During the 43rd AAGL Global Congress, held November 17–21 in Vancouver, British Columbia, Sarah L. Cohen, MD, MPH, of Brigham and Women’s Hospital in Boston, Massachusetts, stepped attendees through diagnosis and surgical management of adnexal masses in pregnancy, noting the approaches backed by the highest-quality data.

The incidence of adnexal masses in pregnancy is 1 in every 600 live births. A mass can be benign or malignant. Among benign masses found in pregnancy are functional cysts, teratomas, and the corpus luteum.

Work-up
Ultrasound imaging is a valuable component of the work-up, owing to its risk-free nature. Magnetic resonance imaging may be appropriate in selected cases, but gadolinium contrast should be avoided.

In pregnancy, the aim is to limit ionizing radiation to less than 5 to 10 rads to minimize the risk of childhood malignancy/leukemia, with no single imaging study exceeding 5 rads.

Tumor markers may be helpful, but careful interpretation is critical, taking into account the effects of pregnancy itself on CA-125 (which peaks in the first trimester), human chorionic gonadotropin, alpha fetoprotein, inhibin A, and lactate dehydrogenase.

When expectant management may be appropriate
Watchful waiting may be considered for simple cysts less than 6 cm in size, provided the patient is asymptomatic with no signs of malignancy.

Surgery is indicated when the patient is symptomatic, when there is a concern for malignancy, and when a persistent mass exceeds 10 cm in size.

As always, elective surgery is preferable, as emergent surgery in pregnancy is associated with a risk of preterm labor of 22% to 35%.

Optimal timing of surgery
Surgery can be performed safely in any trimester, provided the gynecologist is aware of special concerns. For example, in the first trimester, organogenesis is under way and the corpus luteum is still present. If the corpus luteum is removed, progesterone supplementation is necessary.

When surgery can be postponed to the second trimester, it allows time for possible resolution of the mass.

Mode of surgery
Laparoscopy allows for faster recovery, less pain (and, therefore, lower narcotic exposure to the fetus), and improved maternal ventilation.

Prophylaxis for venous thromboembolism is indicated through the use of pneumatic compression devices and, when appropriate, heparin.

Initial port placement can be performed using a Hassan technique, Veress needle, or optical trocar.

Insufflation pressures of 10 to 15 mm Hg are safe, with intraoperative monitoring of carbon dioxide. 

Availability of guidelines
Surgeons should make use of guidelines, when feasible, to guide surgery. For example, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) publishes guidelines on surgery during pregnancy. The American College of Obstetricians and Gynecologists also offers guidelines.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

During the 43rd AAGL Global Congress, held November 17–21 in Vancouver, British Columbia, Sarah L. Cohen, MD, MPH, of Brigham and Women’s Hospital in Boston, Massachusetts, stepped attendees through diagnosis and surgical management of adnexal masses in pregnancy, noting the approaches backed by the highest-quality data.

The incidence of adnexal masses in pregnancy is 1 in every 600 live births. A mass can be benign or malignant. Among benign masses found in pregnancy are functional cysts, teratomas, and the corpus luteum.

Work-up
Ultrasound imaging is a valuable component of the work-up, owing to its risk-free nature. Magnetic resonance imaging may be appropriate in selected cases, but gadolinium contrast should be avoided.

In pregnancy, the aim is to limit ionizing radiation to less than 5 to 10 rads to minimize the risk of childhood malignancy/leukemia, with no single imaging study exceeding 5 rads.

Tumor markers may be helpful, but careful interpretation is critical, taking into account the effects of pregnancy itself on CA-125 (which peaks in the first trimester), human chorionic gonadotropin, alpha fetoprotein, inhibin A, and lactate dehydrogenase.

When expectant management may be appropriate
Watchful waiting may be considered for simple cysts less than 6 cm in size, provided the patient is asymptomatic with no signs of malignancy.

Surgery is indicated when the patient is symptomatic, when there is a concern for malignancy, and when a persistent mass exceeds 10 cm in size.

As always, elective surgery is preferable, as emergent surgery in pregnancy is associated with a risk of preterm labor of 22% to 35%.

Optimal timing of surgery
Surgery can be performed safely in any trimester, provided the gynecologist is aware of special concerns. For example, in the first trimester, organogenesis is under way and the corpus luteum is still present. If the corpus luteum is removed, progesterone supplementation is necessary.

When surgery can be postponed to the second trimester, it allows time for possible resolution of the mass.

Mode of surgery
Laparoscopy allows for faster recovery, less pain (and, therefore, lower narcotic exposure to the fetus), and improved maternal ventilation.

Prophylaxis for venous thromboembolism is indicated through the use of pneumatic compression devices and, when appropriate, heparin.

Initial port placement can be performed using a Hassan technique, Veress needle, or optical trocar.

Insufflation pressures of 10 to 15 mm Hg are safe, with intraoperative monitoring of carbon dioxide. 

Availability of guidelines
Surgeons should make use of guidelines, when feasible, to guide surgery. For example, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) publishes guidelines on surgery during pregnancy. The American College of Obstetricians and Gynecologists also offers guidelines.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

During the 43rd AAGL Global Congress, held November 17–21 in Vancouver, British Columbia, Sarah L. Cohen, MD, MPH, of Brigham and Women’s Hospital in Boston, Massachusetts, stepped attendees through diagnosis and surgical management of adnexal masses in pregnancy, noting the approaches backed by the highest-quality data.

The incidence of adnexal masses in pregnancy is 1 in every 600 live births. A mass can be benign or malignant. Among benign masses found in pregnancy are functional cysts, teratomas, and the corpus luteum.

Work-up
Ultrasound imaging is a valuable component of the work-up, owing to its risk-free nature. Magnetic resonance imaging may be appropriate in selected cases, but gadolinium contrast should be avoided.

In pregnancy, the aim is to limit ionizing radiation to less than 5 to 10 rads to minimize the risk of childhood malignancy/leukemia, with no single imaging study exceeding 5 rads.

Tumor markers may be helpful, but careful interpretation is critical, taking into account the effects of pregnancy itself on CA-125 (which peaks in the first trimester), human chorionic gonadotropin, alpha fetoprotein, inhibin A, and lactate dehydrogenase.

When expectant management may be appropriate
Watchful waiting may be considered for simple cysts less than 6 cm in size, provided the patient is asymptomatic with no signs of malignancy.

Surgery is indicated when the patient is symptomatic, when there is a concern for malignancy, and when a persistent mass exceeds 10 cm in size.

As always, elective surgery is preferable, as emergent surgery in pregnancy is associated with a risk of preterm labor of 22% to 35%.

Optimal timing of surgery
Surgery can be performed safely in any trimester, provided the gynecologist is aware of special concerns. For example, in the first trimester, organogenesis is under way and the corpus luteum is still present. If the corpus luteum is removed, progesterone supplementation is necessary.

When surgery can be postponed to the second trimester, it allows time for possible resolution of the mass.

Mode of surgery
Laparoscopy allows for faster recovery, less pain (and, therefore, lower narcotic exposure to the fetus), and improved maternal ventilation.

Prophylaxis for venous thromboembolism is indicated through the use of pneumatic compression devices and, when appropriate, heparin.

Initial port placement can be performed using a Hassan technique, Veress needle, or optical trocar.

Insufflation pressures of 10 to 15 mm Hg are safe, with intraoperative monitoring of carbon dioxide. 

Availability of guidelines
Surgeons should make use of guidelines, when feasible, to guide surgery. For example, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) publishes guidelines on surgery during pregnancy. The American College of Obstetricians and Gynecologists also offers guidelines.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The National Heart, Lung, and Blood Institute announced the premature termination of TWiTCH, its clinical trial of children with sickle cell disease, because researchers met their goal ahead of schedule.

The NHLBI stated in a press release that the trial was stopped in agreement with the recommendations of the Data and Safety Monitoring Board (DSMB) – an independent group of experts that regularly reviews accumulating data from ongoing clinical trials and makes recommendations to investigators and sponsors on how to move forward.

“The DSMB’s planned first interim analysis of the TWiTCH study data indicated that the study had reached its primary and most important endpoint,” the NHLBI said in the statement. “As such, they recommended that the study end due to early results, particularly given that the strength of the statistical finding was unlikely to change with the collection of additional data.”

TWiTCH (Transcranial Doppler with Transfusions Changing to Hydroxyurea) was a phase III clinical trial created to determine whether daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with sickle cell disease with the same efficacy as that of blood transfusions. Currently, hydroxyurea is the only Food and Drug Administration–approved drug for sickle cell disease, a disorder that affects children and puts them at increased risk for stroke if they have high TCD blood flow velocities.

According to the data accrued by the researchers prior to the study’s termination, hydroxyurea was found to be “not inferior to (that is, no worse than) regular blood transfusions in lowering TCD velocities in children with sickle cell disease who are at high risk for stroke.”

“The results of TWiTCH will allow the families of children with sickle cell disease and who are at increased risk of stroke, to choose between two equally effective preventive therapies,” Dr. Keith Hoots, director of the NHLBI’s division of blood diseases and resources, said in an interview. “The TWiTCH trial is the most recent example of NHLBI’s ongoing commitment to the development of new therapies for the prevention and treatment of stroke in children with sickle cell disease.”

According to information from the American Society of Hematology, the trial included 25 participating centers from around the United States, and was funded by the NHLBI with sponsorship from Cincinnati Children’s Hospital Medical Center.

[email protected]

The National Heart, Lung, and Blood Institute announced the premature termination of TWiTCH, its clinical trial of children with sickle cell disease, because researchers met their goal ahead of schedule.

The NHLBI stated in a press release that the trial was stopped in agreement with the recommendations of the Data and Safety Monitoring Board (DSMB) – an independent group of experts that regularly reviews accumulating data from ongoing clinical trials and makes recommendations to investigators and sponsors on how to move forward.

“The DSMB’s planned first interim analysis of the TWiTCH study data indicated that the study had reached its primary and most important endpoint,” the NHLBI said in the statement. “As such, they recommended that the study end due to early results, particularly given that the strength of the statistical finding was unlikely to change with the collection of additional data.”

TWiTCH (Transcranial Doppler with Transfusions Changing to Hydroxyurea) was a phase III clinical trial created to determine whether daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with sickle cell disease with the same efficacy as that of blood transfusions. Currently, hydroxyurea is the only Food and Drug Administration–approved drug for sickle cell disease, a disorder that affects children and puts them at increased risk for stroke if they have high TCD blood flow velocities.

According to the data accrued by the researchers prior to the study’s termination, hydroxyurea was found to be “not inferior to (that is, no worse than) regular blood transfusions in lowering TCD velocities in children with sickle cell disease who are at high risk for stroke.”

“The results of TWiTCH will allow the families of children with sickle cell disease and who are at increased risk of stroke, to choose between two equally effective preventive therapies,” Dr. Keith Hoots, director of the NHLBI’s division of blood diseases and resources, said in an interview. “The TWiTCH trial is the most recent example of NHLBI’s ongoing commitment to the development of new therapies for the prevention and treatment of stroke in children with sickle cell disease.”

According to information from the American Society of Hematology, the trial included 25 participating centers from around the United States, and was funded by the NHLBI with sponsorship from Cincinnati Children’s Hospital Medical Center.

[email protected]

The National Heart, Lung, and Blood Institute announced the premature termination of TWiTCH, its clinical trial of children with sickle cell disease, because researchers met their goal ahead of schedule.

The NHLBI stated in a press release that the trial was stopped in agreement with the recommendations of the Data and Safety Monitoring Board (DSMB) – an independent group of experts that regularly reviews accumulating data from ongoing clinical trials and makes recommendations to investigators and sponsors on how to move forward.

“The DSMB’s planned first interim analysis of the TWiTCH study data indicated that the study had reached its primary and most important endpoint,” the NHLBI said in the statement. “As such, they recommended that the study end due to early results, particularly given that the strength of the statistical finding was unlikely to change with the collection of additional data.”

TWiTCH (Transcranial Doppler with Transfusions Changing to Hydroxyurea) was a phase III clinical trial created to determine whether daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with sickle cell disease with the same efficacy as that of blood transfusions. Currently, hydroxyurea is the only Food and Drug Administration–approved drug for sickle cell disease, a disorder that affects children and puts them at increased risk for stroke if they have high TCD blood flow velocities.

According to the data accrued by the researchers prior to the study’s termination, hydroxyurea was found to be “not inferior to (that is, no worse than) regular blood transfusions in lowering TCD velocities in children with sickle cell disease who are at high risk for stroke.”

“The results of TWiTCH will allow the families of children with sickle cell disease and who are at increased risk of stroke, to choose between two equally effective preventive therapies,” Dr. Keith Hoots, director of the NHLBI’s division of blood diseases and resources, said in an interview. “The TWiTCH trial is the most recent example of NHLBI’s ongoing commitment to the development of new therapies for the prevention and treatment of stroke in children with sickle cell disease.”

According to information from the American Society of Hematology, the trial included 25 participating centers from around the United States, and was funded by the NHLBI with sponsorship from Cincinnati Children’s Hospital Medical Center.

[email protected]

Two-year folic acid and vitamin B12 supplementation did not improve performance in four cognitive domains in elderly people with elevated homocysteine levels, according to a study published online ahead of print November 12 in Neurology. A total of 2,919 participants with an average age of 74 took either a tablet with 400 μg of folic acid and 500 μg of vitamin B12, or a placebo every day for two years. Tests of memory and thinking skills were performed at the beginning and end of the study. All participants had high blood levels of homocysteine. “While the homocysteine levels decreased by more in the group taking the B vitamins than in the group taking the placebo, unfortunately, there was no difference between the two groups in the scores on the thinking and memory tests,” the researchers stated.

Among more than 43,000 children treated in 25 emergency departments for blunt head trauma, traumatic brain injury (TBI) was identified on CT scans in 7% of the patients, according to a study published November 13 in the New England Journal of Medicine. In children 12 and younger, falls were the most common cause of head injury—among those younger than 2, falls accounted for 77% of head injuries, and in those 2 to 12, falls accounted for 38% of injuries. In children ages 13 to 17, 24% of injuries were due to assault, 19% were sports-related, and 18% resulted from motor vehicle accidents. Among all cases, 98% had mild head trauma. During diagnosis and treatment, cranial CT scans were performed on 37% of the children, “many arguably unnecessarily,” according to the researchers.

Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke, according to a study published online ahead of print November 5 in Neurology. Researchers analyzed records of 100,243 patients hospitalized for a first stroke between 2004 and 2012 and deaths within one month after the stroke. The investigators examined whether participants were current, former, or nonusers of these drugs within two months of the stroke. Overall, people who were current users of COX-2 inhibitors were 19% more likely to die after stroke than were people who did not take the drugs. New users of the older COX-2 drugs were 42% more likely to die from stroke than were those who were not taking the drugs.

Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among patients age 60 or older with atherosclerotic risk factors, according to a study published online ahead of print November 17 in JAMA. This study included 14,464 Japanese patients with hypertension, dyslipidemia, or diabetes mellitus who were randomized to aspirin (100 mg/d) or no aspirin in addition to ongoing medications. The researchers found no statistically significant difference between the two groups in time to the primary end point. The cumulative primary event rate was similar in participants in the aspirin group (2.77%) and those in the no-aspirin group (2.96%) five years after randomization. Aspirin significantly reduced the incidence of nonfatal heart attack and transient ischemic attack, and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization.

Overall symptom burden is the only independent predictor of prolonged symptoms after sport-related concussion, investigators reported online ahead of print November 7 in Neurology. The researchers conducted a prospective cohort study of 531 patients in a sports concussion clinic. Participants completed questionnaires that included the Post-Concussion Symptom Scale (PCSS). Patients ranged in age from 7 to 26 (mean age, 14.6). The mean PCSS score at the initial visit was 26, and mean time to presentation was 12 days. Only total score on symptom inventory was independently associated with symptoms lasting longer than 28 days. No other potential predictor variables were independently associated with symptom duration or were useful in developing the optimal regression decision tree. Most participants with an initial PCSS score of less than 13 had resolution of their symptoms within 28 days of injury.

The ketogenic diet and modified Atkins diet show modest efficacy, although in some patients the effect is “remarkable” in the treatment of refractory epilepsy in adults, according to a study published online ahead of print October 29 in Neurology. Researchers reviewed five studies on the ketogenic diet that included 47 people and five studies on the modified Atkins diet that included 85 people. The investigators found that across all studies, 32% of people treated with the ketogenic diet and 29% of those treated with the modified Atkins diet had a 50% or better reduction in their seizures. Nine percent in the ketogenic treatment group and 5% in the modified Atkins group had a greater than 90% reduction in seizures. “These studies show the diets are moderately to very effective as another option for people with epilepsy,” stated the study authors.

The evaluation of serum micro-RNAs may help to identify the severity of brain injury and the risk of developing adverse effects after traumatic brain injury (TBI), according to a study published November 7 in PLoS One. Researchers identified a unique and specific group of microRNAs, which were detected in blood immediately after injury to the brain in mice. The results suggest that the microRNAs can be measured in the blood as proxies for mild TBI. The microRNA panel identified in this study is unique and does not overlap with blood microRNAs of post-traumatic stress disorder, as previously reported. “This important finding is a step forward in identifying objective biomarkers for mild TBI that may be further validated to accurately and cost effectively identify mild TBI in service members and civilians with brain injuries,” said the investigators.

The FDA has approved Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The approval comes nearly one year after the FDA declined to approve the drug, citing a lack of well-controlled data from clinical studies at the time indicating that the benefits had outweighed the risks. After an appeal by Genzyme (Cambridge, Massachusetts) and a new review by the FDA, the agency approved the drug based on two pivotal, randomized phase III, open-label, rater-blinded studies, comparing treatment with Lemtrada to interferon beta-1a, in patients with relapsing-remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). Lemtrada is recommended for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Angiotensin-converting enzyme inhibitors (ACEIs) exhibited a dose-dependent inverse association with amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print November 10 in JAMA Neurology. Researchers included 729 patients diagnosed with ALS between January 2002 and December 2008. The patients were compared with 14,580 controls. Fifteen percent of patients with ALS reported ACEI use between two and five years before their ALS diagnosis, and 18% of the control group without ALS reported ACEI use. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 for the group prescribed ACEIs lower than 449.5 of the cumulative defined daily dose (cDDD) and 0.43 cDDD for the group with a cumulative ACEI use of greater than 449.5 cDDD.

Patients treated at hospitals with higher volumes of subarachnoid hemorrhage (SAH) cases have lower in-hospital mortality, independent of patient and hospital characteristics, according to a study published in the November Neurosurgery. In a large nationwide registry, researchers identified nearly 32,000 patients with SAH treated at 685 United States hospitals between 2003 and 2012. The median annual case volume per hospital was 8.5 patients. Mean in-hospital mortality was 25.7% but was lower with increasing annual SAH volume. Hospital SAH volume was independently associated with in-hospital mortality (adjusted odds ratio, 0.79 for quartile 4 vs quartile 1), independent of patient and other hospital characteristics. “Our results may have significant implications for regional stroke policies and procedures and affirm the recent recommendations that patients with SAH be treated at high-volume centers,” said study authors.

The use of a specialized ambulance—stroke emergency mobile unit (STEMO)—increases the percentage of patients receiving thrombolysis within 60 minutes, according to a study published online ahead of print November 17 in JAMA Neurology. A total of 3,213 emergency calls for suspected stroke occurred during weeks when STEMO was available, and 2,969 calls occurred during control weeks when STEMO was not available. Two hundred of 614 patients with stroke (32.6%) received thrombolysis when the STEMO was deployed, and 330 of 1,497 patients (22%) received thrombolysis in conventional care. Median onset to treatment was 24.5 minutes shorter after STEMO deployment, compared with conventional care. In all ischemic strokes, the rate of “golden hour” thrombolysis increased from 16 of the 1,497 patients (1.1%) during conventional care to 62 of 614 (10.1%) after STEMO deployment. Overall, golden hour thrombolysis entails no risk to the patients’ safety and is associated with better short-term outcomes, according to the researchers.

Granger causality (GC) analysis of intracranial EEG (iEEG) has the potential to increase understanding of preictal network activity and help improve surgical outcomes in cases of otherwise ambiguous iEEG onset, according to a study published online ahead of print November 4 in Epilepsia. In 10 retrospective and two prospective patients with epilepsy, iEEG was recorded at 500 or 1,000 Hz, using as many as 128 surface and depth electrodes. In all patients, the researchers found significant, widespread preictal GC network activity at peak frequencies from 80 to 250 Hz, beginning two to 42 seconds before visible electrographic onset. In the two prospective patients, GC source/sink comparisons supported the exclusion of early ictal regions that were not the dominant causal sources and contributed to planning of more limited surgical resections. Both groups of patients had a class 1 outcome at one year.

Tiny silent acute infarcts may be a cause of leukoaraiosis, a finding that points toward a potentially treatable form of dementia, investigators reported online ahead of print October 4 in Annals of Neurology. The study involved five patients with leukoaraiosis who underwent detailed MRI scanning of their brains every week for 16 consecutive weeks. The MRI scans revealed new tiny spots arising de novo in the cerebral white matter. The lesions were “clinically silent and had the signature features of acute ischemic stroke, according to the researchers. “With time, the characteristics of these lesions approached those of pre-existing leukoaraiosis,” the study authors stated.

—Kimberly D. Williams

Two-year folic acid and vitamin B12 supplementation did not improve performance in four cognitive domains in elderly people with elevated homocysteine levels, according to a study published online ahead of print November 12 in Neurology. A total of 2,919 participants with an average age of 74 took either a tablet with 400 μg of folic acid and 500 μg of vitamin B12, or a placebo every day for two years. Tests of memory and thinking skills were performed at the beginning and end of the study. All participants had high blood levels of homocysteine. “While the homocysteine levels decreased by more in the group taking the B vitamins than in the group taking the placebo, unfortunately, there was no difference between the two groups in the scores on the thinking and memory tests,” the researchers stated.

Among more than 43,000 children treated in 25 emergency departments for blunt head trauma, traumatic brain injury (TBI) was identified on CT scans in 7% of the patients, according to a study published November 13 in the New England Journal of Medicine. In children 12 and younger, falls were the most common cause of head injury—among those younger than 2, falls accounted for 77% of head injuries, and in those 2 to 12, falls accounted for 38% of injuries. In children ages 13 to 17, 24% of injuries were due to assault, 19% were sports-related, and 18% resulted from motor vehicle accidents. Among all cases, 98% had mild head trauma. During diagnosis and treatment, cranial CT scans were performed on 37% of the children, “many arguably unnecessarily,” according to the researchers.

Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke, according to a study published online ahead of print November 5 in Neurology. Researchers analyzed records of 100,243 patients hospitalized for a first stroke between 2004 and 2012 and deaths within one month after the stroke. The investigators examined whether participants were current, former, or nonusers of these drugs within two months of the stroke. Overall, people who were current users of COX-2 inhibitors were 19% more likely to die after stroke than were people who did not take the drugs. New users of the older COX-2 drugs were 42% more likely to die from stroke than were those who were not taking the drugs.

Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among patients age 60 or older with atherosclerotic risk factors, according to a study published online ahead of print November 17 in JAMA. This study included 14,464 Japanese patients with hypertension, dyslipidemia, or diabetes mellitus who were randomized to aspirin (100 mg/d) or no aspirin in addition to ongoing medications. The researchers found no statistically significant difference between the two groups in time to the primary end point. The cumulative primary event rate was similar in participants in the aspirin group (2.77%) and those in the no-aspirin group (2.96%) five years after randomization. Aspirin significantly reduced the incidence of nonfatal heart attack and transient ischemic attack, and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization.

Overall symptom burden is the only independent predictor of prolonged symptoms after sport-related concussion, investigators reported online ahead of print November 7 in Neurology. The researchers conducted a prospective cohort study of 531 patients in a sports concussion clinic. Participants completed questionnaires that included the Post-Concussion Symptom Scale (PCSS). Patients ranged in age from 7 to 26 (mean age, 14.6). The mean PCSS score at the initial visit was 26, and mean time to presentation was 12 days. Only total score on symptom inventory was independently associated with symptoms lasting longer than 28 days. No other potential predictor variables were independently associated with symptom duration or were useful in developing the optimal regression decision tree. Most participants with an initial PCSS score of less than 13 had resolution of their symptoms within 28 days of injury.

The ketogenic diet and modified Atkins diet show modest efficacy, although in some patients the effect is “remarkable” in the treatment of refractory epilepsy in adults, according to a study published online ahead of print October 29 in Neurology. Researchers reviewed five studies on the ketogenic diet that included 47 people and five studies on the modified Atkins diet that included 85 people. The investigators found that across all studies, 32% of people treated with the ketogenic diet and 29% of those treated with the modified Atkins diet had a 50% or better reduction in their seizures. Nine percent in the ketogenic treatment group and 5% in the modified Atkins group had a greater than 90% reduction in seizures. “These studies show the diets are moderately to very effective as another option for people with epilepsy,” stated the study authors.

The evaluation of serum micro-RNAs may help to identify the severity of brain injury and the risk of developing adverse effects after traumatic brain injury (TBI), according to a study published November 7 in PLoS One. Researchers identified a unique and specific group of microRNAs, which were detected in blood immediately after injury to the brain in mice. The results suggest that the microRNAs can be measured in the blood as proxies for mild TBI. The microRNA panel identified in this study is unique and does not overlap with blood microRNAs of post-traumatic stress disorder, as previously reported. “This important finding is a step forward in identifying objective biomarkers for mild TBI that may be further validated to accurately and cost effectively identify mild TBI in service members and civilians with brain injuries,” said the investigators.

The FDA has approved Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The approval comes nearly one year after the FDA declined to approve the drug, citing a lack of well-controlled data from clinical studies at the time indicating that the benefits had outweighed the risks. After an appeal by Genzyme (Cambridge, Massachusetts) and a new review by the FDA, the agency approved the drug based on two pivotal, randomized phase III, open-label, rater-blinded studies, comparing treatment with Lemtrada to interferon beta-1a, in patients with relapsing-remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). Lemtrada is recommended for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Angiotensin-converting enzyme inhibitors (ACEIs) exhibited a dose-dependent inverse association with amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print November 10 in JAMA Neurology. Researchers included 729 patients diagnosed with ALS between January 2002 and December 2008. The patients were compared with 14,580 controls. Fifteen percent of patients with ALS reported ACEI use between two and five years before their ALS diagnosis, and 18% of the control group without ALS reported ACEI use. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 for the group prescribed ACEIs lower than 449.5 of the cumulative defined daily dose (cDDD) and 0.43 cDDD for the group with a cumulative ACEI use of greater than 449.5 cDDD.

Patients treated at hospitals with higher volumes of subarachnoid hemorrhage (SAH) cases have lower in-hospital mortality, independent of patient and hospital characteristics, according to a study published in the November Neurosurgery. In a large nationwide registry, researchers identified nearly 32,000 patients with SAH treated at 685 United States hospitals between 2003 and 2012. The median annual case volume per hospital was 8.5 patients. Mean in-hospital mortality was 25.7% but was lower with increasing annual SAH volume. Hospital SAH volume was independently associated with in-hospital mortality (adjusted odds ratio, 0.79 for quartile 4 vs quartile 1), independent of patient and other hospital characteristics. “Our results may have significant implications for regional stroke policies and procedures and affirm the recent recommendations that patients with SAH be treated at high-volume centers,” said study authors.

The use of a specialized ambulance—stroke emergency mobile unit (STEMO)—increases the percentage of patients receiving thrombolysis within 60 minutes, according to a study published online ahead of print November 17 in JAMA Neurology. A total of 3,213 emergency calls for suspected stroke occurred during weeks when STEMO was available, and 2,969 calls occurred during control weeks when STEMO was not available. Two hundred of 614 patients with stroke (32.6%) received thrombolysis when the STEMO was deployed, and 330 of 1,497 patients (22%) received thrombolysis in conventional care. Median onset to treatment was 24.5 minutes shorter after STEMO deployment, compared with conventional care. In all ischemic strokes, the rate of “golden hour” thrombolysis increased from 16 of the 1,497 patients (1.1%) during conventional care to 62 of 614 (10.1%) after STEMO deployment. Overall, golden hour thrombolysis entails no risk to the patients’ safety and is associated with better short-term outcomes, according to the researchers.

Granger causality (GC) analysis of intracranial EEG (iEEG) has the potential to increase understanding of preictal network activity and help improve surgical outcomes in cases of otherwise ambiguous iEEG onset, according to a study published online ahead of print November 4 in Epilepsia. In 10 retrospective and two prospective patients with epilepsy, iEEG was recorded at 500 or 1,000 Hz, using as many as 128 surface and depth electrodes. In all patients, the researchers found significant, widespread preictal GC network activity at peak frequencies from 80 to 250 Hz, beginning two to 42 seconds before visible electrographic onset. In the two prospective patients, GC source/sink comparisons supported the exclusion of early ictal regions that were not the dominant causal sources and contributed to planning of more limited surgical resections. Both groups of patients had a class 1 outcome at one year.

Tiny silent acute infarcts may be a cause of leukoaraiosis, a finding that points toward a potentially treatable form of dementia, investigators reported online ahead of print October 4 in Annals of Neurology. The study involved five patients with leukoaraiosis who underwent detailed MRI scanning of their brains every week for 16 consecutive weeks. The MRI scans revealed new tiny spots arising de novo in the cerebral white matter. The lesions were “clinically silent and had the signature features of acute ischemic stroke, according to the researchers. “With time, the characteristics of these lesions approached those of pre-existing leukoaraiosis,” the study authors stated.

—Kimberly D. Williams

Two-year folic acid and vitamin B12 supplementation did not improve performance in four cognitive domains in elderly people with elevated homocysteine levels, according to a study published online ahead of print November 12 in Neurology. A total of 2,919 participants with an average age of 74 took either a tablet with 400 μg of folic acid and 500 μg of vitamin B12, or a placebo every day for two years. Tests of memory and thinking skills were performed at the beginning and end of the study. All participants had high blood levels of homocysteine. “While the homocysteine levels decreased by more in the group taking the B vitamins than in the group taking the placebo, unfortunately, there was no difference between the two groups in the scores on the thinking and memory tests,” the researchers stated.

Among more than 43,000 children treated in 25 emergency departments for blunt head trauma, traumatic brain injury (TBI) was identified on CT scans in 7% of the patients, according to a study published November 13 in the New England Journal of Medicine. In children 12 and younger, falls were the most common cause of head injury—among those younger than 2, falls accounted for 77% of head injuries, and in those 2 to 12, falls accounted for 38% of injuries. In children ages 13 to 17, 24% of injuries were due to assault, 19% were sports-related, and 18% resulted from motor vehicle accidents. Among all cases, 98% had mild head trauma. During diagnosis and treatment, cranial CT scans were performed on 37% of the children, “many arguably unnecessarily,” according to the researchers.

Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke, according to a study published online ahead of print November 5 in Neurology. Researchers analyzed records of 100,243 patients hospitalized for a first stroke between 2004 and 2012 and deaths within one month after the stroke. The investigators examined whether participants were current, former, or nonusers of these drugs within two months of the stroke. Overall, people who were current users of COX-2 inhibitors were 19% more likely to die after stroke than were people who did not take the drugs. New users of the older COX-2 drugs were 42% more likely to die from stroke than were those who were not taking the drugs.

Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among patients age 60 or older with atherosclerotic risk factors, according to a study published online ahead of print November 17 in JAMA. This study included 14,464 Japanese patients with hypertension, dyslipidemia, or diabetes mellitus who were randomized to aspirin (100 mg/d) or no aspirin in addition to ongoing medications. The researchers found no statistically significant difference between the two groups in time to the primary end point. The cumulative primary event rate was similar in participants in the aspirin group (2.77%) and those in the no-aspirin group (2.96%) five years after randomization. Aspirin significantly reduced the incidence of nonfatal heart attack and transient ischemic attack, and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization.

Overall symptom burden is the only independent predictor of prolonged symptoms after sport-related concussion, investigators reported online ahead of print November 7 in Neurology. The researchers conducted a prospective cohort study of 531 patients in a sports concussion clinic. Participants completed questionnaires that included the Post-Concussion Symptom Scale (PCSS). Patients ranged in age from 7 to 26 (mean age, 14.6). The mean PCSS score at the initial visit was 26, and mean time to presentation was 12 days. Only total score on symptom inventory was independently associated with symptoms lasting longer than 28 days. No other potential predictor variables were independently associated with symptom duration or were useful in developing the optimal regression decision tree. Most participants with an initial PCSS score of less than 13 had resolution of their symptoms within 28 days of injury.

The ketogenic diet and modified Atkins diet show modest efficacy, although in some patients the effect is “remarkable” in the treatment of refractory epilepsy in adults, according to a study published online ahead of print October 29 in Neurology. Researchers reviewed five studies on the ketogenic diet that included 47 people and five studies on the modified Atkins diet that included 85 people. The investigators found that across all studies, 32% of people treated with the ketogenic diet and 29% of those treated with the modified Atkins diet had a 50% or better reduction in their seizures. Nine percent in the ketogenic treatment group and 5% in the modified Atkins group had a greater than 90% reduction in seizures. “These studies show the diets are moderately to very effective as another option for people with epilepsy,” stated the study authors.

The evaluation of serum micro-RNAs may help to identify the severity of brain injury and the risk of developing adverse effects after traumatic brain injury (TBI), according to a study published November 7 in PLoS One. Researchers identified a unique and specific group of microRNAs, which were detected in blood immediately after injury to the brain in mice. The results suggest that the microRNAs can be measured in the blood as proxies for mild TBI. The microRNA panel identified in this study is unique and does not overlap with blood microRNAs of post-traumatic stress disorder, as previously reported. “This important finding is a step forward in identifying objective biomarkers for mild TBI that may be further validated to accurately and cost effectively identify mild TBI in service members and civilians with brain injuries,” said the investigators.

The FDA has approved Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis (MS). The approval comes nearly one year after the FDA declined to approve the drug, citing a lack of well-controlled data from clinical studies at the time indicating that the benefits had outweighed the risks. After an appeal by Genzyme (Cambridge, Massachusetts) and a new review by the FDA, the agency approved the drug based on two pivotal, randomized phase III, open-label, rater-blinded studies, comparing treatment with Lemtrada to interferon beta-1a, in patients with relapsing-remitting MS who were either new to treatment (CARE-MS I) or who had relapsed while on prior therapy (CARE-MS II). Lemtrada is recommended for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.

Angiotensin-converting enzyme inhibitors (ACEIs) exhibited a dose-dependent inverse association with amyotrophic lateral sclerosis (ALS), according to a study published online ahead of print November 10 in JAMA Neurology. Researchers included 729 patients diagnosed with ALS between January 2002 and December 2008. The patients were compared with 14,580 controls. Fifteen percent of patients with ALS reported ACEI use between two and five years before their ALS diagnosis, and 18% of the control group without ALS reported ACEI use. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 for the group prescribed ACEIs lower than 449.5 of the cumulative defined daily dose (cDDD) and 0.43 cDDD for the group with a cumulative ACEI use of greater than 449.5 cDDD.

Patients treated at hospitals with higher volumes of subarachnoid hemorrhage (SAH) cases have lower in-hospital mortality, independent of patient and hospital characteristics, according to a study published in the November Neurosurgery. In a large nationwide registry, researchers identified nearly 32,000 patients with SAH treated at 685 United States hospitals between 2003 and 2012. The median annual case volume per hospital was 8.5 patients. Mean in-hospital mortality was 25.7% but was lower with increasing annual SAH volume. Hospital SAH volume was independently associated with in-hospital mortality (adjusted odds ratio, 0.79 for quartile 4 vs quartile 1), independent of patient and other hospital characteristics. “Our results may have significant implications for regional stroke policies and procedures and affirm the recent recommendations that patients with SAH be treated at high-volume centers,” said study authors.

The use of a specialized ambulance—stroke emergency mobile unit (STEMO)—increases the percentage of patients receiving thrombolysis within 60 minutes, according to a study published online ahead of print November 17 in JAMA Neurology. A total of 3,213 emergency calls for suspected stroke occurred during weeks when STEMO was available, and 2,969 calls occurred during control weeks when STEMO was not available. Two hundred of 614 patients with stroke (32.6%) received thrombolysis when the STEMO was deployed, and 330 of 1,497 patients (22%) received thrombolysis in conventional care. Median onset to treatment was 24.5 minutes shorter after STEMO deployment, compared with conventional care. In all ischemic strokes, the rate of “golden hour” thrombolysis increased from 16 of the 1,497 patients (1.1%) during conventional care to 62 of 614 (10.1%) after STEMO deployment. Overall, golden hour thrombolysis entails no risk to the patients’ safety and is associated with better short-term outcomes, according to the researchers.

Granger causality (GC) analysis of intracranial EEG (iEEG) has the potential to increase understanding of preictal network activity and help improve surgical outcomes in cases of otherwise ambiguous iEEG onset, according to a study published online ahead of print November 4 in Epilepsia. In 10 retrospective and two prospective patients with epilepsy, iEEG was recorded at 500 or 1,000 Hz, using as many as 128 surface and depth electrodes. In all patients, the researchers found significant, widespread preictal GC network activity at peak frequencies from 80 to 250 Hz, beginning two to 42 seconds before visible electrographic onset. In the two prospective patients, GC source/sink comparisons supported the exclusion of early ictal regions that were not the dominant causal sources and contributed to planning of more limited surgical resections. Both groups of patients had a class 1 outcome at one year.

Tiny silent acute infarcts may be a cause of leukoaraiosis, a finding that points toward a potentially treatable form of dementia, investigators reported online ahead of print October 4 in Annals of Neurology. The study involved five patients with leukoaraiosis who underwent detailed MRI scanning of their brains every week for 16 consecutive weeks. The MRI scans revealed new tiny spots arising de novo in the cerebral white matter. The lesions were “clinically silent and had the signature features of acute ischemic stroke, according to the researchers. “With time, the characteristics of these lesions approached those of pre-existing leukoaraiosis,” the study authors stated.

—Kimberly D. Williams

Amit Nathwani, MBChB, PhD

Credit: University College

London Hospitals

A novel gene therapy can provide lasting clinical improvement for men with severe hemophilia B, according to research published in NEJM.

In a study of 10 men, the therapy increased factor IX levels, reduced bleeding episodes, and decreased the use of prophylactic factor IX concentrate. The therapy also allowed some patients to adopt a more active lifestyle.

Four patients experienced temporary increases in liver enzymes, but none reported late toxic effects at a median follow-up of 3 years.

“The data we are reporting mark a paradigm shift in treatment of hemophilia B and lay the groundwork for curing this major bleeding disorder,” said study author Amit Nathwani, MBChB, PhD, of the University College London Cancer Institute in the UK.

“The results also provide a solid platform for developing this gene transfer approach for treatment of other disorders, ranging from other congenital clotting deficiencies like hemophilia A to inborn errors of metabolism such as phenylketonuria.”

The therapy consists of a serotype 8 pseudotyped, self-complementary adeno-associated virus (AAV8) vector expressing a codon-optimized factor IX transgene (scAAV2/8-LP1-hFIXco).

Dr Nathwani and his colleagues tested scAAV2/8-LP1-hFIXco in 10 men with severe hemophilia B to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity.

Six of the patients had been enrolled in a phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose of the therapy. The other 4 patients received the high dose (2 × 10¹² vector genomes per kg of body weight). Patients received scAAV2/8-LP1-hFIXco as a single infusion.

Factor IX levels rose in all 10 men following the infusion and have remained stable for a median of 3.2 years (range, 1.5 to 4.3 years).

Overall, episodes of spontaneous bleeding declined 90%. The use of factor IX replacement therapy dropped about 92% in the first 12 months after treatment with scAAV2/8-LP1-hFIXco.

In the 6 participants who received the highest dose of therapy, factor IX levels increased from less than 1% of normal levels to 5% or more.

The increase transformed their disease from severe to mild and enabled participation in sports such as soccer without the need for factor IX replacement therapy or an increase in the risk of bleeding.

Episodes of spontaneous bleeding and the use of factor IX replacement therapy declined for these patients more than 94% in the next 12 months.

Liver enzymes rose in 4 of the 6 patients who received the highest dose of scAAV2/8-LP1-hFIXco, possibly due to an immune response against the vector. The men had no symptoms and remained otherwise healthy. Their liver enzymes returned to the normal range following brief treatment with steroids.

“This study provides the first clear demonstration of the long-term safety and efficacy of gene therapy,” said study author Andrew Davidoff, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

“The results so far have made a profound difference in the lives of study participants by dramatically reducing their risk of bleeding.”

Prior to receiving scAAV2/8-LP1-hFIXco, 7 of the men received factor IX replacement therapy at least once a week to prevent bleeding episodes. Others used replacement therapy as needed to halt bleeding or prior to surgeries.

Since joining the trial, 4 of these men ended the routine factor IX injections. And none have suffered spontaneous bleeding despite increased physical activity.

“Some patients have not required clotting factor injections for more than 4 years, which has been life-changing,” Dr Nathwani said.

The researchers estimated that overall spending on factor IX replacement therapy for study participants is down more than $2.5 million.

Twelve men have now joined this ongoing phase 1/2 trial. Half were treated at the University College London and half at St. Jude.

Discussions are underway about expanding the trial to include younger patients with hemophilia B. Meanwhile, work continues to improve and expand use of the vector for the treatment of hemophilia A.

Amit Nathwani, MBChB, PhD

Credit: University College

London Hospitals

A novel gene therapy can provide lasting clinical improvement for men with severe hemophilia B, according to research published in NEJM.

In a study of 10 men, the therapy increased factor IX levels, reduced bleeding episodes, and decreased the use of prophylactic factor IX concentrate. The therapy also allowed some patients to adopt a more active lifestyle.

Four patients experienced temporary increases in liver enzymes, but none reported late toxic effects at a median follow-up of 3 years.

“The data we are reporting mark a paradigm shift in treatment of hemophilia B and lay the groundwork for curing this major bleeding disorder,” said study author Amit Nathwani, MBChB, PhD, of the University College London Cancer Institute in the UK.

“The results also provide a solid platform for developing this gene transfer approach for treatment of other disorders, ranging from other congenital clotting deficiencies like hemophilia A to inborn errors of metabolism such as phenylketonuria.”

The therapy consists of a serotype 8 pseudotyped, self-complementary adeno-associated virus (AAV8) vector expressing a codon-optimized factor IX transgene (scAAV2/8-LP1-hFIXco).

Dr Nathwani and his colleagues tested scAAV2/8-LP1-hFIXco in 10 men with severe hemophilia B to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity.

Six of the patients had been enrolled in a phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose of the therapy. The other 4 patients received the high dose (2 × 10¹² vector genomes per kg of body weight). Patients received scAAV2/8-LP1-hFIXco as a single infusion.

Factor IX levels rose in all 10 men following the infusion and have remained stable for a median of 3.2 years (range, 1.5 to 4.3 years).

Overall, episodes of spontaneous bleeding declined 90%. The use of factor IX replacement therapy dropped about 92% in the first 12 months after treatment with scAAV2/8-LP1-hFIXco.

In the 6 participants who received the highest dose of therapy, factor IX levels increased from less than 1% of normal levels to 5% or more.

The increase transformed their disease from severe to mild and enabled participation in sports such as soccer without the need for factor IX replacement therapy or an increase in the risk of bleeding.

Episodes of spontaneous bleeding and the use of factor IX replacement therapy declined for these patients more than 94% in the next 12 months.

Liver enzymes rose in 4 of the 6 patients who received the highest dose of scAAV2/8-LP1-hFIXco, possibly due to an immune response against the vector. The men had no symptoms and remained otherwise healthy. Their liver enzymes returned to the normal range following brief treatment with steroids.

“This study provides the first clear demonstration of the long-term safety and efficacy of gene therapy,” said study author Andrew Davidoff, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

“The results so far have made a profound difference in the lives of study participants by dramatically reducing their risk of bleeding.”

Prior to receiving scAAV2/8-LP1-hFIXco, 7 of the men received factor IX replacement therapy at least once a week to prevent bleeding episodes. Others used replacement therapy as needed to halt bleeding or prior to surgeries.

Since joining the trial, 4 of these men ended the routine factor IX injections. And none have suffered spontaneous bleeding despite increased physical activity.

“Some patients have not required clotting factor injections for more than 4 years, which has been life-changing,” Dr Nathwani said.

The researchers estimated that overall spending on factor IX replacement therapy for study participants is down more than $2.5 million.

Twelve men have now joined this ongoing phase 1/2 trial. Half were treated at the University College London and half at St. Jude.

Discussions are underway about expanding the trial to include younger patients with hemophilia B. Meanwhile, work continues to improve and expand use of the vector for the treatment of hemophilia A.

Amit Nathwani, MBChB, PhD

Credit: University College

London Hospitals

A novel gene therapy can provide lasting clinical improvement for men with severe hemophilia B, according to research published in NEJM.

In a study of 10 men, the therapy increased factor IX levels, reduced bleeding episodes, and decreased the use of prophylactic factor IX concentrate. The therapy also allowed some patients to adopt a more active lifestyle.

Four patients experienced temporary increases in liver enzymes, but none reported late toxic effects at a median follow-up of 3 years.

“The data we are reporting mark a paradigm shift in treatment of hemophilia B and lay the groundwork for curing this major bleeding disorder,” said study author Amit Nathwani, MBChB, PhD, of the University College London Cancer Institute in the UK.

“The results also provide a solid platform for developing this gene transfer approach for treatment of other disorders, ranging from other congenital clotting deficiencies like hemophilia A to inborn errors of metabolism such as phenylketonuria.”

The therapy consists of a serotype 8 pseudotyped, self-complementary adeno-associated virus (AAV8) vector expressing a codon-optimized factor IX transgene (scAAV2/8-LP1-hFIXco).

Dr Nathwani and his colleagues tested scAAV2/8-LP1-hFIXco in 10 men with severe hemophilia B to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity.

Six of the patients had been enrolled in a phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose of the therapy. The other 4 patients received the high dose (2 × 10¹² vector genomes per kg of body weight). Patients received scAAV2/8-LP1-hFIXco as a single infusion.

Factor IX levels rose in all 10 men following the infusion and have remained stable for a median of 3.2 years (range, 1.5 to 4.3 years).

Overall, episodes of spontaneous bleeding declined 90%. The use of factor IX replacement therapy dropped about 92% in the first 12 months after treatment with scAAV2/8-LP1-hFIXco.

In the 6 participants who received the highest dose of therapy, factor IX levels increased from less than 1% of normal levels to 5% or more.

The increase transformed their disease from severe to mild and enabled participation in sports such as soccer without the need for factor IX replacement therapy or an increase in the risk of bleeding.

Episodes of spontaneous bleeding and the use of factor IX replacement therapy declined for these patients more than 94% in the next 12 months.

Liver enzymes rose in 4 of the 6 patients who received the highest dose of scAAV2/8-LP1-hFIXco, possibly due to an immune response against the vector. The men had no symptoms and remained otherwise healthy. Their liver enzymes returned to the normal range following brief treatment with steroids.

“This study provides the first clear demonstration of the long-term safety and efficacy of gene therapy,” said study author Andrew Davidoff, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.

“The results so far have made a profound difference in the lives of study participants by dramatically reducing their risk of bleeding.”

Prior to receiving scAAV2/8-LP1-hFIXco, 7 of the men received factor IX replacement therapy at least once a week to prevent bleeding episodes. Others used replacement therapy as needed to halt bleeding or prior to surgeries.

Since joining the trial, 4 of these men ended the routine factor IX injections. And none have suffered spontaneous bleeding despite increased physical activity.

“Some patients have not required clotting factor injections for more than 4 years, which has been life-changing,” Dr Nathwani said.

The researchers estimated that overall spending on factor IX replacement therapy for study participants is down more than $2.5 million.

Twelve men have now joined this ongoing phase 1/2 trial. Half were treated at the University College London and half at St. Jude.

Discussions are underway about expanding the trial to include younger patients with hemophilia B. Meanwhile, work continues to improve and expand use of the vector for the treatment of hemophilia A.

Doctor examines SCD patient

Credit: St Jude Children’s

Research Hospital

Treatment with hydroxyurea is a comparable alternative to blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), according to the National Heart Lung and Blood Institute (NHLBI).

Early results of the phase 3 TWiTCH trial showed that daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.

Based on these findings, the NHLBI has terminated the trial early, about a year before it was originally scheduled to end.

“Early results indicate that TWiTCH is a success,” said Russell E. Ware, MD, PhD, principal investigator of the study and director of hematology at Cincinnati Children’s Hospital Medical Center.

“A group of outside experts has been reviewing the TWiTCH data every few months to ensure the safety of children in the clinical trial and to monitor the data. This group met recently and, after careful consideration of the interim data results, recommended that the study be stopped since hydroxyurea worked as well as transfusions to lower TCD velocities.”

The NHLBI said it cannot release results from the TWiTCH trial, but some details are available. Researchers enrolled 121 children between the ages of 4 and 16 who had SCD and abnormally elevated TCD velocities.

Half of patients received transfusions, and the other half received daily hydroxyurea, which has not yet been approved for children with SCD.

The clinical data-collection portion of the study was originally scheduled for the 24-month mark, but collection was stopped after only half of the children completed the treatment phase.

At the first interim analysis, a data and safety monitoring board found that hydroxyurea was not inferior to regular blood transfusions in lowering TCD velocities. And the board said the strength of the statistical finding was unlikely to change with the collection of additional data.

After reviewing the board’s recommendation, the NHLBI decided to end the study early, as the primary endpoint had been met.

Study participants have been notified about the trial’s ending, and they will have the opportunity to receive the care they feel is best suited for them.

“No child should ever suffer a stroke, which is why it was so important for the NHLBI to support the TWiTCH trial,” said Gary Gibbons, MD, director of the NHLBI. “This critical research finding opens the door to more treatment options for clinicians trying to prevent strokes in children living with the sickle cell disease.”

Doctor examines SCD patient

Credit: St Jude Children’s

Research Hospital

Treatment with hydroxyurea is a comparable alternative to blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), according to the National Heart Lung and Blood Institute (NHLBI).

Early results of the phase 3 TWiTCH trial showed that daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.

Based on these findings, the NHLBI has terminated the trial early, about a year before it was originally scheduled to end.

“Early results indicate that TWiTCH is a success,” said Russell E. Ware, MD, PhD, principal investigator of the study and director of hematology at Cincinnati Children’s Hospital Medical Center.

“A group of outside experts has been reviewing the TWiTCH data every few months to ensure the safety of children in the clinical trial and to monitor the data. This group met recently and, after careful consideration of the interim data results, recommended that the study be stopped since hydroxyurea worked as well as transfusions to lower TCD velocities.”

The NHLBI said it cannot release results from the TWiTCH trial, but some details are available. Researchers enrolled 121 children between the ages of 4 and 16 who had SCD and abnormally elevated TCD velocities.

Half of patients received transfusions, and the other half received daily hydroxyurea, which has not yet been approved for children with SCD.

The clinical data-collection portion of the study was originally scheduled for the 24-month mark, but collection was stopped after only half of the children completed the treatment phase.

At the first interim analysis, a data and safety monitoring board found that hydroxyurea was not inferior to regular blood transfusions in lowering TCD velocities. And the board said the strength of the statistical finding was unlikely to change with the collection of additional data.

After reviewing the board’s recommendation, the NHLBI decided to end the study early, as the primary endpoint had been met.

Study participants have been notified about the trial’s ending, and they will have the opportunity to receive the care they feel is best suited for them.

“No child should ever suffer a stroke, which is why it was so important for the NHLBI to support the TWiTCH trial,” said Gary Gibbons, MD, director of the NHLBI. “This critical research finding opens the door to more treatment options for clinicians trying to prevent strokes in children living with the sickle cell disease.”

Doctor examines SCD patient

Credit: St Jude Children’s

Research Hospital

Treatment with hydroxyurea is a comparable alternative to blood transfusions for reducing the risk of stroke in children with sickle cell disease (SCD), according to the National Heart Lung and Blood Institute (NHLBI).

Early results of the phase 3 TWiTCH trial showed that daily doses of hydroxyurea lower the transcranial Doppler (TCD) blood velocity in children with SCD to a similar degree as blood transfusions, thereby decreasing the risk of stroke.

Based on these findings, the NHLBI has terminated the trial early, about a year before it was originally scheduled to end.

“Early results indicate that TWiTCH is a success,” said Russell E. Ware, MD, PhD, principal investigator of the study and director of hematology at Cincinnati Children’s Hospital Medical Center.

“A group of outside experts has been reviewing the TWiTCH data every few months to ensure the safety of children in the clinical trial and to monitor the data. This group met recently and, after careful consideration of the interim data results, recommended that the study be stopped since hydroxyurea worked as well as transfusions to lower TCD velocities.”

The NHLBI said it cannot release results from the TWiTCH trial, but some details are available. Researchers enrolled 121 children between the ages of 4 and 16 who had SCD and abnormally elevated TCD velocities.

Half of patients received transfusions, and the other half received daily hydroxyurea, which has not yet been approved for children with SCD.

The clinical data-collection portion of the study was originally scheduled for the 24-month mark, but collection was stopped after only half of the children completed the treatment phase.

At the first interim analysis, a data and safety monitoring board found that hydroxyurea was not inferior to regular blood transfusions in lowering TCD velocities. And the board said the strength of the statistical finding was unlikely to change with the collection of additional data.

After reviewing the board’s recommendation, the NHLBI decided to end the study early, as the primary endpoint had been met.

Study participants have been notified about the trial’s ending, and they will have the opportunity to receive the care they feel is best suited for them.

“No child should ever suffer a stroke, which is why it was so important for the NHLBI to support the TWiTCH trial,” said Gary Gibbons, MD, director of the NHLBI. “This critical research finding opens the door to more treatment options for clinicians trying to prevent strokes in children living with the sickle cell disease.”

Diffuse large B-cell lymphoma

BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.

In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.

And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.

The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.

“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.

The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.

The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.

All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.

E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).

‘Encouraging activity’

Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.

Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.

Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.

Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.

The patient with marginal zone lymphoma achieved stable disease and remains on study.

Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.

“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.

“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”

‘Little toxicity’

All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.

The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.

There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.

“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”

E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.

Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.

Diffuse large B-cell lymphoma

BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.

In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.

And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.

The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.

“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.

The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.

The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.

All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.

E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).

‘Encouraging activity’

Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.

Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.

Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.

Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.

The patient with marginal zone lymphoma achieved stable disease and remains on study.

Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.

“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.

“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”

‘Little toxicity’

All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.

The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.

There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.

“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”

E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.

Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.

Diffuse large B-cell lymphoma

BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.

In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.

And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.

The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.

“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.

The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.

The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.

All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.

E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).

‘Encouraging activity’

Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.

Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.

Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.

Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.

The patient with marginal zone lymphoma achieved stable disease and remains on study.

Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.

“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.

“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”

‘Little toxicity’

All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.

The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.

There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.

“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”

E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.

Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.

AML cells

Credit: Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation for the Axl inhibitor BGB324 to treat acute myeloid leukemia (AML).

BGB324 is a highly selective small molecule inhibitor of the Axl receptor tyrosine kinase. It blocks the epithelial-mesenchymal transition, a key driver in drug resistance and metastasis.

BerGenBio, the company developing BGB324, has estimated that more than 50% of AML patients have elevated levels of Axl.

And a study published in Blood last year showed that Axl inhibition by BGB324 prompts antileukemic activity in FLT3-mutated and FLT3-wild-type AML.

Earlier this month, BerGenBio said the first patient had been dosed in its multicenter phase 1b trial of BGB324 in patients with AML.

The primary goal of this 2-part trial is to investigate the safety and tolerability of BGB324 as a single agent and in combination with cytarabine. Secondary endpoints include clinical response and assessment of novel biomarkers.

The study will be conducted at 6 sites in Norway, Germany, and the US. BerGenBio expects data from this trial to be available in 2015.

The FDA’s orphan designation will provide BerGenBio with access to various development incentives for BGB324.

This includes tax credits for qualified clinical testing, exemption from prescription drug user fees for BGB324 in AML, and 7 years of market exclusivity in the US upon FDA approval.

AML cells

Credit: Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation for the Axl inhibitor BGB324 to treat acute myeloid leukemia (AML).

BGB324 is a highly selective small molecule inhibitor of the Axl receptor tyrosine kinase. It blocks the epithelial-mesenchymal transition, a key driver in drug resistance and metastasis.

BerGenBio, the company developing BGB324, has estimated that more than 50% of AML patients have elevated levels of Axl.

And a study published in Blood last year showed that Axl inhibition by BGB324 prompts antileukemic activity in FLT3-mutated and FLT3-wild-type AML.

Earlier this month, BerGenBio said the first patient had been dosed in its multicenter phase 1b trial of BGB324 in patients with AML.

The primary goal of this 2-part trial is to investigate the safety and tolerability of BGB324 as a single agent and in combination with cytarabine. Secondary endpoints include clinical response and assessment of novel biomarkers.

The study will be conducted at 6 sites in Norway, Germany, and the US. BerGenBio expects data from this trial to be available in 2015.

The FDA’s orphan designation will provide BerGenBio with access to various development incentives for BGB324.

This includes tax credits for qualified clinical testing, exemption from prescription drug user fees for BGB324 in AML, and 7 years of market exclusivity in the US upon FDA approval.

AML cells

Credit: Lance Liotta

The US Food and Drug Administration (FDA) has granted orphan drug designation for the Axl inhibitor BGB324 to treat acute myeloid leukemia (AML).

BGB324 is a highly selective small molecule inhibitor of the Axl receptor tyrosine kinase. It blocks the epithelial-mesenchymal transition, a key driver in drug resistance and metastasis.

BerGenBio, the company developing BGB324, has estimated that more than 50% of AML patients have elevated levels of Axl.

And a study published in Blood last year showed that Axl inhibition by BGB324 prompts antileukemic activity in FLT3-mutated and FLT3-wild-type AML.

Earlier this month, BerGenBio said the first patient had been dosed in its multicenter phase 1b trial of BGB324 in patients with AML.

The primary goal of this 2-part trial is to investigate the safety and tolerability of BGB324 as a single agent and in combination with cytarabine. Secondary endpoints include clinical response and assessment of novel biomarkers.

The study will be conducted at 6 sites in Norway, Germany, and the US. BerGenBio expects data from this trial to be available in 2015.

The FDA’s orphan designation will provide BerGenBio with access to various development incentives for BGB324.

This includes tax credits for qualified clinical testing, exemption from prescription drug user fees for BGB324 in AML, and 7 years of market exclusivity in the US upon FDA approval.