Hematology

The Food and Drug Administration has approved the first treatment for anemia in adults with transfusion-dependent beta thalassemia.

Olivier Le Moal/Getty Images

Luspatercept-aamt (Reblozyl) is an erythroid maturation agent that reduced the transfusion burden for patients with beta thalassemia in the BELIEVE trial of 336 patients. In total, 21% of patients who received luspatercept-aamt achieved at least a 33% reduction in red blood cell transfusions, compared with 4.5% of patients who received placebo, according to the FDA.

Common side effects associated with luspatercept-aamt were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. Patients taking the agent should be monitored for thrombosis, the FDA advised.

Celgene, which makes luspatercept-aamt, said the agent would be available about 1 week following the FDA approval.

The FDA is also evaluating luspatercept-aamt as an anemia treatment in adults with very-low– to intermediate-risk myelodysplastic syndromes who have ring sideroblasts and require red blood cell transfusions. The agency is expected to take action on that application in April 2020.

[email protected]

The Food and Drug Administration has approved the first treatment for anemia in adults with transfusion-dependent beta thalassemia.

Olivier Le Moal/Getty Images

Luspatercept-aamt (Reblozyl) is an erythroid maturation agent that reduced the transfusion burden for patients with beta thalassemia in the BELIEVE trial of 336 patients. In total, 21% of patients who received luspatercept-aamt achieved at least a 33% reduction in red blood cell transfusions, compared with 4.5% of patients who received placebo, according to the FDA.

Common side effects associated with luspatercept-aamt were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. Patients taking the agent should be monitored for thrombosis, the FDA advised.

Celgene, which makes luspatercept-aamt, said the agent would be available about 1 week following the FDA approval.

The FDA is also evaluating luspatercept-aamt as an anemia treatment in adults with very-low– to intermediate-risk myelodysplastic syndromes who have ring sideroblasts and require red blood cell transfusions. The agency is expected to take action on that application in April 2020.

[email protected]

The Food and Drug Administration has approved the first treatment for anemia in adults with transfusion-dependent beta thalassemia.

Olivier Le Moal/Getty Images

Luspatercept-aamt (Reblozyl) is an erythroid maturation agent that reduced the transfusion burden for patients with beta thalassemia in the BELIEVE trial of 336 patients. In total, 21% of patients who received luspatercept-aamt achieved at least a 33% reduction in red blood cell transfusions, compared with 4.5% of patients who received placebo, according to the FDA.

Common side effects associated with luspatercept-aamt were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. Patients taking the agent should be monitored for thrombosis, the FDA advised.

Celgene, which makes luspatercept-aamt, said the agent would be available about 1 week following the FDA approval.

The FDA is also evaluating luspatercept-aamt as an anemia treatment in adults with very-low– to intermediate-risk myelodysplastic syndromes who have ring sideroblasts and require red blood cell transfusions. The agency is expected to take action on that application in April 2020.

[email protected]

The most rural counties in the United States had higher percentages of potentially preventable deaths from the five leading causes of mortality, compared with the most urban counties during 2010-2017, according to study published in CDC’s Morbidity and Mortality Weekly Report.

These leading causes of death comprised heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke and accounted for approximately 1.7 million deaths or 61% of all deaths in 2017.

The study presents estimates, percentages, and annual percent changes for potentially excess deaths by urban-rural classification from heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke. Urban-rural categories were identified using the National Center for Health Statistics 2013 urban-rural classification scheme for counties.

The report’s main findings include the following statistics:

• In 2010, 28.7% of deaths from cancer in the most rural counties were potentially preventable, compared with 17.9% in the most urban counties. By 2017, 21.7% of cancer deaths in the most rural counties were potentially preventable, compared with 3.2% in the most urban counties.
• In 2010, 45.1% of deaths from heart disease in the most rural counties were potentially preventable, compared with 33.5% in the most urban counties. By 2017, 44.9% of deaths from heart disease in the most rural counties were potentially preventable, compared with 28.0% in the most urban counties.
• In 2010, 60.9% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 25.4% in the most urban counties. By 2017, 64.1% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 47.8% in the most urban counties.
• In 2010, 54.3% of deaths from chronic lower respiratory disease (such as COPD) in the most rural counties were potentially preventable, compared with 23.4% in the most urban counties. By 2017, 57.1% of deaths from chronic lower respiratory disease in the most rural counties were potentially preventable, compared with 13% in the most urban counties.
• In 2010, 41.6% of deaths from stroke in the most rural counties were potentially preventable, compared with 31.7% in most urban areas. By 2017, 37.8% of deaths from stroke in the most rural counties were potentially preventable, compared with 27.4% most urban counties.

“This report demonstrates the value of analyzing potentially excess deaths according to the six 2013 [National Center for Health Statistics] urban-rural county classifications. Reporting trends in potentially excess deaths over an 8-year period highlights differences over time, independent of traditional underlying structural, environmental, and genetic factors,” wrote Macarena C. Garcia, DrPH, and coauthors.

“Because of increasing percentages of potentially excess deaths in recent years for certain causes of death and certain demographic groups, these data can be used, with traditional rate comparisons, by public health practitioners who are involved in planning interventions. Comparing the findings in this report with data from tools such as the CDC Interactive Atlas of Heart Disease and Stroke might help identify the social determinants, health care infrastructures, and public policies that could increase or decrease numbers of deaths in specific nonmetropolitan areas,” they added.

The study authors did not disclose any potential conflicts of interest.
 

[email protected]

SOURCE: Garcia MC et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(10);1-11.

The most rural counties in the United States had higher percentages of potentially preventable deaths from the five leading causes of mortality, compared with the most urban counties during 2010-2017, according to study published in CDC’s Morbidity and Mortality Weekly Report.

These leading causes of death comprised heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke and accounted for approximately 1.7 million deaths or 61% of all deaths in 2017.

The study presents estimates, percentages, and annual percent changes for potentially excess deaths by urban-rural classification from heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke. Urban-rural categories were identified using the National Center for Health Statistics 2013 urban-rural classification scheme for counties.

The report’s main findings include the following statistics:

• In 2010, 28.7% of deaths from cancer in the most rural counties were potentially preventable, compared with 17.9% in the most urban counties. By 2017, 21.7% of cancer deaths in the most rural counties were potentially preventable, compared with 3.2% in the most urban counties.
• In 2010, 45.1% of deaths from heart disease in the most rural counties were potentially preventable, compared with 33.5% in the most urban counties. By 2017, 44.9% of deaths from heart disease in the most rural counties were potentially preventable, compared with 28.0% in the most urban counties.
• In 2010, 60.9% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 25.4% in the most urban counties. By 2017, 64.1% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 47.8% in the most urban counties.
• In 2010, 54.3% of deaths from chronic lower respiratory disease (such as COPD) in the most rural counties were potentially preventable, compared with 23.4% in the most urban counties. By 2017, 57.1% of deaths from chronic lower respiratory disease in the most rural counties were potentially preventable, compared with 13% in the most urban counties.
• In 2010, 41.6% of deaths from stroke in the most rural counties were potentially preventable, compared with 31.7% in most urban areas. By 2017, 37.8% of deaths from stroke in the most rural counties were potentially preventable, compared with 27.4% most urban counties.

“This report demonstrates the value of analyzing potentially excess deaths according to the six 2013 [National Center for Health Statistics] urban-rural county classifications. Reporting trends in potentially excess deaths over an 8-year period highlights differences over time, independent of traditional underlying structural, environmental, and genetic factors,” wrote Macarena C. Garcia, DrPH, and coauthors.

“Because of increasing percentages of potentially excess deaths in recent years for certain causes of death and certain demographic groups, these data can be used, with traditional rate comparisons, by public health practitioners who are involved in planning interventions. Comparing the findings in this report with data from tools such as the CDC Interactive Atlas of Heart Disease and Stroke might help identify the social determinants, health care infrastructures, and public policies that could increase or decrease numbers of deaths in specific nonmetropolitan areas,” they added.

The study authors did not disclose any potential conflicts of interest.
 

[email protected]

SOURCE: Garcia MC et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(10);1-11.

The most rural counties in the United States had higher percentages of potentially preventable deaths from the five leading causes of mortality, compared with the most urban counties during 2010-2017, according to study published in CDC’s Morbidity and Mortality Weekly Report.

These leading causes of death comprised heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke and accounted for approximately 1.7 million deaths or 61% of all deaths in 2017.

The study presents estimates, percentages, and annual percent changes for potentially excess deaths by urban-rural classification from heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke. Urban-rural categories were identified using the National Center for Health Statistics 2013 urban-rural classification scheme for counties.

The report’s main findings include the following statistics:

• In 2010, 28.7% of deaths from cancer in the most rural counties were potentially preventable, compared with 17.9% in the most urban counties. By 2017, 21.7% of cancer deaths in the most rural counties were potentially preventable, compared with 3.2% in the most urban counties.
• In 2010, 45.1% of deaths from heart disease in the most rural counties were potentially preventable, compared with 33.5% in the most urban counties. By 2017, 44.9% of deaths from heart disease in the most rural counties were potentially preventable, compared with 28.0% in the most urban counties.
• In 2010, 60.9% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 25.4% in the most urban counties. By 2017, 64.1% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 47.8% in the most urban counties.
• In 2010, 54.3% of deaths from chronic lower respiratory disease (such as COPD) in the most rural counties were potentially preventable, compared with 23.4% in the most urban counties. By 2017, 57.1% of deaths from chronic lower respiratory disease in the most rural counties were potentially preventable, compared with 13% in the most urban counties.
• In 2010, 41.6% of deaths from stroke in the most rural counties were potentially preventable, compared with 31.7% in most urban areas. By 2017, 37.8% of deaths from stroke in the most rural counties were potentially preventable, compared with 27.4% most urban counties.

“This report demonstrates the value of analyzing potentially excess deaths according to the six 2013 [National Center for Health Statistics] urban-rural county classifications. Reporting trends in potentially excess deaths over an 8-year period highlights differences over time, independent of traditional underlying structural, environmental, and genetic factors,” wrote Macarena C. Garcia, DrPH, and coauthors.

“Because of increasing percentages of potentially excess deaths in recent years for certain causes of death and certain demographic groups, these data can be used, with traditional rate comparisons, by public health practitioners who are involved in planning interventions. Comparing the findings in this report with data from tools such as the CDC Interactive Atlas of Heart Disease and Stroke might help identify the social determinants, health care infrastructures, and public policies that could increase or decrease numbers of deaths in specific nonmetropolitan areas,” they added.

The study authors did not disclose any potential conflicts of interest.
 

[email protected]

SOURCE: Garcia MC et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(10);1-11.

SAN ANTONIO – Clinicians don’t appear to mind too much when their red blood cell orders are flagged for review by a best practice alert system, and alert fatigue doesn’t seem to hamper patient blood management efforts, investigators in a single-center study reported.

Neil Osterweil/MDedge News

At the Medical University of South Carolina, Charleston (MUSC), if clinicians order RBC transfusions for patients with hemoglobin levels over 7.0 g/dL or for patients who did not have a hemoglobin determination over the past 24 hours, they receive a best practice alert. They must acknowledge it and cancel the order, or override it and document a reason in the medical record.

Although approximately 70% of alerts were overridden, the reasons for the overrides “were consistent over time and appropriate,” reported Jerry E. Squires, MD, PhD, and colleagues from MUSC in a poster presentation at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The goal of the study was to find out if the effectiveness of the alert was wearing out after months of active use by clinicians. “Is it true that they’re clicking too much and they’re inundated with other [best practice alerts], and are they even paying attention?” said coauthor Heather Toeppner, RN, also from MUSC, in an interview. “All in all, we found that the alert is making a lasting impression in our institution,” she said.

Transfusion clinical decision support systems that produce automated alerts for clinicians can improve usage and reduce waste of RBCs, but whether the effect is sustained over time was unknown, Ms. Toeppner said, prompting the investigators to study the effect of the RBC best practice alert over 10 months.

As noted, the alert is triggered when providers order RBCs for patients with hemoglobin levels over 7.0 g/dL or when there is no record of a hemoglobin test in the chart within the past 24 hours. Before the alert is triggered, however, the system reviews the record and excludes alerts for patients with specific conditions, such as concurrent surgery or sickle cell disease.

The authors found that the alert was triggered an average of 195 times per month over the 10 months studied. On average, 16% of the alerts resulted in a cancellation of the RBC order, and 71% of alerts were overridden.

“Most importantly, there was no trend suggesting that either cancellation of the RBC order or overriding the alert became more frequent over time,” the investigators wrote. “Similarly, reasons for overriding the alert were consistent over time, with ‘preparation for an invasive procedure’ and ‘active bleeding’ being the most common reasons for overriding the alert (32% and 23% of all overrides, respectively).”

Other common reasons for overrides included tachycardia, shortness of breath, hypotension, onset of chest pain, and acute coronary syndrome.

Interestingly, but perhaps not surprisingly, they found that overrides dropped sharply and changed orders rose by the same magnitude in July, when new residents started their rotations.

The investigators wrote that the relatively small number of alerts may be attributable to their institution’s robust patient blood management program and the intentional exclusion of orders for patients with specific diagnostic codes, including intraoperative patients, those with sickle cell disease, and all patients aged younger than 18 years.

The study was internally funded. The authors reported having no conflicts of interest.

SAN ANTONIO – Clinicians don’t appear to mind too much when their red blood cell orders are flagged for review by a best practice alert system, and alert fatigue doesn’t seem to hamper patient blood management efforts, investigators in a single-center study reported.

Neil Osterweil/MDedge News

At the Medical University of South Carolina, Charleston (MUSC), if clinicians order RBC transfusions for patients with hemoglobin levels over 7.0 g/dL or for patients who did not have a hemoglobin determination over the past 24 hours, they receive a best practice alert. They must acknowledge it and cancel the order, or override it and document a reason in the medical record.

Although approximately 70% of alerts were overridden, the reasons for the overrides “were consistent over time and appropriate,” reported Jerry E. Squires, MD, PhD, and colleagues from MUSC in a poster presentation at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The goal of the study was to find out if the effectiveness of the alert was wearing out after months of active use by clinicians. “Is it true that they’re clicking too much and they’re inundated with other [best practice alerts], and are they even paying attention?” said coauthor Heather Toeppner, RN, also from MUSC, in an interview. “All in all, we found that the alert is making a lasting impression in our institution,” she said.

Transfusion clinical decision support systems that produce automated alerts for clinicians can improve usage and reduce waste of RBCs, but whether the effect is sustained over time was unknown, Ms. Toeppner said, prompting the investigators to study the effect of the RBC best practice alert over 10 months.

As noted, the alert is triggered when providers order RBCs for patients with hemoglobin levels over 7.0 g/dL or when there is no record of a hemoglobin test in the chart within the past 24 hours. Before the alert is triggered, however, the system reviews the record and excludes alerts for patients with specific conditions, such as concurrent surgery or sickle cell disease.

The authors found that the alert was triggered an average of 195 times per month over the 10 months studied. On average, 16% of the alerts resulted in a cancellation of the RBC order, and 71% of alerts were overridden.

“Most importantly, there was no trend suggesting that either cancellation of the RBC order or overriding the alert became more frequent over time,” the investigators wrote. “Similarly, reasons for overriding the alert were consistent over time, with ‘preparation for an invasive procedure’ and ‘active bleeding’ being the most common reasons for overriding the alert (32% and 23% of all overrides, respectively).”

Other common reasons for overrides included tachycardia, shortness of breath, hypotension, onset of chest pain, and acute coronary syndrome.

Interestingly, but perhaps not surprisingly, they found that overrides dropped sharply and changed orders rose by the same magnitude in July, when new residents started their rotations.

The investigators wrote that the relatively small number of alerts may be attributable to their institution’s robust patient blood management program and the intentional exclusion of orders for patients with specific diagnostic codes, including intraoperative patients, those with sickle cell disease, and all patients aged younger than 18 years.

The study was internally funded. The authors reported having no conflicts of interest.

SAN ANTONIO – Clinicians don’t appear to mind too much when their red blood cell orders are flagged for review by a best practice alert system, and alert fatigue doesn’t seem to hamper patient blood management efforts, investigators in a single-center study reported.

Neil Osterweil/MDedge News

At the Medical University of South Carolina, Charleston (MUSC), if clinicians order RBC transfusions for patients with hemoglobin levels over 7.0 g/dL or for patients who did not have a hemoglobin determination over the past 24 hours, they receive a best practice alert. They must acknowledge it and cancel the order, or override it and document a reason in the medical record.

Although approximately 70% of alerts were overridden, the reasons for the overrides “were consistent over time and appropriate,” reported Jerry E. Squires, MD, PhD, and colleagues from MUSC in a poster presentation at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The goal of the study was to find out if the effectiveness of the alert was wearing out after months of active use by clinicians. “Is it true that they’re clicking too much and they’re inundated with other [best practice alerts], and are they even paying attention?” said coauthor Heather Toeppner, RN, also from MUSC, in an interview. “All in all, we found that the alert is making a lasting impression in our institution,” she said.

Transfusion clinical decision support systems that produce automated alerts for clinicians can improve usage and reduce waste of RBCs, but whether the effect is sustained over time was unknown, Ms. Toeppner said, prompting the investigators to study the effect of the RBC best practice alert over 10 months.

As noted, the alert is triggered when providers order RBCs for patients with hemoglobin levels over 7.0 g/dL or when there is no record of a hemoglobin test in the chart within the past 24 hours. Before the alert is triggered, however, the system reviews the record and excludes alerts for patients with specific conditions, such as concurrent surgery or sickle cell disease.

The authors found that the alert was triggered an average of 195 times per month over the 10 months studied. On average, 16% of the alerts resulted in a cancellation of the RBC order, and 71% of alerts were overridden.

“Most importantly, there was no trend suggesting that either cancellation of the RBC order or overriding the alert became more frequent over time,” the investigators wrote. “Similarly, reasons for overriding the alert were consistent over time, with ‘preparation for an invasive procedure’ and ‘active bleeding’ being the most common reasons for overriding the alert (32% and 23% of all overrides, respectively).”

Other common reasons for overrides included tachycardia, shortness of breath, hypotension, onset of chest pain, and acute coronary syndrome.

Interestingly, but perhaps not surprisingly, they found that overrides dropped sharply and changed orders rose by the same magnitude in July, when new residents started their rotations.

The investigators wrote that the relatively small number of alerts may be attributable to their institution’s robust patient blood management program and the intentional exclusion of orders for patients with specific diagnostic codes, including intraoperative patients, those with sickle cell disease, and all patients aged younger than 18 years.

The study was internally funded. The authors reported having no conflicts of interest.

SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.

Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.

“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”

Is fresh really better?

The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.

Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.

Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.

The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.

There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.

The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.

There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).

Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.

Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.

Why no difference?

Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.

“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.

Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.

ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.

SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.

Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.

“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”

Is fresh really better?

The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.

Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.

Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.

The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.

There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.

The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.

There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).

Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.

Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.

Why no difference?

Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.

“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.

Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.

ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.

SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.

Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.

“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”

Is fresh really better?

The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.

Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.

Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.

The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.

There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.

The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.

There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).

Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.

Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.

Why no difference?

Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.

“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.

Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.

ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.

Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.

Wikimedia Commons/KGH/Creative Commons License

The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.

The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.

Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.

At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.

After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).

With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).

“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.

One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.

“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.

The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.

SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.

Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.

Wikimedia Commons/KGH/Creative Commons License

The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.

The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.

Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.

At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.

After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).

With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).

“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.

One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.

“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.

The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.

SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.

Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.

Wikimedia Commons/KGH/Creative Commons License

The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.

The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.

Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.

At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.

After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).

With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).

“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.

One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.

“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.

The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.

SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.

A 50-year-old man with acute myeloid leukemia (AML) with a complex karyotype was admitted to the hospital with several days of dull, left-sided abdominal pain. His most recent bone marrow biopsy showed 30% blasts, and immunophenotyping was suggestive of persistent AML (CD13+, CD34+, CD117+, CD33+, CD7+, MPO–). He was on treatment with venetoclax and cytarabine after induction therapy had failed.

On admission, his heart rate was 101 beats per minute and his blood pressure was 122/85 mm Hg. Abdominal examination revealed mild distention, hepatomegaly, and previously known massive splenomegaly, with the splenic tip extending to the umbilicus, and mild tenderness.

Results of laboratory testing revealed persistent pancytopenia:

• Hemoglobin level 6.8 g/dL (reference range 13.0–17.0)
• Total white blood cell count 0.8 × 10⁹/L (4.5–11.0)
• Platelet count 8 × 10⁹/L (150–400).

The next day, he developed severe, acute-onset left-sided abdominal pain. A check of vital signs showed worsening sinus tachycardia at 132 beats per minute and a drop in blood pressure to 90/56 mm Hg. He had worsening diffuse abdominal tenderness with sluggish bowel sounds. His hemoglobin concentration was 6.4 g/dL and platelet count 12 × 10⁹/L.

He received supportive transfusions of blood products. Surgical exploration was deemed risky, given his overall condition and severe thrombocytopenia. Splenic angiography showed no evidence of pseudoaneurysm or focal contrast extravasation. He underwent empiric embolization of the midsplenic artery, after which his hemodynamic status stabilized. He died 4 weeks later of acute respiratory failure from pneumonia.

SPLENIC RUPTURE IN AML

Atraumatic splenic rupture is rare but potentially life-threatening, especially if the diagnosis is delayed. Conditions that can cause splenomegaly and predispose to rupture include infection (infectious mononucleosis, malaria), malignant hematologic disorders (leukemia, lymphoma), other neoplasms, and amyloidosis.¹

The literature includes a few reports of splenic rupture in patients with AML.^2–4 The proposed mechanisms include bleeding from infarction sites or tumor foci, dysregulated hemostasis, and leukostasis.

The classic presentation of splenic rupture is acute-onset left-sided abdominal pain associated with hypotension and decreasing hemoglobin levels. CT of the abdomen is confirmatory, and resuscitation with crystalloids and blood products is a vital initial step in management. Choice of treatment depends on the patient’s surgical risk and hemodynamic status; options include conservative medical management, splenic artery embolization, and exploratory laparotomy.

In patients with AML and splenomegaly presenting with acute abdominal pain, clinicians need to be aware of this potential hematologic emergency.

A 50-year-old man with acute myeloid leukemia (AML) with a complex karyotype was admitted to the hospital with several days of dull, left-sided abdominal pain. His most recent bone marrow biopsy showed 30% blasts, and immunophenotyping was suggestive of persistent AML (CD13+, CD34+, CD117+, CD33+, CD7+, MPO–). He was on treatment with venetoclax and cytarabine after induction therapy had failed.

On admission, his heart rate was 101 beats per minute and his blood pressure was 122/85 mm Hg. Abdominal examination revealed mild distention, hepatomegaly, and previously known massive splenomegaly, with the splenic tip extending to the umbilicus, and mild tenderness.

Results of laboratory testing revealed persistent pancytopenia:

• Hemoglobin level 6.8 g/dL (reference range 13.0–17.0)
• Total white blood cell count 0.8 × 10⁹/L (4.5–11.0)
• Platelet count 8 × 10⁹/L (150–400).

The next day, he developed severe, acute-onset left-sided abdominal pain. A check of vital signs showed worsening sinus tachycardia at 132 beats per minute and a drop in blood pressure to 90/56 mm Hg. He had worsening diffuse abdominal tenderness with sluggish bowel sounds. His hemoglobin concentration was 6.4 g/dL and platelet count 12 × 10⁹/L.

He received supportive transfusions of blood products. Surgical exploration was deemed risky, given his overall condition and severe thrombocytopenia. Splenic angiography showed no evidence of pseudoaneurysm or focal contrast extravasation. He underwent empiric embolization of the midsplenic artery, after which his hemodynamic status stabilized. He died 4 weeks later of acute respiratory failure from pneumonia.

SPLENIC RUPTURE IN AML

Atraumatic splenic rupture is rare but potentially life-threatening, especially if the diagnosis is delayed. Conditions that can cause splenomegaly and predispose to rupture include infection (infectious mononucleosis, malaria), malignant hematologic disorders (leukemia, lymphoma), other neoplasms, and amyloidosis.¹

The literature includes a few reports of splenic rupture in patients with AML.^2–4 The proposed mechanisms include bleeding from infarction sites or tumor foci, dysregulated hemostasis, and leukostasis.

The classic presentation of splenic rupture is acute-onset left-sided abdominal pain associated with hypotension and decreasing hemoglobin levels. CT of the abdomen is confirmatory, and resuscitation with crystalloids and blood products is a vital initial step in management. Choice of treatment depends on the patient’s surgical risk and hemodynamic status; options include conservative medical management, splenic artery embolization, and exploratory laparotomy.

In patients with AML and splenomegaly presenting with acute abdominal pain, clinicians need to be aware of this potential hematologic emergency.

A 50-year-old man with acute myeloid leukemia (AML) with a complex karyotype was admitted to the hospital with several days of dull, left-sided abdominal pain. His most recent bone marrow biopsy showed 30% blasts, and immunophenotyping was suggestive of persistent AML (CD13+, CD34+, CD117+, CD33+, CD7+, MPO–). He was on treatment with venetoclax and cytarabine after induction therapy had failed.

On admission, his heart rate was 101 beats per minute and his blood pressure was 122/85 mm Hg. Abdominal examination revealed mild distention, hepatomegaly, and previously known massive splenomegaly, with the splenic tip extending to the umbilicus, and mild tenderness.

Results of laboratory testing revealed persistent pancytopenia:

• Hemoglobin level 6.8 g/dL (reference range 13.0–17.0)
• Total white blood cell count 0.8 × 10⁹/L (4.5–11.0)
• Platelet count 8 × 10⁹/L (150–400).

The next day, he developed severe, acute-onset left-sided abdominal pain. A check of vital signs showed worsening sinus tachycardia at 132 beats per minute and a drop in blood pressure to 90/56 mm Hg. He had worsening diffuse abdominal tenderness with sluggish bowel sounds. His hemoglobin concentration was 6.4 g/dL and platelet count 12 × 10⁹/L.

He received supportive transfusions of blood products. Surgical exploration was deemed risky, given his overall condition and severe thrombocytopenia. Splenic angiography showed no evidence of pseudoaneurysm or focal contrast extravasation. He underwent empiric embolization of the midsplenic artery, after which his hemodynamic status stabilized. He died 4 weeks later of acute respiratory failure from pneumonia.

SPLENIC RUPTURE IN AML

Atraumatic splenic rupture is rare but potentially life-threatening, especially if the diagnosis is delayed. Conditions that can cause splenomegaly and predispose to rupture include infection (infectious mononucleosis, malaria), malignant hematologic disorders (leukemia, lymphoma), other neoplasms, and amyloidosis.¹

The literature includes a few reports of splenic rupture in patients with AML.^2–4 The proposed mechanisms include bleeding from infarction sites or tumor foci, dysregulated hemostasis, and leukostasis.

The classic presentation of splenic rupture is acute-onset left-sided abdominal pain associated with hypotension and decreasing hemoglobin levels. CT of the abdomen is confirmatory, and resuscitation with crystalloids and blood products is a vital initial step in management. Choice of treatment depends on the patient’s surgical risk and hemodynamic status; options include conservative medical management, splenic artery embolization, and exploratory laparotomy.

In patients with AML and splenomegaly presenting with acute abdominal pain, clinicians need to be aware of this potential hematologic emergency.

The rapid development and identification of novel drugs has translated into innovative therapies in hematology and oncology. The aim of this piece is to present newly approved drugs and expanded indications to serve as a reference guide for practicing clinicians.

This article reviews therapies that were newly approved so far in 2019, as well as those previously approved whose indications were expanded this past year. The list highlights the most clinically important approvals, as well as adverse events that are unique or especially severe.
 

New approvals

Fedratinib (Inrebic)

Class: JAK2 and FLT3 selective kinase inhibitor.

Disease: Intermediate or high-risk primary or secondary (postpolycythemia vera or postessential thrombocythemia) myelofibrosis.

Dose: 400 mg orally once daily, with or without food.

Adverse events (AEs): Black box warning: Fatal encephalopathy, including Wernicke’s (thiamine level monitoring suggested).

Trials: In JAKARTA (NCT01437787), 37% of patients achieved a 35% or greater reduction in spleen volume and 40% received a 50% or greater reduction in myelofibrosis-related symptoms. In Jakarta-2, there was a 55% spleen response in patients resistant or intolerant to ruxolitinib.

Entrectinib (Rozlytrek)

Class: Tropomyosin receptor tyrosine kinase inhibitor.

Disease: Solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and for ROS-1 positive non–small cell lung cancer (NSCLC).

Dose: 600 mg orally once daily.

AEs: Heart failure, QT prolongation, skeletal fractures, hepatotoxicity, central nervous system effects, and hyperuricemia.

Trial: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267): Overall response rate of 57% for NTRK positive patients; response rate of 77% in ROS-1 positive NSCLC.

Pexidartinib (Turalio)

Class: Small molecule tyrosine kinase inhibitor targeting CSF1R.

Disease: Symptomatic tenosynovial giant cell tumor.

Dose: 400 mg orally twice daily without food.

AEs: Black box warning on hepatotoxicity.

Trial: ENLIVEN (NCT02371369): Overall response rate of 38% at 25 weeks, with a 15% complete response rate and a 23% partial response rate.

Darolutamide (Nubeqa)

Class: Androgen receptor inhibitor.

Disease: Nonmetastatic castration-resistant prostate cancer.

Dose: 600 mg orally twice daily with food with concomitant androgen deprivation therapy.

AEs: Fatigue, extremity pain, and rash.

Trial: ARAMIS (NCT02200614): Median metastasis free survival was 40.4 months for patients with darolutamide, compared with 18.4 months for controls.

Selinexor (Xpovio)

Class: Reversible inhibitor of nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins.

Disease: Relapsed or refractory multiple myeloma. Indicated for patients who have received at least four prior therapies, including at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.

Dose: 80 mg orally in combination with oral dexamethasone on days 1 and 3 of each week.

AEs: Thrombocytopenia, fatigue, pancytopenia, and hyponatremia.

Trial: STORM (NCT02336815): Overall response rate 25.3% with a median time to first response of 4 weeks and 3.8-month median duration of response.

Polatuzumab vedotin-piiq (Polivy)

Class: CD79b-directed antibody-drug conjugate.

Disease: Relapsed or refractory diffuse large B-cell lymphoma. Indicated for patients who have had at least two prior therapies.

Dose: 1.8 mg/kg intravenous infusion every 21 days for six cycles in combination with bendamustine and a rituximab product.

AEs: Pancytopenia, peripheral neuropathy.

Trial: GO29365 (NCT02257567): Complete response rate was 40% for polatuzumab vedotin-piiq plus bendamustine/rituximab, compared with 18% with bendamustine/rituximab alone.*

Caplacizumab-yhdp (Cablivi)

Class: Monoclonal antibody fragment directed against von Willebrand factor.

Disease: Thrombotic thrombocytopenic purpura.

Dose: 11 mg IV initially, then daily subcutaneously; in combination with plasma exchange and immunosuppressive therapy.

AEs: Epistaxis, headache, and gingival bleeding.

Trial: Hercules trial (NCT02553317): More rapid normalization of platelets, lower incidence of composite TTP-related death, and lower rate of recurrence when added to plasma exchange and steroids.
 

Alpelisib (Piqray)

Class: Phosphatidylinositol-3-kinase (PI3K) inhibitor.

Disease: Hormone receptor positive HER2-negative PIK3CA-mutated, advanced or metastatic breast cancer.

Dose: 300 mg orally once daily with food with concomitant fulvestrant.

AEs: Hyperglycemia, pancytopenia.

Trial: SOLAR-1 (NCT02437318): 11-month progression-free survival among patients treated with alpelisib and fulvestrant, compared with 5.7 months in fulvestrant alone control arm; overall response rate of 36% versus 16%, respectively.

Erdafitinib (Balversa)

Class: Fibroblast growth factor receptor kinase inhibitor.

Disease: Locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 mutations.

Dose: 8 mg orally once daily, with or without food.

AEs: Ocular disorders including retinopathy or retinal detachment.

Trial: BLC2001 (NCT02365597): Objective response rate of 32.2%, with a complete response in 2.3% of patients and partial response in 29.9% of patients.

Biosimilar approvals

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta)

Biosimilar to: Trastuzumab.

Indication: HER2-overexpressing breast cancer.
 

Dr. Bryer is a resident in the department of internal medicine at the University of Pennsylvania, Philadelphia. Dr. Mintzer is chief of hematology-oncology at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania. Dr. Henry is a hematologist-oncologist at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania.

*Correction, 11/7/2019: An earlier version of this article misstated the drug combination in the GO29365 trial. 

The rapid development and identification of novel drugs has translated into innovative therapies in hematology and oncology. The aim of this piece is to present newly approved drugs and expanded indications to serve as a reference guide for practicing clinicians.

This article reviews therapies that were newly approved so far in 2019, as well as those previously approved whose indications were expanded this past year. The list highlights the most clinically important approvals, as well as adverse events that are unique or especially severe.
 

New approvals

Fedratinib (Inrebic)

Class: JAK2 and FLT3 selective kinase inhibitor.

Disease: Intermediate or high-risk primary or secondary (postpolycythemia vera or postessential thrombocythemia) myelofibrosis.

Dose: 400 mg orally once daily, with or without food.

Adverse events (AEs): Black box warning: Fatal encephalopathy, including Wernicke’s (thiamine level monitoring suggested).

Trials: In JAKARTA (NCT01437787), 37% of patients achieved a 35% or greater reduction in spleen volume and 40% received a 50% or greater reduction in myelofibrosis-related symptoms. In Jakarta-2, there was a 55% spleen response in patients resistant or intolerant to ruxolitinib.

Entrectinib (Rozlytrek)

Class: Tropomyosin receptor tyrosine kinase inhibitor.

Disease: Solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and for ROS-1 positive non–small cell lung cancer (NSCLC).

Dose: 600 mg orally once daily.

AEs: Heart failure, QT prolongation, skeletal fractures, hepatotoxicity, central nervous system effects, and hyperuricemia.

Trial: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267): Overall response rate of 57% for NTRK positive patients; response rate of 77% in ROS-1 positive NSCLC.

Pexidartinib (Turalio)

Class: Small molecule tyrosine kinase inhibitor targeting CSF1R.

Disease: Symptomatic tenosynovial giant cell tumor.

Dose: 400 mg orally twice daily without food.

AEs: Black box warning on hepatotoxicity.

Trial: ENLIVEN (NCT02371369): Overall response rate of 38% at 25 weeks, with a 15% complete response rate and a 23% partial response rate.

Darolutamide (Nubeqa)

Class: Androgen receptor inhibitor.

Disease: Nonmetastatic castration-resistant prostate cancer.

Dose: 600 mg orally twice daily with food with concomitant androgen deprivation therapy.

AEs: Fatigue, extremity pain, and rash.

Trial: ARAMIS (NCT02200614): Median metastasis free survival was 40.4 months for patients with darolutamide, compared with 18.4 months for controls.

Selinexor (Xpovio)

Class: Reversible inhibitor of nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins.

Disease: Relapsed or refractory multiple myeloma. Indicated for patients who have received at least four prior therapies, including at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.

Dose: 80 mg orally in combination with oral dexamethasone on days 1 and 3 of each week.

AEs: Thrombocytopenia, fatigue, pancytopenia, and hyponatremia.

Trial: STORM (NCT02336815): Overall response rate 25.3% with a median time to first response of 4 weeks and 3.8-month median duration of response.

Polatuzumab vedotin-piiq (Polivy)

Class: CD79b-directed antibody-drug conjugate.

Disease: Relapsed or refractory diffuse large B-cell lymphoma. Indicated for patients who have had at least two prior therapies.

Dose: 1.8 mg/kg intravenous infusion every 21 days for six cycles in combination with bendamustine and a rituximab product.

AEs: Pancytopenia, peripheral neuropathy.

Trial: GO29365 (NCT02257567): Complete response rate was 40% for polatuzumab vedotin-piiq plus bendamustine/rituximab, compared with 18% with bendamustine/rituximab alone.*

Caplacizumab-yhdp (Cablivi)

Class: Monoclonal antibody fragment directed against von Willebrand factor.

Disease: Thrombotic thrombocytopenic purpura.

Dose: 11 mg IV initially, then daily subcutaneously; in combination with plasma exchange and immunosuppressive therapy.

AEs: Epistaxis, headache, and gingival bleeding.

Trial: Hercules trial (NCT02553317): More rapid normalization of platelets, lower incidence of composite TTP-related death, and lower rate of recurrence when added to plasma exchange and steroids.
 

Alpelisib (Piqray)

Class: Phosphatidylinositol-3-kinase (PI3K) inhibitor.

Disease: Hormone receptor positive HER2-negative PIK3CA-mutated, advanced or metastatic breast cancer.

Dose: 300 mg orally once daily with food with concomitant fulvestrant.

AEs: Hyperglycemia, pancytopenia.

Trial: SOLAR-1 (NCT02437318): 11-month progression-free survival among patients treated with alpelisib and fulvestrant, compared with 5.7 months in fulvestrant alone control arm; overall response rate of 36% versus 16%, respectively.

Erdafitinib (Balversa)

Class: Fibroblast growth factor receptor kinase inhibitor.

Disease: Locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 mutations.

Dose: 8 mg orally once daily, with or without food.

AEs: Ocular disorders including retinopathy or retinal detachment.

Trial: BLC2001 (NCT02365597): Objective response rate of 32.2%, with a complete response in 2.3% of patients and partial response in 29.9% of patients.

Biosimilar approvals

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta)

Biosimilar to: Trastuzumab.

Indication: HER2-overexpressing breast cancer.
 

Dr. Bryer is a resident in the department of internal medicine at the University of Pennsylvania, Philadelphia. Dr. Mintzer is chief of hematology-oncology at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania. Dr. Henry is a hematologist-oncologist at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania.

*Correction, 11/7/2019: An earlier version of this article misstated the drug combination in the GO29365 trial. 

The rapid development and identification of novel drugs has translated into innovative therapies in hematology and oncology. The aim of this piece is to present newly approved drugs and expanded indications to serve as a reference guide for practicing clinicians.

This article reviews therapies that were newly approved so far in 2019, as well as those previously approved whose indications were expanded this past year. The list highlights the most clinically important approvals, as well as adverse events that are unique or especially severe.
 

New approvals

Fedratinib (Inrebic)

Class: JAK2 and FLT3 selective kinase inhibitor.

Disease: Intermediate or high-risk primary or secondary (postpolycythemia vera or postessential thrombocythemia) myelofibrosis.

Dose: 400 mg orally once daily, with or without food.

Adverse events (AEs): Black box warning: Fatal encephalopathy, including Wernicke’s (thiamine level monitoring suggested).

Trials: In JAKARTA (NCT01437787), 37% of patients achieved a 35% or greater reduction in spleen volume and 40% received a 50% or greater reduction in myelofibrosis-related symptoms. In Jakarta-2, there was a 55% spleen response in patients resistant or intolerant to ruxolitinib.

Entrectinib (Rozlytrek)

Class: Tropomyosin receptor tyrosine kinase inhibitor.

Disease: Solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and for ROS-1 positive non–small cell lung cancer (NSCLC).

Dose: 600 mg orally once daily.

AEs: Heart failure, QT prolongation, skeletal fractures, hepatotoxicity, central nervous system effects, and hyperuricemia.

Trial: ALKA, STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267): Overall response rate of 57% for NTRK positive patients; response rate of 77% in ROS-1 positive NSCLC.

Pexidartinib (Turalio)

Class: Small molecule tyrosine kinase inhibitor targeting CSF1R.

Disease: Symptomatic tenosynovial giant cell tumor.

Dose: 400 mg orally twice daily without food.

AEs: Black box warning on hepatotoxicity.

Trial: ENLIVEN (NCT02371369): Overall response rate of 38% at 25 weeks, with a 15% complete response rate and a 23% partial response rate.

Darolutamide (Nubeqa)

Class: Androgen receptor inhibitor.

Disease: Nonmetastatic castration-resistant prostate cancer.

Dose: 600 mg orally twice daily with food with concomitant androgen deprivation therapy.

AEs: Fatigue, extremity pain, and rash.

Trial: ARAMIS (NCT02200614): Median metastasis free survival was 40.4 months for patients with darolutamide, compared with 18.4 months for controls.

Selinexor (Xpovio)

Class: Reversible inhibitor of nuclear export of tumor suppressor proteins, growth regulators, and mRNAs of oncogenic proteins.

Disease: Relapsed or refractory multiple myeloma. Indicated for patients who have received at least four prior therapies, including at least two immunomodulatory agents and an anti-CD38 monoclonal antibody.

Dose: 80 mg orally in combination with oral dexamethasone on days 1 and 3 of each week.

AEs: Thrombocytopenia, fatigue, pancytopenia, and hyponatremia.

Trial: STORM (NCT02336815): Overall response rate 25.3% with a median time to first response of 4 weeks and 3.8-month median duration of response.

Polatuzumab vedotin-piiq (Polivy)

Class: CD79b-directed antibody-drug conjugate.

Disease: Relapsed or refractory diffuse large B-cell lymphoma. Indicated for patients who have had at least two prior therapies.

Dose: 1.8 mg/kg intravenous infusion every 21 days for six cycles in combination with bendamustine and a rituximab product.

AEs: Pancytopenia, peripheral neuropathy.

Trial: GO29365 (NCT02257567): Complete response rate was 40% for polatuzumab vedotin-piiq plus bendamustine/rituximab, compared with 18% with bendamustine/rituximab alone.*

Caplacizumab-yhdp (Cablivi)

Class: Monoclonal antibody fragment directed against von Willebrand factor.

Disease: Thrombotic thrombocytopenic purpura.

Dose: 11 mg IV initially, then daily subcutaneously; in combination with plasma exchange and immunosuppressive therapy.

AEs: Epistaxis, headache, and gingival bleeding.

Trial: Hercules trial (NCT02553317): More rapid normalization of platelets, lower incidence of composite TTP-related death, and lower rate of recurrence when added to plasma exchange and steroids.
 

Alpelisib (Piqray)

Class: Phosphatidylinositol-3-kinase (PI3K) inhibitor.

Disease: Hormone receptor positive HER2-negative PIK3CA-mutated, advanced or metastatic breast cancer.

Dose: 300 mg orally once daily with food with concomitant fulvestrant.

AEs: Hyperglycemia, pancytopenia.

Trial: SOLAR-1 (NCT02437318): 11-month progression-free survival among patients treated with alpelisib and fulvestrant, compared with 5.7 months in fulvestrant alone control arm; overall response rate of 36% versus 16%, respectively.

Erdafitinib (Balversa)

Class: Fibroblast growth factor receptor kinase inhibitor.

Disease: Locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 mutations.

Dose: 8 mg orally once daily, with or without food.

AEs: Ocular disorders including retinopathy or retinal detachment.

Trial: BLC2001 (NCT02365597): Objective response rate of 32.2%, with a complete response in 2.3% of patients and partial response in 29.9% of patients.

Biosimilar approvals

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta)

Biosimilar to: Trastuzumab.

Indication: HER2-overexpressing breast cancer.
 

Dr. Bryer is a resident in the department of internal medicine at the University of Pennsylvania, Philadelphia. Dr. Mintzer is chief of hematology-oncology at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania. Dr. Henry is a hematologist-oncologist at Pennsylvania Hospital and professor of medicine at the University of Pennsylvania.

*Correction, 11/7/2019: An earlier version of this article misstated the drug combination in the GO29365 trial. 

Background: Prior studies have suggested that NOACs have a favorable risk-benefit profile when compared with warfarin, but it is unclear if this advantage also is present for those high-risk patients for whom NOAC dose reduction is recommended.

Dr. Biddick is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine Harvard Medical School.

Background: Prior studies have suggested that NOACs have a favorable risk-benefit profile when compared with warfarin, but it is unclear if this advantage also is present for those high-risk patients for whom NOAC dose reduction is recommended.

Dr. Biddick is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine Harvard Medical School.

Background: Prior studies have suggested that NOACs have a favorable risk-benefit profile when compared with warfarin, but it is unclear if this advantage also is present for those high-risk patients for whom NOAC dose reduction is recommended.

Dr. Biddick is a hospitalist at Beth Israel Deaconess Medical Center and instructor in medicine Harvard Medical School.

AUSTIN, TEX. – Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive intravenous immunoglobulin (IVIg) appear to have an increased risk of thromboembolic events if it is administered with a central venous access device (CVAD) when compared against those without a CVAD, according to a recent study.

Although CVADs can reliably deliver IVIg, they also represent an established risk factor for thromboembolic events, Ami Patel, PhD, a senior epidemiologist at CSL Behring, and colleagues noted on their poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The results suggest a need for physicians to be vigilant about patients’ potential risk factors for thromboembolic events, Dr. Patel said in an interview. Further research is planned, however, because the current study did not control for other risk factors or explore other possible confounding, she said.

Dr. Patel and her associates analyzed U.S. claims data (IBM/Truven MarketScan) from 2006 to 2018 and included all patients with a CIDP diagnosis claim and a postdiagnosis code for IVIg. A code for CVAD up to 2 months before CIDP diagnosis without removal before IVIg treatment ended determined those with CVAD exposure, and thromboembolic events included any codes related to arterial, venous, or vascular prostheses.

The researchers then compared patients in a case-control fashion, matching each one with a CVAD to five patients of similar demographics without a CVAD. Characteristics used for matching included medical insurance type, prescription data availability, sex, age, geographic region, and years enrolled in the database.

Among 7,447 patients with at least one IVIg claim, 11.8% (n = 882) had CVAD exposure and 88.2% (n = 6,565) did not. Of those without a CVAD, 3,642 patients were matched to patients with CVAD. A quarter (25.4%) of patients with a CVAD had a thromboembolic event, compared with 11.2% of matched patients without CVADs (P less than .0001).

In the year leading up to IVIg therapy, 16.9% of those with a CVAD and 10.9% of matched patients without one had a previous thromboembolic event (P less than .0001). Patients with a CVAD also had significantly higher rates of hypertension (51.9% vs. 45.0% with placebo; P less than .001) and anticoagulation therapy (7.0% vs. 5.2% with placebo; P less than .05). Differences between the groups were not significant for diabetes (26.9% vs. 24.2%) and hyperlipidemia (19.1% vs. 17.8%).

Occlusion and stenosis of the carotid artery was the most common arterial thromboembolic outcome, occurring in 5.3% of those with a CVAD and in 2.8% of those without a CVAD. The most common venous thromboembolic event was acute venous embolism and thrombosis of lower-extremity deep vessels, which occurred in 7% of those with a CVAD and in 1.8% of those without.

The researchers also compared inpatient admissions and emergency department visits among those with and without a CVAD; both rates were higher in patients with a CVAD. Visits to the emergency department occurred at a rate of 0.14 events per month for those with a CVAD (2.01 distinct months with a claim) and 0.09 events per month for those without a CVAD (0.65 distinct months with a claim). Patients with a CVAD had 1.44 months with an inpatient admissions claim, in comparison with 0.41 months among matched patients without a CVAD. Inpatient admission frequency per month was 0.14 for those with a CVAD and 0.08 for those without.

The research was funded by CSL Behring. Dr. Patel and two of the other five authors are employees of CSL Behring.

SOURCE: Patel A et al. AANEM 2019, Abstract 94.

AUSTIN, TEX. – Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive intravenous immunoglobulin (IVIg) appear to have an increased risk of thromboembolic events if it is administered with a central venous access device (CVAD) when compared against those without a CVAD, according to a recent study.

Although CVADs can reliably deliver IVIg, they also represent an established risk factor for thromboembolic events, Ami Patel, PhD, a senior epidemiologist at CSL Behring, and colleagues noted on their poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The results suggest a need for physicians to be vigilant about patients’ potential risk factors for thromboembolic events, Dr. Patel said in an interview. Further research is planned, however, because the current study did not control for other risk factors or explore other possible confounding, she said.

Dr. Patel and her associates analyzed U.S. claims data (IBM/Truven MarketScan) from 2006 to 2018 and included all patients with a CIDP diagnosis claim and a postdiagnosis code for IVIg. A code for CVAD up to 2 months before CIDP diagnosis without removal before IVIg treatment ended determined those with CVAD exposure, and thromboembolic events included any codes related to arterial, venous, or vascular prostheses.

The researchers then compared patients in a case-control fashion, matching each one with a CVAD to five patients of similar demographics without a CVAD. Characteristics used for matching included medical insurance type, prescription data availability, sex, age, geographic region, and years enrolled in the database.

Among 7,447 patients with at least one IVIg claim, 11.8% (n = 882) had CVAD exposure and 88.2% (n = 6,565) did not. Of those without a CVAD, 3,642 patients were matched to patients with CVAD. A quarter (25.4%) of patients with a CVAD had a thromboembolic event, compared with 11.2% of matched patients without CVADs (P less than .0001).

In the year leading up to IVIg therapy, 16.9% of those with a CVAD and 10.9% of matched patients without one had a previous thromboembolic event (P less than .0001). Patients with a CVAD also had significantly higher rates of hypertension (51.9% vs. 45.0% with placebo; P less than .001) and anticoagulation therapy (7.0% vs. 5.2% with placebo; P less than .05). Differences between the groups were not significant for diabetes (26.9% vs. 24.2%) and hyperlipidemia (19.1% vs. 17.8%).

Occlusion and stenosis of the carotid artery was the most common arterial thromboembolic outcome, occurring in 5.3% of those with a CVAD and in 2.8% of those without a CVAD. The most common venous thromboembolic event was acute venous embolism and thrombosis of lower-extremity deep vessels, which occurred in 7% of those with a CVAD and in 1.8% of those without.

The researchers also compared inpatient admissions and emergency department visits among those with and without a CVAD; both rates were higher in patients with a CVAD. Visits to the emergency department occurred at a rate of 0.14 events per month for those with a CVAD (2.01 distinct months with a claim) and 0.09 events per month for those without a CVAD (0.65 distinct months with a claim). Patients with a CVAD had 1.44 months with an inpatient admissions claim, in comparison with 0.41 months among matched patients without a CVAD. Inpatient admission frequency per month was 0.14 for those with a CVAD and 0.08 for those without.

The research was funded by CSL Behring. Dr. Patel and two of the other five authors are employees of CSL Behring.

SOURCE: Patel A et al. AANEM 2019, Abstract 94.

AUSTIN, TEX. – Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who receive intravenous immunoglobulin (IVIg) appear to have an increased risk of thromboembolic events if it is administered with a central venous access device (CVAD) when compared against those without a CVAD, according to a recent study.

Although CVADs can reliably deliver IVIg, they also represent an established risk factor for thromboembolic events, Ami Patel, PhD, a senior epidemiologist at CSL Behring, and colleagues noted on their poster at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine.

The results suggest a need for physicians to be vigilant about patients’ potential risk factors for thromboembolic events, Dr. Patel said in an interview. Further research is planned, however, because the current study did not control for other risk factors or explore other possible confounding, she said.

Dr. Patel and her associates analyzed U.S. claims data (IBM/Truven MarketScan) from 2006 to 2018 and included all patients with a CIDP diagnosis claim and a postdiagnosis code for IVIg. A code for CVAD up to 2 months before CIDP diagnosis without removal before IVIg treatment ended determined those with CVAD exposure, and thromboembolic events included any codes related to arterial, venous, or vascular prostheses.

The researchers then compared patients in a case-control fashion, matching each one with a CVAD to five patients of similar demographics without a CVAD. Characteristics used for matching included medical insurance type, prescription data availability, sex, age, geographic region, and years enrolled in the database.

Among 7,447 patients with at least one IVIg claim, 11.8% (n = 882) had CVAD exposure and 88.2% (n = 6,565) did not. Of those without a CVAD, 3,642 patients were matched to patients with CVAD. A quarter (25.4%) of patients with a CVAD had a thromboembolic event, compared with 11.2% of matched patients without CVADs (P less than .0001).

In the year leading up to IVIg therapy, 16.9% of those with a CVAD and 10.9% of matched patients without one had a previous thromboembolic event (P less than .0001). Patients with a CVAD also had significantly higher rates of hypertension (51.9% vs. 45.0% with placebo; P less than .001) and anticoagulation therapy (7.0% vs. 5.2% with placebo; P less than .05). Differences between the groups were not significant for diabetes (26.9% vs. 24.2%) and hyperlipidemia (19.1% vs. 17.8%).

Occlusion and stenosis of the carotid artery was the most common arterial thromboembolic outcome, occurring in 5.3% of those with a CVAD and in 2.8% of those without a CVAD. The most common venous thromboembolic event was acute venous embolism and thrombosis of lower-extremity deep vessels, which occurred in 7% of those with a CVAD and in 1.8% of those without.

The researchers also compared inpatient admissions and emergency department visits among those with and without a CVAD; both rates were higher in patients with a CVAD. Visits to the emergency department occurred at a rate of 0.14 events per month for those with a CVAD (2.01 distinct months with a claim) and 0.09 events per month for those without a CVAD (0.65 distinct months with a claim). Patients with a CVAD had 1.44 months with an inpatient admissions claim, in comparison with 0.41 months among matched patients without a CVAD. Inpatient admission frequency per month was 0.14 for those with a CVAD and 0.08 for those without.

The research was funded by CSL Behring. Dr. Patel and two of the other five authors are employees of CSL Behring.

SOURCE: Patel A et al. AANEM 2019, Abstract 94.

Emicizumab (Hemlibra) is well tolerated and has substantial, clinically meaningful efficacy in pediatric patients with hemophilia A and factor VIII inhibitors, according to an analysis of data from the HAVEN 2 trial in this bispecific humanized monoclonal antibody.

Among those receiving once-weekly emicizumab prophylaxis, 77% had no treated bleeding events and 100% of evaluable target joints resolved in the HAVEN 2 study, which investigators say is the largest prospective study so far of bleed prevention in pediatric patients with hemophilia A and inhibitors.

Moreover, emicizumab resulted in a 99% reduction in bleeding rate versus previous bypassing agent prophylaxis, subsequent, according to an intraindividual comparison described in the report.

Based on these results, emicizumab stands to become the “next-generation standard of care” for pediatric patients with hemophilia A and factor VIII inhibitors, reported Guy Young, MD, of Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, and his coinvestigators.

“Despite a rapidly evolving treatment landscape in hemophilia, children have been largely excluded from recent trials of novel agents,” they said in the report, which appears in the journal Blood.

Before emicizumab, current treatment options for pediatric patients with factor VIII inhibitors were limited to immune tolerance induction, or use of bypassing agents with efficacy that “can be suboptimal and unpredictable,” said Dr. Young and colleagues.

“More effective prophylactic options with reduced treatment burden are needed,” they said.

Emicizumab works in hemophilia A by bridging activated factor IX and factor X, restoring the function of missing factor VIIIa, according to the report.

A total of 88 male pediatric patients with congenital hemophilia A were enrolled in HAVEN 2, an ongoing phase 3 multicenter study that is nonrandomized and open label. The median age of patients was 7 years (range, 1-15 years). Most participants (97%) had severe hemophilia A, 72% had previously undergone immune tolerance induction, and 75% were receiving treatment with prophylactic bypassing agents.

Most participants received 4 once-weekly loading doses of 3 mg/kg body weight of emicizumab subcutaneously, followed by a maintenance regimen of 1.5 mg/kg weekly.

The annualized bleed rate was 0.3, with 77% of participants having zero bleeding events, for the 65 participants in the trial who were under 12 and received emicizumab 1.5 mg/kg weekly, according to the report.

In the subset of those patients with target joints, the mean annualized bleed rate was 3.3 for the first 24 weeks, and 0 for the next 24 weeks; these findings suggest that bleed rates decrease over time with continuing emicizumab treatment “even in patients with a more severe phenotype,” the investigators wrote.

For 15 patients younger than 12 years of age receiving bypassing agent prophylaxis, emicizumab 1.5 mg/kg once weekly resulted in an annualized bleed rate of 0.3, compared to 21.1 for the prior bypassing agent, which translates into a 99% reduction in bleeding risk, according to investigators.

Annualized bleed rates for patients receiving emicizumab 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks were 0.2 and 2.2, respectively; hover, the numerically higher annualized bleed rate in the 6 mg/kg every-4-weeks group was based on 2 out of the 10 patients treated with that maintenance regimen, including one who had 6 target joint bleeds in the 24 weeks before enrolling in the study, and another who developed antidrug antibodies within the first 8 weeks of emicizumab treatment.

Out of 23 patients who had target joints and received emicizumab prophylaxis for at least 52 weeks, 100% (45 of 45) target joints resolved, according to the report.

“Notably, this is the first report of a treatment resolving target joints in an inhibitor population, which until now has only been reported when using factor VIII products in patients without inhibitors,” Dr. Young and colleagues said.

The most common of the 721 adverse events reported in HAVEN 2 were nasopharyngitis and injection-site reactions. Of 21 serious adverse events, only 1 (antidrug antibodies with neutralizing potential) was thought by investigators to be related to emicizumab.

The Food and Drug Administration (FDA) initially approved emicizumab in November 2017 on the basis of the HAVEN 2 pediatric trial, and on HAVEN 1, a randomized, multicenter, open-label, phase 3 trial including 109 adult and adolescent males with hemophilia A and FVIII inhibitors. The indication for emicizumab was expanded to include patients without inhibitors in October 2018, on the basis of the HAVEN 3 and HAVEN 4 randomized phase 3 trials.

Dr. Young reported disclosures related to Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Shire, Spark, and uniQure.

SOURCE: Young G, et al. Blood. 2019 Oct 10. doi: 10.1182/blood.2019001869.

Emicizumab (Hemlibra) is well tolerated and has substantial, clinically meaningful efficacy in pediatric patients with hemophilia A and factor VIII inhibitors, according to an analysis of data from the HAVEN 2 trial in this bispecific humanized monoclonal antibody.

Among those receiving once-weekly emicizumab prophylaxis, 77% had no treated bleeding events and 100% of evaluable target joints resolved in the HAVEN 2 study, which investigators say is the largest prospective study so far of bleed prevention in pediatric patients with hemophilia A and inhibitors.

Moreover, emicizumab resulted in a 99% reduction in bleeding rate versus previous bypassing agent prophylaxis, subsequent, according to an intraindividual comparison described in the report.

Based on these results, emicizumab stands to become the “next-generation standard of care” for pediatric patients with hemophilia A and factor VIII inhibitors, reported Guy Young, MD, of Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, and his coinvestigators.

“Despite a rapidly evolving treatment landscape in hemophilia, children have been largely excluded from recent trials of novel agents,” they said in the report, which appears in the journal Blood.

Before emicizumab, current treatment options for pediatric patients with factor VIII inhibitors were limited to immune tolerance induction, or use of bypassing agents with efficacy that “can be suboptimal and unpredictable,” said Dr. Young and colleagues.

“More effective prophylactic options with reduced treatment burden are needed,” they said.

Emicizumab works in hemophilia A by bridging activated factor IX and factor X, restoring the function of missing factor VIIIa, according to the report.

A total of 88 male pediatric patients with congenital hemophilia A were enrolled in HAVEN 2, an ongoing phase 3 multicenter study that is nonrandomized and open label. The median age of patients was 7 years (range, 1-15 years). Most participants (97%) had severe hemophilia A, 72% had previously undergone immune tolerance induction, and 75% were receiving treatment with prophylactic bypassing agents.

Most participants received 4 once-weekly loading doses of 3 mg/kg body weight of emicizumab subcutaneously, followed by a maintenance regimen of 1.5 mg/kg weekly.

The annualized bleed rate was 0.3, with 77% of participants having zero bleeding events, for the 65 participants in the trial who were under 12 and received emicizumab 1.5 mg/kg weekly, according to the report.

In the subset of those patients with target joints, the mean annualized bleed rate was 3.3 for the first 24 weeks, and 0 for the next 24 weeks; these findings suggest that bleed rates decrease over time with continuing emicizumab treatment “even in patients with a more severe phenotype,” the investigators wrote.

For 15 patients younger than 12 years of age receiving bypassing agent prophylaxis, emicizumab 1.5 mg/kg once weekly resulted in an annualized bleed rate of 0.3, compared to 21.1 for the prior bypassing agent, which translates into a 99% reduction in bleeding risk, according to investigators.

Annualized bleed rates for patients receiving emicizumab 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks were 0.2 and 2.2, respectively; hover, the numerically higher annualized bleed rate in the 6 mg/kg every-4-weeks group was based on 2 out of the 10 patients treated with that maintenance regimen, including one who had 6 target joint bleeds in the 24 weeks before enrolling in the study, and another who developed antidrug antibodies within the first 8 weeks of emicizumab treatment.

Out of 23 patients who had target joints and received emicizumab prophylaxis for at least 52 weeks, 100% (45 of 45) target joints resolved, according to the report.

“Notably, this is the first report of a treatment resolving target joints in an inhibitor population, which until now has only been reported when using factor VIII products in patients without inhibitors,” Dr. Young and colleagues said.

The most common of the 721 adverse events reported in HAVEN 2 were nasopharyngitis and injection-site reactions. Of 21 serious adverse events, only 1 (antidrug antibodies with neutralizing potential) was thought by investigators to be related to emicizumab.

The Food and Drug Administration (FDA) initially approved emicizumab in November 2017 on the basis of the HAVEN 2 pediatric trial, and on HAVEN 1, a randomized, multicenter, open-label, phase 3 trial including 109 adult and adolescent males with hemophilia A and FVIII inhibitors. The indication for emicizumab was expanded to include patients without inhibitors in October 2018, on the basis of the HAVEN 3 and HAVEN 4 randomized phase 3 trials.

Dr. Young reported disclosures related to Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Shire, Spark, and uniQure.

SOURCE: Young G, et al. Blood. 2019 Oct 10. doi: 10.1182/blood.2019001869.

Emicizumab (Hemlibra) is well tolerated and has substantial, clinically meaningful efficacy in pediatric patients with hemophilia A and factor VIII inhibitors, according to an analysis of data from the HAVEN 2 trial in this bispecific humanized monoclonal antibody.

Among those receiving once-weekly emicizumab prophylaxis, 77% had no treated bleeding events and 100% of evaluable target joints resolved in the HAVEN 2 study, which investigators say is the largest prospective study so far of bleed prevention in pediatric patients with hemophilia A and inhibitors.

Moreover, emicizumab resulted in a 99% reduction in bleeding rate versus previous bypassing agent prophylaxis, subsequent, according to an intraindividual comparison described in the report.

Based on these results, emicizumab stands to become the “next-generation standard of care” for pediatric patients with hemophilia A and factor VIII inhibitors, reported Guy Young, MD, of Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, and his coinvestigators.

“Despite a rapidly evolving treatment landscape in hemophilia, children have been largely excluded from recent trials of novel agents,” they said in the report, which appears in the journal Blood.

Before emicizumab, current treatment options for pediatric patients with factor VIII inhibitors were limited to immune tolerance induction, or use of bypassing agents with efficacy that “can be suboptimal and unpredictable,” said Dr. Young and colleagues.

“More effective prophylactic options with reduced treatment burden are needed,” they said.

Emicizumab works in hemophilia A by bridging activated factor IX and factor X, restoring the function of missing factor VIIIa, according to the report.

A total of 88 male pediatric patients with congenital hemophilia A were enrolled in HAVEN 2, an ongoing phase 3 multicenter study that is nonrandomized and open label. The median age of patients was 7 years (range, 1-15 years). Most participants (97%) had severe hemophilia A, 72% had previously undergone immune tolerance induction, and 75% were receiving treatment with prophylactic bypassing agents.

Most participants received 4 once-weekly loading doses of 3 mg/kg body weight of emicizumab subcutaneously, followed by a maintenance regimen of 1.5 mg/kg weekly.

The annualized bleed rate was 0.3, with 77% of participants having zero bleeding events, for the 65 participants in the trial who were under 12 and received emicizumab 1.5 mg/kg weekly, according to the report.

In the subset of those patients with target joints, the mean annualized bleed rate was 3.3 for the first 24 weeks, and 0 for the next 24 weeks; these findings suggest that bleed rates decrease over time with continuing emicizumab treatment “even in patients with a more severe phenotype,” the investigators wrote.

For 15 patients younger than 12 years of age receiving bypassing agent prophylaxis, emicizumab 1.5 mg/kg once weekly resulted in an annualized bleed rate of 0.3, compared to 21.1 for the prior bypassing agent, which translates into a 99% reduction in bleeding risk, according to investigators.

Annualized bleed rates for patients receiving emicizumab 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks were 0.2 and 2.2, respectively; hover, the numerically higher annualized bleed rate in the 6 mg/kg every-4-weeks group was based on 2 out of the 10 patients treated with that maintenance regimen, including one who had 6 target joint bleeds in the 24 weeks before enrolling in the study, and another who developed antidrug antibodies within the first 8 weeks of emicizumab treatment.

Out of 23 patients who had target joints and received emicizumab prophylaxis for at least 52 weeks, 100% (45 of 45) target joints resolved, according to the report.

“Notably, this is the first report of a treatment resolving target joints in an inhibitor population, which until now has only been reported when using factor VIII products in patients without inhibitors,” Dr. Young and colleagues said.

The most common of the 721 adverse events reported in HAVEN 2 were nasopharyngitis and injection-site reactions. Of 21 serious adverse events, only 1 (antidrug antibodies with neutralizing potential) was thought by investigators to be related to emicizumab.

The Food and Drug Administration (FDA) initially approved emicizumab in November 2017 on the basis of the HAVEN 2 pediatric trial, and on HAVEN 1, a randomized, multicenter, open-label, phase 3 trial including 109 adult and adolescent males with hemophilia A and FVIII inhibitors. The indication for emicizumab was expanded to include patients without inhibitors in October 2018, on the basis of the HAVEN 3 and HAVEN 4 randomized phase 3 trials.

Dr. Young reported disclosures related to Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Shire, Spark, and uniQure.

SOURCE: Young G, et al. Blood. 2019 Oct 10. doi: 10.1182/blood.2019001869.