User login
Motor abnormalities drive decreased function in schizophrenia
Approximately half of adults with schizophrenia suffer from motor abnormalities that may impair their ability to work and decrease their quality of life, wrote Niluja Nadesalingam, MD, of the University of Bern, Switzerland, and colleagues. “Although previous reports show strong associations between single movement abnormalities and global as well as social functioning, we still struggle to understand the contribution of various motor domains,” they said.
The impact of these abnormalities on social and global functioning and on functional capacity remains unclear, but the researchers proposed that motor abnormalities would be associated with worse functional outcomes in schizophrenia patients.
In a study published in Comprehensive Psychiatry, the researchers identified patients with diagnosed schizophrenia spectrum disorders who were treated on an inpatient or outpatient basis at a single center. They collected data on five motor abnormalities: parkinsonism, catatonia, dyskinesia, neurological soft signs (NSS), and psychomotor slowing (PS). They assessed functional outcomes using the Global Assessment of Functioning (GAF), the Social and Occupational Functioning Assessment Scale (SOFAS), and the UCSD Performance-Based Skills Assessment (UPSA-B). The average age of the participants was 37.9 years and 88 of the 156 were male. The average duration of illness was 12.5 years.
Overall, patients with catatonia and parkinsonism scored significantly lower on GAF and SOFAS scale compared to those without catatonia and parkinsonism (P < .035 and P < .027, respectively).
No significant differences in functional outcomes appeared between patients with and without dyskinesia.
However, significant negative correlations were identified for parkinsonism and PS with GAF, SOFAS, and UPSA-B (P < .036 for all). “Our study further found that parkinsonism and psychomotor slowing also impair the functional capacity of patients,” which may be influenced by factors including deficits in social interaction and cognitive impairment, the researchers said.
Overall, the study findings demonstrate that motor abnormalities in patients with schizophrenia are strongly associated with poor functional outcomes, and the stronger the motor impairment, the worse the global and social functioning, the researchers said.
As for potential pathways, “motor abnormalities are readily observable signs, allowing laypersons to perceive subjects with schizophrenia as somebody with severe mental illness. Thus, motor abnormalities might lead to stigmatization of patients suffering from schizophrenia,” they wrote in their discussion.
The researchers emphasized the need to explore alternative treatment options that might improve motor abnormalities, such as transcranial magnetic stimulation, given the potential of antipsychotic medications to introduce additional motor abnormalities.
The study findings were limited by several factors including the potential for missed confounding variables, the small number of patients with dyskinesia, and the inability to deduce the course of illness because most of the patients were in psychotic episodes, the researchers noted.
However, the results suggest that specific motor abnormalities are associated with poor global and social functioning, and with reduced functional capacity, in adults with schizophrenia, the researchers said. “Future studies need to test whether amelioration of motor abnormalities may improve community functioning,” they concluded.
The study was supported by the Swiss National Science Foundation, the Bangerter Rhyner Foundation, and the Adrian and Simone Frutiger Foundation. Lead author Dr. Nadesalingam had no financial conflicts to disclose.
Approximately half of adults with schizophrenia suffer from motor abnormalities that may impair their ability to work and decrease their quality of life, wrote Niluja Nadesalingam, MD, of the University of Bern, Switzerland, and colleagues. “Although previous reports show strong associations between single movement abnormalities and global as well as social functioning, we still struggle to understand the contribution of various motor domains,” they said.
The impact of these abnormalities on social and global functioning and on functional capacity remains unclear, but the researchers proposed that motor abnormalities would be associated with worse functional outcomes in schizophrenia patients.
In a study published in Comprehensive Psychiatry, the researchers identified patients with diagnosed schizophrenia spectrum disorders who were treated on an inpatient or outpatient basis at a single center. They collected data on five motor abnormalities: parkinsonism, catatonia, dyskinesia, neurological soft signs (NSS), and psychomotor slowing (PS). They assessed functional outcomes using the Global Assessment of Functioning (GAF), the Social and Occupational Functioning Assessment Scale (SOFAS), and the UCSD Performance-Based Skills Assessment (UPSA-B). The average age of the participants was 37.9 years and 88 of the 156 were male. The average duration of illness was 12.5 years.
Overall, patients with catatonia and parkinsonism scored significantly lower on GAF and SOFAS scale compared to those without catatonia and parkinsonism (P < .035 and P < .027, respectively).
No significant differences in functional outcomes appeared between patients with and without dyskinesia.
However, significant negative correlations were identified for parkinsonism and PS with GAF, SOFAS, and UPSA-B (P < .036 for all). “Our study further found that parkinsonism and psychomotor slowing also impair the functional capacity of patients,” which may be influenced by factors including deficits in social interaction and cognitive impairment, the researchers said.
Overall, the study findings demonstrate that motor abnormalities in patients with schizophrenia are strongly associated with poor functional outcomes, and the stronger the motor impairment, the worse the global and social functioning, the researchers said.
As for potential pathways, “motor abnormalities are readily observable signs, allowing laypersons to perceive subjects with schizophrenia as somebody with severe mental illness. Thus, motor abnormalities might lead to stigmatization of patients suffering from schizophrenia,” they wrote in their discussion.
The researchers emphasized the need to explore alternative treatment options that might improve motor abnormalities, such as transcranial magnetic stimulation, given the potential of antipsychotic medications to introduce additional motor abnormalities.
The study findings were limited by several factors including the potential for missed confounding variables, the small number of patients with dyskinesia, and the inability to deduce the course of illness because most of the patients were in psychotic episodes, the researchers noted.
However, the results suggest that specific motor abnormalities are associated with poor global and social functioning, and with reduced functional capacity, in adults with schizophrenia, the researchers said. “Future studies need to test whether amelioration of motor abnormalities may improve community functioning,” they concluded.
The study was supported by the Swiss National Science Foundation, the Bangerter Rhyner Foundation, and the Adrian and Simone Frutiger Foundation. Lead author Dr. Nadesalingam had no financial conflicts to disclose.
Approximately half of adults with schizophrenia suffer from motor abnormalities that may impair their ability to work and decrease their quality of life, wrote Niluja Nadesalingam, MD, of the University of Bern, Switzerland, and colleagues. “Although previous reports show strong associations between single movement abnormalities and global as well as social functioning, we still struggle to understand the contribution of various motor domains,” they said.
The impact of these abnormalities on social and global functioning and on functional capacity remains unclear, but the researchers proposed that motor abnormalities would be associated with worse functional outcomes in schizophrenia patients.
In a study published in Comprehensive Psychiatry, the researchers identified patients with diagnosed schizophrenia spectrum disorders who were treated on an inpatient or outpatient basis at a single center. They collected data on five motor abnormalities: parkinsonism, catatonia, dyskinesia, neurological soft signs (NSS), and psychomotor slowing (PS). They assessed functional outcomes using the Global Assessment of Functioning (GAF), the Social and Occupational Functioning Assessment Scale (SOFAS), and the UCSD Performance-Based Skills Assessment (UPSA-B). The average age of the participants was 37.9 years and 88 of the 156 were male. The average duration of illness was 12.5 years.
Overall, patients with catatonia and parkinsonism scored significantly lower on GAF and SOFAS scale compared to those without catatonia and parkinsonism (P < .035 and P < .027, respectively).
No significant differences in functional outcomes appeared between patients with and without dyskinesia.
However, significant negative correlations were identified for parkinsonism and PS with GAF, SOFAS, and UPSA-B (P < .036 for all). “Our study further found that parkinsonism and psychomotor slowing also impair the functional capacity of patients,” which may be influenced by factors including deficits in social interaction and cognitive impairment, the researchers said.
Overall, the study findings demonstrate that motor abnormalities in patients with schizophrenia are strongly associated with poor functional outcomes, and the stronger the motor impairment, the worse the global and social functioning, the researchers said.
As for potential pathways, “motor abnormalities are readily observable signs, allowing laypersons to perceive subjects with schizophrenia as somebody with severe mental illness. Thus, motor abnormalities might lead to stigmatization of patients suffering from schizophrenia,” they wrote in their discussion.
The researchers emphasized the need to explore alternative treatment options that might improve motor abnormalities, such as transcranial magnetic stimulation, given the potential of antipsychotic medications to introduce additional motor abnormalities.
The study findings were limited by several factors including the potential for missed confounding variables, the small number of patients with dyskinesia, and the inability to deduce the course of illness because most of the patients were in psychotic episodes, the researchers noted.
However, the results suggest that specific motor abnormalities are associated with poor global and social functioning, and with reduced functional capacity, in adults with schizophrenia, the researchers said. “Future studies need to test whether amelioration of motor abnormalities may improve community functioning,” they concluded.
The study was supported by the Swiss National Science Foundation, the Bangerter Rhyner Foundation, and the Adrian and Simone Frutiger Foundation. Lead author Dr. Nadesalingam had no financial conflicts to disclose.
FROM COMPREHENSIVE PSYCHIATRY
Cochlear implants benefit deaf children with developmental delays
Deaf babies and toddlers with developmental delays may benefit significantly from receiving cochlear implants over hearing aids.
A new study, published in the journal Pediatrics, pushes against the notion that children with low nonverbal cognition and adaptive functioning skills won’t improve if given cochlear implants. Some insurers cover hearing aids for children with developmental disorders but not the implants, which can cost between $60,000 and $100,000 per ear.
“We were surprised [by] the large magnitude of the improvements, not only in quality of life, but also in cognition, ability to function in daily living situations, and speech and language,” lead author John S. Oghalai, MD, of the University of Southern California, Los Angeles, told this news organization. “Remember, these are children with substantial developmental delays. Any improvements are incredibly important and meaningful.”
All children with severe hearing loss should be referred for cochlear implant evaluation, “regardless of the presence of other disabilities,” Dr. Oghalai said. “The younger this referral happens, the better the outcomes will be.”
Dr. Oghalai and his colleagues reviewed data from 204 children approximately 1-3 years old with hearing aids receiving treatment in Texas and California. Of these, 138 received a cochlear implant and had normal cognitive skills and social competence (referred to as adaptive behavior). Another 37 received a cochlear implant and also met criteria for early developmental impairment (EDI), defined by measures of nonverbal cognitive scores and adaptive functioning.
A third group of 29 children with EDI continued with hearing aids without a cochlear implant.
The children were evaluated annually for 1-5 years, with the average follow-up of 2 years. At baseline, no significant differences were noted between the children with EDI who received implants and those who did not on cognition, language, auditory skills, or measures of parental or child stress.
Overall, children who received implants scored higher on cognitive and social measures than those who continued using hearing aids.
Compared with children with EDI who received implants, children without EDI who received implants had significantly higher developmental scores by the study’s end (P ≤ .001), whereas children with EDI who did not receive implants had significantly lower scores (P ≤ .04).
Children who received implants, and their parents, also experienced less stress than those who did not receive the devices, according to the researchers.
Dr. Oghalai and colleagues also measured developmental trajectories for each cohort. Children without delays who received implants had the best outcomes, but those with EDI who received implants had better outcomes than those with EDI and hearing aids.
Findings ‘overdue’
“This study is overdue,” Howard Francis, MD, chair of the department of head and neck surgery & communication sciences at Duke University, Durham, N.C., told this news organization.
Dr. Francis called the new research “reasonably powered and designed,” and said it “documents benefits in the cognitive, language, and patient-child relationship domains” in children who received cochlear implants “compared to children with similar levels of developmental delay whose hearing loss was treated using hearing aids.”
However, “larger studies will be needed to account for potential effects of older age at intervention in the hearing aid group,” he said. Socioeconomic effects are a topic for future research as well, Dr. Francis added.
The researchers initially wanted to perform a controlled clinical trial. However, by the time they secured funding, health insurance policy had changed to cover cochlear implants for children without EDI because of demonstrated benefits shown in studies.
They also were unable to determine the reasons for families’ decisions to choose implants or hearing aids and were unable to assess the impact of insurance on the choice of implantation. But they did find that families with insurers who would cover implants often did choose the devices. Children were also followed for an average of 2 years, so long-term outcomes are unknown.
Despite these limitations, the results support the value of cochlear implantation in children with disabilities and developmental delays, and it should be discussed with parents, the researchers concluded.
“Cochlear implants are just a tool; they do not provide speech and language,” Dr. Oghalai said. “Any child with severe hearing loss requires significant therapy and education via sign language, auditory-verbal therapy, or both. Making the decision about what type of therapy to do is personal, and it depends upon the family and the options that are available to them in their community.”
The study was funded by the National Institutes of Health. The researchers and Dr. Francis have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Deaf babies and toddlers with developmental delays may benefit significantly from receiving cochlear implants over hearing aids.
A new study, published in the journal Pediatrics, pushes against the notion that children with low nonverbal cognition and adaptive functioning skills won’t improve if given cochlear implants. Some insurers cover hearing aids for children with developmental disorders but not the implants, which can cost between $60,000 and $100,000 per ear.
“We were surprised [by] the large magnitude of the improvements, not only in quality of life, but also in cognition, ability to function in daily living situations, and speech and language,” lead author John S. Oghalai, MD, of the University of Southern California, Los Angeles, told this news organization. “Remember, these are children with substantial developmental delays. Any improvements are incredibly important and meaningful.”
All children with severe hearing loss should be referred for cochlear implant evaluation, “regardless of the presence of other disabilities,” Dr. Oghalai said. “The younger this referral happens, the better the outcomes will be.”
Dr. Oghalai and his colleagues reviewed data from 204 children approximately 1-3 years old with hearing aids receiving treatment in Texas and California. Of these, 138 received a cochlear implant and had normal cognitive skills and social competence (referred to as adaptive behavior). Another 37 received a cochlear implant and also met criteria for early developmental impairment (EDI), defined by measures of nonverbal cognitive scores and adaptive functioning.
A third group of 29 children with EDI continued with hearing aids without a cochlear implant.
The children were evaluated annually for 1-5 years, with the average follow-up of 2 years. At baseline, no significant differences were noted between the children with EDI who received implants and those who did not on cognition, language, auditory skills, or measures of parental or child stress.
Overall, children who received implants scored higher on cognitive and social measures than those who continued using hearing aids.
Compared with children with EDI who received implants, children without EDI who received implants had significantly higher developmental scores by the study’s end (P ≤ .001), whereas children with EDI who did not receive implants had significantly lower scores (P ≤ .04).
Children who received implants, and their parents, also experienced less stress than those who did not receive the devices, according to the researchers.
Dr. Oghalai and colleagues also measured developmental trajectories for each cohort. Children without delays who received implants had the best outcomes, but those with EDI who received implants had better outcomes than those with EDI and hearing aids.
Findings ‘overdue’
“This study is overdue,” Howard Francis, MD, chair of the department of head and neck surgery & communication sciences at Duke University, Durham, N.C., told this news organization.
Dr. Francis called the new research “reasonably powered and designed,” and said it “documents benefits in the cognitive, language, and patient-child relationship domains” in children who received cochlear implants “compared to children with similar levels of developmental delay whose hearing loss was treated using hearing aids.”
However, “larger studies will be needed to account for potential effects of older age at intervention in the hearing aid group,” he said. Socioeconomic effects are a topic for future research as well, Dr. Francis added.
The researchers initially wanted to perform a controlled clinical trial. However, by the time they secured funding, health insurance policy had changed to cover cochlear implants for children without EDI because of demonstrated benefits shown in studies.
They also were unable to determine the reasons for families’ decisions to choose implants or hearing aids and were unable to assess the impact of insurance on the choice of implantation. But they did find that families with insurers who would cover implants often did choose the devices. Children were also followed for an average of 2 years, so long-term outcomes are unknown.
Despite these limitations, the results support the value of cochlear implantation in children with disabilities and developmental delays, and it should be discussed with parents, the researchers concluded.
“Cochlear implants are just a tool; they do not provide speech and language,” Dr. Oghalai said. “Any child with severe hearing loss requires significant therapy and education via sign language, auditory-verbal therapy, or both. Making the decision about what type of therapy to do is personal, and it depends upon the family and the options that are available to them in their community.”
The study was funded by the National Institutes of Health. The researchers and Dr. Francis have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Deaf babies and toddlers with developmental delays may benefit significantly from receiving cochlear implants over hearing aids.
A new study, published in the journal Pediatrics, pushes against the notion that children with low nonverbal cognition and adaptive functioning skills won’t improve if given cochlear implants. Some insurers cover hearing aids for children with developmental disorders but not the implants, which can cost between $60,000 and $100,000 per ear.
“We were surprised [by] the large magnitude of the improvements, not only in quality of life, but also in cognition, ability to function in daily living situations, and speech and language,” lead author John S. Oghalai, MD, of the University of Southern California, Los Angeles, told this news organization. “Remember, these are children with substantial developmental delays. Any improvements are incredibly important and meaningful.”
All children with severe hearing loss should be referred for cochlear implant evaluation, “regardless of the presence of other disabilities,” Dr. Oghalai said. “The younger this referral happens, the better the outcomes will be.”
Dr. Oghalai and his colleagues reviewed data from 204 children approximately 1-3 years old with hearing aids receiving treatment in Texas and California. Of these, 138 received a cochlear implant and had normal cognitive skills and social competence (referred to as adaptive behavior). Another 37 received a cochlear implant and also met criteria for early developmental impairment (EDI), defined by measures of nonverbal cognitive scores and adaptive functioning.
A third group of 29 children with EDI continued with hearing aids without a cochlear implant.
The children were evaluated annually for 1-5 years, with the average follow-up of 2 years. At baseline, no significant differences were noted between the children with EDI who received implants and those who did not on cognition, language, auditory skills, or measures of parental or child stress.
Overall, children who received implants scored higher on cognitive and social measures than those who continued using hearing aids.
Compared with children with EDI who received implants, children without EDI who received implants had significantly higher developmental scores by the study’s end (P ≤ .001), whereas children with EDI who did not receive implants had significantly lower scores (P ≤ .04).
Children who received implants, and their parents, also experienced less stress than those who did not receive the devices, according to the researchers.
Dr. Oghalai and colleagues also measured developmental trajectories for each cohort. Children without delays who received implants had the best outcomes, but those with EDI who received implants had better outcomes than those with EDI and hearing aids.
Findings ‘overdue’
“This study is overdue,” Howard Francis, MD, chair of the department of head and neck surgery & communication sciences at Duke University, Durham, N.C., told this news organization.
Dr. Francis called the new research “reasonably powered and designed,” and said it “documents benefits in the cognitive, language, and patient-child relationship domains” in children who received cochlear implants “compared to children with similar levels of developmental delay whose hearing loss was treated using hearing aids.”
However, “larger studies will be needed to account for potential effects of older age at intervention in the hearing aid group,” he said. Socioeconomic effects are a topic for future research as well, Dr. Francis added.
The researchers initially wanted to perform a controlled clinical trial. However, by the time they secured funding, health insurance policy had changed to cover cochlear implants for children without EDI because of demonstrated benefits shown in studies.
They also were unable to determine the reasons for families’ decisions to choose implants or hearing aids and were unable to assess the impact of insurance on the choice of implantation. But they did find that families with insurers who would cover implants often did choose the devices. Children were also followed for an average of 2 years, so long-term outcomes are unknown.
Despite these limitations, the results support the value of cochlear implantation in children with disabilities and developmental delays, and it should be discussed with parents, the researchers concluded.
“Cochlear implants are just a tool; they do not provide speech and language,” Dr. Oghalai said. “Any child with severe hearing loss requires significant therapy and education via sign language, auditory-verbal therapy, or both. Making the decision about what type of therapy to do is personal, and it depends upon the family and the options that are available to them in their community.”
The study was funded by the National Institutes of Health. The researchers and Dr. Francis have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM PEDIATRICS
‘Exciting’ new gene therapy yields promising results
In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.
The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.
The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.
The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m2/day.
Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.
“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.
Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.
Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.
Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.
Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.
In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
Study provides solid stepping stone
“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.
“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.
Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.
As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
Response and side effects show promise for future research
The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.
Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.
Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.
The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.
Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.
In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.
The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.
The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.
The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m2/day.
Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.
“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.
Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.
Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.
Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.
Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.
In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
Study provides solid stepping stone
“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.
“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.
Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.
As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
Response and side effects show promise for future research
The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.
Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.
Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.
The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.
Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.
In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.
The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.
The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.
The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m2/day.
Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.
“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.
Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.
Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.
Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.
Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.
In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
Study provides solid stepping stone
“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.
“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.
Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.
As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
Response and side effects show promise for future research
The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.
Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.
Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.
The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.
Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.
‘Very impressive’ data promise new blood cancer option
“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.
Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.
After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.
The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.
The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.
“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.
The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.
A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.
A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).
The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.
Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.
“The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”
However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.
As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
Be ready to manage infections
Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.
Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.
A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.
He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.
Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.
The study was funded by Janssen Research and Development.
Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.
“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.
Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.
After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.
The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.
The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.
“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.
The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.
A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.
A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).
The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.
Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.
“The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”
However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.
As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
Be ready to manage infections
Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.
Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.
A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.
He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.
Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.
The study was funded by Janssen Research and Development.
Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.
“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.
Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.
After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.
The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.
The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.
“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.
The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.
A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.
A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).
The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.
Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.
“The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”
However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.
As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
Be ready to manage infections
Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.
Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.
A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.
He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.
Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.
The study was funded by Janssen Research and Development.
Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.
FROM ASCO 2022
Hospital medicine gains popularity among newly minted physicians
In a new study, published in Annals of Internal Medicine, researchers from ABIM reviewed certification data from 67,902 general internists, accounting for 80% of all general internists certified in the United States from 1990 to 2017.
The researchers also used data from Medicare fee-for-service claims from 2008-2018 to measure and categorize practice setting types. The claims were from patients aged 65 years or older with at least 20 evaluation and management visits each year. Practice settings were categorized as hospitalist, outpatient, or mixed.
“ABIM is always working to understand the real-life experience of physicians, and this project grew out of that sort of analysis,” lead author Bradley M. Gray, PhD, a health services researcher at ABIM in Philadelphia, said in an interview. “We wanted to better understand practice setting, because that relates to the kinds of questions that we ask on our certifying exams. When we did this, we noticed a trend toward hospital medicine.”
Overall, the percentages of general internists in hospitalist practice and outpatient-only practice increased during the study period, from 25% to 40% and from 23% to 38%, respectively. By contrast, the percentage of general internists in a mixed-practice setting decreased from 52% to 23%, a 56% decline. Most of the physicians who left the mixed practice setting switched to outpatient-only practices.
Among the internists certified in 2017, 71% practiced as hospitalists, compared with 8% practicing as outpatient-only physicians. Most physicians remained in their original choice of practice setting. For physicians certified in 1999 and 2012, 86% and 85%, respectively, of those who chose hospitalist medicine remained in the hospital setting 5 years later, as did 95% of outpatient physicians, but only 57% of mixed-practice physicians.
The shift to outpatient practice among senior physicians offset the potential decline in outpatient primary care resulting from the increased choice of hospitalist medicine by new internists, the researchers noted.
The study findings were limited by several factors, including the reliance on Medicare fee-for-service claims, the researchers noted.
“We were surprised by both the dramatic shift toward hospital medicine by new physicians and the shift to outpatient only (an extreme category) for more senior physicians,” Dr. Gray said in an interview.
The shift toward outpatient practice among older physicians may be driven by convenience, said Dr. Gray. “I suspect that it is more efficient to specialize in terms of practice setting. Only seeing patients in the outpatient setting means that you don’t have to travel to the hospital, which can be time consuming.
“Also, with fewer new physicians going into primary care, older physicians need to focus on outpatient visits. This could be problematic in the future as more senior physicians retire and are replaced by new physicians who focus on hospital care,” which could lead to more shortages in primary care physicians, he explained.
The trend toward hospital medicine as a career has been going on since before the pandemic, said Dr. Gray. “I don’t think the pandemic will ultimately impact this trend. That said, at least in the short run, there may have been a decreased demand for primary care, but that is just my speculation. As more data flow in we will be able to answer this question more directly.”
Next steps for research included digging deeper into the data to understand the nature of conditions facing hospitalists, Dr. Gray said.
Implications for primary care
“This study provides an updated snapshot of the popularity of hospital medicine,” said Bradley A. Sharpe, MD, of the division of hospital medicine at the University of California, San Francisco. “It is also important to conduct this study now as health systems think about the challenge of providing high-quality primary care with a rapidly decreasing number of internists choosing to practice outpatient medicine.” Dr. Sharpe was not involved in the study.
“The most surprising finding to me was not the increase in general internists focusing on hospital medicine, but the amount of the increase; it is remarkable that nearly three quarters of general internists are choosing to practice as hospitalists,” Dr. Sharpe noted.
“I think there are a number of key factors at play,” he said. “First, as hospital medicine as a field is now more than 25 years old, hospitals and health systems have evolved to create hospital medicine jobs that are interesting, engaging, rewarding (financially and otherwise), doable, and sustainable. Second, being an outpatient internist is incredibly challenging; multiple studies have shown that it is essentially impossible to complete the evidence-based preventive care for a panel of patients on top of everything else. We know burnout rates are often higher among primary care and family medicine providers. On top of that, the expansion of electronic health records and patient access has led to a massive increase in messages to providers; this has been shown to be associated with burnout.”
The potential impact of the pandemic on physicians’ choices and the trend toward hospital medicine is an interested question, Dr. Sharpe said. The current study showed only trends through 2017.
“To be honest, I think it is difficult to predict,” he said. “Hospitalists shouldered much of the burden of COVID care nationally and burnout rates are high. One could imagine the extra work (as well as concern for personal safety) could lead to fewer providers choosing hospital medicine.
“At the same time, the pandemic has driven many of us to reflect on life and our values and what is important and, through that lens, providers might choose hospital medicine as a more sustainable, do-able, rewarding, and enjoyable career choice,” Dr. Sharpe emphasized.
“Additional research could explore the drivers of this clear trend toward hospital medicine. Determining what is motivating this trend could help hospitals and health systems ensure they have the right workforce for the future and, in particular, how to create outpatient positions that are attractive and rewarding,” he said.
The study received no outside funding. The researchers and Dr. Sharpe disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a new study, published in Annals of Internal Medicine, researchers from ABIM reviewed certification data from 67,902 general internists, accounting for 80% of all general internists certified in the United States from 1990 to 2017.
The researchers also used data from Medicare fee-for-service claims from 2008-2018 to measure and categorize practice setting types. The claims were from patients aged 65 years or older with at least 20 evaluation and management visits each year. Practice settings were categorized as hospitalist, outpatient, or mixed.
“ABIM is always working to understand the real-life experience of physicians, and this project grew out of that sort of analysis,” lead author Bradley M. Gray, PhD, a health services researcher at ABIM in Philadelphia, said in an interview. “We wanted to better understand practice setting, because that relates to the kinds of questions that we ask on our certifying exams. When we did this, we noticed a trend toward hospital medicine.”
Overall, the percentages of general internists in hospitalist practice and outpatient-only practice increased during the study period, from 25% to 40% and from 23% to 38%, respectively. By contrast, the percentage of general internists in a mixed-practice setting decreased from 52% to 23%, a 56% decline. Most of the physicians who left the mixed practice setting switched to outpatient-only practices.
Among the internists certified in 2017, 71% practiced as hospitalists, compared with 8% practicing as outpatient-only physicians. Most physicians remained in their original choice of practice setting. For physicians certified in 1999 and 2012, 86% and 85%, respectively, of those who chose hospitalist medicine remained in the hospital setting 5 years later, as did 95% of outpatient physicians, but only 57% of mixed-practice physicians.
The shift to outpatient practice among senior physicians offset the potential decline in outpatient primary care resulting from the increased choice of hospitalist medicine by new internists, the researchers noted.
The study findings were limited by several factors, including the reliance on Medicare fee-for-service claims, the researchers noted.
“We were surprised by both the dramatic shift toward hospital medicine by new physicians and the shift to outpatient only (an extreme category) for more senior physicians,” Dr. Gray said in an interview.
The shift toward outpatient practice among older physicians may be driven by convenience, said Dr. Gray. “I suspect that it is more efficient to specialize in terms of practice setting. Only seeing patients in the outpatient setting means that you don’t have to travel to the hospital, which can be time consuming.
“Also, with fewer new physicians going into primary care, older physicians need to focus on outpatient visits. This could be problematic in the future as more senior physicians retire and are replaced by new physicians who focus on hospital care,” which could lead to more shortages in primary care physicians, he explained.
The trend toward hospital medicine as a career has been going on since before the pandemic, said Dr. Gray. “I don’t think the pandemic will ultimately impact this trend. That said, at least in the short run, there may have been a decreased demand for primary care, but that is just my speculation. As more data flow in we will be able to answer this question more directly.”
Next steps for research included digging deeper into the data to understand the nature of conditions facing hospitalists, Dr. Gray said.
Implications for primary care
“This study provides an updated snapshot of the popularity of hospital medicine,” said Bradley A. Sharpe, MD, of the division of hospital medicine at the University of California, San Francisco. “It is also important to conduct this study now as health systems think about the challenge of providing high-quality primary care with a rapidly decreasing number of internists choosing to practice outpatient medicine.” Dr. Sharpe was not involved in the study.
“The most surprising finding to me was not the increase in general internists focusing on hospital medicine, but the amount of the increase; it is remarkable that nearly three quarters of general internists are choosing to practice as hospitalists,” Dr. Sharpe noted.
“I think there are a number of key factors at play,” he said. “First, as hospital medicine as a field is now more than 25 years old, hospitals and health systems have evolved to create hospital medicine jobs that are interesting, engaging, rewarding (financially and otherwise), doable, and sustainable. Second, being an outpatient internist is incredibly challenging; multiple studies have shown that it is essentially impossible to complete the evidence-based preventive care for a panel of patients on top of everything else. We know burnout rates are often higher among primary care and family medicine providers. On top of that, the expansion of electronic health records and patient access has led to a massive increase in messages to providers; this has been shown to be associated with burnout.”
The potential impact of the pandemic on physicians’ choices and the trend toward hospital medicine is an interested question, Dr. Sharpe said. The current study showed only trends through 2017.
“To be honest, I think it is difficult to predict,” he said. “Hospitalists shouldered much of the burden of COVID care nationally and burnout rates are high. One could imagine the extra work (as well as concern for personal safety) could lead to fewer providers choosing hospital medicine.
“At the same time, the pandemic has driven many of us to reflect on life and our values and what is important and, through that lens, providers might choose hospital medicine as a more sustainable, do-able, rewarding, and enjoyable career choice,” Dr. Sharpe emphasized.
“Additional research could explore the drivers of this clear trend toward hospital medicine. Determining what is motivating this trend could help hospitals and health systems ensure they have the right workforce for the future and, in particular, how to create outpatient positions that are attractive and rewarding,” he said.
The study received no outside funding. The researchers and Dr. Sharpe disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a new study, published in Annals of Internal Medicine, researchers from ABIM reviewed certification data from 67,902 general internists, accounting for 80% of all general internists certified in the United States from 1990 to 2017.
The researchers also used data from Medicare fee-for-service claims from 2008-2018 to measure and categorize practice setting types. The claims were from patients aged 65 years or older with at least 20 evaluation and management visits each year. Practice settings were categorized as hospitalist, outpatient, or mixed.
“ABIM is always working to understand the real-life experience of physicians, and this project grew out of that sort of analysis,” lead author Bradley M. Gray, PhD, a health services researcher at ABIM in Philadelphia, said in an interview. “We wanted to better understand practice setting, because that relates to the kinds of questions that we ask on our certifying exams. When we did this, we noticed a trend toward hospital medicine.”
Overall, the percentages of general internists in hospitalist practice and outpatient-only practice increased during the study period, from 25% to 40% and from 23% to 38%, respectively. By contrast, the percentage of general internists in a mixed-practice setting decreased from 52% to 23%, a 56% decline. Most of the physicians who left the mixed practice setting switched to outpatient-only practices.
Among the internists certified in 2017, 71% practiced as hospitalists, compared with 8% practicing as outpatient-only physicians. Most physicians remained in their original choice of practice setting. For physicians certified in 1999 and 2012, 86% and 85%, respectively, of those who chose hospitalist medicine remained in the hospital setting 5 years later, as did 95% of outpatient physicians, but only 57% of mixed-practice physicians.
The shift to outpatient practice among senior physicians offset the potential decline in outpatient primary care resulting from the increased choice of hospitalist medicine by new internists, the researchers noted.
The study findings were limited by several factors, including the reliance on Medicare fee-for-service claims, the researchers noted.
“We were surprised by both the dramatic shift toward hospital medicine by new physicians and the shift to outpatient only (an extreme category) for more senior physicians,” Dr. Gray said in an interview.
The shift toward outpatient practice among older physicians may be driven by convenience, said Dr. Gray. “I suspect that it is more efficient to specialize in terms of practice setting. Only seeing patients in the outpatient setting means that you don’t have to travel to the hospital, which can be time consuming.
“Also, with fewer new physicians going into primary care, older physicians need to focus on outpatient visits. This could be problematic in the future as more senior physicians retire and are replaced by new physicians who focus on hospital care,” which could lead to more shortages in primary care physicians, he explained.
The trend toward hospital medicine as a career has been going on since before the pandemic, said Dr. Gray. “I don’t think the pandemic will ultimately impact this trend. That said, at least in the short run, there may have been a decreased demand for primary care, but that is just my speculation. As more data flow in we will be able to answer this question more directly.”
Next steps for research included digging deeper into the data to understand the nature of conditions facing hospitalists, Dr. Gray said.
Implications for primary care
“This study provides an updated snapshot of the popularity of hospital medicine,” said Bradley A. Sharpe, MD, of the division of hospital medicine at the University of California, San Francisco. “It is also important to conduct this study now as health systems think about the challenge of providing high-quality primary care with a rapidly decreasing number of internists choosing to practice outpatient medicine.” Dr. Sharpe was not involved in the study.
“The most surprising finding to me was not the increase in general internists focusing on hospital medicine, but the amount of the increase; it is remarkable that nearly three quarters of general internists are choosing to practice as hospitalists,” Dr. Sharpe noted.
“I think there are a number of key factors at play,” he said. “First, as hospital medicine as a field is now more than 25 years old, hospitals and health systems have evolved to create hospital medicine jobs that are interesting, engaging, rewarding (financially and otherwise), doable, and sustainable. Second, being an outpatient internist is incredibly challenging; multiple studies have shown that it is essentially impossible to complete the evidence-based preventive care for a panel of patients on top of everything else. We know burnout rates are often higher among primary care and family medicine providers. On top of that, the expansion of electronic health records and patient access has led to a massive increase in messages to providers; this has been shown to be associated with burnout.”
The potential impact of the pandemic on physicians’ choices and the trend toward hospital medicine is an interested question, Dr. Sharpe said. The current study showed only trends through 2017.
“To be honest, I think it is difficult to predict,” he said. “Hospitalists shouldered much of the burden of COVID care nationally and burnout rates are high. One could imagine the extra work (as well as concern for personal safety) could lead to fewer providers choosing hospital medicine.
“At the same time, the pandemic has driven many of us to reflect on life and our values and what is important and, through that lens, providers might choose hospital medicine as a more sustainable, do-able, rewarding, and enjoyable career choice,” Dr. Sharpe emphasized.
“Additional research could explore the drivers of this clear trend toward hospital medicine. Determining what is motivating this trend could help hospitals and health systems ensure they have the right workforce for the future and, in particular, how to create outpatient positions that are attractive and rewarding,” he said.
The study received no outside funding. The researchers and Dr. Sharpe disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Mother’s distress disrupts fetal brain development
Babies of mothers who experience significant psychological distress during pregnancy showed evidence of altered brain development in utero and reduced cognitive outcomes at 18 months, based on data from a pair of studies including approximately 300 women.
In a longitudinal study published in JAMA Network Open, Yao Wu, PhD, of Children’s National Hospital, Washington, and colleagues recruited 97 healthy mother-infant dyads between January 2016 and October 2020 at a single center. Of these, 87 underwent two fetal brain imaging studies each, and 10 completed the first MRI visit, for a total of 184 fetal MRIs.
Neurodevelopment and social-emotional development for infants at 18 months of age was measured using the Bayley Scales of Infant and Toddler Development and Infant-Toddler Social and Emotional Assessment. The mean age of the mothers was 35 years; maternal distress was assessed between 24 and 40 weeks’ gestation using validated self-report questionnaires. Parenting stress was assessed at the 18-month infant testing using the Parenting Stress Index-Short Form.
Overall, prenatal maternal stress was negatively associated with infant cognitive performance (P = .01) at 18 months, mediated by fetal left hippocampal volume.
In addition, increased fetal cortical local gyrification index and sulcal depth measured during reported times of prenatal maternal distress were associated with significantly poorer social-emotional scores and competence scores at age 18 months. The beta coefficients for local gyrification index and sulcal depth were –54.62 and –14.22, respectively, for social-emotional and competence scores, –24.01 and –7.53, respectively; P values were P < .001, P < .002, P = .003, P < .001, respectively.
“Increased cortical gyrification has been suggested in children with dyslexia and autism, and sulcal depth has been associated with the severity of impaired performance on working memory and executive function in adults with schizophrenia,” the researchers wrote in their discussion of the findings.
The current study “extends our previous findings and suggests a critical role for disturbances in emerging fetal cerebral cortical folding development in mediating the association between prenatal maternal distress and neurodevelopmental problems that later manifest in infancy,” they explained.
The researchers also found that prenatal maternal anxiety, stress, and depression were positively associated with all measures of parenting stress at the 18-month testing visit.
The study findings were limited by several factors including the use of self-reports for both maternal distress and infant social-emotional assessment, despite the use of validated questionnaires, and the fact that assessment of maternal distress at specific times may not reflect the entire pregnancy, the researchers noted. Other potential limitations included the inability to use some MRI data because of fetal movement and the homogenous population of relatively highly educated women with access to health care that may not reflect other areas, they said.
“Identifying early brain developmental biomarkers may help improve the identification of infants at risk for later neurodevelopmental impairment who might benefit from early targeted interventions,” the researchers concluded.
Technology enhances health and disease models
The effect of the prenatal period on future well-being is recognized, but the current study makes “substantial contributions to prenatal programming science, with implications for ways to transform the prenatal care ecosystem for two-generation impact,” Catherine Monk, PhD, and Cristina R. Fernández, MD, both of Columbia University, New York, wrote in an accompanying editorial.
The developmental origins of health and disease (DOHaD) conceptual model introduced by Dr. David Barker in 1995 were later applied to show that maternal stress, depression, and anxiety affected child prenatal and future development, they said. However, the current study uses cutting-edge neuroscience to directly assess developing fetal brains. The finding of reduced cognitive functioning at 18 months associated with maternal stress is consistent with other findings, they noted.
“Finding an association between maternal prenatal stress and infant cognitive outcomes in the setting of what may be modest stress relative to that of a low-resourced or historically marginalized sample underscores the importance of this research; presumably, with higher stress, and greater social determinants of health burden, the effect sizes would be even greater and of greater concern,” they said.
However, studies such as the current one “have the potential to transform the prenatal and postpartum care ecosystems,” by encouraging a whole-person approach to the care of pregnant women, including attention to mental well-being and quality of life, they emphasized.
COVID-19 stress considerations
In a separate study published in Communications Medicine, Yuan-Chiao Lu, MD, also of Children’s National Hospital in Washington, and colleagues found a similar effect of maternal stress on fetal brain development.
The researchers imaged the brains of fetuses before and during the COVID-19 pandemic and interviewed mothers about any distress they experienced during pregnancy.
The study population included 65 women with known COVID-19 exposures who underwent 92 fetal MRIs and 137 prepandemic controls who underwent 182 fetal MRIs. Maternal distress was measured via the Spielberger State Anxiety Inventory, Spielberger Trait Anxiety Inventory, Perceived Stress Scale, and Edinburgh Postnatal Depression Scale.
Overall, scores on measures of stress and depression were significantly higher for women in the pandemic group compared with controls. Of the 173 women for whom maternal distress measures were available, 28% of the prepandemic group and 52% of the pandemic group met criteria for elevated maternal psychological distress, defined as above the threshold for distress on any one of the four measures.
After the researchers controlled for maternal distress, MRI data showed decreases in fetal white matter and in hippocampal and cerebellar volumes in fetuses in the pandemic group compared with controls.
Other signs of impaired brain development were similar to those seen in the JAMA Network Open study, including decreased cortical surface area and local gyrification index, as well as reduced sulcal depth in multiple brain lobes, indicating delayed cerebral cortical gyrification.
The second study was limited by a lack of data on other lifestyle changes during the pandemic that might influence maternal health and fetal development, the researchers noted. Other limitations were the possible lack of generalizability to a range of racial and ethnic populations and geographic areas outside of Washington, and the inability to control for unknown COVID-19 exposures or subclinical infections in controls, they said.
However, the results support findings from previous studies, and provide a unique opportunity to study the effect of prenatal stress on early development, as well as a chance to implement “novel and timely interventions,” the researchers wrote.
“Monitoring the COVID generation of infants for long-term cognitive and health outcomes after birth is warranted and currently underway,” and continued research may inform preventive strategies for pregnant women experiencing multiple stressors beyond the pandemic, they concluded.
Interpret pandemic effect with caution
“Research studies, as well as our own daily experiences, have made it abundantly clear that stress is on the rise as a consequence of the COVID-19 pandemic,” said editorial author Dr. Monk, who commented on the second study in an interview. “This is an important public health question: Early identification of pandemic effects on child development can help garner the necessary resources to intervene early, dramatically increasing the likelihood of improving that child’s developmental trajectory,” she said.
“The pandemic is an unprecedented experience that has widespread impact on people’s lives, how could it not also alter gestational biology and the developing brain? That being said, we need to be cautious in that we do not yet know the functional implications of these brain changes for longer-term development,” Dr. Monk said. “Also, we do not know what aspects of women’s pandemic-affected lives had an influence on fetal brain development. The authors found higher stress in pandemic versus nonpandemic women, but not evidence that distress was the mediating variable relating pregnancy during the pandemic to altered brain development,” she explained.
The take-home message for clinicians is to “provide your patients with realistic avenues for neurodevelopmental assessments of their children if they, or you, have concerns,” Dr. Monk said. “However, do not prejudge ‘pandemic babies,’ as not all children will be affected by these potential pandemic effects,” she emphasized. “It is possible to misjudge normal variation in children’s development and unnecessarily raise parents’ anxiety levels. Importantly, this period of brain plasticity means any needed intervention likely can have a big, ameliorating impact,” she added.
“We need follow-up studies looking at pandemic effects on prenatal and postnatal development and what factors protect the fetus and birthing person from the negative influences,” she said.
The JAMA study was supported by the National Institutes of Health and the A. James & Alice B. Clark Foundation. The study in Communications Medicine was supported by the National Institutes of Health, the Intellectual and Developmental Disabilities Research Center, and the A. James & Alice B. Clark Foundation. None of the researchers in either study disclosed conflicts of interest. Dr. Monk disclosed grants from the National Institutes of Health, the Bezos Family Foundation, and the Robin Hood Foundation outside the submitted work.
Babies of mothers who experience significant psychological distress during pregnancy showed evidence of altered brain development in utero and reduced cognitive outcomes at 18 months, based on data from a pair of studies including approximately 300 women.
In a longitudinal study published in JAMA Network Open, Yao Wu, PhD, of Children’s National Hospital, Washington, and colleagues recruited 97 healthy mother-infant dyads between January 2016 and October 2020 at a single center. Of these, 87 underwent two fetal brain imaging studies each, and 10 completed the first MRI visit, for a total of 184 fetal MRIs.
Neurodevelopment and social-emotional development for infants at 18 months of age was measured using the Bayley Scales of Infant and Toddler Development and Infant-Toddler Social and Emotional Assessment. The mean age of the mothers was 35 years; maternal distress was assessed between 24 and 40 weeks’ gestation using validated self-report questionnaires. Parenting stress was assessed at the 18-month infant testing using the Parenting Stress Index-Short Form.
Overall, prenatal maternal stress was negatively associated with infant cognitive performance (P = .01) at 18 months, mediated by fetal left hippocampal volume.
In addition, increased fetal cortical local gyrification index and sulcal depth measured during reported times of prenatal maternal distress were associated with significantly poorer social-emotional scores and competence scores at age 18 months. The beta coefficients for local gyrification index and sulcal depth were –54.62 and –14.22, respectively, for social-emotional and competence scores, –24.01 and –7.53, respectively; P values were P < .001, P < .002, P = .003, P < .001, respectively.
“Increased cortical gyrification has been suggested in children with dyslexia and autism, and sulcal depth has been associated with the severity of impaired performance on working memory and executive function in adults with schizophrenia,” the researchers wrote in their discussion of the findings.
The current study “extends our previous findings and suggests a critical role for disturbances in emerging fetal cerebral cortical folding development in mediating the association between prenatal maternal distress and neurodevelopmental problems that later manifest in infancy,” they explained.
The researchers also found that prenatal maternal anxiety, stress, and depression were positively associated with all measures of parenting stress at the 18-month testing visit.
The study findings were limited by several factors including the use of self-reports for both maternal distress and infant social-emotional assessment, despite the use of validated questionnaires, and the fact that assessment of maternal distress at specific times may not reflect the entire pregnancy, the researchers noted. Other potential limitations included the inability to use some MRI data because of fetal movement and the homogenous population of relatively highly educated women with access to health care that may not reflect other areas, they said.
“Identifying early brain developmental biomarkers may help improve the identification of infants at risk for later neurodevelopmental impairment who might benefit from early targeted interventions,” the researchers concluded.
Technology enhances health and disease models
The effect of the prenatal period on future well-being is recognized, but the current study makes “substantial contributions to prenatal programming science, with implications for ways to transform the prenatal care ecosystem for two-generation impact,” Catherine Monk, PhD, and Cristina R. Fernández, MD, both of Columbia University, New York, wrote in an accompanying editorial.
The developmental origins of health and disease (DOHaD) conceptual model introduced by Dr. David Barker in 1995 were later applied to show that maternal stress, depression, and anxiety affected child prenatal and future development, they said. However, the current study uses cutting-edge neuroscience to directly assess developing fetal brains. The finding of reduced cognitive functioning at 18 months associated with maternal stress is consistent with other findings, they noted.
“Finding an association between maternal prenatal stress and infant cognitive outcomes in the setting of what may be modest stress relative to that of a low-resourced or historically marginalized sample underscores the importance of this research; presumably, with higher stress, and greater social determinants of health burden, the effect sizes would be even greater and of greater concern,” they said.
However, studies such as the current one “have the potential to transform the prenatal and postpartum care ecosystems,” by encouraging a whole-person approach to the care of pregnant women, including attention to mental well-being and quality of life, they emphasized.
COVID-19 stress considerations
In a separate study published in Communications Medicine, Yuan-Chiao Lu, MD, also of Children’s National Hospital in Washington, and colleagues found a similar effect of maternal stress on fetal brain development.
The researchers imaged the brains of fetuses before and during the COVID-19 pandemic and interviewed mothers about any distress they experienced during pregnancy.
The study population included 65 women with known COVID-19 exposures who underwent 92 fetal MRIs and 137 prepandemic controls who underwent 182 fetal MRIs. Maternal distress was measured via the Spielberger State Anxiety Inventory, Spielberger Trait Anxiety Inventory, Perceived Stress Scale, and Edinburgh Postnatal Depression Scale.
Overall, scores on measures of stress and depression were significantly higher for women in the pandemic group compared with controls. Of the 173 women for whom maternal distress measures were available, 28% of the prepandemic group and 52% of the pandemic group met criteria for elevated maternal psychological distress, defined as above the threshold for distress on any one of the four measures.
After the researchers controlled for maternal distress, MRI data showed decreases in fetal white matter and in hippocampal and cerebellar volumes in fetuses in the pandemic group compared with controls.
Other signs of impaired brain development were similar to those seen in the JAMA Network Open study, including decreased cortical surface area and local gyrification index, as well as reduced sulcal depth in multiple brain lobes, indicating delayed cerebral cortical gyrification.
The second study was limited by a lack of data on other lifestyle changes during the pandemic that might influence maternal health and fetal development, the researchers noted. Other limitations were the possible lack of generalizability to a range of racial and ethnic populations and geographic areas outside of Washington, and the inability to control for unknown COVID-19 exposures or subclinical infections in controls, they said.
However, the results support findings from previous studies, and provide a unique opportunity to study the effect of prenatal stress on early development, as well as a chance to implement “novel and timely interventions,” the researchers wrote.
“Monitoring the COVID generation of infants for long-term cognitive and health outcomes after birth is warranted and currently underway,” and continued research may inform preventive strategies for pregnant women experiencing multiple stressors beyond the pandemic, they concluded.
Interpret pandemic effect with caution
“Research studies, as well as our own daily experiences, have made it abundantly clear that stress is on the rise as a consequence of the COVID-19 pandemic,” said editorial author Dr. Monk, who commented on the second study in an interview. “This is an important public health question: Early identification of pandemic effects on child development can help garner the necessary resources to intervene early, dramatically increasing the likelihood of improving that child’s developmental trajectory,” she said.
“The pandemic is an unprecedented experience that has widespread impact on people’s lives, how could it not also alter gestational biology and the developing brain? That being said, we need to be cautious in that we do not yet know the functional implications of these brain changes for longer-term development,” Dr. Monk said. “Also, we do not know what aspects of women’s pandemic-affected lives had an influence on fetal brain development. The authors found higher stress in pandemic versus nonpandemic women, but not evidence that distress was the mediating variable relating pregnancy during the pandemic to altered brain development,” she explained.
The take-home message for clinicians is to “provide your patients with realistic avenues for neurodevelopmental assessments of their children if they, or you, have concerns,” Dr. Monk said. “However, do not prejudge ‘pandemic babies,’ as not all children will be affected by these potential pandemic effects,” she emphasized. “It is possible to misjudge normal variation in children’s development and unnecessarily raise parents’ anxiety levels. Importantly, this period of brain plasticity means any needed intervention likely can have a big, ameliorating impact,” she added.
“We need follow-up studies looking at pandemic effects on prenatal and postnatal development and what factors protect the fetus and birthing person from the negative influences,” she said.
The JAMA study was supported by the National Institutes of Health and the A. James & Alice B. Clark Foundation. The study in Communications Medicine was supported by the National Institutes of Health, the Intellectual and Developmental Disabilities Research Center, and the A. James & Alice B. Clark Foundation. None of the researchers in either study disclosed conflicts of interest. Dr. Monk disclosed grants from the National Institutes of Health, the Bezos Family Foundation, and the Robin Hood Foundation outside the submitted work.
Babies of mothers who experience significant psychological distress during pregnancy showed evidence of altered brain development in utero and reduced cognitive outcomes at 18 months, based on data from a pair of studies including approximately 300 women.
In a longitudinal study published in JAMA Network Open, Yao Wu, PhD, of Children’s National Hospital, Washington, and colleagues recruited 97 healthy mother-infant dyads between January 2016 and October 2020 at a single center. Of these, 87 underwent two fetal brain imaging studies each, and 10 completed the first MRI visit, for a total of 184 fetal MRIs.
Neurodevelopment and social-emotional development for infants at 18 months of age was measured using the Bayley Scales of Infant and Toddler Development and Infant-Toddler Social and Emotional Assessment. The mean age of the mothers was 35 years; maternal distress was assessed between 24 and 40 weeks’ gestation using validated self-report questionnaires. Parenting stress was assessed at the 18-month infant testing using the Parenting Stress Index-Short Form.
Overall, prenatal maternal stress was negatively associated with infant cognitive performance (P = .01) at 18 months, mediated by fetal left hippocampal volume.
In addition, increased fetal cortical local gyrification index and sulcal depth measured during reported times of prenatal maternal distress were associated with significantly poorer social-emotional scores and competence scores at age 18 months. The beta coefficients for local gyrification index and sulcal depth were –54.62 and –14.22, respectively, for social-emotional and competence scores, –24.01 and –7.53, respectively; P values were P < .001, P < .002, P = .003, P < .001, respectively.
“Increased cortical gyrification has been suggested in children with dyslexia and autism, and sulcal depth has been associated with the severity of impaired performance on working memory and executive function in adults with schizophrenia,” the researchers wrote in their discussion of the findings.
The current study “extends our previous findings and suggests a critical role for disturbances in emerging fetal cerebral cortical folding development in mediating the association between prenatal maternal distress and neurodevelopmental problems that later manifest in infancy,” they explained.
The researchers also found that prenatal maternal anxiety, stress, and depression were positively associated with all measures of parenting stress at the 18-month testing visit.
The study findings were limited by several factors including the use of self-reports for both maternal distress and infant social-emotional assessment, despite the use of validated questionnaires, and the fact that assessment of maternal distress at specific times may not reflect the entire pregnancy, the researchers noted. Other potential limitations included the inability to use some MRI data because of fetal movement and the homogenous population of relatively highly educated women with access to health care that may not reflect other areas, they said.
“Identifying early brain developmental biomarkers may help improve the identification of infants at risk for later neurodevelopmental impairment who might benefit from early targeted interventions,” the researchers concluded.
Technology enhances health and disease models
The effect of the prenatal period on future well-being is recognized, but the current study makes “substantial contributions to prenatal programming science, with implications for ways to transform the prenatal care ecosystem for two-generation impact,” Catherine Monk, PhD, and Cristina R. Fernández, MD, both of Columbia University, New York, wrote in an accompanying editorial.
The developmental origins of health and disease (DOHaD) conceptual model introduced by Dr. David Barker in 1995 were later applied to show that maternal stress, depression, and anxiety affected child prenatal and future development, they said. However, the current study uses cutting-edge neuroscience to directly assess developing fetal brains. The finding of reduced cognitive functioning at 18 months associated with maternal stress is consistent with other findings, they noted.
“Finding an association between maternal prenatal stress and infant cognitive outcomes in the setting of what may be modest stress relative to that of a low-resourced or historically marginalized sample underscores the importance of this research; presumably, with higher stress, and greater social determinants of health burden, the effect sizes would be even greater and of greater concern,” they said.
However, studies such as the current one “have the potential to transform the prenatal and postpartum care ecosystems,” by encouraging a whole-person approach to the care of pregnant women, including attention to mental well-being and quality of life, they emphasized.
COVID-19 stress considerations
In a separate study published in Communications Medicine, Yuan-Chiao Lu, MD, also of Children’s National Hospital in Washington, and colleagues found a similar effect of maternal stress on fetal brain development.
The researchers imaged the brains of fetuses before and during the COVID-19 pandemic and interviewed mothers about any distress they experienced during pregnancy.
The study population included 65 women with known COVID-19 exposures who underwent 92 fetal MRIs and 137 prepandemic controls who underwent 182 fetal MRIs. Maternal distress was measured via the Spielberger State Anxiety Inventory, Spielberger Trait Anxiety Inventory, Perceived Stress Scale, and Edinburgh Postnatal Depression Scale.
Overall, scores on measures of stress and depression were significantly higher for women in the pandemic group compared with controls. Of the 173 women for whom maternal distress measures were available, 28% of the prepandemic group and 52% of the pandemic group met criteria for elevated maternal psychological distress, defined as above the threshold for distress on any one of the four measures.
After the researchers controlled for maternal distress, MRI data showed decreases in fetal white matter and in hippocampal and cerebellar volumes in fetuses in the pandemic group compared with controls.
Other signs of impaired brain development were similar to those seen in the JAMA Network Open study, including decreased cortical surface area and local gyrification index, as well as reduced sulcal depth in multiple brain lobes, indicating delayed cerebral cortical gyrification.
The second study was limited by a lack of data on other lifestyle changes during the pandemic that might influence maternal health and fetal development, the researchers noted. Other limitations were the possible lack of generalizability to a range of racial and ethnic populations and geographic areas outside of Washington, and the inability to control for unknown COVID-19 exposures or subclinical infections in controls, they said.
However, the results support findings from previous studies, and provide a unique opportunity to study the effect of prenatal stress on early development, as well as a chance to implement “novel and timely interventions,” the researchers wrote.
“Monitoring the COVID generation of infants for long-term cognitive and health outcomes after birth is warranted and currently underway,” and continued research may inform preventive strategies for pregnant women experiencing multiple stressors beyond the pandemic, they concluded.
Interpret pandemic effect with caution
“Research studies, as well as our own daily experiences, have made it abundantly clear that stress is on the rise as a consequence of the COVID-19 pandemic,” said editorial author Dr. Monk, who commented on the second study in an interview. “This is an important public health question: Early identification of pandemic effects on child development can help garner the necessary resources to intervene early, dramatically increasing the likelihood of improving that child’s developmental trajectory,” she said.
“The pandemic is an unprecedented experience that has widespread impact on people’s lives, how could it not also alter gestational biology and the developing brain? That being said, we need to be cautious in that we do not yet know the functional implications of these brain changes for longer-term development,” Dr. Monk said. “Also, we do not know what aspects of women’s pandemic-affected lives had an influence on fetal brain development. The authors found higher stress in pandemic versus nonpandemic women, but not evidence that distress was the mediating variable relating pregnancy during the pandemic to altered brain development,” she explained.
The take-home message for clinicians is to “provide your patients with realistic avenues for neurodevelopmental assessments of their children if they, or you, have concerns,” Dr. Monk said. “However, do not prejudge ‘pandemic babies,’ as not all children will be affected by these potential pandemic effects,” she emphasized. “It is possible to misjudge normal variation in children’s development and unnecessarily raise parents’ anxiety levels. Importantly, this period of brain plasticity means any needed intervention likely can have a big, ameliorating impact,” she added.
“We need follow-up studies looking at pandemic effects on prenatal and postnatal development and what factors protect the fetus and birthing person from the negative influences,” she said.
The JAMA study was supported by the National Institutes of Health and the A. James & Alice B. Clark Foundation. The study in Communications Medicine was supported by the National Institutes of Health, the Intellectual and Developmental Disabilities Research Center, and the A. James & Alice B. Clark Foundation. None of the researchers in either study disclosed conflicts of interest. Dr. Monk disclosed grants from the National Institutes of Health, the Bezos Family Foundation, and the Robin Hood Foundation outside the submitted work.
FROM JAMA NETWORK OPEN AND COMMUNICATIONS MEDICINE
Parents fall short on infant sleep safety
Less than 10% of parents followed recommended safe sleep practices for their infants aged 12 months and younger at both sleep onset and after nighttime waking, based on data from a survey of 1,500 parents published in Pediatrics.
Sleep-related death remains a major cause of infant mortality in the United States despite the early success of public health campaigns for safe sleep practices, such as “Back to Sleep,” and many parents persist in unsafe practices such as prone positioning and bed-sharing, Mersine A. Bryan, MD, of the University of Washington, Seattle, and colleagues wrote. “Though nighttime waking is common for infants, less attention has been paid to the safety of second-sleep practices.”
To examine the prevalence and safety of infant second-sleep practices, the researchers used a cross-sectional online survey to collect information on sleep practices from parents of infants aged 12 months and younger; 74% of the respondents were female, 65% were White, 12% were Black, and 17% were Hispanic. The mean age of the infants was 6.6 months, and 24% were aged 3 months and younger.
The survey included parent reports of three safe sleep practices based on the American Academy of Pediatrics 2016 Safe Infant Sleep Guidelines: supine infant sleep position, use of a separate sleep space (vs. bed sharing), and use of an approved surface/safe location (such as a bassinet, crib, cradle, or play yard vs. an adult bed).
Parents were asked to report sleep practices at sleep onset and at nighttime waking, and the researchers used a composite score to determine safe practices were met at each of these two time points.
Of the 1,500 participants, 581 (39%), reported any second-sleep practice. Of the 482 who reported on all three sleep practices at both time points, 29% met all three safe sleep criteria at sleep onset and 9% met all three safe sleep criteria at sleep onset and nighttime waking.
Of the parents who reported second sleep practices, 39% reported changes in practice after nighttime waking from sleep onset. Significantly more parents who switched practices between sleep onset and nighttime waking shifted from a safer to a less safe practice, the researchers noted.
For positioning, 67% of respondents overall reported placing infants on their backs at sleep onset. Among the 564 who reported a second sleep position, 42% placed infants on their backs again; 13% switched from supine to nonsupine positions and 7% changed from nonsupine to supine.
For sleep spaces, 72% of participants overall reported a separate sleep space for infants at sleep onset. Of the 508 who reported on second-sleep spaces, 54% kept infants in a separate space after nighttime waking, 18% shifted to a shared space after nighttime waking. Of those in shared spaces at sleep onset, 8% shifted to separate spaces after nighttime waking.
For sleep location, 71% of respondents overall used an approved sleep surface at sleep onset. Of the 560 who reported sleep location at both time points, 42% remained in a safe location after nighttime waking, while 30% were moved from a safe to an unsafe location, and 10% of those in an unsafe location were moved from an unsafe to a safe location.
In a multivariate analysis, the researchers examined the demographics associated with changes in sleep practice after nighttime waking. Parents younger than 25 years, first-time parents, those who identified as Black non-Hispanic or Hispanic, smokers, and those with preterm infants (less than 37 weeks’ gestation) were more likely to change sleep practices after nighttime waking. However, parents who reported a safe sleep practice at sleep onset were more likely to do so after nighttime waking.
“We hypothesize that expansion of existing strategies to promote infant safe sleep practices to include sleep practices after nighttime waking can have a positive impact on infant safe sleep,” the researchers wrote.
The study findings were limited by several factors including the use of an online survey, which limited the study population to those with internet and computer access, and the reliance on self-reports and only two time points, the researchers noted. Other limitations included the inclusion of only three of the AAP sleep recommendations, and the inclusion of only English speakers.
However, the results were strengthened by the large, diverse, and geographically representative sample of parents.
“When advising families about infant sleep, pediatricians should discuss nighttime wakings with parents because they are common and reinforce the need for safe sleep practices every time,” the researchers noted.
Increase opportunities for education
The current study is important because infants continue to die or experience life-long catastrophic health outcomes as a result of not following safe sleep practices, Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., said in an interview.
“I am not surprised by the study findings,” said Dr. Haut, who was not involved in the study. “As a pediatric nurse practitioner for over 35 years, I see infant sleep as a continuing challenge for families. In today’s fast-paced world, multiple priorities leave parents few resources for managing their own well-being, with adequate sleep being one health requirement that is often not met for them.”
To improve safe sleep practices, “it is imperative for health care providers in any setting to address safe sleep practices for infants and children,” said Dr. Haut. “In addition to safety, opportunity for adequate hours of sleep is also important.” She acknowledged that, “in the office setting, time is a huge barrier to completing comprehensive anticipatory guidance. When parents ask questions about sleep, they are often doing everything they can to physically make it through the night with a crying infant. Enforcing safe practices at this point is extremely difficult.”
However, some opportunities for safe sleep education include the prenatal period when parents can take time to listen and plan, not just for feeding preferences but for safe infant sleep practices, Dr. Haut noted.
“When sleep is a problem, families can be invited back to the office for additional counseling and education, which allows more time than within a scheduled health visit,” Dr. Haut emphasized. “Finally, enhanced public awareness is an aspect of learning. In my career I have seen the devastating results of suffocation while cosleeping as well as injuries from falling from a bed or inappropriate sleeping space, and other poor outcomes from inadequate support for safe sleep habits.”
As for additional research, studies are needed to include larger populations and “to further quantify positive outcomes of following safe sleeping practices,” said Dr. Haut. The results of these studies should be made available to the general public, not only to health care professionals.
The study was supported by Seattle Children’s Research Institute. The researchers had no financial conflicts to disclose. Dr. Haut had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
Less than 10% of parents followed recommended safe sleep practices for their infants aged 12 months and younger at both sleep onset and after nighttime waking, based on data from a survey of 1,500 parents published in Pediatrics.
Sleep-related death remains a major cause of infant mortality in the United States despite the early success of public health campaigns for safe sleep practices, such as “Back to Sleep,” and many parents persist in unsafe practices such as prone positioning and bed-sharing, Mersine A. Bryan, MD, of the University of Washington, Seattle, and colleagues wrote. “Though nighttime waking is common for infants, less attention has been paid to the safety of second-sleep practices.”
To examine the prevalence and safety of infant second-sleep practices, the researchers used a cross-sectional online survey to collect information on sleep practices from parents of infants aged 12 months and younger; 74% of the respondents were female, 65% were White, 12% were Black, and 17% were Hispanic. The mean age of the infants was 6.6 months, and 24% were aged 3 months and younger.
The survey included parent reports of three safe sleep practices based on the American Academy of Pediatrics 2016 Safe Infant Sleep Guidelines: supine infant sleep position, use of a separate sleep space (vs. bed sharing), and use of an approved surface/safe location (such as a bassinet, crib, cradle, or play yard vs. an adult bed).
Parents were asked to report sleep practices at sleep onset and at nighttime waking, and the researchers used a composite score to determine safe practices were met at each of these two time points.
Of the 1,500 participants, 581 (39%), reported any second-sleep practice. Of the 482 who reported on all three sleep practices at both time points, 29% met all three safe sleep criteria at sleep onset and 9% met all three safe sleep criteria at sleep onset and nighttime waking.
Of the parents who reported second sleep practices, 39% reported changes in practice after nighttime waking from sleep onset. Significantly more parents who switched practices between sleep onset and nighttime waking shifted from a safer to a less safe practice, the researchers noted.
For positioning, 67% of respondents overall reported placing infants on their backs at sleep onset. Among the 564 who reported a second sleep position, 42% placed infants on their backs again; 13% switched from supine to nonsupine positions and 7% changed from nonsupine to supine.
For sleep spaces, 72% of participants overall reported a separate sleep space for infants at sleep onset. Of the 508 who reported on second-sleep spaces, 54% kept infants in a separate space after nighttime waking, 18% shifted to a shared space after nighttime waking. Of those in shared spaces at sleep onset, 8% shifted to separate spaces after nighttime waking.
For sleep location, 71% of respondents overall used an approved sleep surface at sleep onset. Of the 560 who reported sleep location at both time points, 42% remained in a safe location after nighttime waking, while 30% were moved from a safe to an unsafe location, and 10% of those in an unsafe location were moved from an unsafe to a safe location.
In a multivariate analysis, the researchers examined the demographics associated with changes in sleep practice after nighttime waking. Parents younger than 25 years, first-time parents, those who identified as Black non-Hispanic or Hispanic, smokers, and those with preterm infants (less than 37 weeks’ gestation) were more likely to change sleep practices after nighttime waking. However, parents who reported a safe sleep practice at sleep onset were more likely to do so after nighttime waking.
“We hypothesize that expansion of existing strategies to promote infant safe sleep practices to include sleep practices after nighttime waking can have a positive impact on infant safe sleep,” the researchers wrote.
The study findings were limited by several factors including the use of an online survey, which limited the study population to those with internet and computer access, and the reliance on self-reports and only two time points, the researchers noted. Other limitations included the inclusion of only three of the AAP sleep recommendations, and the inclusion of only English speakers.
However, the results were strengthened by the large, diverse, and geographically representative sample of parents.
“When advising families about infant sleep, pediatricians should discuss nighttime wakings with parents because they are common and reinforce the need for safe sleep practices every time,” the researchers noted.
Increase opportunities for education
The current study is important because infants continue to die or experience life-long catastrophic health outcomes as a result of not following safe sleep practices, Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., said in an interview.
“I am not surprised by the study findings,” said Dr. Haut, who was not involved in the study. “As a pediatric nurse practitioner for over 35 years, I see infant sleep as a continuing challenge for families. In today’s fast-paced world, multiple priorities leave parents few resources for managing their own well-being, with adequate sleep being one health requirement that is often not met for them.”
To improve safe sleep practices, “it is imperative for health care providers in any setting to address safe sleep practices for infants and children,” said Dr. Haut. “In addition to safety, opportunity for adequate hours of sleep is also important.” She acknowledged that, “in the office setting, time is a huge barrier to completing comprehensive anticipatory guidance. When parents ask questions about sleep, they are often doing everything they can to physically make it through the night with a crying infant. Enforcing safe practices at this point is extremely difficult.”
However, some opportunities for safe sleep education include the prenatal period when parents can take time to listen and plan, not just for feeding preferences but for safe infant sleep practices, Dr. Haut noted.
“When sleep is a problem, families can be invited back to the office for additional counseling and education, which allows more time than within a scheduled health visit,” Dr. Haut emphasized. “Finally, enhanced public awareness is an aspect of learning. In my career I have seen the devastating results of suffocation while cosleeping as well as injuries from falling from a bed or inappropriate sleeping space, and other poor outcomes from inadequate support for safe sleep habits.”
As for additional research, studies are needed to include larger populations and “to further quantify positive outcomes of following safe sleeping practices,” said Dr. Haut. The results of these studies should be made available to the general public, not only to health care professionals.
The study was supported by Seattle Children’s Research Institute. The researchers had no financial conflicts to disclose. Dr. Haut had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
Less than 10% of parents followed recommended safe sleep practices for their infants aged 12 months and younger at both sleep onset and after nighttime waking, based on data from a survey of 1,500 parents published in Pediatrics.
Sleep-related death remains a major cause of infant mortality in the United States despite the early success of public health campaigns for safe sleep practices, such as “Back to Sleep,” and many parents persist in unsafe practices such as prone positioning and bed-sharing, Mersine A. Bryan, MD, of the University of Washington, Seattle, and colleagues wrote. “Though nighttime waking is common for infants, less attention has been paid to the safety of second-sleep practices.”
To examine the prevalence and safety of infant second-sleep practices, the researchers used a cross-sectional online survey to collect information on sleep practices from parents of infants aged 12 months and younger; 74% of the respondents were female, 65% were White, 12% were Black, and 17% were Hispanic. The mean age of the infants was 6.6 months, and 24% were aged 3 months and younger.
The survey included parent reports of three safe sleep practices based on the American Academy of Pediatrics 2016 Safe Infant Sleep Guidelines: supine infant sleep position, use of a separate sleep space (vs. bed sharing), and use of an approved surface/safe location (such as a bassinet, crib, cradle, or play yard vs. an adult bed).
Parents were asked to report sleep practices at sleep onset and at nighttime waking, and the researchers used a composite score to determine safe practices were met at each of these two time points.
Of the 1,500 participants, 581 (39%), reported any second-sleep practice. Of the 482 who reported on all three sleep practices at both time points, 29% met all three safe sleep criteria at sleep onset and 9% met all three safe sleep criteria at sleep onset and nighttime waking.
Of the parents who reported second sleep practices, 39% reported changes in practice after nighttime waking from sleep onset. Significantly more parents who switched practices between sleep onset and nighttime waking shifted from a safer to a less safe practice, the researchers noted.
For positioning, 67% of respondents overall reported placing infants on their backs at sleep onset. Among the 564 who reported a second sleep position, 42% placed infants on their backs again; 13% switched from supine to nonsupine positions and 7% changed from nonsupine to supine.
For sleep spaces, 72% of participants overall reported a separate sleep space for infants at sleep onset. Of the 508 who reported on second-sleep spaces, 54% kept infants in a separate space after nighttime waking, 18% shifted to a shared space after nighttime waking. Of those in shared spaces at sleep onset, 8% shifted to separate spaces after nighttime waking.
For sleep location, 71% of respondents overall used an approved sleep surface at sleep onset. Of the 560 who reported sleep location at both time points, 42% remained in a safe location after nighttime waking, while 30% were moved from a safe to an unsafe location, and 10% of those in an unsafe location were moved from an unsafe to a safe location.
In a multivariate analysis, the researchers examined the demographics associated with changes in sleep practice after nighttime waking. Parents younger than 25 years, first-time parents, those who identified as Black non-Hispanic or Hispanic, smokers, and those with preterm infants (less than 37 weeks’ gestation) were more likely to change sleep practices after nighttime waking. However, parents who reported a safe sleep practice at sleep onset were more likely to do so after nighttime waking.
“We hypothesize that expansion of existing strategies to promote infant safe sleep practices to include sleep practices after nighttime waking can have a positive impact on infant safe sleep,” the researchers wrote.
The study findings were limited by several factors including the use of an online survey, which limited the study population to those with internet and computer access, and the reliance on self-reports and only two time points, the researchers noted. Other limitations included the inclusion of only three of the AAP sleep recommendations, and the inclusion of only English speakers.
However, the results were strengthened by the large, diverse, and geographically representative sample of parents.
“When advising families about infant sleep, pediatricians should discuss nighttime wakings with parents because they are common and reinforce the need for safe sleep practices every time,” the researchers noted.
Increase opportunities for education
The current study is important because infants continue to die or experience life-long catastrophic health outcomes as a result of not following safe sleep practices, Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., said in an interview.
“I am not surprised by the study findings,” said Dr. Haut, who was not involved in the study. “As a pediatric nurse practitioner for over 35 years, I see infant sleep as a continuing challenge for families. In today’s fast-paced world, multiple priorities leave parents few resources for managing their own well-being, with adequate sleep being one health requirement that is often not met for them.”
To improve safe sleep practices, “it is imperative for health care providers in any setting to address safe sleep practices for infants and children,” said Dr. Haut. “In addition to safety, opportunity for adequate hours of sleep is also important.” She acknowledged that, “in the office setting, time is a huge barrier to completing comprehensive anticipatory guidance. When parents ask questions about sleep, they are often doing everything they can to physically make it through the night with a crying infant. Enforcing safe practices at this point is extremely difficult.”
However, some opportunities for safe sleep education include the prenatal period when parents can take time to listen and plan, not just for feeding preferences but for safe infant sleep practices, Dr. Haut noted.
“When sleep is a problem, families can be invited back to the office for additional counseling and education, which allows more time than within a scheduled health visit,” Dr. Haut emphasized. “Finally, enhanced public awareness is an aspect of learning. In my career I have seen the devastating results of suffocation while cosleeping as well as injuries from falling from a bed or inappropriate sleeping space, and other poor outcomes from inadequate support for safe sleep habits.”
As for additional research, studies are needed to include larger populations and “to further quantify positive outcomes of following safe sleeping practices,” said Dr. Haut. The results of these studies should be made available to the general public, not only to health care professionals.
The study was supported by Seattle Children’s Research Institute. The researchers had no financial conflicts to disclose. Dr. Haut had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
FROM PEDIATRICS
Phase-3 study: Leukemia patients live longer with ibrutinib
“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.
In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).
The long-term outcome data were published in Blood Advances.
Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).
At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.
Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).
Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).
Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.
Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.
The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.
“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.
“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.
However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
Safety and efficacy remain promising
“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.
“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.
The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.
Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.
“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.
The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.
“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.
In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).
The long-term outcome data were published in Blood Advances.
Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).
At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.
Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).
Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).
Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.
Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.
The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.
“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.
“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.
However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
Safety and efficacy remain promising
“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.
“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.
The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.
Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.
“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.
The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.
“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.
In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).
The long-term outcome data were published in Blood Advances.
Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).
At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.
Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).
Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).
Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.
Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.
The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.
“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.
“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.
However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
Safety and efficacy remain promising
“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.
“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.
The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.
Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.
“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.
The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.
FROM BLOOD ADVANCES
FDA approves topical tapinarof for plaque psoriasis
The the manufacturer announced.
Tapinarof is an aryl hydrocarbon receptor agonist and is the first FDA-approved steroid-free topical medication in this class, according to a press release from the manufacturer, Dermavant.
Approval was based on results of three studies in a phase 3 clinical trial program (PSOARING 1, PSOARING 2), and an open-label extension study, (PSOARING 3), the company release said. In PSOARING 1 and 2, approximately 1,000 adults aged 18-75 years (median age, 51 years) with plaque psoriasis were randomized to once-daily topical tapinarof or placebo for up to 12 weeks; 85% were White and 57% were men. The study findings were published in the New England Journal of Medicine in December 2021.
The primary endpoint for both trials was the proportion of patients who achieved Physician Global Assessment (PGA) scores score of “clear” (0) or “almost clear” (1) and improvement of at least two grades from baseline.
After 12 weeks, 36% of the patients in PSOARING 1 and 40% in PSOARING 2 who received tapinarof met the primary outcome, compared with 6% of patients on placebo (P < .001 for both studies). Of these, a total of 73 patients from both studies who achieved PGA scores of 0 were entered in PSOARING 3, a 40-week open-label extension study, in which they stopped tapinarof treatment and retained PGA scores of 0 or 1 for approximately 4 months off treatment. An additional 312 patients who were enrolled in the PSOARING 3 extension study achieved PGA scores of 0 at least once during the study period, with “remittive” effects lasting a mean of 130 days off of treatment.
In addition, patients who received tapinarof in the PSOARING 1 and 2 studies showed significant improvement from baseline, compared with patients on placebo, across a range of secondary endpoints including a 75% or greater improvement in Psoriasis Area and Severity Index score (PASI 75).
In PSOARING 1, and 2, respectively, 36.1% and 47.6% of those on tapinarof achieved a PASI 75 response at week 12, compared with 10.2% and 6.9% of those on the vehicle (P < .001 for both).
Across all three studies, the majority adverse events were mild to moderate, and limited to the application site.
The most common adverse events reported by patients in the tapinarof groups were folliculitis, nasopharyngitis, and contact dermatitis. Headaches were more common among those treated with tapinarof than those on vehicle in the studies (3.8% vs. 2.4% in PSOARING 1, and 3.8% vs. 0.6% in PSOARING 2), leading to only three treatment discontinuations.
At the end of the PSOARING 3 study (at either week 40 or early termination), 599 participants responded to satisfaction questionnaires. Of these, 83.6% said they were satisfied with the results of tapinarof treatment, and 81.7% said it was more effective than previous topical treatments they had used, according to the company’s release.
Tapinarof cream can be used on all areas of the body, including the face, skin folds, neck, genitalia, anal crux, inflammatory areas, and axillae, according to the company release.
Full prescribing information is available here.
The the manufacturer announced.
Tapinarof is an aryl hydrocarbon receptor agonist and is the first FDA-approved steroid-free topical medication in this class, according to a press release from the manufacturer, Dermavant.
Approval was based on results of three studies in a phase 3 clinical trial program (PSOARING 1, PSOARING 2), and an open-label extension study, (PSOARING 3), the company release said. In PSOARING 1 and 2, approximately 1,000 adults aged 18-75 years (median age, 51 years) with plaque psoriasis were randomized to once-daily topical tapinarof or placebo for up to 12 weeks; 85% were White and 57% were men. The study findings were published in the New England Journal of Medicine in December 2021.
The primary endpoint for both trials was the proportion of patients who achieved Physician Global Assessment (PGA) scores score of “clear” (0) or “almost clear” (1) and improvement of at least two grades from baseline.
After 12 weeks, 36% of the patients in PSOARING 1 and 40% in PSOARING 2 who received tapinarof met the primary outcome, compared with 6% of patients on placebo (P < .001 for both studies). Of these, a total of 73 patients from both studies who achieved PGA scores of 0 were entered in PSOARING 3, a 40-week open-label extension study, in which they stopped tapinarof treatment and retained PGA scores of 0 or 1 for approximately 4 months off treatment. An additional 312 patients who were enrolled in the PSOARING 3 extension study achieved PGA scores of 0 at least once during the study period, with “remittive” effects lasting a mean of 130 days off of treatment.
In addition, patients who received tapinarof in the PSOARING 1 and 2 studies showed significant improvement from baseline, compared with patients on placebo, across a range of secondary endpoints including a 75% or greater improvement in Psoriasis Area and Severity Index score (PASI 75).
In PSOARING 1, and 2, respectively, 36.1% and 47.6% of those on tapinarof achieved a PASI 75 response at week 12, compared with 10.2% and 6.9% of those on the vehicle (P < .001 for both).
Across all three studies, the majority adverse events were mild to moderate, and limited to the application site.
The most common adverse events reported by patients in the tapinarof groups were folliculitis, nasopharyngitis, and contact dermatitis. Headaches were more common among those treated with tapinarof than those on vehicle in the studies (3.8% vs. 2.4% in PSOARING 1, and 3.8% vs. 0.6% in PSOARING 2), leading to only three treatment discontinuations.
At the end of the PSOARING 3 study (at either week 40 or early termination), 599 participants responded to satisfaction questionnaires. Of these, 83.6% said they were satisfied with the results of tapinarof treatment, and 81.7% said it was more effective than previous topical treatments they had used, according to the company’s release.
Tapinarof cream can be used on all areas of the body, including the face, skin folds, neck, genitalia, anal crux, inflammatory areas, and axillae, according to the company release.
Full prescribing information is available here.
The the manufacturer announced.
Tapinarof is an aryl hydrocarbon receptor agonist and is the first FDA-approved steroid-free topical medication in this class, according to a press release from the manufacturer, Dermavant.
Approval was based on results of three studies in a phase 3 clinical trial program (PSOARING 1, PSOARING 2), and an open-label extension study, (PSOARING 3), the company release said. In PSOARING 1 and 2, approximately 1,000 adults aged 18-75 years (median age, 51 years) with plaque psoriasis were randomized to once-daily topical tapinarof or placebo for up to 12 weeks; 85% were White and 57% were men. The study findings were published in the New England Journal of Medicine in December 2021.
The primary endpoint for both trials was the proportion of patients who achieved Physician Global Assessment (PGA) scores score of “clear” (0) or “almost clear” (1) and improvement of at least two grades from baseline.
After 12 weeks, 36% of the patients in PSOARING 1 and 40% in PSOARING 2 who received tapinarof met the primary outcome, compared with 6% of patients on placebo (P < .001 for both studies). Of these, a total of 73 patients from both studies who achieved PGA scores of 0 were entered in PSOARING 3, a 40-week open-label extension study, in which they stopped tapinarof treatment and retained PGA scores of 0 or 1 for approximately 4 months off treatment. An additional 312 patients who were enrolled in the PSOARING 3 extension study achieved PGA scores of 0 at least once during the study period, with “remittive” effects lasting a mean of 130 days off of treatment.
In addition, patients who received tapinarof in the PSOARING 1 and 2 studies showed significant improvement from baseline, compared with patients on placebo, across a range of secondary endpoints including a 75% or greater improvement in Psoriasis Area and Severity Index score (PASI 75).
In PSOARING 1, and 2, respectively, 36.1% and 47.6% of those on tapinarof achieved a PASI 75 response at week 12, compared with 10.2% and 6.9% of those on the vehicle (P < .001 for both).
Across all three studies, the majority adverse events were mild to moderate, and limited to the application site.
The most common adverse events reported by patients in the tapinarof groups were folliculitis, nasopharyngitis, and contact dermatitis. Headaches were more common among those treated with tapinarof than those on vehicle in the studies (3.8% vs. 2.4% in PSOARING 1, and 3.8% vs. 0.6% in PSOARING 2), leading to only three treatment discontinuations.
At the end of the PSOARING 3 study (at either week 40 or early termination), 599 participants responded to satisfaction questionnaires. Of these, 83.6% said they were satisfied with the results of tapinarof treatment, and 81.7% said it was more effective than previous topical treatments they had used, according to the company’s release.
Tapinarof cream can be used on all areas of the body, including the face, skin folds, neck, genitalia, anal crux, inflammatory areas, and axillae, according to the company release.
Full prescribing information is available here.
Contraceptive use boosted by enhanced counseling
Contraceptive counseling and interventions beyond usual care significantly increased the use of contraceptives with no accompanying increase in sexually transmitted infections or reduction in condom use, based on data from a new meta-analysis.
“Although effective contraception is available in the United States and guidelines support contraceptive care in clinical practice, providing contraceptive care has not been widely adopted across medical specialties as a preventive health service that is routinely offered to eligible patients, such as mammography screening,” lead author Heidi D. Nelson, MD, of Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif., said in an interview.
“Access to and coverage of contraceptive care are frequently challenged by legislation and insurance policies, and influential preventive services guideline groups, such as the U.S. Preventive Services Task Force, have not issued recommendations for contraceptive care,” Dr. Nelson said.
“The evidence to determine the benefits and harms of contraceptive care as a preventive health service has not been examined using methods similar to those used for other preventive services and clinicians may lack guidance on the effectiveness of contraception services relevant to their practices,” she added.
In a study published in Annals of Internal Medicine, Dr. Nelson and colleagues reviewed data from 38 randomized, controlled trials with a total of 25,472 participants. The trials evaluated the effectiveness of various types of contraceptive counseling and provision interventions beyond usual care on subsequent contraception use, compared with nonintervention comparison groups.
Overall, higher contraceptive use was associated with counseling interventions (risk ratio, 1.39), advance provision of emergency contraception (RR, 2.12), counseling or provision of emergency contraception postpartum (RR, 1.15), or counseling or provision of emergency contraception at the time of abortion (RR, 1.19), compared with usual care or active controls across studies.
Most of the included trials were not powered to distinguish intended versus unintended pregnancy rates, but pregnancy rates were lower among intervention groups, compared with controls.
Five of the selected studies assessed the potential negative effect of contraceptive counseling with regard to increased rates of STIs and two studies examined decreased condom use. However, neither STI rates nor condom use were significantly different between study participants who received various contraceptive counseling interventions (such as advanced provision of emergency contraception, clinician training, and individual counseling) and those who did not (RR, 1.05 and RR, 1.03, respectively).
“These results indicate that additional efforts to assist patients with their contraception decisions improve its subsequent use,” and are not surprising, said Dr. Nelson.
“All clinicians providing health care to women, not only clinicians providing reproductive health care specifically, need to recognize contraceptive care as an essential preventive health service and assume responsibility for delivering contraceptive counseling and provision services appropriate for each patient,” Dr. Nelson emphasized. “Clinicians lacking contraceptive care clinical skills may require additional training or refer their patients if needed to assure high quality care.”
The study findings were limited by several factors including the variability of interventions across studies and the lack of data on unintended pregnancy outcomes, the researchers noted. However, the results suggest that various contraceptive counseling and interventions beyond usual care increased contraceptive use with no reduction in condom use or increase in STIs, they wrote.
“Additional research should further evaluate approaches to contraceptive counseling and provision to determine best practices,” Dr. Nelson said in an interview. “This is particularly important for medically high-risk populations, those with limited access to care, and additional populations and settings that have not yet been studied, including transgender and nonbinary patients. Research is needed to refine measures of pregnancy intention and planning; and create uniform definitions of contraceptive care, interventions, measures of use, and outcomes.”.
Make easy, effective contraception accessible to all
The news of a potential overturn of the 1973 Roe v. Wade Supreme Court decision that protects a pregnant person’s ability to choose abortion “shines a bright light on the importance of promoting the use of contraception,” and on the findings of the current review, Christine Laine, MD, editor-in-chief of Annals of Internal Medicine, wrote in an accompanying editorial. “Easy, effective, accessible, and affordable contraception becomes increasingly essential as ending unintended pregnancy becomes increasingly difficult, unsafe, inaccessible, and legally risky.”
The available evidence showed the benefits of enhanced counseling, providing emergency contraception in advance, and providing contraceptive interventions immediately after delivery or pregnancy termination, she wrote. The findings have strong clinical implications, especially with regard to the Healthy People 2030 goal of reducing unintended pregnancy from the current 43% to 36.5%.
Dr. Laine called on internal medicine physicians in particular to recognize the negative health consequences of unintended pregnancy, and to consider contraceptive counseling part of their responsibility to their patients.
“To expand the numbers of people who receive this essential preventive service, we must systematically incorporate contraceptive counseling into health care with the same fervor that we devote to other preventive services. The health of our patients – and their families – depends on it,” she concluded.
The study was supported by the Resources Legacy Fund. The researchers had no financial conflicts to disclose. Dr. Laine had no financial conflicts to disclose.
Contraceptive counseling and interventions beyond usual care significantly increased the use of contraceptives with no accompanying increase in sexually transmitted infections or reduction in condom use, based on data from a new meta-analysis.
“Although effective contraception is available in the United States and guidelines support contraceptive care in clinical practice, providing contraceptive care has not been widely adopted across medical specialties as a preventive health service that is routinely offered to eligible patients, such as mammography screening,” lead author Heidi D. Nelson, MD, of Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif., said in an interview.
“Access to and coverage of contraceptive care are frequently challenged by legislation and insurance policies, and influential preventive services guideline groups, such as the U.S. Preventive Services Task Force, have not issued recommendations for contraceptive care,” Dr. Nelson said.
“The evidence to determine the benefits and harms of contraceptive care as a preventive health service has not been examined using methods similar to those used for other preventive services and clinicians may lack guidance on the effectiveness of contraception services relevant to their practices,” she added.
In a study published in Annals of Internal Medicine, Dr. Nelson and colleagues reviewed data from 38 randomized, controlled trials with a total of 25,472 participants. The trials evaluated the effectiveness of various types of contraceptive counseling and provision interventions beyond usual care on subsequent contraception use, compared with nonintervention comparison groups.
Overall, higher contraceptive use was associated with counseling interventions (risk ratio, 1.39), advance provision of emergency contraception (RR, 2.12), counseling or provision of emergency contraception postpartum (RR, 1.15), or counseling or provision of emergency contraception at the time of abortion (RR, 1.19), compared with usual care or active controls across studies.
Most of the included trials were not powered to distinguish intended versus unintended pregnancy rates, but pregnancy rates were lower among intervention groups, compared with controls.
Five of the selected studies assessed the potential negative effect of contraceptive counseling with regard to increased rates of STIs and two studies examined decreased condom use. However, neither STI rates nor condom use were significantly different between study participants who received various contraceptive counseling interventions (such as advanced provision of emergency contraception, clinician training, and individual counseling) and those who did not (RR, 1.05 and RR, 1.03, respectively).
“These results indicate that additional efforts to assist patients with their contraception decisions improve its subsequent use,” and are not surprising, said Dr. Nelson.
“All clinicians providing health care to women, not only clinicians providing reproductive health care specifically, need to recognize contraceptive care as an essential preventive health service and assume responsibility for delivering contraceptive counseling and provision services appropriate for each patient,” Dr. Nelson emphasized. “Clinicians lacking contraceptive care clinical skills may require additional training or refer their patients if needed to assure high quality care.”
The study findings were limited by several factors including the variability of interventions across studies and the lack of data on unintended pregnancy outcomes, the researchers noted. However, the results suggest that various contraceptive counseling and interventions beyond usual care increased contraceptive use with no reduction in condom use or increase in STIs, they wrote.
“Additional research should further evaluate approaches to contraceptive counseling and provision to determine best practices,” Dr. Nelson said in an interview. “This is particularly important for medically high-risk populations, those with limited access to care, and additional populations and settings that have not yet been studied, including transgender and nonbinary patients. Research is needed to refine measures of pregnancy intention and planning; and create uniform definitions of contraceptive care, interventions, measures of use, and outcomes.”.
Make easy, effective contraception accessible to all
The news of a potential overturn of the 1973 Roe v. Wade Supreme Court decision that protects a pregnant person’s ability to choose abortion “shines a bright light on the importance of promoting the use of contraception,” and on the findings of the current review, Christine Laine, MD, editor-in-chief of Annals of Internal Medicine, wrote in an accompanying editorial. “Easy, effective, accessible, and affordable contraception becomes increasingly essential as ending unintended pregnancy becomes increasingly difficult, unsafe, inaccessible, and legally risky.”
The available evidence showed the benefits of enhanced counseling, providing emergency contraception in advance, and providing contraceptive interventions immediately after delivery or pregnancy termination, she wrote. The findings have strong clinical implications, especially with regard to the Healthy People 2030 goal of reducing unintended pregnancy from the current 43% to 36.5%.
Dr. Laine called on internal medicine physicians in particular to recognize the negative health consequences of unintended pregnancy, and to consider contraceptive counseling part of their responsibility to their patients.
“To expand the numbers of people who receive this essential preventive service, we must systematically incorporate contraceptive counseling into health care with the same fervor that we devote to other preventive services. The health of our patients – and their families – depends on it,” she concluded.
The study was supported by the Resources Legacy Fund. The researchers had no financial conflicts to disclose. Dr. Laine had no financial conflicts to disclose.
Contraceptive counseling and interventions beyond usual care significantly increased the use of contraceptives with no accompanying increase in sexually transmitted infections or reduction in condom use, based on data from a new meta-analysis.
“Although effective contraception is available in the United States and guidelines support contraceptive care in clinical practice, providing contraceptive care has not been widely adopted across medical specialties as a preventive health service that is routinely offered to eligible patients, such as mammography screening,” lead author Heidi D. Nelson, MD, of Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif., said in an interview.
“Access to and coverage of contraceptive care are frequently challenged by legislation and insurance policies, and influential preventive services guideline groups, such as the U.S. Preventive Services Task Force, have not issued recommendations for contraceptive care,” Dr. Nelson said.
“The evidence to determine the benefits and harms of contraceptive care as a preventive health service has not been examined using methods similar to those used for other preventive services and clinicians may lack guidance on the effectiveness of contraception services relevant to their practices,” she added.
In a study published in Annals of Internal Medicine, Dr. Nelson and colleagues reviewed data from 38 randomized, controlled trials with a total of 25,472 participants. The trials evaluated the effectiveness of various types of contraceptive counseling and provision interventions beyond usual care on subsequent contraception use, compared with nonintervention comparison groups.
Overall, higher contraceptive use was associated with counseling interventions (risk ratio, 1.39), advance provision of emergency contraception (RR, 2.12), counseling or provision of emergency contraception postpartum (RR, 1.15), or counseling or provision of emergency contraception at the time of abortion (RR, 1.19), compared with usual care or active controls across studies.
Most of the included trials were not powered to distinguish intended versus unintended pregnancy rates, but pregnancy rates were lower among intervention groups, compared with controls.
Five of the selected studies assessed the potential negative effect of contraceptive counseling with regard to increased rates of STIs and two studies examined decreased condom use. However, neither STI rates nor condom use were significantly different between study participants who received various contraceptive counseling interventions (such as advanced provision of emergency contraception, clinician training, and individual counseling) and those who did not (RR, 1.05 and RR, 1.03, respectively).
“These results indicate that additional efforts to assist patients with their contraception decisions improve its subsequent use,” and are not surprising, said Dr. Nelson.
“All clinicians providing health care to women, not only clinicians providing reproductive health care specifically, need to recognize contraceptive care as an essential preventive health service and assume responsibility for delivering contraceptive counseling and provision services appropriate for each patient,” Dr. Nelson emphasized. “Clinicians lacking contraceptive care clinical skills may require additional training or refer their patients if needed to assure high quality care.”
The study findings were limited by several factors including the variability of interventions across studies and the lack of data on unintended pregnancy outcomes, the researchers noted. However, the results suggest that various contraceptive counseling and interventions beyond usual care increased contraceptive use with no reduction in condom use or increase in STIs, they wrote.
“Additional research should further evaluate approaches to contraceptive counseling and provision to determine best practices,” Dr. Nelson said in an interview. “This is particularly important for medically high-risk populations, those with limited access to care, and additional populations and settings that have not yet been studied, including transgender and nonbinary patients. Research is needed to refine measures of pregnancy intention and planning; and create uniform definitions of contraceptive care, interventions, measures of use, and outcomes.”.
Make easy, effective contraception accessible to all
The news of a potential overturn of the 1973 Roe v. Wade Supreme Court decision that protects a pregnant person’s ability to choose abortion “shines a bright light on the importance of promoting the use of contraception,” and on the findings of the current review, Christine Laine, MD, editor-in-chief of Annals of Internal Medicine, wrote in an accompanying editorial. “Easy, effective, accessible, and affordable contraception becomes increasingly essential as ending unintended pregnancy becomes increasingly difficult, unsafe, inaccessible, and legally risky.”
The available evidence showed the benefits of enhanced counseling, providing emergency contraception in advance, and providing contraceptive interventions immediately after delivery or pregnancy termination, she wrote. The findings have strong clinical implications, especially with regard to the Healthy People 2030 goal of reducing unintended pregnancy from the current 43% to 36.5%.
Dr. Laine called on internal medicine physicians in particular to recognize the negative health consequences of unintended pregnancy, and to consider contraceptive counseling part of their responsibility to their patients.
“To expand the numbers of people who receive this essential preventive service, we must systematically incorporate contraceptive counseling into health care with the same fervor that we devote to other preventive services. The health of our patients – and their families – depends on it,” she concluded.
The study was supported by the Resources Legacy Fund. The researchers had no financial conflicts to disclose. Dr. Laine had no financial conflicts to disclose.
FROM ANNALS OF INTERNAL MEDICINE