For decades, bullying has been viewed as an unpleasant but generally benign rite of passage that many children experience and overcome without significant consequences. Some high-profile examples of youth suicide coupled with several stunning research studies demonstrating major negative effects of bullying that rival the impact of things like child abuse and out-of-home placement on future physical and mental health, however, have caused many clinicians across specialties to stop and take notice (Lancet Psychiatry 2015;2:524-31). The result has been concerted antibullying efforts from varied sources including the federal government, such as stopbullying.gov, and many professional organizations. Pediatricians are in a prime position both to help individual children and families and to serve as community advocates against this significant public health concern.

Case summary

Jeremy is an 11-year-old boy who has been followed by his pediatrician since birth. He has had few health concerns over the years other than some low levels of anxiety and being somewhat overweight. At an annual checkup, his mother reports that Jeremy has missed much more school this year, often making somewhat vague physical complaints. He also has told his mother that a couple of peers at school are particularly “mean” to him. He doesn’t elaborate and doesn’t want his parents to make “a big deal” about it for fear of causing further embarrassment at school.

Discussion

At least moderate levels of bullying are estimated to occur in about 30% of school-age children, resulting in approximately160,000 lost days of school. Bullying behavior can include anything from name calling to outright physical assault. Online bullying in the form of texts, e-mails, and social media also is increasingly common. School grounds remain the most common site for bullying, and physical appearance is the most common target of bullying behavior. What is thought to separate bullying from other forms of peer conflict is that there exists some sort of power differential between the bully and the victim in terms of physical size, social status, or other features. Some interesting data also suggest some sex differences regarding bullying with boys being more likely to bully children outside of their core group of friends, and girls being more likely to bully individuals within the network of individuals with whom they typically interact.

A key element of helping bullied children involves getting them to talk about the experience with a parent, teacher, physician, or counselor. Some tips that can help get kids to talk include reassurance that the child has control over what will happen with the information (within legal limits) and that no action will be taken without their knowledge and agreement, and having adults relate stories about their own past experience with bullying. Pediatricians also may want to consider opening up the conversation more broadly by asking if bullying is a problem “at your school” rather than in a particular child’s life.

In making an appropriate intervention, parents and physicians may want to differentiate lower levels of bullying (name calling, teasing) from higher levels (overt threats, physical violence, and intimidation), keeping in mind that all forms can be potentially harmful.

For lower-level bullying, the following tips can be helpful to keep in mind in working with kids directly and in helping parents help their children:

1. Don’t underestimate the power of sympathetic listening. Overt expressions to a child that he or she doesn’t deserve this, and that such behaviors are really hurtful can be very important to many kids. Positive experiences with friends and families also can go a long way to counteract a negative encounter with a bully.

2. Coach bully victims about how to respond. The old adage of telling a bully that he or she is hurting your feelings has been replaced with advice to react emotionally as little as possible. Some children also can be helped by rehearsing specific responses or learning to join groups during higher-risk activities.

3. If the bullying is occurring online, encourage kids to save the texts or social media posts if needed as evidence.

4. Consider the option of an anonymous report to a school principal or guidance counselor. While school personnel will be unable to make a direct response, they might be able, for example, to provide more monitoring in high-risk areas such as bathrooms, school buses, or locker rooms.

For higher levels of bullying, it often is important to have more direct involvement with school staff or even the police. Many states now have mandatory bullying prevention and intervention policies. While parents of bullying victims may have strong and natural urges to confront directly the parents of the alleged bully, this step often does not help the situation and often can makes things worse.

Finally, if there is evidence that bullying is having a strong negative impact on the child, a more in-depth evaluation to rule out anxiety disorders, depression, and the presence of any suicidal or homicidal thinking should be strongly considered (JAMA 2001;285:2094-100).

Case follow-up

After reassuring Jeremy that action would not be taken without his consent, the pediatrician was able to elicit more information. She learned that two older boys have been teasing Jeremy in the cafeteria and once took away part of his lunch while telling him he was too fat to need it. After some discussion, the pediatrician agreed to call the school principal to inform the school anonymously about bullying in the cafeteria. The mother, now aware of the situation, was able to offer some support and suggestions such as having lunch in a larger group and sitting at a table that is closer to adult supervision. They agreed to meet again to make sure improvements were occurring.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. E-mail him at [email protected].

For decades, bullying has been viewed as an unpleasant but generally benign rite of passage that many children experience and overcome without significant consequences. Some high-profile examples of youth suicide coupled with several stunning research studies demonstrating major negative effects of bullying that rival the impact of things like child abuse and out-of-home placement on future physical and mental health, however, have caused many clinicians across specialties to stop and take notice (Lancet Psychiatry 2015;2:524-31). The result has been concerted antibullying efforts from varied sources including the federal government, such as stopbullying.gov, and many professional organizations. Pediatricians are in a prime position both to help individual children and families and to serve as community advocates against this significant public health concern.

Case summary

Jeremy is an 11-year-old boy who has been followed by his pediatrician since birth. He has had few health concerns over the years other than some low levels of anxiety and being somewhat overweight. At an annual checkup, his mother reports that Jeremy has missed much more school this year, often making somewhat vague physical complaints. He also has told his mother that a couple of peers at school are particularly “mean” to him. He doesn’t elaborate and doesn’t want his parents to make “a big deal” about it for fear of causing further embarrassment at school.

Discussion

At least moderate levels of bullying are estimated to occur in about 30% of school-age children, resulting in approximately160,000 lost days of school. Bullying behavior can include anything from name calling to outright physical assault. Online bullying in the form of texts, e-mails, and social media also is increasingly common. School grounds remain the most common site for bullying, and physical appearance is the most common target of bullying behavior. What is thought to separate bullying from other forms of peer conflict is that there exists some sort of power differential between the bully and the victim in terms of physical size, social status, or other features. Some interesting data also suggest some sex differences regarding bullying with boys being more likely to bully children outside of their core group of friends, and girls being more likely to bully individuals within the network of individuals with whom they typically interact.

A key element of helping bullied children involves getting them to talk about the experience with a parent, teacher, physician, or counselor. Some tips that can help get kids to talk include reassurance that the child has control over what will happen with the information (within legal limits) and that no action will be taken without their knowledge and agreement, and having adults relate stories about their own past experience with bullying. Pediatricians also may want to consider opening up the conversation more broadly by asking if bullying is a problem “at your school” rather than in a particular child’s life.

In making an appropriate intervention, parents and physicians may want to differentiate lower levels of bullying (name calling, teasing) from higher levels (overt threats, physical violence, and intimidation), keeping in mind that all forms can be potentially harmful.

For lower-level bullying, the following tips can be helpful to keep in mind in working with kids directly and in helping parents help their children:

1. Don’t underestimate the power of sympathetic listening. Overt expressions to a child that he or she doesn’t deserve this, and that such behaviors are really hurtful can be very important to many kids. Positive experiences with friends and families also can go a long way to counteract a negative encounter with a bully.

2. Coach bully victims about how to respond. The old adage of telling a bully that he or she is hurting your feelings has been replaced with advice to react emotionally as little as possible. Some children also can be helped by rehearsing specific responses or learning to join groups during higher-risk activities.

3. If the bullying is occurring online, encourage kids to save the texts or social media posts if needed as evidence.

4. Consider the option of an anonymous report to a school principal or guidance counselor. While school personnel will be unable to make a direct response, they might be able, for example, to provide more monitoring in high-risk areas such as bathrooms, school buses, or locker rooms.

For higher levels of bullying, it often is important to have more direct involvement with school staff or even the police. Many states now have mandatory bullying prevention and intervention policies. While parents of bullying victims may have strong and natural urges to confront directly the parents of the alleged bully, this step often does not help the situation and often can makes things worse.

Finally, if there is evidence that bullying is having a strong negative impact on the child, a more in-depth evaluation to rule out anxiety disorders, depression, and the presence of any suicidal or homicidal thinking should be strongly considered (JAMA 2001;285:2094-100).

Case follow-up

After reassuring Jeremy that action would not be taken without his consent, the pediatrician was able to elicit more information. She learned that two older boys have been teasing Jeremy in the cafeteria and once took away part of his lunch while telling him he was too fat to need it. After some discussion, the pediatrician agreed to call the school principal to inform the school anonymously about bullying in the cafeteria. The mother, now aware of the situation, was able to offer some support and suggestions such as having lunch in a larger group and sitting at a table that is closer to adult supervision. They agreed to meet again to make sure improvements were occurring.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. E-mail him at [email protected].

For decades, bullying has been viewed as an unpleasant but generally benign rite of passage that many children experience and overcome without significant consequences. Some high-profile examples of youth suicide coupled with several stunning research studies demonstrating major negative effects of bullying that rival the impact of things like child abuse and out-of-home placement on future physical and mental health, however, have caused many clinicians across specialties to stop and take notice (Lancet Psychiatry 2015;2:524-31). The result has been concerted antibullying efforts from varied sources including the federal government, such as stopbullying.gov, and many professional organizations. Pediatricians are in a prime position both to help individual children and families and to serve as community advocates against this significant public health concern.

Case summary

Jeremy is an 11-year-old boy who has been followed by his pediatrician since birth. He has had few health concerns over the years other than some low levels of anxiety and being somewhat overweight. At an annual checkup, his mother reports that Jeremy has missed much more school this year, often making somewhat vague physical complaints. He also has told his mother that a couple of peers at school are particularly “mean” to him. He doesn’t elaborate and doesn’t want his parents to make “a big deal” about it for fear of causing further embarrassment at school.

Discussion

At least moderate levels of bullying are estimated to occur in about 30% of school-age children, resulting in approximately160,000 lost days of school. Bullying behavior can include anything from name calling to outright physical assault. Online bullying in the form of texts, e-mails, and social media also is increasingly common. School grounds remain the most common site for bullying, and physical appearance is the most common target of bullying behavior. What is thought to separate bullying from other forms of peer conflict is that there exists some sort of power differential between the bully and the victim in terms of physical size, social status, or other features. Some interesting data also suggest some sex differences regarding bullying with boys being more likely to bully children outside of their core group of friends, and girls being more likely to bully individuals within the network of individuals with whom they typically interact.

A key element of helping bullied children involves getting them to talk about the experience with a parent, teacher, physician, or counselor. Some tips that can help get kids to talk include reassurance that the child has control over what will happen with the information (within legal limits) and that no action will be taken without their knowledge and agreement, and having adults relate stories about their own past experience with bullying. Pediatricians also may want to consider opening up the conversation more broadly by asking if bullying is a problem “at your school” rather than in a particular child’s life.

In making an appropriate intervention, parents and physicians may want to differentiate lower levels of bullying (name calling, teasing) from higher levels (overt threats, physical violence, and intimidation), keeping in mind that all forms can be potentially harmful.

For lower-level bullying, the following tips can be helpful to keep in mind in working with kids directly and in helping parents help their children:

1. Don’t underestimate the power of sympathetic listening. Overt expressions to a child that he or she doesn’t deserve this, and that such behaviors are really hurtful can be very important to many kids. Positive experiences with friends and families also can go a long way to counteract a negative encounter with a bully.

2. Coach bully victims about how to respond. The old adage of telling a bully that he or she is hurting your feelings has been replaced with advice to react emotionally as little as possible. Some children also can be helped by rehearsing specific responses or learning to join groups during higher-risk activities.

3. If the bullying is occurring online, encourage kids to save the texts or social media posts if needed as evidence.

4. Consider the option of an anonymous report to a school principal or guidance counselor. While school personnel will be unable to make a direct response, they might be able, for example, to provide more monitoring in high-risk areas such as bathrooms, school buses, or locker rooms.

For higher levels of bullying, it often is important to have more direct involvement with school staff or even the police. Many states now have mandatory bullying prevention and intervention policies. While parents of bullying victims may have strong and natural urges to confront directly the parents of the alleged bully, this step often does not help the situation and often can makes things worse.

Finally, if there is evidence that bullying is having a strong negative impact on the child, a more in-depth evaluation to rule out anxiety disorders, depression, and the presence of any suicidal or homicidal thinking should be strongly considered (JAMA 2001;285:2094-100).

Case follow-up

After reassuring Jeremy that action would not be taken without his consent, the pediatrician was able to elicit more information. She learned that two older boys have been teasing Jeremy in the cafeteria and once took away part of his lunch while telling him he was too fat to need it. After some discussion, the pediatrician agreed to call the school principal to inform the school anonymously about bullying in the cafeteria. The mother, now aware of the situation, was able to offer some support and suggestions such as having lunch in a larger group and sitting at a table that is closer to adult supervision. They agreed to meet again to make sure improvements were occurring.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. E-mail him at [email protected].

The newly developed Pediatric All-Cause Harm Measurement Tool (PACHMT) improved detection of harms in pediatric inpatients in a recent pilot study.

Using the tool, researchers found a rate of 40 harms per 100 patients admitted, and at least one harm in nearly a quarter of the children in the study. Close to half of the events were potentially or definitely preventable.

"Safety is measured inconsistently in health care, and the only way to make progress to improving these rates of harm is to understand how our patients are impacted by the care they receive," says Dr. David C. Stockwell, of George Washington University and Children's National Medical Center in Washington, D.C. "Therefore, we would like to see wider adoption of active surveillance of safety events with an approach like the PACHMT.

“While not replacing voluntarily reported events, it would greatly augment the understanding of all-cause harm." TH

—Reuters Health

The newly developed Pediatric All-Cause Harm Measurement Tool (PACHMT) improved detection of harms in pediatric inpatients in a recent pilot study.

Using the tool, researchers found a rate of 40 harms per 100 patients admitted, and at least one harm in nearly a quarter of the children in the study. Close to half of the events were potentially or definitely preventable.

"Safety is measured inconsistently in health care, and the only way to make progress to improving these rates of harm is to understand how our patients are impacted by the care they receive," says Dr. David C. Stockwell, of George Washington University and Children's National Medical Center in Washington, D.C. "Therefore, we would like to see wider adoption of active surveillance of safety events with an approach like the PACHMT.

“While not replacing voluntarily reported events, it would greatly augment the understanding of all-cause harm." TH

—Reuters Health

The newly developed Pediatric All-Cause Harm Measurement Tool (PACHMT) improved detection of harms in pediatric inpatients in a recent pilot study.

Using the tool, researchers found a rate of 40 harms per 100 patients admitted, and at least one harm in nearly a quarter of the children in the study. Close to half of the events were potentially or definitely preventable.

"Safety is measured inconsistently in health care, and the only way to make progress to improving these rates of harm is to understand how our patients are impacted by the care they receive," says Dr. David C. Stockwell, of George Washington University and Children's National Medical Center in Washington, D.C. "Therefore, we would like to see wider adoption of active surveillance of safety events with an approach like the PACHMT.

“While not replacing voluntarily reported events, it would greatly augment the understanding of all-cause harm." TH

—Reuters Health

Jorge Cortes, MD

VIENNA—Administering ponatinib at lower doses can reduce the risk of arterial occlusive events (AOE) without hindering responses in patients with chronic-phase chronic myeloid leukemia (CP-CML), data from the PACE trial suggest.

When earlier results of this phase 2 study showed that ponatinib can cause AOEs, trials of the drug were put on partial clinical hold. Enrollment was stalled temporarily, and investigators began reducing ponatinib doses.

Now, updated data from the PACE trial suggest ponatinib can be administered safely and effectively in certain patients with CP-CML.

At a median follow-up of about 3.5 years, 95% of CP-CML patients who underwent dose reductions maintained a major cytogenetic response (MCyR). And AOEs occurred in 7% of patients who underwent dose reductions, compared to 13% of patients who did not.

“These continued responses . . . in such a heavily pretreated patient population are very encouraging,” said study investigator Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Careful assessment of the benefit and risk of initiating ponatinib therapy, particularly in patients who may be at increased risk for arterial occlusive events, can help identify patients with refractory, Ph+ leukemias who can benefit most from this treatment.”

Dr Cortes and his colleagues presented data from the PACE trial at the 20th Congress of the European Hematology Association as abstract P234*. The study was sponsored by Ariad Pharmaceuticals, the company developing ponatinib.

Updated results

The trial included patients with resistant or intolerant CML or Philadelphia chromosome-positive acute lymphoblastic leukemia. A total of 449 patients received ponatinib at a starting dose of 45 mg/day.

Ninety-three percent of patients had previously received 2 or more approved tyrosine kinase inhibitors (TKI), and 55% had previously received 3 or more approved TKIs.

Dr Cortes and his colleagues presented data on 270 CP-CML patients. At a median follow-up of 42.3 months (data as of February 2, 2015), 114 patients (42%) continue to receive ponatinib.

Eighteen percent of patients discontinued treatment due to adverse events (AEs), 10% due to disease progression, 3% due to death, and 27% for other reasons.

Fifty-nine percent of CP-CML patients achieved an MCyR at any time during the study, and 83% of responders are estimated to remain in MCyR at 3 years. Thirty-nine percent of patients achieved a major molecular response (MMR).

The estimated progression-free survival at 3 years is 60%, and the estimated overall survival is 81%.

Twenty-three percent of CP-CML patients experienced an AOE designated a serious AE, and 28%  experienced any AOE. The median time to onset for AOEs was 14.1 months (range, 0.3–44.0).

Four percent of CP-CML patients experienced a venous thromboembolism (VTE) that was considered an serious AE, and 5% experienced any VTE.

The most common all-grade, treatment-emergent AEs occurring in at least 40% of CP-CML patients were abdominal pain (46%), rash (46%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (41%).

Outcomes after dose reductions

On October 10, 2013, Ariad provided dose-reduction recommendations to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:

• CP-CML patients who already achieved an MCyR should have their ponatinib dose reduced to 15 mg/day
• CP-CML patients who had not already achieved an MCyR should have their dose reduced to 30 mg/day
• Advanced-phase patients should have their dose reduced to 30 mg/day.

As of February 2015, with 1.3 years (16 months) of follow-up after these recommendations, 95% of CP-CML patients maintained their response, whether or not they underwent prospective dose reductions.

Of the patients who were in MCyR as of October 10, 2013, and had a prospective dose reduction, 95% (61/64) maintained their response at 1.3 years. Of the patients who were in MMR as of October 10, 2013, and had a prospective dose reduction, 94% (44/47) maintained their response at 1.3 years.

Forty-two patients in MCyR did not undergo prospective dose reductions (the majority of which were already at a reduced dose of 30 mg or 15 mg as of October 10, 2013). Of these patients, 93% (n=39) maintained an MCyR after 1.3 more years of ponatinib treatment.

Twenty-four patients in MMR did not undergo prospective dose reductions, and 96% of these patients (n=22) maintained their response at 1.3 years.

Seven percent (5/71) of patients without prior AOEs who underwent dose reductions had a new AOE during the 1.3-year interval after dose reduction.

Thirteen percent (9/67) of patients without prior AOEs who did not undergo dose reductions had a new AOE in the same time interval.

*Information in the abstract differs from that presented at the meeting.

Jorge Cortes, MD

VIENNA—Administering ponatinib at lower doses can reduce the risk of arterial occlusive events (AOE) without hindering responses in patients with chronic-phase chronic myeloid leukemia (CP-CML), data from the PACE trial suggest.

When earlier results of this phase 2 study showed that ponatinib can cause AOEs, trials of the drug were put on partial clinical hold. Enrollment was stalled temporarily, and investigators began reducing ponatinib doses.

Now, updated data from the PACE trial suggest ponatinib can be administered safely and effectively in certain patients with CP-CML.

At a median follow-up of about 3.5 years, 95% of CP-CML patients who underwent dose reductions maintained a major cytogenetic response (MCyR). And AOEs occurred in 7% of patients who underwent dose reductions, compared to 13% of patients who did not.

“These continued responses . . . in such a heavily pretreated patient population are very encouraging,” said study investigator Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Careful assessment of the benefit and risk of initiating ponatinib therapy, particularly in patients who may be at increased risk for arterial occlusive events, can help identify patients with refractory, Ph+ leukemias who can benefit most from this treatment.”

Dr Cortes and his colleagues presented data from the PACE trial at the 20th Congress of the European Hematology Association as abstract P234*. The study was sponsored by Ariad Pharmaceuticals, the company developing ponatinib.

Updated results

The trial included patients with resistant or intolerant CML or Philadelphia chromosome-positive acute lymphoblastic leukemia. A total of 449 patients received ponatinib at a starting dose of 45 mg/day.

Ninety-three percent of patients had previously received 2 or more approved tyrosine kinase inhibitors (TKI), and 55% had previously received 3 or more approved TKIs.

Dr Cortes and his colleagues presented data on 270 CP-CML patients. At a median follow-up of 42.3 months (data as of February 2, 2015), 114 patients (42%) continue to receive ponatinib.

Eighteen percent of patients discontinued treatment due to adverse events (AEs), 10% due to disease progression, 3% due to death, and 27% for other reasons.

Fifty-nine percent of CP-CML patients achieved an MCyR at any time during the study, and 83% of responders are estimated to remain in MCyR at 3 years. Thirty-nine percent of patients achieved a major molecular response (MMR).

The estimated progression-free survival at 3 years is 60%, and the estimated overall survival is 81%.

Twenty-three percent of CP-CML patients experienced an AOE designated a serious AE, and 28%  experienced any AOE. The median time to onset for AOEs was 14.1 months (range, 0.3–44.0).

Four percent of CP-CML patients experienced a venous thromboembolism (VTE) that was considered an serious AE, and 5% experienced any VTE.

The most common all-grade, treatment-emergent AEs occurring in at least 40% of CP-CML patients were abdominal pain (46%), rash (46%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (41%).

Outcomes after dose reductions

On October 10, 2013, Ariad provided dose-reduction recommendations to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:

• CP-CML patients who already achieved an MCyR should have their ponatinib dose reduced to 15 mg/day
• CP-CML patients who had not already achieved an MCyR should have their dose reduced to 30 mg/day
• Advanced-phase patients should have their dose reduced to 30 mg/day.

As of February 2015, with 1.3 years (16 months) of follow-up after these recommendations, 95% of CP-CML patients maintained their response, whether or not they underwent prospective dose reductions.

Of the patients who were in MCyR as of October 10, 2013, and had a prospective dose reduction, 95% (61/64) maintained their response at 1.3 years. Of the patients who were in MMR as of October 10, 2013, and had a prospective dose reduction, 94% (44/47) maintained their response at 1.3 years.

Forty-two patients in MCyR did not undergo prospective dose reductions (the majority of which were already at a reduced dose of 30 mg or 15 mg as of October 10, 2013). Of these patients, 93% (n=39) maintained an MCyR after 1.3 more years of ponatinib treatment.

Twenty-four patients in MMR did not undergo prospective dose reductions, and 96% of these patients (n=22) maintained their response at 1.3 years.

Seven percent (5/71) of patients without prior AOEs who underwent dose reductions had a new AOE during the 1.3-year interval after dose reduction.

Thirteen percent (9/67) of patients without prior AOEs who did not undergo dose reductions had a new AOE in the same time interval.

*Information in the abstract differs from that presented at the meeting.

Jorge Cortes, MD

VIENNA—Administering ponatinib at lower doses can reduce the risk of arterial occlusive events (AOE) without hindering responses in patients with chronic-phase chronic myeloid leukemia (CP-CML), data from the PACE trial suggest.

When earlier results of this phase 2 study showed that ponatinib can cause AOEs, trials of the drug were put on partial clinical hold. Enrollment was stalled temporarily, and investigators began reducing ponatinib doses.

Now, updated data from the PACE trial suggest ponatinib can be administered safely and effectively in certain patients with CP-CML.

At a median follow-up of about 3.5 years, 95% of CP-CML patients who underwent dose reductions maintained a major cytogenetic response (MCyR). And AOEs occurred in 7% of patients who underwent dose reductions, compared to 13% of patients who did not.

“These continued responses . . . in such a heavily pretreated patient population are very encouraging,” said study investigator Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“Careful assessment of the benefit and risk of initiating ponatinib therapy, particularly in patients who may be at increased risk for arterial occlusive events, can help identify patients with refractory, Ph+ leukemias who can benefit most from this treatment.”

Dr Cortes and his colleagues presented data from the PACE trial at the 20th Congress of the European Hematology Association as abstract P234*. The study was sponsored by Ariad Pharmaceuticals, the company developing ponatinib.

Updated results

The trial included patients with resistant or intolerant CML or Philadelphia chromosome-positive acute lymphoblastic leukemia. A total of 449 patients received ponatinib at a starting dose of 45 mg/day.

Ninety-three percent of patients had previously received 2 or more approved tyrosine kinase inhibitors (TKI), and 55% had previously received 3 or more approved TKIs.

Dr Cortes and his colleagues presented data on 270 CP-CML patients. At a median follow-up of 42.3 months (data as of February 2, 2015), 114 patients (42%) continue to receive ponatinib.

Eighteen percent of patients discontinued treatment due to adverse events (AEs), 10% due to disease progression, 3% due to death, and 27% for other reasons.

Fifty-nine percent of CP-CML patients achieved an MCyR at any time during the study, and 83% of responders are estimated to remain in MCyR at 3 years. Thirty-nine percent of patients achieved a major molecular response (MMR).

The estimated progression-free survival at 3 years is 60%, and the estimated overall survival is 81%.

Twenty-three percent of CP-CML patients experienced an AOE designated a serious AE, and 28%  experienced any AOE. The median time to onset for AOEs was 14.1 months (range, 0.3–44.0).

Four percent of CP-CML patients experienced a venous thromboembolism (VTE) that was considered an serious AE, and 5% experienced any VTE.

The most common all-grade, treatment-emergent AEs occurring in at least 40% of CP-CML patients were abdominal pain (46%), rash (46%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (41%).

Outcomes after dose reductions

On October 10, 2013, Ariad provided dose-reduction recommendations to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:

• CP-CML patients who already achieved an MCyR should have their ponatinib dose reduced to 15 mg/day
• CP-CML patients who had not already achieved an MCyR should have their dose reduced to 30 mg/day
• Advanced-phase patients should have their dose reduced to 30 mg/day.

As of February 2015, with 1.3 years (16 months) of follow-up after these recommendations, 95% of CP-CML patients maintained their response, whether or not they underwent prospective dose reductions.

Of the patients who were in MCyR as of October 10, 2013, and had a prospective dose reduction, 95% (61/64) maintained their response at 1.3 years. Of the patients who were in MMR as of October 10, 2013, and had a prospective dose reduction, 94% (44/47) maintained their response at 1.3 years.

Forty-two patients in MCyR did not undergo prospective dose reductions (the majority of which were already at a reduced dose of 30 mg or 15 mg as of October 10, 2013). Of these patients, 93% (n=39) maintained an MCyR after 1.3 more years of ponatinib treatment.

Twenty-four patients in MMR did not undergo prospective dose reductions, and 96% of these patients (n=22) maintained their response at 1.3 years.

Seven percent (5/71) of patients without prior AOEs who underwent dose reductions had a new AOE during the 1.3-year interval after dose reduction.

Thirteen percent (9/67) of patients without prior AOEs who did not undergo dose reductions had a new AOE in the same time interval.

*Information in the abstract differs from that presented at the meeting.

Blood smear showing PV

Image courtesy of AFIP

VIENNA—Updated results from the phase 3 RESPONSE trial suggest the JAK1/2 inhibitor ruxolitinib can provide long-term disease control in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea.

At 18 months of follow-up, 80% of patients had achieved a durable response to ruxolitinib, sustaining hematocrit levels below 45% without the use of phlebotomy and experiencing reductions in spleen size.

In addition, 83% of patients were still receiving ruxolitinib at last follow-up.

“Polycythemia vera can lead to serious complications if inadequately controlled, and these data demonstrate the ability of [ruxolitinib] to provide a durable and comprehensive clinical benefit in this patient population,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis et Université Paris Diderot in France.

Dr Kiladjian presented these results at the 20th Congress of the European Hematology Association (abstract S447). The RESPONSE trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.

The study included 222 patients with PV whose were resistant to or could not tolerate hydroxyurea. They were randomized 1:1 to receive either ruxolitinib (at a starting dose of 10 mg twice daily) or best available therapy (BAT), which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the trial.

The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from week 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

Patients were deemed eligible for phlebotomy if they had hematocrit that was greater than 45% and had increased 3 or more percentage points from the time they entered the trial or if they had hematocrit greater than 48%.

The researchers performed a second, preplanned analysis at 80 weeks (18 months), evaluating the durability of primary response, hematocrit control, spleen size reduction, complete hematologic remission, and safety. The team also conducted a separate analysis evaluating hematologic parameters.

Results at 32 and 80 weeks

Twenty-one percent of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved the primary endpoint (P<0.0001). All but 1 of the responders in the ruxolitinib arm maintained this response at 80 weeks.

Sixty percent of patients in the ruxolitinib arm and 20% in the BAT arm achieved hematocrit control without phlebotomy through week 32. Patients in the ruxolitinib arm had an 89% probability of maintaining this response for 80 weeks from the time of initial response. Of the 98 patients on ruxolitinib at week 32, 90% did not have a phlebotomy between weeks 32 and 80.

At week 32, 38% of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved a 35% or greater reduction in spleen volume. All of the ruxolitinib-treated patients maintained this response at 80 weeks.

At week 32, 24% of patients in the ruxolitinib arm had a complete hematologic remission, as did 9% of patients in the BAT arm. Patients in the ruxolitinib arm had a 69% probability of maintaining this response for 80 weeks.

A separate analysis of the data at 18 months demonstrated that ruxolitinib treatment also led to sustained control of white blood cell and platelet levels, with the largest reductions occurring in patients who had the most elevated values at baseline.

At week 80, 83% of patients in the ruxolitinib arm remained on treatment (median exposure of 111 weeks), but none of the patients in the BAT arm were still receiving their assigned therapy.

At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued treatment due to adverse events.

“There is currently a significant unmet need for patients with polycythemia vera who are unable to tolerate or control their disease on other treatments,” Dr Kiladjian said. “For these patients, [ruxolitinib] represents a valuable new option, as confirmed by results from the long-term, phase 3 study.”

Blood smear showing PV

Image courtesy of AFIP

VIENNA—Updated results from the phase 3 RESPONSE trial suggest the JAK1/2 inhibitor ruxolitinib can provide long-term disease control in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea.

At 18 months of follow-up, 80% of patients had achieved a durable response to ruxolitinib, sustaining hematocrit levels below 45% without the use of phlebotomy and experiencing reductions in spleen size.

In addition, 83% of patients were still receiving ruxolitinib at last follow-up.

“Polycythemia vera can lead to serious complications if inadequately controlled, and these data demonstrate the ability of [ruxolitinib] to provide a durable and comprehensive clinical benefit in this patient population,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis et Université Paris Diderot in France.

Dr Kiladjian presented these results at the 20th Congress of the European Hematology Association (abstract S447). The RESPONSE trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.

The study included 222 patients with PV whose were resistant to or could not tolerate hydroxyurea. They were randomized 1:1 to receive either ruxolitinib (at a starting dose of 10 mg twice daily) or best available therapy (BAT), which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the trial.

The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from week 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

Patients were deemed eligible for phlebotomy if they had hematocrit that was greater than 45% and had increased 3 or more percentage points from the time they entered the trial or if they had hematocrit greater than 48%.

The researchers performed a second, preplanned analysis at 80 weeks (18 months), evaluating the durability of primary response, hematocrit control, spleen size reduction, complete hematologic remission, and safety. The team also conducted a separate analysis evaluating hematologic parameters.

Results at 32 and 80 weeks

Twenty-one percent of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved the primary endpoint (P<0.0001). All but 1 of the responders in the ruxolitinib arm maintained this response at 80 weeks.

Sixty percent of patients in the ruxolitinib arm and 20% in the BAT arm achieved hematocrit control without phlebotomy through week 32. Patients in the ruxolitinib arm had an 89% probability of maintaining this response for 80 weeks from the time of initial response. Of the 98 patients on ruxolitinib at week 32, 90% did not have a phlebotomy between weeks 32 and 80.

At week 32, 38% of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved a 35% or greater reduction in spleen volume. All of the ruxolitinib-treated patients maintained this response at 80 weeks.

At week 32, 24% of patients in the ruxolitinib arm had a complete hematologic remission, as did 9% of patients in the BAT arm. Patients in the ruxolitinib arm had a 69% probability of maintaining this response for 80 weeks.

A separate analysis of the data at 18 months demonstrated that ruxolitinib treatment also led to sustained control of white blood cell and platelet levels, with the largest reductions occurring in patients who had the most elevated values at baseline.

At week 80, 83% of patients in the ruxolitinib arm remained on treatment (median exposure of 111 weeks), but none of the patients in the BAT arm were still receiving their assigned therapy.

At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued treatment due to adverse events.

“There is currently a significant unmet need for patients with polycythemia vera who are unable to tolerate or control their disease on other treatments,” Dr Kiladjian said. “For these patients, [ruxolitinib] represents a valuable new option, as confirmed by results from the long-term, phase 3 study.”

Blood smear showing PV

Image courtesy of AFIP

VIENNA—Updated results from the phase 3 RESPONSE trial suggest the JAK1/2 inhibitor ruxolitinib can provide long-term disease control in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea.

At 18 months of follow-up, 80% of patients had achieved a durable response to ruxolitinib, sustaining hematocrit levels below 45% without the use of phlebotomy and experiencing reductions in spleen size.

In addition, 83% of patients were still receiving ruxolitinib at last follow-up.

“Polycythemia vera can lead to serious complications if inadequately controlled, and these data demonstrate the ability of [ruxolitinib] to provide a durable and comprehensive clinical benefit in this patient population,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis et Université Paris Diderot in France.

Dr Kiladjian presented these results at the 20th Congress of the European Hematology Association (abstract S447). The RESPONSE trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.

The study included 222 patients with PV whose were resistant to or could not tolerate hydroxyurea. They were randomized 1:1 to receive either ruxolitinib (at a starting dose of 10 mg twice daily) or best available therapy (BAT), which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the trial.

The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from week 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

Patients were deemed eligible for phlebotomy if they had hematocrit that was greater than 45% and had increased 3 or more percentage points from the time they entered the trial or if they had hematocrit greater than 48%.

The researchers performed a second, preplanned analysis at 80 weeks (18 months), evaluating the durability of primary response, hematocrit control, spleen size reduction, complete hematologic remission, and safety. The team also conducted a separate analysis evaluating hematologic parameters.

Results at 32 and 80 weeks

Twenty-one percent of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved the primary endpoint (P<0.0001). All but 1 of the responders in the ruxolitinib arm maintained this response at 80 weeks.

Sixty percent of patients in the ruxolitinib arm and 20% in the BAT arm achieved hematocrit control without phlebotomy through week 32. Patients in the ruxolitinib arm had an 89% probability of maintaining this response for 80 weeks from the time of initial response. Of the 98 patients on ruxolitinib at week 32, 90% did not have a phlebotomy between weeks 32 and 80.

At week 32, 38% of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved a 35% or greater reduction in spleen volume. All of the ruxolitinib-treated patients maintained this response at 80 weeks.

At week 32, 24% of patients in the ruxolitinib arm had a complete hematologic remission, as did 9% of patients in the BAT arm. Patients in the ruxolitinib arm had a 69% probability of maintaining this response for 80 weeks.

A separate analysis of the data at 18 months demonstrated that ruxolitinib treatment also led to sustained control of white blood cell and platelet levels, with the largest reductions occurring in patients who had the most elevated values at baseline.

At week 80, 83% of patients in the ruxolitinib arm remained on treatment (median exposure of 111 weeks), but none of the patients in the BAT arm were still receiving their assigned therapy.

At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued treatment due to adverse events.

“There is currently a significant unmet need for patients with polycythemia vera who are unable to tolerate or control their disease on other treatments,” Dr Kiladjian said. “For these patients, [ruxolitinib] represents a valuable new option, as confirmed by results from the long-term, phase 3 study.”

Cardiac amyloidosis

VIENNA—A monoclonal antibody (mAb) can produce responses in patients with light chain (AL) amyloidosis and persistent organ dysfunction, according to research presented at the 20th Congress of the European Hematology Association.

In an ongoing phase 1/2 trial, the mAb, known as NEOD001, produced a cardiac response in 57% of evaluable patients and a renal response in 60% of evaluable patients.

Michaela Liedtke, MD, of the Stanford University School of Medicine in California, presented these results as abstract S104*. The research was sponsored by Prothena Therapeutics Ltd., the company developing NEOD001.

Dr Liedtke presented results of an interim analysis as of February 28, 2015. The analysis included 27 patients with AL amyloidosis who had received 1 or more anti-plasma-cell systemic therapies, had a partial response or better, and did not require additional chemotherapy. The patients also had persistent organ dysfunction.

Patients received a dose of NEOD001 every 28 days, in 1 of 7 dosing cohorts (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, 16 mg/kg, and 24 mg/kg). They received a total of 327 infusions, with an average treatment duration of 12 months.

The patients’ median age was 60 (range, 38-80), and they had received a median of 2 prior treatments (range, 1-7). A third of patients each had 1 organ system involved (n=9), 2 organ systems involved (n=9), or 3 or more organ systems involved (n=9).

Safety data

The most frequently reported treatment-emergent adverse events (occurring in more than 10% of subjects) were fatigue (37%), upper respiratory tract infection (26%), cough (19%), dyspnea (19%), headache (15%), anemia (15%), increased blood creatinine (15%), peripheral edema (15%), edema (11%), diarrhea (11%), nausea (11%), and hyponatremia (11%).

There were no reports of hypersensitivity reactions to NEOD001 or drug-related serious adverse events, and no anti-NEOD001 antibodies were detected. There were no dose-limiting toxicities, and none of the patients discontinued treatment due to drug-related adverse events.

All patients remaining in the study were escalated to a dose of 24 mg/kg as of December 2, 2014.

Renal and cardiac responses

In a best-response analysis, 60% (9/15) of renal-evaluable patients demonstrated a renal response to NEOD001, defined as a 30% decrease in proteinuria in the absence of estimated glomerular filtration rate (eGFR) worsening. The other 40% of patients (n=6) had stable disease.

In another best-response analysis, 57% (8/14) of cardiac-evaluable patients had a cardiac response to NEOD001, defined as more than 30% and 300 pg/mL decrease in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). The other 43% of patients (n=6) had stable disease.

Longer treatment with NEOD001 was significantly associated with NT-proBNP decline (P<0.0001).

“[M]onthly infusions of NEOD001 correlate significantly with decreases in both cardiac and renal biomarkers over time,” Dr Liedtke said. “Decreases in cardiac biomarkers predict increased survival, and decreases in renal biomarkers predict delayed time to kidney failure.”

*Information in the abstract differs from that presented at the meeting.

Cardiac amyloidosis

VIENNA—A monoclonal antibody (mAb) can produce responses in patients with light chain (AL) amyloidosis and persistent organ dysfunction, according to research presented at the 20th Congress of the European Hematology Association.

In an ongoing phase 1/2 trial, the mAb, known as NEOD001, produced a cardiac response in 57% of evaluable patients and a renal response in 60% of evaluable patients.

Michaela Liedtke, MD, of the Stanford University School of Medicine in California, presented these results as abstract S104*. The research was sponsored by Prothena Therapeutics Ltd., the company developing NEOD001.

Dr Liedtke presented results of an interim analysis as of February 28, 2015. The analysis included 27 patients with AL amyloidosis who had received 1 or more anti-plasma-cell systemic therapies, had a partial response or better, and did not require additional chemotherapy. The patients also had persistent organ dysfunction.

Patients received a dose of NEOD001 every 28 days, in 1 of 7 dosing cohorts (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, 16 mg/kg, and 24 mg/kg). They received a total of 327 infusions, with an average treatment duration of 12 months.

The patients’ median age was 60 (range, 38-80), and they had received a median of 2 prior treatments (range, 1-7). A third of patients each had 1 organ system involved (n=9), 2 organ systems involved (n=9), or 3 or more organ systems involved (n=9).

Safety data

The most frequently reported treatment-emergent adverse events (occurring in more than 10% of subjects) were fatigue (37%), upper respiratory tract infection (26%), cough (19%), dyspnea (19%), headache (15%), anemia (15%), increased blood creatinine (15%), peripheral edema (15%), edema (11%), diarrhea (11%), nausea (11%), and hyponatremia (11%).

There were no reports of hypersensitivity reactions to NEOD001 or drug-related serious adverse events, and no anti-NEOD001 antibodies were detected. There were no dose-limiting toxicities, and none of the patients discontinued treatment due to drug-related adverse events.

All patients remaining in the study were escalated to a dose of 24 mg/kg as of December 2, 2014.

Renal and cardiac responses

In a best-response analysis, 60% (9/15) of renal-evaluable patients demonstrated a renal response to NEOD001, defined as a 30% decrease in proteinuria in the absence of estimated glomerular filtration rate (eGFR) worsening. The other 40% of patients (n=6) had stable disease.

In another best-response analysis, 57% (8/14) of cardiac-evaluable patients had a cardiac response to NEOD001, defined as more than 30% and 300 pg/mL decrease in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). The other 43% of patients (n=6) had stable disease.

Longer treatment with NEOD001 was significantly associated with NT-proBNP decline (P<0.0001).

“[M]onthly infusions of NEOD001 correlate significantly with decreases in both cardiac and renal biomarkers over time,” Dr Liedtke said. “Decreases in cardiac biomarkers predict increased survival, and decreases in renal biomarkers predict delayed time to kidney failure.”

*Information in the abstract differs from that presented at the meeting.

Cardiac amyloidosis

VIENNA—A monoclonal antibody (mAb) can produce responses in patients with light chain (AL) amyloidosis and persistent organ dysfunction, according to research presented at the 20th Congress of the European Hematology Association.

In an ongoing phase 1/2 trial, the mAb, known as NEOD001, produced a cardiac response in 57% of evaluable patients and a renal response in 60% of evaluable patients.

Michaela Liedtke, MD, of the Stanford University School of Medicine in California, presented these results as abstract S104*. The research was sponsored by Prothena Therapeutics Ltd., the company developing NEOD001.

Dr Liedtke presented results of an interim analysis as of February 28, 2015. The analysis included 27 patients with AL amyloidosis who had received 1 or more anti-plasma-cell systemic therapies, had a partial response or better, and did not require additional chemotherapy. The patients also had persistent organ dysfunction.

Patients received a dose of NEOD001 every 28 days, in 1 of 7 dosing cohorts (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, 16 mg/kg, and 24 mg/kg). They received a total of 327 infusions, with an average treatment duration of 12 months.

The patients’ median age was 60 (range, 38-80), and they had received a median of 2 prior treatments (range, 1-7). A third of patients each had 1 organ system involved (n=9), 2 organ systems involved (n=9), or 3 or more organ systems involved (n=9).

Safety data

The most frequently reported treatment-emergent adverse events (occurring in more than 10% of subjects) were fatigue (37%), upper respiratory tract infection (26%), cough (19%), dyspnea (19%), headache (15%), anemia (15%), increased blood creatinine (15%), peripheral edema (15%), edema (11%), diarrhea (11%), nausea (11%), and hyponatremia (11%).

There were no reports of hypersensitivity reactions to NEOD001 or drug-related serious adverse events, and no anti-NEOD001 antibodies were detected. There were no dose-limiting toxicities, and none of the patients discontinued treatment due to drug-related adverse events.

All patients remaining in the study were escalated to a dose of 24 mg/kg as of December 2, 2014.

Renal and cardiac responses

In a best-response analysis, 60% (9/15) of renal-evaluable patients demonstrated a renal response to NEOD001, defined as a 30% decrease in proteinuria in the absence of estimated glomerular filtration rate (eGFR) worsening. The other 40% of patients (n=6) had stable disease.

In another best-response analysis, 57% (8/14) of cardiac-evaluable patients had a cardiac response to NEOD001, defined as more than 30% and 300 pg/mL decrease in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). The other 43% of patients (n=6) had stable disease.

Longer treatment with NEOD001 was significantly associated with NT-proBNP decline (P<0.0001).

“[M]onthly infusions of NEOD001 correlate significantly with decreases in both cardiac and renal biomarkers over time,” Dr Liedtke said. “Decreases in cardiac biomarkers predict increased survival, and decreases in renal biomarkers predict delayed time to kidney failure.”

*Information in the abstract differs from that presented at the meeting.

Farhad Ravandi, MD

Photo courtesy of ASH

VIENNA—Adding the anticancer quinolone derivative vosaroxin to treatment with cytarabine can improve outcomes for some older patients with relapsed/refractory acute myeloid leukemia (AML), results of the phase 3 VALOR trial suggest.

AML patients age 60 and older with refractory and early relapse disease had improved survival rates when they received vosaroxin and cytarabine, compared to patients who received cytarabine and placebo.

However, for older patients with late-relapse AML, the addition of vosaroxin had no significant impact on survival.

Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented these result at the 20th Congress of the European Hematology Association (abstract P197*). The trial was sponsored by Sunesis Pharmaceuticals, the company developing vosaroxin.

“AML is a disease that primarily affects older patients, and clinical outcomes among these patients is abysmal,” Dr Ravandi noted. “These patients have had few options outside of clinical trial enrollment.”

“Results from the analyses presented today show compelling survival and durable responses, with comparable early mortality, for the vosaroxin and cytarabine treatment arm in the older refractory and early relapse patients. Given these results, I believe vosaroxin represents an important new treatment option.”

VALOR is a randomized, double-blind, phase 3 trial that enrolled 711 adult patients with relapsed or refractory AML. Patients were stratified for age, geographic region, and disease status, then randomized 1:1 to receive vosaroxin and cytarabine or placebo and cytarabine.

Dr Ravandi and his colleagues presented results from the subgroups of patients age 60 years and older (451/711) with late-relapse disease (n=87) and refractory or early relapse disease (combined n=364).

Late-relapse disease

Patients with late-relapse disease had a significantly higher complete response (CR) rate if they received vosaroxin/cytarabine rather than placebo/cytarabine. The rates were 57% and 28%, respectively (P=0.0064).

However, there was no significant difference between the treatment arms with regard to overall survival (OS), leukemia-free survival (LFS), or event-free survival (EFS).

The median OS was 9.2 months in the vosaroxin/cytarabine arm and 9.8 months in the placebo/cytarabine arm (hazard ratio [HR]=1.06, P=0.82). The median OS, censored for transplant, was 9.1 months in both arms (HR=0.92, P=0.78).

The median LFS was 10.3 months in the vosaroxin/cytarabine arm and 8.7 months in the placebo/cytarabine arm (HR=1.16, P=0.77). And the median EFS was 5.5 months and 2.3 months, respectively (HR=0.65, P=0.0852).

Thirty-day all-cause mortality was 11% the vosaroxin/cytarabine arm and 2% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 18% and 14%, respectively.

Refractory/early relapse disease

Patients with refractory AML (n=210) and those with early relapse disease (n=154) had significant improvements in CR and survival when they received vosaroxin and cytarabine. The CR rate was 26% in the vosaroxin/cytarabine arm and 10% in the placebo/cytarabine arm (P=0.0001).

The median OS was 6.5 months in the vosaroxin/cytarabine arm and 3.9 months in the placebo/cytarabine arm (HR=0.69, P=0.0008). The median OS, censored for transplant, was 6.2 months and 3.9 months, respectively (HR=0.71, P=0.0048).

The median LFS was 9.7 months in the vosaroxin/cytarabine arm and 5.5 months in the placebo/cytarabine arm (HR=0.50, P=0.0424). And the median EFS was 1.7 months and 1.3 months, respectively (HR=0.59, P<0.0001).

Rates of all-cause mortality were comparable between the arms. Thirty-day all-cause mortality was 10% in the vosaroxin/cytarabine arm and 11% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 21% and 25%, respectively.

Adverse events

Ninety-four percent of patients in the vosaroxin/cytarabine arm and 86% of those in the placebo/cytarabine arm experienced a grade 3 or higher adverse event (AE). The rate of treatment-related, grade 3 or higher AEs was 74% and 60%, respectively.

The most common grade 3 or higher AEs—occurring in at least 10% of patients in the vosaroxin/cytarabine and placebo/cytarabine arms, respectively—were febrile neutropenia (43% vs 30%), thrombocytopenia (24% vs 25%), anemia (23% vs 24%), neutropenia (19% vs 14%), hypokalemia (15% vs 7%), stomatitis (16% vs 4%), sepsis (12% vs 6%), and pneumonia (11% vs 8%).

*Information in the abstract differs from that presented at the meeting.

Farhad Ravandi, MD

Photo courtesy of ASH

VIENNA—Adding the anticancer quinolone derivative vosaroxin to treatment with cytarabine can improve outcomes for some older patients with relapsed/refractory acute myeloid leukemia (AML), results of the phase 3 VALOR trial suggest.

AML patients age 60 and older with refractory and early relapse disease had improved survival rates when they received vosaroxin and cytarabine, compared to patients who received cytarabine and placebo.

However, for older patients with late-relapse AML, the addition of vosaroxin had no significant impact on survival.

Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented these result at the 20th Congress of the European Hematology Association (abstract P197*). The trial was sponsored by Sunesis Pharmaceuticals, the company developing vosaroxin.

“AML is a disease that primarily affects older patients, and clinical outcomes among these patients is abysmal,” Dr Ravandi noted. “These patients have had few options outside of clinical trial enrollment.”

“Results from the analyses presented today show compelling survival and durable responses, with comparable early mortality, for the vosaroxin and cytarabine treatment arm in the older refractory and early relapse patients. Given these results, I believe vosaroxin represents an important new treatment option.”

VALOR is a randomized, double-blind, phase 3 trial that enrolled 711 adult patients with relapsed or refractory AML. Patients were stratified for age, geographic region, and disease status, then randomized 1:1 to receive vosaroxin and cytarabine or placebo and cytarabine.

Dr Ravandi and his colleagues presented results from the subgroups of patients age 60 years and older (451/711) with late-relapse disease (n=87) and refractory or early relapse disease (combined n=364).

Late-relapse disease

Patients with late-relapse disease had a significantly higher complete response (CR) rate if they received vosaroxin/cytarabine rather than placebo/cytarabine. The rates were 57% and 28%, respectively (P=0.0064).

However, there was no significant difference between the treatment arms with regard to overall survival (OS), leukemia-free survival (LFS), or event-free survival (EFS).

The median OS was 9.2 months in the vosaroxin/cytarabine arm and 9.8 months in the placebo/cytarabine arm (hazard ratio [HR]=1.06, P=0.82). The median OS, censored for transplant, was 9.1 months in both arms (HR=0.92, P=0.78).

The median LFS was 10.3 months in the vosaroxin/cytarabine arm and 8.7 months in the placebo/cytarabine arm (HR=1.16, P=0.77). And the median EFS was 5.5 months and 2.3 months, respectively (HR=0.65, P=0.0852).

Thirty-day all-cause mortality was 11% the vosaroxin/cytarabine arm and 2% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 18% and 14%, respectively.

Refractory/early relapse disease

Patients with refractory AML (n=210) and those with early relapse disease (n=154) had significant improvements in CR and survival when they received vosaroxin and cytarabine. The CR rate was 26% in the vosaroxin/cytarabine arm and 10% in the placebo/cytarabine arm (P=0.0001).

The median OS was 6.5 months in the vosaroxin/cytarabine arm and 3.9 months in the placebo/cytarabine arm (HR=0.69, P=0.0008). The median OS, censored for transplant, was 6.2 months and 3.9 months, respectively (HR=0.71, P=0.0048).

The median LFS was 9.7 months in the vosaroxin/cytarabine arm and 5.5 months in the placebo/cytarabine arm (HR=0.50, P=0.0424). And the median EFS was 1.7 months and 1.3 months, respectively (HR=0.59, P<0.0001).

Rates of all-cause mortality were comparable between the arms. Thirty-day all-cause mortality was 10% in the vosaroxin/cytarabine arm and 11% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 21% and 25%, respectively.

Adverse events

Ninety-four percent of patients in the vosaroxin/cytarabine arm and 86% of those in the placebo/cytarabine arm experienced a grade 3 or higher adverse event (AE). The rate of treatment-related, grade 3 or higher AEs was 74% and 60%, respectively.

The most common grade 3 or higher AEs—occurring in at least 10% of patients in the vosaroxin/cytarabine and placebo/cytarabine arms, respectively—were febrile neutropenia (43% vs 30%), thrombocytopenia (24% vs 25%), anemia (23% vs 24%), neutropenia (19% vs 14%), hypokalemia (15% vs 7%), stomatitis (16% vs 4%), sepsis (12% vs 6%), and pneumonia (11% vs 8%).

*Information in the abstract differs from that presented at the meeting.

Farhad Ravandi, MD

Photo courtesy of ASH

VIENNA—Adding the anticancer quinolone derivative vosaroxin to treatment with cytarabine can improve outcomes for some older patients with relapsed/refractory acute myeloid leukemia (AML), results of the phase 3 VALOR trial suggest.

AML patients age 60 and older with refractory and early relapse disease had improved survival rates when they received vosaroxin and cytarabine, compared to patients who received cytarabine and placebo.

However, for older patients with late-relapse AML, the addition of vosaroxin had no significant impact on survival.

Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented these result at the 20th Congress of the European Hematology Association (abstract P197*). The trial was sponsored by Sunesis Pharmaceuticals, the company developing vosaroxin.

“AML is a disease that primarily affects older patients, and clinical outcomes among these patients is abysmal,” Dr Ravandi noted. “These patients have had few options outside of clinical trial enrollment.”

“Results from the analyses presented today show compelling survival and durable responses, with comparable early mortality, for the vosaroxin and cytarabine treatment arm in the older refractory and early relapse patients. Given these results, I believe vosaroxin represents an important new treatment option.”

VALOR is a randomized, double-blind, phase 3 trial that enrolled 711 adult patients with relapsed or refractory AML. Patients were stratified for age, geographic region, and disease status, then randomized 1:1 to receive vosaroxin and cytarabine or placebo and cytarabine.

Dr Ravandi and his colleagues presented results from the subgroups of patients age 60 years and older (451/711) with late-relapse disease (n=87) and refractory or early relapse disease (combined n=364).

Late-relapse disease

Patients with late-relapse disease had a significantly higher complete response (CR) rate if they received vosaroxin/cytarabine rather than placebo/cytarabine. The rates were 57% and 28%, respectively (P=0.0064).

However, there was no significant difference between the treatment arms with regard to overall survival (OS), leukemia-free survival (LFS), or event-free survival (EFS).

The median OS was 9.2 months in the vosaroxin/cytarabine arm and 9.8 months in the placebo/cytarabine arm (hazard ratio [HR]=1.06, P=0.82). The median OS, censored for transplant, was 9.1 months in both arms (HR=0.92, P=0.78).

The median LFS was 10.3 months in the vosaroxin/cytarabine arm and 8.7 months in the placebo/cytarabine arm (HR=1.16, P=0.77). And the median EFS was 5.5 months and 2.3 months, respectively (HR=0.65, P=0.0852).

Thirty-day all-cause mortality was 11% the vosaroxin/cytarabine arm and 2% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 18% and 14%, respectively.

Refractory/early relapse disease

Patients with refractory AML (n=210) and those with early relapse disease (n=154) had significant improvements in CR and survival when they received vosaroxin and cytarabine. The CR rate was 26% in the vosaroxin/cytarabine arm and 10% in the placebo/cytarabine arm (P=0.0001).

The median OS was 6.5 months in the vosaroxin/cytarabine arm and 3.9 months in the placebo/cytarabine arm (HR=0.69, P=0.0008). The median OS, censored for transplant, was 6.2 months and 3.9 months, respectively (HR=0.71, P=0.0048).

The median LFS was 9.7 months in the vosaroxin/cytarabine arm and 5.5 months in the placebo/cytarabine arm (HR=0.50, P=0.0424). And the median EFS was 1.7 months and 1.3 months, respectively (HR=0.59, P<0.0001).

Rates of all-cause mortality were comparable between the arms. Thirty-day all-cause mortality was 10% in the vosaroxin/cytarabine arm and 11% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 21% and 25%, respectively.

Adverse events

Ninety-four percent of patients in the vosaroxin/cytarabine arm and 86% of those in the placebo/cytarabine arm experienced a grade 3 or higher adverse event (AE). The rate of treatment-related, grade 3 or higher AEs was 74% and 60%, respectively.

The most common grade 3 or higher AEs—occurring in at least 10% of patients in the vosaroxin/cytarabine and placebo/cytarabine arms, respectively—were febrile neutropenia (43% vs 30%), thrombocytopenia (24% vs 25%), anemia (23% vs 24%), neutropenia (19% vs 14%), hypokalemia (15% vs 7%), stomatitis (16% vs 4%), sepsis (12% vs 6%), and pneumonia (11% vs 8%).

*Information in the abstract differs from that presented at the meeting.

There is a persistent, unresolved debate regarding the perioperative management of clopidogrel (Plavix) among patients undergoing carotid endarterectomy (CEA).

”Surgeons often have to decide whether or not to continue antiplatelet drugs at the time of carotid endarterectomy.  Most feel comfortable continuing aspirin but there is uncertainty about how to manage patients on clopidogrel as well.

“Our goal was to try and address this frequently encountered problem in a way that helps surgeons decide how to manage these medications,” according to Dr. Douglas W. Jones of New York Presbyterian Hospital Weill-Cornell Medical Center, New York, and Dr. David H. Stone of Dartmouth-Hitchcock Medical Center.

Dr. Jones will reported on their study examining the impact of dual antiplatelet therapy (clopidogrel plus aspirin) on perioperative CEA outcomes in more than 34,000 patients treated over the period 2003 to 2014 at the 2015 Vascular Annual Meeting.

Among the 34,477 patients undergoing CEA in the Vascular Quality Initiative database, 63% (21,624) were on aspirin and 20% (7,059) were on clopidogrel and aspirin.  

In order to isolate the effect of clopidogrel, patients on clopidogrel and aspirin (dual therapy) were compared to patients taking aspirin alone.

Multivariate analyses and propensity score matching were employed to control for subgroup heterogeneity. The outcomes of the study included reoperation for bleeding (RTOR), neurologic events (transient ischemic attack or stroke), stroke, death, myocardial infarction (MI), and stroke/death.

Dr. Jones and his colleagues found that those patients who were on dual therapy were significantly more likely to have multiple comorbidities, including coronary artery disease, congestive heart failure, COPD, as well as diabetes.

However, after controlling for these differences, multivariate analysis showed that dual therapy was independently and significantly associated with increased RTOR (OR 1.74), but was also significantly protective against neurologic events (OR 0.61), any stroke (OR 0.62), and stroke/death (0.65).

Further analysis with propensity score matching yielded 2 well-matched groups of 4,548 patients.

Propensity score matching confirmed that patients on dual therapy were more likely to return to the OR for bleeding but were less likely to suffer neurologic events, stroke, or stroke/death.

“Our study shows that continuation of clopidogrel at the time of CEA was associated with a near 40% reduction in neurologic events, but it exposed patients to an increased bleeding risk,” said Dr. Jones.

“Accordingly, surgeons must judiciously assess the perioperative risk/benefit trade-off at the time of CEA for patients on dual antiplatelet therapy,” he concluded.

There is a persistent, unresolved debate regarding the perioperative management of clopidogrel (Plavix) among patients undergoing carotid endarterectomy (CEA).

”Surgeons often have to decide whether or not to continue antiplatelet drugs at the time of carotid endarterectomy.  Most feel comfortable continuing aspirin but there is uncertainty about how to manage patients on clopidogrel as well.

“Our goal was to try and address this frequently encountered problem in a way that helps surgeons decide how to manage these medications,” according to Dr. Douglas W. Jones of New York Presbyterian Hospital Weill-Cornell Medical Center, New York, and Dr. David H. Stone of Dartmouth-Hitchcock Medical Center.

Dr. Jones will reported on their study examining the impact of dual antiplatelet therapy (clopidogrel plus aspirin) on perioperative CEA outcomes in more than 34,000 patients treated over the period 2003 to 2014 at the 2015 Vascular Annual Meeting.

Among the 34,477 patients undergoing CEA in the Vascular Quality Initiative database, 63% (21,624) were on aspirin and 20% (7,059) were on clopidogrel and aspirin.  

In order to isolate the effect of clopidogrel, patients on clopidogrel and aspirin (dual therapy) were compared to patients taking aspirin alone.

Multivariate analyses and propensity score matching were employed to control for subgroup heterogeneity. The outcomes of the study included reoperation for bleeding (RTOR), neurologic events (transient ischemic attack or stroke), stroke, death, myocardial infarction (MI), and stroke/death.

Dr. Jones and his colleagues found that those patients who were on dual therapy were significantly more likely to have multiple comorbidities, including coronary artery disease, congestive heart failure, COPD, as well as diabetes.

However, after controlling for these differences, multivariate analysis showed that dual therapy was independently and significantly associated with increased RTOR (OR 1.74), but was also significantly protective against neurologic events (OR 0.61), any stroke (OR 0.62), and stroke/death (0.65).

Further analysis with propensity score matching yielded 2 well-matched groups of 4,548 patients.

Propensity score matching confirmed that patients on dual therapy were more likely to return to the OR for bleeding but were less likely to suffer neurologic events, stroke, or stroke/death.

“Our study shows that continuation of clopidogrel at the time of CEA was associated with a near 40% reduction in neurologic events, but it exposed patients to an increased bleeding risk,” said Dr. Jones.

“Accordingly, surgeons must judiciously assess the perioperative risk/benefit trade-off at the time of CEA for patients on dual antiplatelet therapy,” he concluded.

There is a persistent, unresolved debate regarding the perioperative management of clopidogrel (Plavix) among patients undergoing carotid endarterectomy (CEA).

”Surgeons often have to decide whether or not to continue antiplatelet drugs at the time of carotid endarterectomy.  Most feel comfortable continuing aspirin but there is uncertainty about how to manage patients on clopidogrel as well.

“Our goal was to try and address this frequently encountered problem in a way that helps surgeons decide how to manage these medications,” according to Dr. Douglas W. Jones of New York Presbyterian Hospital Weill-Cornell Medical Center, New York, and Dr. David H. Stone of Dartmouth-Hitchcock Medical Center.

Dr. Jones will reported on their study examining the impact of dual antiplatelet therapy (clopidogrel plus aspirin) on perioperative CEA outcomes in more than 34,000 patients treated over the period 2003 to 2014 at the 2015 Vascular Annual Meeting.

Among the 34,477 patients undergoing CEA in the Vascular Quality Initiative database, 63% (21,624) were on aspirin and 20% (7,059) were on clopidogrel and aspirin.  

In order to isolate the effect of clopidogrel, patients on clopidogrel and aspirin (dual therapy) were compared to patients taking aspirin alone.

Multivariate analyses and propensity score matching were employed to control for subgroup heterogeneity. The outcomes of the study included reoperation for bleeding (RTOR), neurologic events (transient ischemic attack or stroke), stroke, death, myocardial infarction (MI), and stroke/death.

Dr. Jones and his colleagues found that those patients who were on dual therapy were significantly more likely to have multiple comorbidities, including coronary artery disease, congestive heart failure, COPD, as well as diabetes.

However, after controlling for these differences, multivariate analysis showed that dual therapy was independently and significantly associated with increased RTOR (OR 1.74), but was also significantly protective against neurologic events (OR 0.61), any stroke (OR 0.62), and stroke/death (0.65).

Further analysis with propensity score matching yielded 2 well-matched groups of 4,548 patients.

Propensity score matching confirmed that patients on dual therapy were more likely to return to the OR for bleeding but were less likely to suffer neurologic events, stroke, or stroke/death.

“Our study shows that continuation of clopidogrel at the time of CEA was associated with a near 40% reduction in neurologic events, but it exposed patients to an increased bleeding risk,” said Dr. Jones.

“Accordingly, surgeons must judiciously assess the perioperative risk/benefit trade-off at the time of CEA for patients on dual antiplatelet therapy,” he concluded.

Sleep deprivation being a health issue in adolescence is no surprise. We hear repeated reports on cellphone use and excessive video gaming as contributors to sleep deprivation, but how many pediatricians are actually warning their patient during annual exams about the health impact of sleep deprivation?

The American Academy of Pediatrics recently published its policy on sleep and recommended adolescents get at least 8.5 hours of sleep per night and that school start time for middle schools be 8:30 a.m. (Pediatrics 2014;134:642-9). Despite this recommendation, more than 60% of U.S. schools have start times earlier than 8:00 a.m. A recent study also showed that 59% of 6th-8th graders and 87% of high school students obtained less the recommended 8.5 hours.

The reasoning behind the recommendation was based on the natural change in sleep cycle that occurs during adolescence, in which the circadian rhythm changes, resulting in decreased secretion of melatonin and delayed onset of sleep. With later start times, adolescents actually get up to an extra hour of sleep, which in turn results in fewer absences, improved focus, concentration, and better behavior (Pediatrics 2014 [doi:10.1542/peds.2014-1697]).

But beyond biologic cause for delayed sleep, social media, texting, and video games further impact the amount of sleep obtained, which leaves the majority of teens sleep deprived. Watching TV more than 3 hours per night impacts your ability not only to fall asleep, but to stay asleep, which again increases daytime sleepiness. Many may think that the “weekend catch-up” might ameliorate the deprivation, but studies show that the inconsistency of appropriate sleep further disrupts the wake-sleep cycles and further reduces the secretion of melatonin.

So how does sleep deprivation impact health? The obvious increased daytime sleepiness which results in poor concentration and focus is well known, and clearly contributes to the number of car accidents in this age group. But there are clear physiologic changes that occur when there is inadequate sleep that result in increased risk for diabetes, obesity, depression, cardiovascular disease, and even Alzheimer’s (Psychiatry Res. 2010;176:34-9; Sleep 2004;27:1351-8; Endocr. Dev. 2010;17:11-21). Lack of sleep has shown alterations in metabolic profiles, such as insulin, cortisol, and leptin, which lead to insulin resistance, increased sympathetic nervous system activity, increased hunger, and decreased satiety (Pediatrics 2014 [doi:10.1542/peds.2014-1697]).

The resulting lack of sleep in adolescence has cause increased intake of caffeine as well. Recent surveys show that caffeine use has skyrocketed this age group. If it is taken in the form of energy drinks, coffee, or soda, people who drink excessive caffeine are twice as likely to have sleep issues and shortened REM sleep (J. Adolesc. 2009;32:1189-207). It suppresses appetite and has withdrawal symptoms that further increase daytime sleepiness.

Adolescents also show increased use of sleep aids and stimulant drinks that have significant side effects of residual daytime sleepiness and tachycardia, respectively. So the treatment is further impacting the problem.

As physicians, we need to emphasize the physiologic impact of sleep deprivation and how it impacts many of the symptoms with which patients present. Many patients may overlook limited sleep as a cause of their symptoms.

Natural alternatives for improved sleep include chamomile, passionflower, or valerian, which come as a tea, capsule, liquid, or essential oil. Magnesium with or without calcium also is commonly used. Although all are deemed generally safe, there is no definitive effective dose in pediatrics, and they are not without side effects, so caution should be used when recommending these. Almond milk is a rich source of calcium, and calcium in the brain gets converted to melatonin.

Suggesting to parents that cellphones, video games, and computers be removed from the bedrooms by 9 p.m. will allow for the required 8.5 hours sleep. Avoiding sleeping until noon on weekends will improve sleep cycles. Avoiding caffeinated drinks and eating at late hours also will improve the quality of sleep and lessen daytime sleepiness. But the best advice to parents is for them to be good role models, and for them to get the appropriate amount of sleep, so that they also can avoid the hazards of sleep deprivation.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected]. Scan this QR code or go to pediatricnews.com.

Sleep deprivation being a health issue in adolescence is no surprise. We hear repeated reports on cellphone use and excessive video gaming as contributors to sleep deprivation, but how many pediatricians are actually warning their patient during annual exams about the health impact of sleep deprivation?

The American Academy of Pediatrics recently published its policy on sleep and recommended adolescents get at least 8.5 hours of sleep per night and that school start time for middle schools be 8:30 a.m. (Pediatrics 2014;134:642-9). Despite this recommendation, more than 60% of U.S. schools have start times earlier than 8:00 a.m. A recent study also showed that 59% of 6th-8th graders and 87% of high school students obtained less the recommended 8.5 hours.

The reasoning behind the recommendation was based on the natural change in sleep cycle that occurs during adolescence, in which the circadian rhythm changes, resulting in decreased secretion of melatonin and delayed onset of sleep. With later start times, adolescents actually get up to an extra hour of sleep, which in turn results in fewer absences, improved focus, concentration, and better behavior (Pediatrics 2014 [doi:10.1542/peds.2014-1697]).

But beyond biologic cause for delayed sleep, social media, texting, and video games further impact the amount of sleep obtained, which leaves the majority of teens sleep deprived. Watching TV more than 3 hours per night impacts your ability not only to fall asleep, but to stay asleep, which again increases daytime sleepiness. Many may think that the “weekend catch-up” might ameliorate the deprivation, but studies show that the inconsistency of appropriate sleep further disrupts the wake-sleep cycles and further reduces the secretion of melatonin.

So how does sleep deprivation impact health? The obvious increased daytime sleepiness which results in poor concentration and focus is well known, and clearly contributes to the number of car accidents in this age group. But there are clear physiologic changes that occur when there is inadequate sleep that result in increased risk for diabetes, obesity, depression, cardiovascular disease, and even Alzheimer’s (Psychiatry Res. 2010;176:34-9; Sleep 2004;27:1351-8; Endocr. Dev. 2010;17:11-21). Lack of sleep has shown alterations in metabolic profiles, such as insulin, cortisol, and leptin, which lead to insulin resistance, increased sympathetic nervous system activity, increased hunger, and decreased satiety (Pediatrics 2014 [doi:10.1542/peds.2014-1697]).

The resulting lack of sleep in adolescence has cause increased intake of caffeine as well. Recent surveys show that caffeine use has skyrocketed this age group. If it is taken in the form of energy drinks, coffee, or soda, people who drink excessive caffeine are twice as likely to have sleep issues and shortened REM sleep (J. Adolesc. 2009;32:1189-207). It suppresses appetite and has withdrawal symptoms that further increase daytime sleepiness.

Adolescents also show increased use of sleep aids and stimulant drinks that have significant side effects of residual daytime sleepiness and tachycardia, respectively. So the treatment is further impacting the problem.

As physicians, we need to emphasize the physiologic impact of sleep deprivation and how it impacts many of the symptoms with which patients present. Many patients may overlook limited sleep as a cause of their symptoms.

Natural alternatives for improved sleep include chamomile, passionflower, or valerian, which come as a tea, capsule, liquid, or essential oil. Magnesium with or without calcium also is commonly used. Although all are deemed generally safe, there is no definitive effective dose in pediatrics, and they are not without side effects, so caution should be used when recommending these. Almond milk is a rich source of calcium, and calcium in the brain gets converted to melatonin.

Suggesting to parents that cellphones, video games, and computers be removed from the bedrooms by 9 p.m. will allow for the required 8.5 hours sleep. Avoiding sleeping until noon on weekends will improve sleep cycles. Avoiding caffeinated drinks and eating at late hours also will improve the quality of sleep and lessen daytime sleepiness. But the best advice to parents is for them to be good role models, and for them to get the appropriate amount of sleep, so that they also can avoid the hazards of sleep deprivation.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected]. Scan this QR code or go to pediatricnews.com.

Sleep deprivation being a health issue in adolescence is no surprise. We hear repeated reports on cellphone use and excessive video gaming as contributors to sleep deprivation, but how many pediatricians are actually warning their patient during annual exams about the health impact of sleep deprivation?

The American Academy of Pediatrics recently published its policy on sleep and recommended adolescents get at least 8.5 hours of sleep per night and that school start time for middle schools be 8:30 a.m. (Pediatrics 2014;134:642-9). Despite this recommendation, more than 60% of U.S. schools have start times earlier than 8:00 a.m. A recent study also showed that 59% of 6th-8th graders and 87% of high school students obtained less the recommended 8.5 hours.

The reasoning behind the recommendation was based on the natural change in sleep cycle that occurs during adolescence, in which the circadian rhythm changes, resulting in decreased secretion of melatonin and delayed onset of sleep. With later start times, adolescents actually get up to an extra hour of sleep, which in turn results in fewer absences, improved focus, concentration, and better behavior (Pediatrics 2014 [doi:10.1542/peds.2014-1697]).

But beyond biologic cause for delayed sleep, social media, texting, and video games further impact the amount of sleep obtained, which leaves the majority of teens sleep deprived. Watching TV more than 3 hours per night impacts your ability not only to fall asleep, but to stay asleep, which again increases daytime sleepiness. Many may think that the “weekend catch-up” might ameliorate the deprivation, but studies show that the inconsistency of appropriate sleep further disrupts the wake-sleep cycles and further reduces the secretion of melatonin.

So how does sleep deprivation impact health? The obvious increased daytime sleepiness which results in poor concentration and focus is well known, and clearly contributes to the number of car accidents in this age group. But there are clear physiologic changes that occur when there is inadequate sleep that result in increased risk for diabetes, obesity, depression, cardiovascular disease, and even Alzheimer’s (Psychiatry Res. 2010;176:34-9; Sleep 2004;27:1351-8; Endocr. Dev. 2010;17:11-21). Lack of sleep has shown alterations in metabolic profiles, such as insulin, cortisol, and leptin, which lead to insulin resistance, increased sympathetic nervous system activity, increased hunger, and decreased satiety (Pediatrics 2014 [doi:10.1542/peds.2014-1697]).

The resulting lack of sleep in adolescence has cause increased intake of caffeine as well. Recent surveys show that caffeine use has skyrocketed this age group. If it is taken in the form of energy drinks, coffee, or soda, people who drink excessive caffeine are twice as likely to have sleep issues and shortened REM sleep (J. Adolesc. 2009;32:1189-207). It suppresses appetite and has withdrawal symptoms that further increase daytime sleepiness.

Adolescents also show increased use of sleep aids and stimulant drinks that have significant side effects of residual daytime sleepiness and tachycardia, respectively. So the treatment is further impacting the problem.

As physicians, we need to emphasize the physiologic impact of sleep deprivation and how it impacts many of the symptoms with which patients present. Many patients may overlook limited sleep as a cause of their symptoms.

Natural alternatives for improved sleep include chamomile, passionflower, or valerian, which come as a tea, capsule, liquid, or essential oil. Magnesium with or without calcium also is commonly used. Although all are deemed generally safe, there is no definitive effective dose in pediatrics, and they are not without side effects, so caution should be used when recommending these. Almond milk is a rich source of calcium, and calcium in the brain gets converted to melatonin.

Suggesting to parents that cellphones, video games, and computers be removed from the bedrooms by 9 p.m. will allow for the required 8.5 hours sleep. Avoiding sleeping until noon on weekends will improve sleep cycles. Avoiding caffeinated drinks and eating at late hours also will improve the quality of sleep and lessen daytime sleepiness. But the best advice to parents is for them to be good role models, and for them to get the appropriate amount of sleep, so that they also can avoid the hazards of sleep deprivation.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected]. Scan this QR code or go to pediatricnews.com.

Our local daily paper, like most other print newspapers, is on its last legs. But I read it faithfully for the obituaries, and to see how my former patients are doing on their school sports teams. Of course, there is always the smattering of motor vehicle accident reports to keep me reading.

One doesn’t have to be an insurance adjuster or an actuary to realize that motor vehicle accident fatalities cluster into two groups: teenagers and older folks (70 plus). One group falls victim to inexperience and a delusional sense of immortality. Those in the other group are losing their ability to sense their environment and respond with sufficient speed. One group makes poor decisions. The other makes them too slowly.

Because my mother died in her early 60s and my father never had a driver’s license, I never faced the difficult task of telling my aging parents that they were too old to drive. But I have heard from some of my friends of how difficult it was to ask Mom and Dad to give up their car keys.

The American Medical Association announced recently that they have to decided to take on a similar challenge by agreeing to “spearhead an effort to create competency guidelines for assessing whether older physicians remain able to provide safe and effective care for patients” (“Aging MDs Prompt Call for Competency Tests at AMA Meeting,” Associated Press, June 8, 2015). Prompted by the reality that one in four physicians in this country is over the age of 65 years, the AMA is beginning to talk about the issue and formulate plans to convene a variety of councils and work groups.

I’m sure there are some older physicians whose clinical skills have eroded with age to a point that they pose a significant threat to the safety of their patients, but I don’t think the situation warrants a full-court press by the AMA or anyone else for that matter.

First, I suspect that most physicians who continue to practice after they turn 70 years are not doing so because they need the money. That might be true 10-15 years from now when today’s young physicians are facing retirement while they are still recovering from the monstrous educational debts they incurred in their 20s. At present, though, I suspect that most physicians continue to practice because they enjoy what they do. I have to believe that a physician whose primary motivation is the joy of seeing patients is, in general, going to be doing a good job of it – and his or her patients probably know it and appreciate it.

Second, we already have in place (or should have) systems for identifying and dealing with physicians who are practicing substandard care for variety of reasons, such as substance abuse, financial malfeasance, inadequate training, or outright incompetence. Do we really need another layer of screening for older physicians? It feels like just another example of profiling. For example, does the Transportation Security Administration need to strip search every male with a dark complexion named Hassan?

The problem is that in many situations our safety nets for identifying and addressing incompetent physicians have too many holes in them. One of the reasons for this inadequacy is the unofficial code of silence that physicians have followed for years. Unless a fellow physician’s behavior is three orders of magnitude beyond the pale, many of us feel uncomfortable about approaching him or her or even lodging an anonymous report to the state board of licensure.

Of course, as physicians age some will lose critical clinical skills. On the other hand, with age many older physicians have gained perspectives on health, life, and death that their younger colleagues need to hear. We don’t need to single out older physicians for closer scrutiny. We simply have to improve our current surveillance systems and attitudes for physicians of all ages. If anyone wants to look more closely at how older physicians practice, the first question to ask should not be “What are they doing wrong?” but “What are these folks doing right that allows them to continue to enjoy practicing medicine at age 75?”

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Coping with a Picky Eater.”

Our local daily paper, like most other print newspapers, is on its last legs. But I read it faithfully for the obituaries, and to see how my former patients are doing on their school sports teams. Of course, there is always the smattering of motor vehicle accident reports to keep me reading.

One doesn’t have to be an insurance adjuster or an actuary to realize that motor vehicle accident fatalities cluster into two groups: teenagers and older folks (70 plus). One group falls victim to inexperience and a delusional sense of immortality. Those in the other group are losing their ability to sense their environment and respond with sufficient speed. One group makes poor decisions. The other makes them too slowly.

Because my mother died in her early 60s and my father never had a driver’s license, I never faced the difficult task of telling my aging parents that they were too old to drive. But I have heard from some of my friends of how difficult it was to ask Mom and Dad to give up their car keys.

The American Medical Association announced recently that they have to decided to take on a similar challenge by agreeing to “spearhead an effort to create competency guidelines for assessing whether older physicians remain able to provide safe and effective care for patients” (“Aging MDs Prompt Call for Competency Tests at AMA Meeting,” Associated Press, June 8, 2015). Prompted by the reality that one in four physicians in this country is over the age of 65 years, the AMA is beginning to talk about the issue and formulate plans to convene a variety of councils and work groups.

I’m sure there are some older physicians whose clinical skills have eroded with age to a point that they pose a significant threat to the safety of their patients, but I don’t think the situation warrants a full-court press by the AMA or anyone else for that matter.

First, I suspect that most physicians who continue to practice after they turn 70 years are not doing so because they need the money. That might be true 10-15 years from now when today’s young physicians are facing retirement while they are still recovering from the monstrous educational debts they incurred in their 20s. At present, though, I suspect that most physicians continue to practice because they enjoy what they do. I have to believe that a physician whose primary motivation is the joy of seeing patients is, in general, going to be doing a good job of it – and his or her patients probably know it and appreciate it.

Second, we already have in place (or should have) systems for identifying and dealing with physicians who are practicing substandard care for variety of reasons, such as substance abuse, financial malfeasance, inadequate training, or outright incompetence. Do we really need another layer of screening for older physicians? It feels like just another example of profiling. For example, does the Transportation Security Administration need to strip search every male with a dark complexion named Hassan?

The problem is that in many situations our safety nets for identifying and addressing incompetent physicians have too many holes in them. One of the reasons for this inadequacy is the unofficial code of silence that physicians have followed for years. Unless a fellow physician’s behavior is three orders of magnitude beyond the pale, many of us feel uncomfortable about approaching him or her or even lodging an anonymous report to the state board of licensure.

Of course, as physicians age some will lose critical clinical skills. On the other hand, with age many older physicians have gained perspectives on health, life, and death that their younger colleagues need to hear. We don’t need to single out older physicians for closer scrutiny. We simply have to improve our current surveillance systems and attitudes for physicians of all ages. If anyone wants to look more closely at how older physicians practice, the first question to ask should not be “What are they doing wrong?” but “What are these folks doing right that allows them to continue to enjoy practicing medicine at age 75?”

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Coping with a Picky Eater.”

Our local daily paper, like most other print newspapers, is on its last legs. But I read it faithfully for the obituaries, and to see how my former patients are doing on their school sports teams. Of course, there is always the smattering of motor vehicle accident reports to keep me reading.

One doesn’t have to be an insurance adjuster or an actuary to realize that motor vehicle accident fatalities cluster into two groups: teenagers and older folks (70 plus). One group falls victim to inexperience and a delusional sense of immortality. Those in the other group are losing their ability to sense their environment and respond with sufficient speed. One group makes poor decisions. The other makes them too slowly.

Because my mother died in her early 60s and my father never had a driver’s license, I never faced the difficult task of telling my aging parents that they were too old to drive. But I have heard from some of my friends of how difficult it was to ask Mom and Dad to give up their car keys.

The American Medical Association announced recently that they have to decided to take on a similar challenge by agreeing to “spearhead an effort to create competency guidelines for assessing whether older physicians remain able to provide safe and effective care for patients” (“Aging MDs Prompt Call for Competency Tests at AMA Meeting,” Associated Press, June 8, 2015). Prompted by the reality that one in four physicians in this country is over the age of 65 years, the AMA is beginning to talk about the issue and formulate plans to convene a variety of councils and work groups.

I’m sure there are some older physicians whose clinical skills have eroded with age to a point that they pose a significant threat to the safety of their patients, but I don’t think the situation warrants a full-court press by the AMA or anyone else for that matter.

First, I suspect that most physicians who continue to practice after they turn 70 years are not doing so because they need the money. That might be true 10-15 years from now when today’s young physicians are facing retirement while they are still recovering from the monstrous educational debts they incurred in their 20s. At present, though, I suspect that most physicians continue to practice because they enjoy what they do. I have to believe that a physician whose primary motivation is the joy of seeing patients is, in general, going to be doing a good job of it – and his or her patients probably know it and appreciate it.

Second, we already have in place (or should have) systems for identifying and dealing with physicians who are practicing substandard care for variety of reasons, such as substance abuse, financial malfeasance, inadequate training, or outright incompetence. Do we really need another layer of screening for older physicians? It feels like just another example of profiling. For example, does the Transportation Security Administration need to strip search every male with a dark complexion named Hassan?

The problem is that in many situations our safety nets for identifying and addressing incompetent physicians have too many holes in them. One of the reasons for this inadequacy is the unofficial code of silence that physicians have followed for years. Unless a fellow physician’s behavior is three orders of magnitude beyond the pale, many of us feel uncomfortable about approaching him or her or even lodging an anonymous report to the state board of licensure.

Of course, as physicians age some will lose critical clinical skills. On the other hand, with age many older physicians have gained perspectives on health, life, and death that their younger colleagues need to hear. We don’t need to single out older physicians for closer scrutiny. We simply have to improve our current surveillance systems and attitudes for physicians of all ages. If anyone wants to look more closely at how older physicians practice, the first question to ask should not be “What are they doing wrong?” but “What are these folks doing right that allows them to continue to enjoy practicing medicine at age 75?”

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “Coping with a Picky Eater.”

The Suicide Prevention Resource Center (SPRC) has released Caring for Adult Patients with Suicide Risk: A Consensus Guide for Emergency Departments.

The Suicide Prevention Resource Center (SPRC) is the nation’s only federally-supported resource center devoted to advancing the National Strategy for Suicide Prevention. The guide includes evidence-based practices in decision support, initial interventions, and discharge planning for adults who have been identified as having some risk of suicide.

“Emergency departments are prime sites for suicide prevention activities in the U.S., but until now clinicians have not had tools to help them steer patients toward treatment options that best meet their health and safety needs,”  Pamela S. Hyde, Administrator of the Substance Abuse and Mental Health Services Administration (SAMHSA) said in a press release.

Funded by SAMHSA, the guide was based on a literature review and developed by a consensus panel of experts from emergency medicine and suicide prevention organizations, as well as individuals who have lived through suicide attempts and suicidal thoughts or feelings.

The ED Guide is endorsed by the American Academy of Emergency Medicine, American Association for Emergency Psychiatry, American Association of Suicidology, and the American Foundation for Suicide Prevention.

SAMHSA’s National Survey on Drug Use and Health indicates that 1.3 million adults aged 18 or older (0.6 percent) attempted suicide in the past year. According to the Centers for Disease Control and Prevention, more than 41,000 individuals died by suicide in 2013. Suicides are the 10th leading cause of death in the U.S.

The ED Guide addresses specific objectives articulated by the 2012 National Strategy for Suicide Prevention, namely, to promote a continuum of care, safety, and well-being for ED patients treated for suicide risk; to collaborate with other health care providers to provide rapid and appropriate follow-up treatment; and to develop standardized protocols that direct clinical responses based on individual patient risk profiles.

The Suicide Prevention Resource Center (SPRC) has released Caring for Adult Patients with Suicide Risk: A Consensus Guide for Emergency Departments.

The Suicide Prevention Resource Center (SPRC) is the nation’s only federally-supported resource center devoted to advancing the National Strategy for Suicide Prevention. The guide includes evidence-based practices in decision support, initial interventions, and discharge planning for adults who have been identified as having some risk of suicide.

“Emergency departments are prime sites for suicide prevention activities in the U.S., but until now clinicians have not had tools to help them steer patients toward treatment options that best meet their health and safety needs,”  Pamela S. Hyde, Administrator of the Substance Abuse and Mental Health Services Administration (SAMHSA) said in a press release.

Funded by SAMHSA, the guide was based on a literature review and developed by a consensus panel of experts from emergency medicine and suicide prevention organizations, as well as individuals who have lived through suicide attempts and suicidal thoughts or feelings.

The ED Guide is endorsed by the American Academy of Emergency Medicine, American Association for Emergency Psychiatry, American Association of Suicidology, and the American Foundation for Suicide Prevention.

SAMHSA’s National Survey on Drug Use and Health indicates that 1.3 million adults aged 18 or older (0.6 percent) attempted suicide in the past year. According to the Centers for Disease Control and Prevention, more than 41,000 individuals died by suicide in 2013. Suicides are the 10th leading cause of death in the U.S.

The ED Guide addresses specific objectives articulated by the 2012 National Strategy for Suicide Prevention, namely, to promote a continuum of care, safety, and well-being for ED patients treated for suicide risk; to collaborate with other health care providers to provide rapid and appropriate follow-up treatment; and to develop standardized protocols that direct clinical responses based on individual patient risk profiles.

The Suicide Prevention Resource Center (SPRC) has released Caring for Adult Patients with Suicide Risk: A Consensus Guide for Emergency Departments.

The Suicide Prevention Resource Center (SPRC) is the nation’s only federally-supported resource center devoted to advancing the National Strategy for Suicide Prevention. The guide includes evidence-based practices in decision support, initial interventions, and discharge planning for adults who have been identified as having some risk of suicide.

“Emergency departments are prime sites for suicide prevention activities in the U.S., but until now clinicians have not had tools to help them steer patients toward treatment options that best meet their health and safety needs,”  Pamela S. Hyde, Administrator of the Substance Abuse and Mental Health Services Administration (SAMHSA) said in a press release.

Funded by SAMHSA, the guide was based on a literature review and developed by a consensus panel of experts from emergency medicine and suicide prevention organizations, as well as individuals who have lived through suicide attempts and suicidal thoughts or feelings.

The ED Guide is endorsed by the American Academy of Emergency Medicine, American Association for Emergency Psychiatry, American Association of Suicidology, and the American Foundation for Suicide Prevention.

SAMHSA’s National Survey on Drug Use and Health indicates that 1.3 million adults aged 18 or older (0.6 percent) attempted suicide in the past year. According to the Centers for Disease Control and Prevention, more than 41,000 individuals died by suicide in 2013. Suicides are the 10th leading cause of death in the U.S.

The ED Guide addresses specific objectives articulated by the 2012 National Strategy for Suicide Prevention, namely, to promote a continuum of care, safety, and well-being for ED patients treated for suicide risk; to collaborate with other health care providers to provide rapid and appropriate follow-up treatment; and to develop standardized protocols that direct clinical responses based on individual patient risk profiles.