase in the use of mice. The use of other species remained mostly unchanged.

This study is the first ever to document figures on the use of mice, rats, birds, fish, reptiles, and amphibians in US laboratories. These species are not protected under the federal law governing the treatment of animals used in experiments—the Animal Welfare Act—and therefore are excluded from the law’s reporting requirements.

PETA’s study showed that these unregulated species comprise 98.8% of animals in laboratories.

The researchers said possible explanations for these results include personal and legal biases toward certain animal species. But the figures highlight a need for greater efforts to curb the use of animals in scientific research and more transparency in reporting on whether such efforts are succeeding.

A linked viewpoint article acknowledges the ongoing tensions between scientists and animal rights advocates but suggests that people on both sides of the divide do want to better understand one another.

It recommends that institutional policies be updated to better inform the public about the use of animals in scientific research, as well as opening up dialogue between a broad base of players to replace the often poorly informed and emotionally charged debate.

Lab mouse

The use of animals in experimental research conducted at leading US laboratories has risen by more than 70% in recent years, according to a study published in the Journal of Medical Ethics.

The data contradict industry claims of reduced animal use and are at odds with government policies designed to curb and replace the use of animals in experiments, according to researchers.

The US is the world’s largest user of animals in experiments. And government data show declines in the use of cats, dogs, primates, rabbits, hamsters, and other larger mammals.

But the exclusion of the species most commonly used in laboratory research—mice, rats, birds, and all cold-blooded animals—from federal regulations has resulted in an absence of published data on how many of these animals are used in experiments.

To fill this gap, researchers at People for the Ethical Treatment of Animals (PETA) analyzed previously unpublished data collected by the National Institutes of Health (NIH) on the use of all vertebrate species at the top 25 institutions in receipt of NIH grants.

This includes such institutions as Harvard University, Yale University, Columbia University, the University of California-San Francisco, the University of Wisconsin-Madison, and Johns Hopkins University. Together, these institutions account for 27% of all NIH grants disbursed.

PETA’s analysis showed that the use of animals in laboratory research at these facilities rose by 72.7% between 1997 and 2012. This increase was largely driven by an increase in the use of mice. The use of other species remained mostly unchanged.

This study is the first ever to document figures on the use of mice, rats, birds, fish, reptiles, and amphibians in US laboratories. These species are not protected under the federal law governing the treatment of animals used in experiments—the Animal Welfare Act—and therefore are excluded from the law’s reporting requirements.

PETA’s study showed that these unregulated species comprise 98.8% of animals in laboratories.

The researchers said possible explanations for these results include personal and legal biases toward certain animal species. But the figures highlight a need for greater efforts to curb the use of animals in scientific research and more transparency in reporting on whether such efforts are succeeding.

A linked viewpoint article acknowledges the ongoing tensions between scientists and animal rights advocates but suggests that people on both sides of the divide do want to better understand one another.

It recommends that institutional policies be updated to better inform the public about the use of animals in scientific research, as well as opening up dialogue between a broad base of players to replace the often poorly informed and emotionally charged debate.

Doctor evaluating a patient

Photo courtesy of CDC

In reviewing 4 clinical trials of ibrutinib, researchers found that a quarter of chronic lymphocytic leukemia (CLL) patients discontinued treatment with the Bruton tyrosine kinase (BTK) inhibitor.

Ten percent of patients stopped taking the drug due to disease progression, and 15% stopped because of adverse and medical events.

Sequencing data indicated that mutations in BTK and PLCG2 were associated with CLL progression but not Richter’s transformation (RT).

Jennifer A. Woyach, MD, of Ohio State University in Columbus, and her colleagues detailed these discoveries in JAMA Oncology.

The researchers evaluated 308 patients participating in 4 trials conducted at a single institution. The team described the characteristics and outcomes of the patients who discontinued treatment with ibrutinib.

At a median follow-up of 20 months, 232 of the patients studied (75%) remained on therapy, including 7 patients who went off study to undergo stem cell transplant or receive ibrutinib commercially at another center.

Forty-five patients (15%) discontinued treatment following adverse or medical events—28 due to infection, 8 for other adverse events, and 9 due to other medical events. This included 2 patients who needed anticoagulation, 2 with comorbid medical conditions, 1 case of progressive multifocal leukoencephalopathy in a patient who had received rituximab, 1 case of noncompliance, 1 failure to thrive, 1 sudden cardiac death, and 1 cerebrovascular event.

Thirty-one patients (10%) discontinued treatment due to disease progression. Progression included RT or progressive CLL. RT appeared to occur early and CLL progression later. The median survival was 3.5 months after RT and 17.6 months after CLL progression.

Deep sequencing performed on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all of them. But sequencing data on peripheral blood from 8 patients with RT showed that only 2 patients had mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2.

Doctor evaluating a patient

Photo courtesy of CDC

In reviewing 4 clinical trials of ibrutinib, researchers found that a quarter of chronic lymphocytic leukemia (CLL) patients discontinued treatment with the Bruton tyrosine kinase (BTK) inhibitor.

Ten percent of patients stopped taking the drug due to disease progression, and 15% stopped because of adverse and medical events.

Sequencing data indicated that mutations in BTK and PLCG2 were associated with CLL progression but not Richter’s transformation (RT).

Jennifer A. Woyach, MD, of Ohio State University in Columbus, and her colleagues detailed these discoveries in JAMA Oncology.

The researchers evaluated 308 patients participating in 4 trials conducted at a single institution. The team described the characteristics and outcomes of the patients who discontinued treatment with ibrutinib.

At a median follow-up of 20 months, 232 of the patients studied (75%) remained on therapy, including 7 patients who went off study to undergo stem cell transplant or receive ibrutinib commercially at another center.

Forty-five patients (15%) discontinued treatment following adverse or medical events—28 due to infection, 8 for other adverse events, and 9 due to other medical events. This included 2 patients who needed anticoagulation, 2 with comorbid medical conditions, 1 case of progressive multifocal leukoencephalopathy in a patient who had received rituximab, 1 case of noncompliance, 1 failure to thrive, 1 sudden cardiac death, and 1 cerebrovascular event.

Thirty-one patients (10%) discontinued treatment due to disease progression. Progression included RT or progressive CLL. RT appeared to occur early and CLL progression later. The median survival was 3.5 months after RT and 17.6 months after CLL progression.

Deep sequencing performed on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all of them. But sequencing data on peripheral blood from 8 patients with RT showed that only 2 patients had mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2.

Doctor evaluating a patient

Photo courtesy of CDC

In reviewing 4 clinical trials of ibrutinib, researchers found that a quarter of chronic lymphocytic leukemia (CLL) patients discontinued treatment with the Bruton tyrosine kinase (BTK) inhibitor.

Ten percent of patients stopped taking the drug due to disease progression, and 15% stopped because of adverse and medical events.

Sequencing data indicated that mutations in BTK and PLCG2 were associated with CLL progression but not Richter’s transformation (RT).

Jennifer A. Woyach, MD, of Ohio State University in Columbus, and her colleagues detailed these discoveries in JAMA Oncology.

The researchers evaluated 308 patients participating in 4 trials conducted at a single institution. The team described the characteristics and outcomes of the patients who discontinued treatment with ibrutinib.

At a median follow-up of 20 months, 232 of the patients studied (75%) remained on therapy, including 7 patients who went off study to undergo stem cell transplant or receive ibrutinib commercially at another center.

Forty-five patients (15%) discontinued treatment following adverse or medical events—28 due to infection, 8 for other adverse events, and 9 due to other medical events. This included 2 patients who needed anticoagulation, 2 with comorbid medical conditions, 1 case of progressive multifocal leukoencephalopathy in a patient who had received rituximab, 1 case of noncompliance, 1 failure to thrive, 1 sudden cardiac death, and 1 cerebrovascular event.

Thirty-one patients (10%) discontinued treatment due to disease progression. Progression included RT or progressive CLL. RT appeared to occur early and CLL progression later. The median survival was 3.5 months after RT and 17.6 months after CLL progression.

Deep sequencing performed on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all of them. But sequencing data on peripheral blood from 8 patients with RT showed that only 2 patients had mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2.