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Eat/sleep/console approach almost eliminates morphine for NAS
ATLANTA – In just 7 months, the University of North Carolina Children’s Hospital, Chapel Hill, dropped the length of stay for neonatal abstinence syndrome from about 11 days to 5 days by moving from scheduled to PRN morphine dosing and abandoning the Finnegan score, according to a report at the Pediatric Hospital Medicine meeting.
The use of morphine fell from 93% of infants transferred to the hospital’s inpatient floors for neonatal abstinence syndrome (NAS) to just 12%, with no downsides for infants or moms.
“Our results have been incredibly encouraging,” said lead investigator and pediatrics resident Thomas Blount, MD. The take-home message is to treat the infant, rather than relying on the Finnegan score.
UNC Children’s, which treats about 50 infants a year for NAS on its inpatient floors, had been using the traditional approach: babies were automatically scheduled for morphine and Finnegan scoring – a withdrawal symptom checklist – every 4 hours, regardless of need. Sometimes infants weren’t even assessed to see if they actually needed morphine before the next dose was given.
“Waking babies up every 4 hours just seemed crazy; of course, they were going to have heightened neurologic signs and symptoms.” Meanwhile, families and providers were frustrated that infants who were otherwise doing well were held for an extra week or more to wean them off morphine, Dr. Blount said at the meeting.
In Nov. 2017, the hospital switched to the eat/sleep/console (ESC) model for NAS on its inpatient floors. The model emphasizes what’s been shown to work in recent years: keeping the infant with the mother; encouraging breast feeding, skin-on-skin contact, and other comfort measures; and supplementing feeds to help with weight gain. Morphine is reserved for when those measures fail and given only with a needs assessment (Hosp Pediatr. 2018 Jan;8(1):1-6).
The hospital ditched Finnegan scoring on its inpatient floors. Nurses were asked instead to check if infants were feeding adequately, sleeping at least an hour between feedings, and able to be consoled within 10 minutes when upset. If the infants met all three of those ESC criteria, providers moved on. They left the baby swaddled, relied on ambient white noise of ocean waves, and checked back on them later. “They didn’t mess with them,” Dr. Blount said at the meeting, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Finnegan scoring “was causing so much anxiety. Staff and families became hypervigilant,” set off by every little twitch and yawn the baby made. It was a good thing when it was abandoned; everyone relaxed, he said.
The changes made a huge difference. The average number of morphine doses dropped from 39 per infant to just 7 total doses among 23 infants in the first 7 months of the ESC initiative. Currently, morphine is used in only about 1 of 10 cases. “We estimate that we’ve given over 900 fewer doses” since ESC was put in place, Dr. Blount said.
There’s been no change in 30-day readmission rates – just one since the changes were made, for bronchiolitis – and no change in weight loss among infants with NAS. Babies are meeting all the ESC criteria to thrive.
“We had a lot of pushback initially, mostly from nursing staff and residents wondering how this was going to work. It quickly went away,” Dr. Blount said.
His team is now considering rolling ESC out to the newborn nursery and NICU.
There was no industry funding for the work, and Dr. Blount didn’t have any disclosures.
ATLANTA – In just 7 months, the University of North Carolina Children’s Hospital, Chapel Hill, dropped the length of stay for neonatal abstinence syndrome from about 11 days to 5 days by moving from scheduled to PRN morphine dosing and abandoning the Finnegan score, according to a report at the Pediatric Hospital Medicine meeting.
The use of morphine fell from 93% of infants transferred to the hospital’s inpatient floors for neonatal abstinence syndrome (NAS) to just 12%, with no downsides for infants or moms.
“Our results have been incredibly encouraging,” said lead investigator and pediatrics resident Thomas Blount, MD. The take-home message is to treat the infant, rather than relying on the Finnegan score.
UNC Children’s, which treats about 50 infants a year for NAS on its inpatient floors, had been using the traditional approach: babies were automatically scheduled for morphine and Finnegan scoring – a withdrawal symptom checklist – every 4 hours, regardless of need. Sometimes infants weren’t even assessed to see if they actually needed morphine before the next dose was given.
“Waking babies up every 4 hours just seemed crazy; of course, they were going to have heightened neurologic signs and symptoms.” Meanwhile, families and providers were frustrated that infants who were otherwise doing well were held for an extra week or more to wean them off morphine, Dr. Blount said at the meeting.
In Nov. 2017, the hospital switched to the eat/sleep/console (ESC) model for NAS on its inpatient floors. The model emphasizes what’s been shown to work in recent years: keeping the infant with the mother; encouraging breast feeding, skin-on-skin contact, and other comfort measures; and supplementing feeds to help with weight gain. Morphine is reserved for when those measures fail and given only with a needs assessment (Hosp Pediatr. 2018 Jan;8(1):1-6).
The hospital ditched Finnegan scoring on its inpatient floors. Nurses were asked instead to check if infants were feeding adequately, sleeping at least an hour between feedings, and able to be consoled within 10 minutes when upset. If the infants met all three of those ESC criteria, providers moved on. They left the baby swaddled, relied on ambient white noise of ocean waves, and checked back on them later. “They didn’t mess with them,” Dr. Blount said at the meeting, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Finnegan scoring “was causing so much anxiety. Staff and families became hypervigilant,” set off by every little twitch and yawn the baby made. It was a good thing when it was abandoned; everyone relaxed, he said.
The changes made a huge difference. The average number of morphine doses dropped from 39 per infant to just 7 total doses among 23 infants in the first 7 months of the ESC initiative. Currently, morphine is used in only about 1 of 10 cases. “We estimate that we’ve given over 900 fewer doses” since ESC was put in place, Dr. Blount said.
There’s been no change in 30-day readmission rates – just one since the changes were made, for bronchiolitis – and no change in weight loss among infants with NAS. Babies are meeting all the ESC criteria to thrive.
“We had a lot of pushback initially, mostly from nursing staff and residents wondering how this was going to work. It quickly went away,” Dr. Blount said.
His team is now considering rolling ESC out to the newborn nursery and NICU.
There was no industry funding for the work, and Dr. Blount didn’t have any disclosures.
ATLANTA – In just 7 months, the University of North Carolina Children’s Hospital, Chapel Hill, dropped the length of stay for neonatal abstinence syndrome from about 11 days to 5 days by moving from scheduled to PRN morphine dosing and abandoning the Finnegan score, according to a report at the Pediatric Hospital Medicine meeting.
The use of morphine fell from 93% of infants transferred to the hospital’s inpatient floors for neonatal abstinence syndrome (NAS) to just 12%, with no downsides for infants or moms.
“Our results have been incredibly encouraging,” said lead investigator and pediatrics resident Thomas Blount, MD. The take-home message is to treat the infant, rather than relying on the Finnegan score.
UNC Children’s, which treats about 50 infants a year for NAS on its inpatient floors, had been using the traditional approach: babies were automatically scheduled for morphine and Finnegan scoring – a withdrawal symptom checklist – every 4 hours, regardless of need. Sometimes infants weren’t even assessed to see if they actually needed morphine before the next dose was given.
“Waking babies up every 4 hours just seemed crazy; of course, they were going to have heightened neurologic signs and symptoms.” Meanwhile, families and providers were frustrated that infants who were otherwise doing well were held for an extra week or more to wean them off morphine, Dr. Blount said at the meeting.
In Nov. 2017, the hospital switched to the eat/sleep/console (ESC) model for NAS on its inpatient floors. The model emphasizes what’s been shown to work in recent years: keeping the infant with the mother; encouraging breast feeding, skin-on-skin contact, and other comfort measures; and supplementing feeds to help with weight gain. Morphine is reserved for when those measures fail and given only with a needs assessment (Hosp Pediatr. 2018 Jan;8(1):1-6).
The hospital ditched Finnegan scoring on its inpatient floors. Nurses were asked instead to check if infants were feeding adequately, sleeping at least an hour between feedings, and able to be consoled within 10 minutes when upset. If the infants met all three of those ESC criteria, providers moved on. They left the baby swaddled, relied on ambient white noise of ocean waves, and checked back on them later. “They didn’t mess with them,” Dr. Blount said at the meeting, sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Finnegan scoring “was causing so much anxiety. Staff and families became hypervigilant,” set off by every little twitch and yawn the baby made. It was a good thing when it was abandoned; everyone relaxed, he said.
The changes made a huge difference. The average number of morphine doses dropped from 39 per infant to just 7 total doses among 23 infants in the first 7 months of the ESC initiative. Currently, morphine is used in only about 1 of 10 cases. “We estimate that we’ve given over 900 fewer doses” since ESC was put in place, Dr. Blount said.
There’s been no change in 30-day readmission rates – just one since the changes were made, for bronchiolitis – and no change in weight loss among infants with NAS. Babies are meeting all the ESC criteria to thrive.
“We had a lot of pushback initially, mostly from nursing staff and residents wondering how this was going to work. It quickly went away,” Dr. Blount said.
His team is now considering rolling ESC out to the newborn nursery and NICU.
There was no industry funding for the work, and Dr. Blount didn’t have any disclosures.
REPORTING FROM PHM 2018
Key clinical point: When it comes to neonatal abstinence syndrome, treat the infant, not the Finnegan score.
Major finding: The University of North Carolina Children’s Hospital dropped the length of stay for neonatal abstinence syndrome from about 11 to 5 days by moving from scheduled to PRN morphine and abandoning Finnegan scoring. Morphine use fell more than 80%.
Study details: Review of a 7-month quality improvement project
Disclosures: There was no industry funding for the work. The lead investigator didn’t have any disclosures.
CT scans overused for children’s head traumas
Approximately one-third of children seen for head trauma visits in EDs underwent CT scans over a 9-year period in the United States, despite quality improvement initiatives to reduce unnecessary scans, based on a data from a cross-sectional survey published in Pediatrics.
“Computed tomography (CT) is the reference standard to provide a rapid and definitive diagnosis of intracranial pathology but must be balanced against the risks of radiation-induced malignancy,” wrote Brett Burstein, MD, PhD, of Harvard T.H. Chan School of Public Health, Cambridge, Mass., and his colleagues.
The researchers reviewed data from National Hospital Ambulatory Care Medical Survey database of nationally representative ED visits by children younger than 18 years for head trauma from 2007 to 2015. The median age of the patients was 6 years; 61% were boys. Approximately 88% were seen in nonteaching or nonpediatric hospitals.
During the 9-year period, 32% of 3,054 children underwent head CT scans; the 3,054 represented an estimated 14.3 million children making pediatric ED visits for head trauma. No significant differences were noted from year to year after the researchers controlled for confounding patient and ED factors.
Overall, use of CT was associated with patient’s age 2 years and older (adjusted odds ratio 1.51), white race (aOR 1.43), highest level of triage (aOR 8.24), and treatment at a nonteaching or nonpediatric hospital (aOR 1.47 and 1.53, respectively).
No significant differences in CT use were observed when the researchers compared the periods before (2007-2009) and after (2010-2015) the introduction of the Pediatric Emergency Care Applied Research Network (PECARN) rules – a clinical prediction protocol to assess head injuries in children in an ED setting. The unadjusted proportion of children who underwent CTs during the before PECARN and after PECARN periods was 33% and 31%, respectively.
“The finding of no decrease in CT neuroimaging during the 9-year study period, and particularly after the publication of the PECARN rules in 2009, was counter to the a priori hypothesis of this study,” Dr. Burstein and his associates noted.
The findings were limited by several factors including the lack of data on the severity of the head injuries, data on repeat visits, and potential misclassification of hospitals, they said. However, the results highlight the need for targeted interventions to disseminate the latest clinical decisions into practice.
Dr. Burstein and his associates had no financial conflicts to disclose.
SOURCE: Burstein B al. Pediatrics. 2018 Sept 4. doi: 10.1542/peds.2018-0814.
The data on the overuse of CT scans in cases of pediatric head trauma suggest that the latest best practices based on clinical research are not necessarily reaching out of academic settings and to the points of care where many children receive treatment, Eric Coon, MD, MS, and Susan L. Bratton, MD, MPH, wrote in an editorial.
The habit of CT use for children with head trauma may stem from an American Academy of Pediatrics 1999 recommendation on CT scans for children with a loss of consciousness, they noted.
Although data on CT use after the introduction of prediction algorithms showed signs of decline, these studies focused on children’s hospitals or teaching hospitals, and closer examination showed that “improvements achieved in refining CT use at children’s and teaching hospitals were the exception, with no measurable change on a broader, national level,” the editorialists said.
“Better diffusion of best practices is likely possible if attention is given to care delivered outside of children’s hospitals,” Dr. Coon and Dr. Bratton concluded.
Dr. Coon and Dr. Bratton are affiliated with the University of Utah, Salt Lake City. They had no relevant financial disclosures. These comments are summarized from their editorial accompanying the article by Burstein et al. (Pediatrics. 2018 Sept 4. doi: 10.1542/peds.2018-2137.)
The data on the overuse of CT scans in cases of pediatric head trauma suggest that the latest best practices based on clinical research are not necessarily reaching out of academic settings and to the points of care where many children receive treatment, Eric Coon, MD, MS, and Susan L. Bratton, MD, MPH, wrote in an editorial.
The habit of CT use for children with head trauma may stem from an American Academy of Pediatrics 1999 recommendation on CT scans for children with a loss of consciousness, they noted.
Although data on CT use after the introduction of prediction algorithms showed signs of decline, these studies focused on children’s hospitals or teaching hospitals, and closer examination showed that “improvements achieved in refining CT use at children’s and teaching hospitals were the exception, with no measurable change on a broader, national level,” the editorialists said.
“Better diffusion of best practices is likely possible if attention is given to care delivered outside of children’s hospitals,” Dr. Coon and Dr. Bratton concluded.
Dr. Coon and Dr. Bratton are affiliated with the University of Utah, Salt Lake City. They had no relevant financial disclosures. These comments are summarized from their editorial accompanying the article by Burstein et al. (Pediatrics. 2018 Sept 4. doi: 10.1542/peds.2018-2137.)
The data on the overuse of CT scans in cases of pediatric head trauma suggest that the latest best practices based on clinical research are not necessarily reaching out of academic settings and to the points of care where many children receive treatment, Eric Coon, MD, MS, and Susan L. Bratton, MD, MPH, wrote in an editorial.
The habit of CT use for children with head trauma may stem from an American Academy of Pediatrics 1999 recommendation on CT scans for children with a loss of consciousness, they noted.
Although data on CT use after the introduction of prediction algorithms showed signs of decline, these studies focused on children’s hospitals or teaching hospitals, and closer examination showed that “improvements achieved in refining CT use at children’s and teaching hospitals were the exception, with no measurable change on a broader, national level,” the editorialists said.
“Better diffusion of best practices is likely possible if attention is given to care delivered outside of children’s hospitals,” Dr. Coon and Dr. Bratton concluded.
Dr. Coon and Dr. Bratton are affiliated with the University of Utah, Salt Lake City. They had no relevant financial disclosures. These comments are summarized from their editorial accompanying the article by Burstein et al. (Pediatrics. 2018 Sept 4. doi: 10.1542/peds.2018-2137.)
Approximately one-third of children seen for head trauma visits in EDs underwent CT scans over a 9-year period in the United States, despite quality improvement initiatives to reduce unnecessary scans, based on a data from a cross-sectional survey published in Pediatrics.
“Computed tomography (CT) is the reference standard to provide a rapid and definitive diagnosis of intracranial pathology but must be balanced against the risks of radiation-induced malignancy,” wrote Brett Burstein, MD, PhD, of Harvard T.H. Chan School of Public Health, Cambridge, Mass., and his colleagues.
The researchers reviewed data from National Hospital Ambulatory Care Medical Survey database of nationally representative ED visits by children younger than 18 years for head trauma from 2007 to 2015. The median age of the patients was 6 years; 61% were boys. Approximately 88% were seen in nonteaching or nonpediatric hospitals.
During the 9-year period, 32% of 3,054 children underwent head CT scans; the 3,054 represented an estimated 14.3 million children making pediatric ED visits for head trauma. No significant differences were noted from year to year after the researchers controlled for confounding patient and ED factors.
Overall, use of CT was associated with patient’s age 2 years and older (adjusted odds ratio 1.51), white race (aOR 1.43), highest level of triage (aOR 8.24), and treatment at a nonteaching or nonpediatric hospital (aOR 1.47 and 1.53, respectively).
No significant differences in CT use were observed when the researchers compared the periods before (2007-2009) and after (2010-2015) the introduction of the Pediatric Emergency Care Applied Research Network (PECARN) rules – a clinical prediction protocol to assess head injuries in children in an ED setting. The unadjusted proportion of children who underwent CTs during the before PECARN and after PECARN periods was 33% and 31%, respectively.
“The finding of no decrease in CT neuroimaging during the 9-year study period, and particularly after the publication of the PECARN rules in 2009, was counter to the a priori hypothesis of this study,” Dr. Burstein and his associates noted.
The findings were limited by several factors including the lack of data on the severity of the head injuries, data on repeat visits, and potential misclassification of hospitals, they said. However, the results highlight the need for targeted interventions to disseminate the latest clinical decisions into practice.
Dr. Burstein and his associates had no financial conflicts to disclose.
SOURCE: Burstein B al. Pediatrics. 2018 Sept 4. doi: 10.1542/peds.2018-0814.
Approximately one-third of children seen for head trauma visits in EDs underwent CT scans over a 9-year period in the United States, despite quality improvement initiatives to reduce unnecessary scans, based on a data from a cross-sectional survey published in Pediatrics.
“Computed tomography (CT) is the reference standard to provide a rapid and definitive diagnosis of intracranial pathology but must be balanced against the risks of radiation-induced malignancy,” wrote Brett Burstein, MD, PhD, of Harvard T.H. Chan School of Public Health, Cambridge, Mass., and his colleagues.
The researchers reviewed data from National Hospital Ambulatory Care Medical Survey database of nationally representative ED visits by children younger than 18 years for head trauma from 2007 to 2015. The median age of the patients was 6 years; 61% were boys. Approximately 88% were seen in nonteaching or nonpediatric hospitals.
During the 9-year period, 32% of 3,054 children underwent head CT scans; the 3,054 represented an estimated 14.3 million children making pediatric ED visits for head trauma. No significant differences were noted from year to year after the researchers controlled for confounding patient and ED factors.
Overall, use of CT was associated with patient’s age 2 years and older (adjusted odds ratio 1.51), white race (aOR 1.43), highest level of triage (aOR 8.24), and treatment at a nonteaching or nonpediatric hospital (aOR 1.47 and 1.53, respectively).
No significant differences in CT use were observed when the researchers compared the periods before (2007-2009) and after (2010-2015) the introduction of the Pediatric Emergency Care Applied Research Network (PECARN) rules – a clinical prediction protocol to assess head injuries in children in an ED setting. The unadjusted proportion of children who underwent CTs during the before PECARN and after PECARN periods was 33% and 31%, respectively.
“The finding of no decrease in CT neuroimaging during the 9-year study period, and particularly after the publication of the PECARN rules in 2009, was counter to the a priori hypothesis of this study,” Dr. Burstein and his associates noted.
The findings were limited by several factors including the lack of data on the severity of the head injuries, data on repeat visits, and potential misclassification of hospitals, they said. However, the results highlight the need for targeted interventions to disseminate the latest clinical decisions into practice.
Dr. Burstein and his associates had no financial conflicts to disclose.
SOURCE: Burstein B al. Pediatrics. 2018 Sept 4. doi: 10.1542/peds.2018-0814.
FROM PEDIATRICS
Key clinical point: Use of CT scans to assess head trauma in children remained constant between 2007 and 2015 in the United States.
Major finding: Thirty-two percent of 3,054 children with head trauma underwent CT scans during a 9-year period.
Study details: A cross-sectional survey of 3,054 children, representing 14.3 million pediatric head trauma visits.
Disclosures: The researchers had no financial conflicts to disclose.
Source: Burstein B al. Pediatrics. 2018 Sept 4. doi: 10.1542/peds.2018-0814.
Click for Credit: Alcohol use while breastfeeding; cigarette smoking in HCV; more
Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Alcohol use during breastfeeding linked to cognitive harms in children
To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019
2. Cigarette smoking epidemic among HCV-infected individuals
To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019
3. Pancreatic surveillance identified resectable cancers
To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019
4. Autoimmune connective tissue disease predicted by interferon status, family history
To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019
Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Alcohol use during breastfeeding linked to cognitive harms in children
To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019
2. Cigarette smoking epidemic among HCV-infected individuals
To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019
3. Pancreatic surveillance identified resectable cancers
To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019
4. Autoimmune connective tissue disease predicted by interferon status, family history
To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019
Here are 4 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Alcohol use during breastfeeding linked to cognitive harms in children
To take the posttest, go to: https://bit.ly/2vJyUDc
Expires July 30, 2019
2. Cigarette smoking epidemic among HCV-infected individuals
To take the posttest, go to: https://bit.ly/2B00JwX
Expires June 26, 2019
3. Pancreatic surveillance identified resectable cancers
To take the posttest, go to: https://bit.ly/2vuSKmj
Expires July 30, 2019
4. Autoimmune connective tissue disease predicted by interferon status, family history
To take the posttest, go to: https://bit.ly/2OkZHNS
Expires July 30, 2019
EC approves blinatumomab for kids
The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto®), a bispecific, CD19-directed, CD3 T-cell engager immunotherapy.
Blinatumomab is now approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL).
The patients must have received at least two prior therapies, or they must have relapsed after allogeneic hematopoietic stem cell transplant.
This approval of blinatumomab extends to all countries in the European Union, as well as Norway, Iceland, and Liechtenstein.
The EC previously approved blinatumomab to treat adults with Philadelphia chromosome-negative, relapsed/refractory B-cell precursor ALL.
’205 study
The EC’s approval of blinatumomab in pediatric patients is based on results from the phase 1/2 ’205 study, which were published in the Journal of Clinical Oncology in 2016.
The study included 93 pediatric patients with relapsed/refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
There were 4 dose-limiting toxicities (DLTs) during the phase 1 portion of the trial, and 2 DLTs were fatal. Three patients had grade 4 cytokine release syndrome (CRS), one had grade 5 cardiac failure (as well as grade 4 CRS), and one had grade 5 respiratory failure.
Recommended dose
Based on the DLTs, the maximum-tolerated dose of blinatumomab was 15 µg/m2/day, but a step-wise dosage was recommended to reduce the risk of CRS. The recommended dose was 5 μg/m2/day on days 1-7 and 15 μg/m2/day on days 8-28 for cycle 1, and 15 μg/m2/day on days 1-28 for subsequent cycles.
Dose adjustment was possible in case of adverse events (AEs). Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.
Seventy patients received at least one infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).
The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease.
Safety
The most common AEs among patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).
The most frequent grade 3 or higher AEs were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).
Eight patients developed CRS. Three had grade 3 and one had grade 4 CRS.
Ten patients (14%) had treatment interruptions due to AEs, and 4 (6%) discontinued treatment permanently because of AEs.
Six patients had fatal AEs. Three died after they went on to allogeneic transplant—one of multiorgan failure, one of sepsis, and one of respiratory failure. The three other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.
Response and follow-up
Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a complete response (CR) within the first 2 cycles. Fourteen of these patients (52%) achieved minimal residual disease negativity.
Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.
At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.
Two of the patients had relapsed but were still alive, three had withdrawn consent (one in CR and two after relapse), three had died in CR after transplant, and 15 had relapsed and died.
Of the 43 patients who did not achieve a CR within the first two treatment cycles, 8 were still alive at the end of the 2-year follow-up.
The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto®), a bispecific, CD19-directed, CD3 T-cell engager immunotherapy.
Blinatumomab is now approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL).
The patients must have received at least two prior therapies, or they must have relapsed after allogeneic hematopoietic stem cell transplant.
This approval of blinatumomab extends to all countries in the European Union, as well as Norway, Iceland, and Liechtenstein.
The EC previously approved blinatumomab to treat adults with Philadelphia chromosome-negative, relapsed/refractory B-cell precursor ALL.
’205 study
The EC’s approval of blinatumomab in pediatric patients is based on results from the phase 1/2 ’205 study, which were published in the Journal of Clinical Oncology in 2016.
The study included 93 pediatric patients with relapsed/refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
There were 4 dose-limiting toxicities (DLTs) during the phase 1 portion of the trial, and 2 DLTs were fatal. Three patients had grade 4 cytokine release syndrome (CRS), one had grade 5 cardiac failure (as well as grade 4 CRS), and one had grade 5 respiratory failure.
Recommended dose
Based on the DLTs, the maximum-tolerated dose of blinatumomab was 15 µg/m2/day, but a step-wise dosage was recommended to reduce the risk of CRS. The recommended dose was 5 μg/m2/day on days 1-7 and 15 μg/m2/day on days 8-28 for cycle 1, and 15 μg/m2/day on days 1-28 for subsequent cycles.
Dose adjustment was possible in case of adverse events (AEs). Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.
Seventy patients received at least one infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).
The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease.
Safety
The most common AEs among patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).
The most frequent grade 3 or higher AEs were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).
Eight patients developed CRS. Three had grade 3 and one had grade 4 CRS.
Ten patients (14%) had treatment interruptions due to AEs, and 4 (6%) discontinued treatment permanently because of AEs.
Six patients had fatal AEs. Three died after they went on to allogeneic transplant—one of multiorgan failure, one of sepsis, and one of respiratory failure. The three other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.
Response and follow-up
Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a complete response (CR) within the first 2 cycles. Fourteen of these patients (52%) achieved minimal residual disease negativity.
Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.
At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.
Two of the patients had relapsed but were still alive, three had withdrawn consent (one in CR and two after relapse), three had died in CR after transplant, and 15 had relapsed and died.
Of the 43 patients who did not achieve a CR within the first two treatment cycles, 8 were still alive at the end of the 2-year follow-up.
The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto®), a bispecific, CD19-directed, CD3 T-cell engager immunotherapy.
Blinatumomab is now approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL).
The patients must have received at least two prior therapies, or they must have relapsed after allogeneic hematopoietic stem cell transplant.
This approval of blinatumomab extends to all countries in the European Union, as well as Norway, Iceland, and Liechtenstein.
The EC previously approved blinatumomab to treat adults with Philadelphia chromosome-negative, relapsed/refractory B-cell precursor ALL.
’205 study
The EC’s approval of blinatumomab in pediatric patients is based on results from the phase 1/2 ’205 study, which were published in the Journal of Clinical Oncology in 2016.
The study included 93 pediatric patients with relapsed/refractory B-cell precursor ALL. Patients received blinatumomab as a continuous intravenous infusion—49 patients in the phase 1 portion of the trial and 44 in phase 2. The patients were followed for 2 years.
There were 4 dose-limiting toxicities (DLTs) during the phase 1 portion of the trial, and 2 DLTs were fatal. Three patients had grade 4 cytokine release syndrome (CRS), one had grade 5 cardiac failure (as well as grade 4 CRS), and one had grade 5 respiratory failure.
Recommended dose
Based on the DLTs, the maximum-tolerated dose of blinatumomab was 15 µg/m2/day, but a step-wise dosage was recommended to reduce the risk of CRS. The recommended dose was 5 μg/m2/day on days 1-7 and 15 μg/m2/day on days 8-28 for cycle 1, and 15 μg/m2/day on days 1-28 for subsequent cycles.
Dose adjustment was possible in case of adverse events (AEs). Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab.
Seventy patients received at least one infusion of blinatumomab at the recommended dose. The median number of treatment cycles was 1 (range, 1 to 5).
The patients’ median age was 8 years (range, 7 months to 17 years). Forty patients (57%) had undergone allogeneic transplant prior to receiving blinatumomab, and 39 (56%) had refractory disease.
Safety
The most common AEs among patients who received the recommended dose of blinatumomab were pyrexia (80%), anemia (41%), nausea (33%), and headache (30%).
The most frequent grade 3 or higher AEs were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%), and neutropenia (17%).
Eight patients developed CRS. Three had grade 3 and one had grade 4 CRS.
Ten patients (14%) had treatment interruptions due to AEs, and 4 (6%) discontinued treatment permanently because of AEs.
Six patients had fatal AEs. Three died after they went on to allogeneic transplant—one of multiorgan failure, one of sepsis, and one of respiratory failure. The three other deaths were due to fungal infection, multiorgan failure, and thrombocytopenia.
Response and follow-up
Among the 70 patients who received the recommended dose of blinatumomab, 27 (39%) achieved a complete response (CR) within the first 2 cycles. Fourteen of these patients (52%) achieved minimal residual disease negativity.
Thirteen of the 27 patients (48%) who achieved a CR went on to receive an allogeneic transplant.
At the end of the 2-year follow-up, 4 of the 27 complete responders were still in remission.
Two of the patients had relapsed but were still alive, three had withdrawn consent (one in CR and two after relapse), three had died in CR after transplant, and 15 had relapsed and died.
Of the 43 patients who did not achieve a CR within the first two treatment cycles, 8 were still alive at the end of the 2-year follow-up.
Orodental issues often associated with facial port-wine stains
LAKE TAHOE, CALIF. – Several years ago, David H. Darrow, MD, DDS, began to notice a pattern in the conversation threads on websites dedicated to support for parents of children with facial port-wine stains (PWS).
, and that the alveolar ridge was lower on the side of the face that harbored the lesion. “Most importantly, parents were concerned that dentists were not touching their children because they were concerned about bleeding,” Dr. Darrow said at the annual meeting of the Society for Pediatric Dermatology. A search in the medical literature for port-wine stains and oral cavity changes, did not turn up much except for a few articles on bleeding. “One said that port-wine stains or capillary malformations rarely present major problems for the oral and maxillofacial surgeon. The other said that periodontal probing should not be done, as even gentle probing can result in uncontrolled bleeding,” he noted.
This prompted Dr. Darrow, who directs the Center for Hemangiomas and Vascular Birthmarks at the Eastern Virginia Medical School, Norfolk, and coinvestigators, Megan B. Dowling, MD, and Yueqin Zhao, PhD, to characterize manifestations of PWS in the oral cavity via an anonymous paired survey of volunteers with facial PWS and their dentists who were recruited from birthmarks.com and 10 collaborating physician practices (J Am Acad Dermatol 2012;67:687-93). Volunteers ranged in age from 1 to 62 years; mean age was 29 years. A total of 30 patients participated, and most (67%) were female.
The five most common oral manifestations reported by the patients were lip hyperplasia (53%), stained gingiva (47%), malocclusion (30%), bleeding gingiva (27%), and spacing between teeth (23%). Only 3% reported bleeding from dental procedures. When the researchers evaluated the orodental findings in the paired patient-physician responses, “most of the time there was good agreement between the patient and the dentist,” Dr. Darrow said. “The only one that fell out of agreement was lip hyperplasia. That’s probably because most dentists look right past the lips and into the oral cavity.”
When the researchers examined patients who had stained gingiva versus those who did not, they found that early-stage lesions demonstrated a reddish blush of the oral mucosa and gingiva, while late-stage lesions demonstrated increased blush of the oral tissues, as well as hyperplasia of the soft tissue or bone in the affected area. “Based on our review of the literature, bleeding of gums is rarely prolonged and dental procedures are safe,” Dr. Darrow said.
The findings are important, he continued, because capillary malformations of the oral cavity may result in periodontal disease associated with gingival overgrowth. The depth of the gingival pocket should be no more than 2-3 mm. “When you have areas of inflammation and deep-pocket formation, plaque and bacteria slowly erode the connection between the tooth and the soft tissue,” he explained. “At some point, that pocket becomes so deep that it reaches down into the bone in which the tooth is anchored. As that bone is eroded, the teeth loosen and begin to fall out. The goals of therapy are prevention of periodontal disease with meticulous oral hygiene.”
Soft tissue hyperplasia may be exacerbated by medications such as calcium channel blockers, cyclosporine, and phenytoin and phenobarbital, which are sometimes used by patients with Sturge-Weber syndrome, he said.
Dr. Darrow reported having no financial disclosures.
LAKE TAHOE, CALIF. – Several years ago, David H. Darrow, MD, DDS, began to notice a pattern in the conversation threads on websites dedicated to support for parents of children with facial port-wine stains (PWS).
, and that the alveolar ridge was lower on the side of the face that harbored the lesion. “Most importantly, parents were concerned that dentists were not touching their children because they were concerned about bleeding,” Dr. Darrow said at the annual meeting of the Society for Pediatric Dermatology. A search in the medical literature for port-wine stains and oral cavity changes, did not turn up much except for a few articles on bleeding. “One said that port-wine stains or capillary malformations rarely present major problems for the oral and maxillofacial surgeon. The other said that periodontal probing should not be done, as even gentle probing can result in uncontrolled bleeding,” he noted.
This prompted Dr. Darrow, who directs the Center for Hemangiomas and Vascular Birthmarks at the Eastern Virginia Medical School, Norfolk, and coinvestigators, Megan B. Dowling, MD, and Yueqin Zhao, PhD, to characterize manifestations of PWS in the oral cavity via an anonymous paired survey of volunteers with facial PWS and their dentists who were recruited from birthmarks.com and 10 collaborating physician practices (J Am Acad Dermatol 2012;67:687-93). Volunteers ranged in age from 1 to 62 years; mean age was 29 years. A total of 30 patients participated, and most (67%) were female.
The five most common oral manifestations reported by the patients were lip hyperplasia (53%), stained gingiva (47%), malocclusion (30%), bleeding gingiva (27%), and spacing between teeth (23%). Only 3% reported bleeding from dental procedures. When the researchers evaluated the orodental findings in the paired patient-physician responses, “most of the time there was good agreement between the patient and the dentist,” Dr. Darrow said. “The only one that fell out of agreement was lip hyperplasia. That’s probably because most dentists look right past the lips and into the oral cavity.”
When the researchers examined patients who had stained gingiva versus those who did not, they found that early-stage lesions demonstrated a reddish blush of the oral mucosa and gingiva, while late-stage lesions demonstrated increased blush of the oral tissues, as well as hyperplasia of the soft tissue or bone in the affected area. “Based on our review of the literature, bleeding of gums is rarely prolonged and dental procedures are safe,” Dr. Darrow said.
The findings are important, he continued, because capillary malformations of the oral cavity may result in periodontal disease associated with gingival overgrowth. The depth of the gingival pocket should be no more than 2-3 mm. “When you have areas of inflammation and deep-pocket formation, plaque and bacteria slowly erode the connection between the tooth and the soft tissue,” he explained. “At some point, that pocket becomes so deep that it reaches down into the bone in which the tooth is anchored. As that bone is eroded, the teeth loosen and begin to fall out. The goals of therapy are prevention of periodontal disease with meticulous oral hygiene.”
Soft tissue hyperplasia may be exacerbated by medications such as calcium channel blockers, cyclosporine, and phenytoin and phenobarbital, which are sometimes used by patients with Sturge-Weber syndrome, he said.
Dr. Darrow reported having no financial disclosures.
LAKE TAHOE, CALIF. – Several years ago, David H. Darrow, MD, DDS, began to notice a pattern in the conversation threads on websites dedicated to support for parents of children with facial port-wine stains (PWS).
, and that the alveolar ridge was lower on the side of the face that harbored the lesion. “Most importantly, parents were concerned that dentists were not touching their children because they were concerned about bleeding,” Dr. Darrow said at the annual meeting of the Society for Pediatric Dermatology. A search in the medical literature for port-wine stains and oral cavity changes, did not turn up much except for a few articles on bleeding. “One said that port-wine stains or capillary malformations rarely present major problems for the oral and maxillofacial surgeon. The other said that periodontal probing should not be done, as even gentle probing can result in uncontrolled bleeding,” he noted.
This prompted Dr. Darrow, who directs the Center for Hemangiomas and Vascular Birthmarks at the Eastern Virginia Medical School, Norfolk, and coinvestigators, Megan B. Dowling, MD, and Yueqin Zhao, PhD, to characterize manifestations of PWS in the oral cavity via an anonymous paired survey of volunteers with facial PWS and their dentists who were recruited from birthmarks.com and 10 collaborating physician practices (J Am Acad Dermatol 2012;67:687-93). Volunteers ranged in age from 1 to 62 years; mean age was 29 years. A total of 30 patients participated, and most (67%) were female.
The five most common oral manifestations reported by the patients were lip hyperplasia (53%), stained gingiva (47%), malocclusion (30%), bleeding gingiva (27%), and spacing between teeth (23%). Only 3% reported bleeding from dental procedures. When the researchers evaluated the orodental findings in the paired patient-physician responses, “most of the time there was good agreement between the patient and the dentist,” Dr. Darrow said. “The only one that fell out of agreement was lip hyperplasia. That’s probably because most dentists look right past the lips and into the oral cavity.”
When the researchers examined patients who had stained gingiva versus those who did not, they found that early-stage lesions demonstrated a reddish blush of the oral mucosa and gingiva, while late-stage lesions demonstrated increased blush of the oral tissues, as well as hyperplasia of the soft tissue or bone in the affected area. “Based on our review of the literature, bleeding of gums is rarely prolonged and dental procedures are safe,” Dr. Darrow said.
The findings are important, he continued, because capillary malformations of the oral cavity may result in periodontal disease associated with gingival overgrowth. The depth of the gingival pocket should be no more than 2-3 mm. “When you have areas of inflammation and deep-pocket formation, plaque and bacteria slowly erode the connection between the tooth and the soft tissue,” he explained. “At some point, that pocket becomes so deep that it reaches down into the bone in which the tooth is anchored. As that bone is eroded, the teeth loosen and begin to fall out. The goals of therapy are prevention of periodontal disease with meticulous oral hygiene.”
Soft tissue hyperplasia may be exacerbated by medications such as calcium channel blockers, cyclosporine, and phenytoin and phenobarbital, which are sometimes used by patients with Sturge-Weber syndrome, he said.
Dr. Darrow reported having no financial disclosures.
REPORTING FROM SPD 2018
Epilepsy often accompanies congenital Zika infections
Epilepsy occurred in approximately two-thirds of infants with congenital Zika virus infection in a study of 141 children.
“When ZIKV [Zika virus] infection is acquired in utero, it may be associated with epilepsy, and we characterized aspects of this complication in a study performed at our referral center,” wrote Hélio van der Linden Jr., MD, of Dr. Henrique Santillo Rehabilitation and Readaptation Center in Goiânia, Brazil, and colleagues in a letter to the editor published in the New England Journal of Medicine.
The researchers reviewed data from 141 infants aged 1-14 months with a median age of 9 months and Zika virus infection confirmed by laboratory analysis; 55% were girls.
The prevalence of epilepsy was 67%, with a mean age at onset of 4.9 months. Based on data provided by parents, 74% of the children experienced seizures at 6 months of age or younger.
Overall, 77% of the infants experienced a single type of seizure. Epileptic spasms, the most common type, occurred in 72% of infants, followed by focal motor seizure (21%) and tonic seizures (4%).
All 95 epileptic infants were treated with antiepileptic medications and 62 (65%) achieved remission. Of those in remission, 24 (39%) received monotherapy and 38 (61%) received polytherapy. The drugs most associated with seizure control were vigabatrin, levetiracetam, valproate, and phenobarbital.
The prevalence of epilepsy in this study was higher than that seen in previous studies, and most patients had early-onset, drug-resistant epilepsy, the researchers noted. However, burst-suppression patterns and hypsarrhythmia on EEG predicted more severe disease and suggest that epilepsy might complicate cases of congenital Zika infection, they said.
The researchers had no financial conflicts to disclose.
SOURCE: van der Linden H et al. N Engl J Med. 2018 Aug 30. doi: 10.1056/NEJMc1716070.
Epilepsy occurred in approximately two-thirds of infants with congenital Zika virus infection in a study of 141 children.
“When ZIKV [Zika virus] infection is acquired in utero, it may be associated with epilepsy, and we characterized aspects of this complication in a study performed at our referral center,” wrote Hélio van der Linden Jr., MD, of Dr. Henrique Santillo Rehabilitation and Readaptation Center in Goiânia, Brazil, and colleagues in a letter to the editor published in the New England Journal of Medicine.
The researchers reviewed data from 141 infants aged 1-14 months with a median age of 9 months and Zika virus infection confirmed by laboratory analysis; 55% were girls.
The prevalence of epilepsy was 67%, with a mean age at onset of 4.9 months. Based on data provided by parents, 74% of the children experienced seizures at 6 months of age or younger.
Overall, 77% of the infants experienced a single type of seizure. Epileptic spasms, the most common type, occurred in 72% of infants, followed by focal motor seizure (21%) and tonic seizures (4%).
All 95 epileptic infants were treated with antiepileptic medications and 62 (65%) achieved remission. Of those in remission, 24 (39%) received monotherapy and 38 (61%) received polytherapy. The drugs most associated with seizure control were vigabatrin, levetiracetam, valproate, and phenobarbital.
The prevalence of epilepsy in this study was higher than that seen in previous studies, and most patients had early-onset, drug-resistant epilepsy, the researchers noted. However, burst-suppression patterns and hypsarrhythmia on EEG predicted more severe disease and suggest that epilepsy might complicate cases of congenital Zika infection, they said.
The researchers had no financial conflicts to disclose.
SOURCE: van der Linden H et al. N Engl J Med. 2018 Aug 30. doi: 10.1056/NEJMc1716070.
Epilepsy occurred in approximately two-thirds of infants with congenital Zika virus infection in a study of 141 children.
“When ZIKV [Zika virus] infection is acquired in utero, it may be associated with epilepsy, and we characterized aspects of this complication in a study performed at our referral center,” wrote Hélio van der Linden Jr., MD, of Dr. Henrique Santillo Rehabilitation and Readaptation Center in Goiânia, Brazil, and colleagues in a letter to the editor published in the New England Journal of Medicine.
The researchers reviewed data from 141 infants aged 1-14 months with a median age of 9 months and Zika virus infection confirmed by laboratory analysis; 55% were girls.
The prevalence of epilepsy was 67%, with a mean age at onset of 4.9 months. Based on data provided by parents, 74% of the children experienced seizures at 6 months of age or younger.
Overall, 77% of the infants experienced a single type of seizure. Epileptic spasms, the most common type, occurred in 72% of infants, followed by focal motor seizure (21%) and tonic seizures (4%).
All 95 epileptic infants were treated with antiepileptic medications and 62 (65%) achieved remission. Of those in remission, 24 (39%) received monotherapy and 38 (61%) received polytherapy. The drugs most associated with seizure control were vigabatrin, levetiracetam, valproate, and phenobarbital.
The prevalence of epilepsy in this study was higher than that seen in previous studies, and most patients had early-onset, drug-resistant epilepsy, the researchers noted. However, burst-suppression patterns and hypsarrhythmia on EEG predicted more severe disease and suggest that epilepsy might complicate cases of congenital Zika infection, they said.
The researchers had no financial conflicts to disclose.
SOURCE: van der Linden H et al. N Engl J Med. 2018 Aug 30. doi: 10.1056/NEJMc1716070.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Epilepsy occurred in 67% of 141 infants with congenital Zika infections.
Study details: The data come from 141 infants aged 1-14 months with congenital Zika infections.
Disclosures: The researchers had no financial conflicts to disclose.
Source: van der Linden H et al. N Engl J Med. 2018 Aug 30. doi: 10.1056/NEJMc1716070.
Spinraza shows motor improvements in older children with SMA type 1
Treatment with nusinersen (Spinraza) produced significant improvements in motor function in children with spinal muscular atrophy type 1 even if treatment was initiated at a later age, new research has suggested.
In a paper published online Aug. 29 in Neurology, researchers presented the results of a prospective cohort study in 33 children who ranged in age from 8.3 months to 9.4 years and had spinal muscular atrophy type 1. In this study, the children were treated with the antisense oligonucleotide nusinersen, which increases production of functional survival motor neuron (SMN) protein. The patients participated in the trial as a part of an Expanded Access Program for nusinersen that’s operated by its manufacturer, Biogen.
All previous trials of nusinersen have enrolled patients younger than 7 months, wrote Karolina Aragon-Gawinska, MD, of the Institute I-motion at Armand Trousseau Hospital, Paris, and her coauthors. The benefits of the drug in older patients were unknown.
The disease has a median survival of 8-13.5 months of age, yet all patients in the study were alive at 6 months after starting the treatment. Researchers saw a 1.5-point median improvement in motor milestones – measured using the Hammersmith Infant Neurologic Examination (HINE) Part 2 – and five patients were able to sit up without support for more than 30 seconds.
On the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, which assesses the motor skills of infants with spinal muscular atrophy, there was a median improvement of four points at 6 months.
There were no significant changes in the need for nutritional support. However, eight patients showed worsening respiratory condition at 6 months, compared with baseline. Three patients – all of whom had a more severe form of the disease by virtue of only having two copies of the nearly identical SMN2 gene – showed no significant motor progress and were placed on full-time ventilation.
Overall, the number of copies of SMN2 gene did not appear to affect the need for ventilator or nutritional support.
“The response to treatment was highly variable, but new motor acquisitions were attained even in 8-year-old patients,” the authors wrote. “In some patients, respiratory worsening was observed despite motor improvement, suggesting a slower action of nusinersen on the respiratory symptoms and the possible intercurrent infections that might destabilize these weak patients.”
They noted that while previous studies had included patients with only two copies of the SMN2 gene – and hence more severe disease – around half the patients in this study had three copies, which may explain why even older patients showed significant responses to treatment.
“Patients with three SMN2 copies were older and had a longer disease duration than patients with two SMN2 copies, which may partially explain the absence of copy number effect.”
The study was funded by the Institute of Myology and AFM-Telethon. Eight authors reported involvement with pharmaceutical-sponsored trials, consultancies, or other funding from the pharmaceutical industry, including Biogen. No other conflicts of interest were declared.
SOURCE: Aragon-Gawinska K et al. Neurology. 2018 Aug 29. doi: 10.1212/WNL.0000000000006281.
Treatment with nusinersen (Spinraza) produced significant improvements in motor function in children with spinal muscular atrophy type 1 even if treatment was initiated at a later age, new research has suggested.
In a paper published online Aug. 29 in Neurology, researchers presented the results of a prospective cohort study in 33 children who ranged in age from 8.3 months to 9.4 years and had spinal muscular atrophy type 1. In this study, the children were treated with the antisense oligonucleotide nusinersen, which increases production of functional survival motor neuron (SMN) protein. The patients participated in the trial as a part of an Expanded Access Program for nusinersen that’s operated by its manufacturer, Biogen.
All previous trials of nusinersen have enrolled patients younger than 7 months, wrote Karolina Aragon-Gawinska, MD, of the Institute I-motion at Armand Trousseau Hospital, Paris, and her coauthors. The benefits of the drug in older patients were unknown.
The disease has a median survival of 8-13.5 months of age, yet all patients in the study were alive at 6 months after starting the treatment. Researchers saw a 1.5-point median improvement in motor milestones – measured using the Hammersmith Infant Neurologic Examination (HINE) Part 2 – and five patients were able to sit up without support for more than 30 seconds.
On the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, which assesses the motor skills of infants with spinal muscular atrophy, there was a median improvement of four points at 6 months.
There were no significant changes in the need for nutritional support. However, eight patients showed worsening respiratory condition at 6 months, compared with baseline. Three patients – all of whom had a more severe form of the disease by virtue of only having two copies of the nearly identical SMN2 gene – showed no significant motor progress and were placed on full-time ventilation.
Overall, the number of copies of SMN2 gene did not appear to affect the need for ventilator or nutritional support.
“The response to treatment was highly variable, but new motor acquisitions were attained even in 8-year-old patients,” the authors wrote. “In some patients, respiratory worsening was observed despite motor improvement, suggesting a slower action of nusinersen on the respiratory symptoms and the possible intercurrent infections that might destabilize these weak patients.”
They noted that while previous studies had included patients with only two copies of the SMN2 gene – and hence more severe disease – around half the patients in this study had three copies, which may explain why even older patients showed significant responses to treatment.
“Patients with three SMN2 copies were older and had a longer disease duration than patients with two SMN2 copies, which may partially explain the absence of copy number effect.”
The study was funded by the Institute of Myology and AFM-Telethon. Eight authors reported involvement with pharmaceutical-sponsored trials, consultancies, or other funding from the pharmaceutical industry, including Biogen. No other conflicts of interest were declared.
SOURCE: Aragon-Gawinska K et al. Neurology. 2018 Aug 29. doi: 10.1212/WNL.0000000000006281.
Treatment with nusinersen (Spinraza) produced significant improvements in motor function in children with spinal muscular atrophy type 1 even if treatment was initiated at a later age, new research has suggested.
In a paper published online Aug. 29 in Neurology, researchers presented the results of a prospective cohort study in 33 children who ranged in age from 8.3 months to 9.4 years and had spinal muscular atrophy type 1. In this study, the children were treated with the antisense oligonucleotide nusinersen, which increases production of functional survival motor neuron (SMN) protein. The patients participated in the trial as a part of an Expanded Access Program for nusinersen that’s operated by its manufacturer, Biogen.
All previous trials of nusinersen have enrolled patients younger than 7 months, wrote Karolina Aragon-Gawinska, MD, of the Institute I-motion at Armand Trousseau Hospital, Paris, and her coauthors. The benefits of the drug in older patients were unknown.
The disease has a median survival of 8-13.5 months of age, yet all patients in the study were alive at 6 months after starting the treatment. Researchers saw a 1.5-point median improvement in motor milestones – measured using the Hammersmith Infant Neurologic Examination (HINE) Part 2 – and five patients were able to sit up without support for more than 30 seconds.
On the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, which assesses the motor skills of infants with spinal muscular atrophy, there was a median improvement of four points at 6 months.
There were no significant changes in the need for nutritional support. However, eight patients showed worsening respiratory condition at 6 months, compared with baseline. Three patients – all of whom had a more severe form of the disease by virtue of only having two copies of the nearly identical SMN2 gene – showed no significant motor progress and were placed on full-time ventilation.
Overall, the number of copies of SMN2 gene did not appear to affect the need for ventilator or nutritional support.
“The response to treatment was highly variable, but new motor acquisitions were attained even in 8-year-old patients,” the authors wrote. “In some patients, respiratory worsening was observed despite motor improvement, suggesting a slower action of nusinersen on the respiratory symptoms and the possible intercurrent infections that might destabilize these weak patients.”
They noted that while previous studies had included patients with only two copies of the SMN2 gene – and hence more severe disease – around half the patients in this study had three copies, which may explain why even older patients showed significant responses to treatment.
“Patients with three SMN2 copies were older and had a longer disease duration than patients with two SMN2 copies, which may partially explain the absence of copy number effect.”
The study was funded by the Institute of Myology and AFM-Telethon. Eight authors reported involvement with pharmaceutical-sponsored trials, consultancies, or other funding from the pharmaceutical industry, including Biogen. No other conflicts of interest were declared.
SOURCE: Aragon-Gawinska K et al. Neurology. 2018 Aug 29. doi: 10.1212/WNL.0000000000006281.
FROM NEUROLOGY
Key clinical point: Nusinersen can produce motor improvements in older children with spinal muscular atrophy type 1.
Major finding: Nusinersen treatment showed a median 1.5-point improvement in HINE-2 score after 6 months.
Study details: Prospective cohort study in 33 children with spinal muscular atrophy type 1.
Disclosures: The study was funded by the Institute of Myology and AFM-Telethon. Eight authors reported involvement with pharmaceutical-sponsored trials, consultancies, or other funding from the pharmaceutical industry, including from nusinersen manufacturer Biogen. No other conflicts of interest were declared.
Source: Aragon-Gawinska K et al. Neurology. 2018 Aug 29. doi: 10.1212/WNL.0000000000006281.
Spinal Muscular Atrophy Added to Recommended Uniform Screening Panel
Screening will enable early detection, but the treatment’s exceptional cost could present a barrier to patients.
Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.
Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.
“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”
Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.
Drug Approval Raised Ethical Questions
An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.1–3
After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.
Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within two years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”
The advisory committee makes its recommendations to HHS about which heritable disorders to include in the RUSP after it has assessed a systematic, evidence-based review conducted by an external, independent group. Alex R. Kemper, MD, MPH, Professor of Pediatrics at the Ohio State University and Division Chief of Ambulatory Pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of Pediatrics and a member of the US Preventive Services Task Force.
According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”
“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”
Symptom Onset Distinguishes the Types of SMA
Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.
A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.
The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.
Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.
Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”
Long-Term Data on Nusinersen Are Lacking
Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.2
Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.2
Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”
Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.
“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.
At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.
The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.
—Tara Haelle
References
1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.
2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.
3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.
Screening will enable early detection, but the treatment’s exceptional cost could present a barrier to patients.
Screening will enable early detection, but the treatment’s exceptional cost could present a barrier to patients.
Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.
Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.
“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”
Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.
Drug Approval Raised Ethical Questions
An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.1–3
After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.
Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within two years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”
The advisory committee makes its recommendations to HHS about which heritable disorders to include in the RUSP after it has assessed a systematic, evidence-based review conducted by an external, independent group. Alex R. Kemper, MD, MPH, Professor of Pediatrics at the Ohio State University and Division Chief of Ambulatory Pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of Pediatrics and a member of the US Preventive Services Task Force.
According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”
“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”
Symptom Onset Distinguishes the Types of SMA
Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.
A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.
The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.
Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.
Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”
Long-Term Data on Nusinersen Are Lacking
Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.2
Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.2
Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”
Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.
“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.
At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.
The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.
—Tara Haelle
References
1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.
2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.
3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.
Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.
Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.
“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”
Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.
Drug Approval Raised Ethical Questions
An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.1–3
After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.
Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within two years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”
The advisory committee makes its recommendations to HHS about which heritable disorders to include in the RUSP after it has assessed a systematic, evidence-based review conducted by an external, independent group. Alex R. Kemper, MD, MPH, Professor of Pediatrics at the Ohio State University and Division Chief of Ambulatory Pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of Pediatrics and a member of the US Preventive Services Task Force.
According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”
“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”
Symptom Onset Distinguishes the Types of SMA
Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.
A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.
The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.
Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.
Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”
Long-Term Data on Nusinersen Are Lacking
Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.2
Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.2
Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”
Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.
“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.
At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.
The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.
—Tara Haelle
References
1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.
2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.
3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.
Speaking the unspeakable: Talking to children about parental mental illness
You probably think you know how to talk with a child about death. But somehow talking about a parent’s mental illness may seem more difficult. Even medical professionals, as most people, can find themselves feeling more judgmental or uneasy talking about mental illness than about physical problems. But with a prevalence of about one in four people having mental disorders, we need to be prepared for this discussion.
Sometimes family members, or even parents themselves, have asked me to tell a child about a parent’s mental illness or substance use. They know the child is confused and scared but don’t know what to say about this still-hushed issue. Other times, children’s behaviors show that they are struggling – by their aggression, depression, decline in school performance, anger, anxiety, or running away – and I find out only by asking that they are experiencing life with a mentally ill parent.
Both are times to get more information about the nature of the parent’s symptoms, what is being done about it; what the child has seen, heard, or experienced; the child’s safety; and what intrinsic or cultural attitudes the family has about the problem. It is best if the affected parents themselves are able to talk realistically about the illness with the child. Sometimes we, as pediatric professionals, can help get the conversation started or may need to step in.
Teens can understand the nature of mental illness as a brain disorder, but often have acquired misinformation from peers, the other parent who is hurt and angry, or the Internet that needs to be respectfully corrected. They may be less willing to have such a discussion than would younger children, as they may have experienced verbal or physical aggression from the parent, embarrassment in front of peers, or teasing by classmates. They may have developed coping strategies of writing off the parent, defiance, aggressive responses, or denial.
It is important to find a relaxed moment and begin by saying, “May I ask what you have noticed about your parent’s behavior?” and “What did you make of it?” If they do not answer, you could add, “You know, like acting different or strange.” It is very valuable to be able to name it, if you know the diagnosis, to make the illness more objective. Teens are typically egocentric and wonder if they are prone to develop a similar condition, as well as anxious about who will be there for them if the parent does not get better; both are good questions to address.
Both adolescents and school-aged children are very attuned to when things in life are “unfair,” and having an ill parent certainly qualifies. It is important for whoever has this discussion to empathize, and to acknowledge that it is unfair and that feeling angry, sad, or confused is natural – without giving them permission for misbehavior. It may be easier for some children to have a journal in which to write questions to have an adult answer later. Any child can be given hope by knowing that the parent is getting help (or that you will work on this), especially if the parents themselves say they are trying to get better. The children need to know that although mental illness tends to get better and worse at unexpected times, mental health can be improved. It is essential that children of school age and older have a clear plan for what to do if the parent loses control or is in danger. This might include getting out of the house and calling the parent’s partner, a trusted neighbor, or 911.
While teens may feel guilty about their anger or things they might have said or done in reaction to the ill parent, school-aged and preschool children are more likely to feel guilty that they somehow contributed to the parent’s condition through misbehavior or some imagined influence. Eliciting these thoughts may simply require asking, “What thoughts have you had about why this happened?” or having another family member prompting them by saying, “I have been wondering if there is something I should have done. Have you wondered about that, too?”
What is harder to explain is the impression children may get that their depressed or psychotic or drug-abusing parents no longer love them; and the parents may have said hurtful things to them. School-aged children can be told and can understand an illness of “the feelings and thinking parts of the brain” as being similar to other physical illnesses, such as the flu, that “make people act tired or grouchy or say things they do not mean.” Children of all ages need to be reassured that, inside, their parents still love them, and “it is the illness talking” if they act or speak otherwise. In the case of substance abuse disorders, which might seem more of a choice by the parent than would other mental illnesses, it can be helpful to point out that “drugs and alcohol can be stronger than people and can take over their brains.” The National Alliance on Mental Illness (www.nami.org) offers support programs that may be helpful for older children.
Sometimes families may resist telling a child about parental mental illness because of personal beliefs, cultural stigma, or privacy concerns. I try to emphasize that by being honest in giving children an understanding of their parents’ mental illness, one is helping them trust the adults in their lives. They need the truth and also to practice formulating things to say to counter those who have incorrect ideas, or who insult or make fun of them. They need the truth about mental illness to make sense of their experiences so they can feel lovable and hopeful about their own futures and can recognize illness symptoms in themselves. Giving them words, ensuring their safety and support, and strengthening their coping can help buffer the impact of this common adverse childhood experience to help prevent long-term negative effects.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.
You probably think you know how to talk with a child about death. But somehow talking about a parent’s mental illness may seem more difficult. Even medical professionals, as most people, can find themselves feeling more judgmental or uneasy talking about mental illness than about physical problems. But with a prevalence of about one in four people having mental disorders, we need to be prepared for this discussion.
Sometimes family members, or even parents themselves, have asked me to tell a child about a parent’s mental illness or substance use. They know the child is confused and scared but don’t know what to say about this still-hushed issue. Other times, children’s behaviors show that they are struggling – by their aggression, depression, decline in school performance, anger, anxiety, or running away – and I find out only by asking that they are experiencing life with a mentally ill parent.
Both are times to get more information about the nature of the parent’s symptoms, what is being done about it; what the child has seen, heard, or experienced; the child’s safety; and what intrinsic or cultural attitudes the family has about the problem. It is best if the affected parents themselves are able to talk realistically about the illness with the child. Sometimes we, as pediatric professionals, can help get the conversation started or may need to step in.
Teens can understand the nature of mental illness as a brain disorder, but often have acquired misinformation from peers, the other parent who is hurt and angry, or the Internet that needs to be respectfully corrected. They may be less willing to have such a discussion than would younger children, as they may have experienced verbal or physical aggression from the parent, embarrassment in front of peers, or teasing by classmates. They may have developed coping strategies of writing off the parent, defiance, aggressive responses, or denial.
It is important to find a relaxed moment and begin by saying, “May I ask what you have noticed about your parent’s behavior?” and “What did you make of it?” If they do not answer, you could add, “You know, like acting different or strange.” It is very valuable to be able to name it, if you know the diagnosis, to make the illness more objective. Teens are typically egocentric and wonder if they are prone to develop a similar condition, as well as anxious about who will be there for them if the parent does not get better; both are good questions to address.
Both adolescents and school-aged children are very attuned to when things in life are “unfair,” and having an ill parent certainly qualifies. It is important for whoever has this discussion to empathize, and to acknowledge that it is unfair and that feeling angry, sad, or confused is natural – without giving them permission for misbehavior. It may be easier for some children to have a journal in which to write questions to have an adult answer later. Any child can be given hope by knowing that the parent is getting help (or that you will work on this), especially if the parents themselves say they are trying to get better. The children need to know that although mental illness tends to get better and worse at unexpected times, mental health can be improved. It is essential that children of school age and older have a clear plan for what to do if the parent loses control or is in danger. This might include getting out of the house and calling the parent’s partner, a trusted neighbor, or 911.
While teens may feel guilty about their anger or things they might have said or done in reaction to the ill parent, school-aged and preschool children are more likely to feel guilty that they somehow contributed to the parent’s condition through misbehavior or some imagined influence. Eliciting these thoughts may simply require asking, “What thoughts have you had about why this happened?” or having another family member prompting them by saying, “I have been wondering if there is something I should have done. Have you wondered about that, too?”
What is harder to explain is the impression children may get that their depressed or psychotic or drug-abusing parents no longer love them; and the parents may have said hurtful things to them. School-aged children can be told and can understand an illness of “the feelings and thinking parts of the brain” as being similar to other physical illnesses, such as the flu, that “make people act tired or grouchy or say things they do not mean.” Children of all ages need to be reassured that, inside, their parents still love them, and “it is the illness talking” if they act or speak otherwise. In the case of substance abuse disorders, which might seem more of a choice by the parent than would other mental illnesses, it can be helpful to point out that “drugs and alcohol can be stronger than people and can take over their brains.” The National Alliance on Mental Illness (www.nami.org) offers support programs that may be helpful for older children.
Sometimes families may resist telling a child about parental mental illness because of personal beliefs, cultural stigma, or privacy concerns. I try to emphasize that by being honest in giving children an understanding of their parents’ mental illness, one is helping them trust the adults in their lives. They need the truth and also to practice formulating things to say to counter those who have incorrect ideas, or who insult or make fun of them. They need the truth about mental illness to make sense of their experiences so they can feel lovable and hopeful about their own futures and can recognize illness symptoms in themselves. Giving them words, ensuring their safety and support, and strengthening their coping can help buffer the impact of this common adverse childhood experience to help prevent long-term negative effects.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.
You probably think you know how to talk with a child about death. But somehow talking about a parent’s mental illness may seem more difficult. Even medical professionals, as most people, can find themselves feeling more judgmental or uneasy talking about mental illness than about physical problems. But with a prevalence of about one in four people having mental disorders, we need to be prepared for this discussion.
Sometimes family members, or even parents themselves, have asked me to tell a child about a parent’s mental illness or substance use. They know the child is confused and scared but don’t know what to say about this still-hushed issue. Other times, children’s behaviors show that they are struggling – by their aggression, depression, decline in school performance, anger, anxiety, or running away – and I find out only by asking that they are experiencing life with a mentally ill parent.
Both are times to get more information about the nature of the parent’s symptoms, what is being done about it; what the child has seen, heard, or experienced; the child’s safety; and what intrinsic or cultural attitudes the family has about the problem. It is best if the affected parents themselves are able to talk realistically about the illness with the child. Sometimes we, as pediatric professionals, can help get the conversation started or may need to step in.
Teens can understand the nature of mental illness as a brain disorder, but often have acquired misinformation from peers, the other parent who is hurt and angry, or the Internet that needs to be respectfully corrected. They may be less willing to have such a discussion than would younger children, as they may have experienced verbal or physical aggression from the parent, embarrassment in front of peers, or teasing by classmates. They may have developed coping strategies of writing off the parent, defiance, aggressive responses, or denial.
It is important to find a relaxed moment and begin by saying, “May I ask what you have noticed about your parent’s behavior?” and “What did you make of it?” If they do not answer, you could add, “You know, like acting different or strange.” It is very valuable to be able to name it, if you know the diagnosis, to make the illness more objective. Teens are typically egocentric and wonder if they are prone to develop a similar condition, as well as anxious about who will be there for them if the parent does not get better; both are good questions to address.
Both adolescents and school-aged children are very attuned to when things in life are “unfair,” and having an ill parent certainly qualifies. It is important for whoever has this discussion to empathize, and to acknowledge that it is unfair and that feeling angry, sad, or confused is natural – without giving them permission for misbehavior. It may be easier for some children to have a journal in which to write questions to have an adult answer later. Any child can be given hope by knowing that the parent is getting help (or that you will work on this), especially if the parents themselves say they are trying to get better. The children need to know that although mental illness tends to get better and worse at unexpected times, mental health can be improved. It is essential that children of school age and older have a clear plan for what to do if the parent loses control or is in danger. This might include getting out of the house and calling the parent’s partner, a trusted neighbor, or 911.
While teens may feel guilty about their anger or things they might have said or done in reaction to the ill parent, school-aged and preschool children are more likely to feel guilty that they somehow contributed to the parent’s condition through misbehavior or some imagined influence. Eliciting these thoughts may simply require asking, “What thoughts have you had about why this happened?” or having another family member prompting them by saying, “I have been wondering if there is something I should have done. Have you wondered about that, too?”
What is harder to explain is the impression children may get that their depressed or psychotic or drug-abusing parents no longer love them; and the parents may have said hurtful things to them. School-aged children can be told and can understand an illness of “the feelings and thinking parts of the brain” as being similar to other physical illnesses, such as the flu, that “make people act tired or grouchy or say things they do not mean.” Children of all ages need to be reassured that, inside, their parents still love them, and “it is the illness talking” if they act or speak otherwise. In the case of substance abuse disorders, which might seem more of a choice by the parent than would other mental illnesses, it can be helpful to point out that “drugs and alcohol can be stronger than people and can take over their brains.” The National Alliance on Mental Illness (www.nami.org) offers support programs that may be helpful for older children.
Sometimes families may resist telling a child about parental mental illness because of personal beliefs, cultural stigma, or privacy concerns. I try to emphasize that by being honest in giving children an understanding of their parents’ mental illness, one is helping them trust the adults in their lives. They need the truth and also to practice formulating things to say to counter those who have incorrect ideas, or who insult or make fun of them. They need the truth about mental illness to make sense of their experiences so they can feel lovable and hopeful about their own futures and can recognize illness symptoms in themselves. Giving them words, ensuring their safety and support, and strengthening their coping can help buffer the impact of this common adverse childhood experience to help prevent long-term negative effects.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.
European Commission approves first CAR T-cell therapies
The , two chimeric antigen receptor (CAR) T-cell therapies.
Tisagenlecleucel is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post transplant, or in second or later relapse.
Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
Axicabtagene ciloleucel is approved for adults with relapsed/refractory DLBCL and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy. The treatment is marketed by Kite, a Gilead company.
The axicabtagene ciloleucel approval is based on results from the single arm, ZUMA-1 trial. During the study of 101 patients who received a single infusion, 72% responded to therapy and 51% achieved a complete response. At 1 year, median overall survival had not been reached.
Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.
The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.
Updated results from JULIET were presented at the annual congress of the European Hematology Association in June 2018. The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so because of disease progression or clinical deterioration.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.
Updated results from ELIANA were published in New England Journal of Medicine (2018;378:439-48).
The trial included 75 children and young adults with relapsed/refractory ALL. The overall remission rate was 81% (61/75), with 60% of patients (n = 45) achieving a complete remission (CR) and 21% (n = 16) achieving a CR with incomplete hematologic recovery (CRi).
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
The , two chimeric antigen receptor (CAR) T-cell therapies.
Tisagenlecleucel is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post transplant, or in second or later relapse.
Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
Axicabtagene ciloleucel is approved for adults with relapsed/refractory DLBCL and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy. The treatment is marketed by Kite, a Gilead company.
The axicabtagene ciloleucel approval is based on results from the single arm, ZUMA-1 trial. During the study of 101 patients who received a single infusion, 72% responded to therapy and 51% achieved a complete response. At 1 year, median overall survival had not been reached.
Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.
The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.
Updated results from JULIET were presented at the annual congress of the European Hematology Association in June 2018. The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so because of disease progression or clinical deterioration.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.
Updated results from ELIANA were published in New England Journal of Medicine (2018;378:439-48).
The trial included 75 children and young adults with relapsed/refractory ALL. The overall remission rate was 81% (61/75), with 60% of patients (n = 45) achieving a complete remission (CR) and 21% (n = 16) achieving a CR with incomplete hematologic recovery (CRi).
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
The , two chimeric antigen receptor (CAR) T-cell therapies.
Tisagenlecleucel is now approved for use in pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post transplant, or in second or later relapse.
Tisagenlecleucel is also approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have received two or more lines of systemic therapy.
Axicabtagene ciloleucel is approved for adults with relapsed/refractory DLBCL and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy. The treatment is marketed by Kite, a Gilead company.
The axicabtagene ciloleucel approval is based on results from the single arm, ZUMA-1 trial. During the study of 101 patients who received a single infusion, 72% responded to therapy and 51% achieved a complete response. At 1 year, median overall survival had not been reached.
Novartis expects to launch tisagenlecleucel initially for pediatric ALL. The company said timing for tisagenlecleucel availability in each country will depend on multiple factors, including the onboarding of qualified treatment centers for the appropriate indications, as well as the completion of national reimbursement procedures.
The EC’s approval of tisagenlecleucel is based on results from the phase 2 JULIET and ELIANA trials.
Updated results from JULIET were presented at the annual congress of the European Hematology Association in June 2018. The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so because of disease progression or clinical deterioration.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. At the time of data cutoff, none of the responders had gone on to receive a stem cell transplant.
Updated results from ELIANA were published in New England Journal of Medicine (2018;378:439-48).
The trial included 75 children and young adults with relapsed/refractory ALL. The overall remission rate was 81% (61/75), with 60% of patients (n = 45) achieving a complete remission (CR) and 21% (n = 16) achieving a CR with incomplete hematologic recovery (CRi).
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.