Rare Diseases

Earlier this week, Medscape spoke with Nora Disis, MD, about vaccinating cancer patients. Disis is a medical oncologist and director of both the Institute of Translational Health Sciences and the Cancer Vaccine Institute, the University of Washington, Seattle, Washington. As editor-in-chief of JAMA Oncology, she has watched COVID-19 developments in the oncology community over the past year.

Here are a few themes that Disis said oncologists should be aware of as vaccines eventually begin reaching cancer patients.

We should expect cancer patients to respond to vaccines. Historically, some believed that cancer patients would be unable to mount an immune response to vaccines. Data on other viral vaccines have shown otherwise. For example, there has been a long history of studies of flu vaccination in cancer patients, and in general, those vaccines confer protection. Likewise for pneumococcal vaccine, which, generally speaking, cancer patients should receive.

Special cases may include hematologic malignancies in which the immune system has been destroyed and profound immunosuppression occurs. Data on immunization during this immunosuppressed period are scarce, but what data are available suggest that once cancer patients are through this immunosuppressed period, they can be vaccinated successfully.

The type of vaccine will probably be important for cancer patients. Currently, there are 61 coronavirus vaccines in human clinical trials, and 17 have reached the final stages of testing. At least 85 preclinical vaccines are under active investigation in animals.

Both the Pfizer-BioNTech and Moderna COVID vaccines are mRNA type. There are many other types, including protein-based vaccines, viral vector vaccines based on adenoviruses, and inactivated or attenuated coronavirus vaccines.

The latter vaccines, particularly attenuated live virus vaccines, may not be a good choice for cancer patients. Especially in those with rapidly progressing disease or on chemotherapy, attenuated live viruses may cause a low-grade infection.

Incidentally, the technology used in the genetic, or mRNA, vaccines developed by both Pfizer-BioNTech and Moderna was initially developed for fighting cancer, and studies have shown that patients can generate immune responses to cancer-associated proteins with this type of vaccine.

These genetic vaccines could turn out to be the most effective for cancer patients, especially those with solid tumors.

Our understanding is very limited right now. Neither the Pfizer-BioNTech nor the Moderna early data discuss cancer patients. Two of the most important questions for cancer patients are dosing and booster scheduling. Potential defects in lymphocyte function among cancer patients may require unique initial dosing and booster schedules. In terms of timing, it is unclear how active therapy might affect a patient’s immune response to vaccination and whether vaccines should be timed with therapy cycles.

Vaccine access may depend on whether cancer patients are viewed as a vulnerable population. Those at higher risk for severe COVID-19 clearly have a greater need for vaccination. While there are data suggesting that cancer patients are at higher risk, they are a bit murky, in part because cancer patients are a heterogeneous group. For example, there are data suggesting that lung and blood cancer patients fare worse. There is also a suggestion that, like in the general population, COVID risk in cancer patients remains driven by comorbidities.

It is likely, then, that personalized risk factors such as type of cancer therapy, site of disease, and comorbidities will shape individual choices about vaccination among cancer patients.

A version of this article first appeared on Medscape.com.

Earlier this week, Medscape spoke with Nora Disis, MD, about vaccinating cancer patients. Disis is a medical oncologist and director of both the Institute of Translational Health Sciences and the Cancer Vaccine Institute, the University of Washington, Seattle, Washington. As editor-in-chief of JAMA Oncology, she has watched COVID-19 developments in the oncology community over the past year.

Here are a few themes that Disis said oncologists should be aware of as vaccines eventually begin reaching cancer patients.

We should expect cancer patients to respond to vaccines. Historically, some believed that cancer patients would be unable to mount an immune response to vaccines. Data on other viral vaccines have shown otherwise. For example, there has been a long history of studies of flu vaccination in cancer patients, and in general, those vaccines confer protection. Likewise for pneumococcal vaccine, which, generally speaking, cancer patients should receive.

Special cases may include hematologic malignancies in which the immune system has been destroyed and profound immunosuppression occurs. Data on immunization during this immunosuppressed period are scarce, but what data are available suggest that once cancer patients are through this immunosuppressed period, they can be vaccinated successfully.

The type of vaccine will probably be important for cancer patients. Currently, there are 61 coronavirus vaccines in human clinical trials, and 17 have reached the final stages of testing. At least 85 preclinical vaccines are under active investigation in animals.

Both the Pfizer-BioNTech and Moderna COVID vaccines are mRNA type. There are many other types, including protein-based vaccines, viral vector vaccines based on adenoviruses, and inactivated or attenuated coronavirus vaccines.

The latter vaccines, particularly attenuated live virus vaccines, may not be a good choice for cancer patients. Especially in those with rapidly progressing disease or on chemotherapy, attenuated live viruses may cause a low-grade infection.

Incidentally, the technology used in the genetic, or mRNA, vaccines developed by both Pfizer-BioNTech and Moderna was initially developed for fighting cancer, and studies have shown that patients can generate immune responses to cancer-associated proteins with this type of vaccine.

These genetic vaccines could turn out to be the most effective for cancer patients, especially those with solid tumors.

Our understanding is very limited right now. Neither the Pfizer-BioNTech nor the Moderna early data discuss cancer patients. Two of the most important questions for cancer patients are dosing and booster scheduling. Potential defects in lymphocyte function among cancer patients may require unique initial dosing and booster schedules. In terms of timing, it is unclear how active therapy might affect a patient’s immune response to vaccination and whether vaccines should be timed with therapy cycles.

Vaccine access may depend on whether cancer patients are viewed as a vulnerable population. Those at higher risk for severe COVID-19 clearly have a greater need for vaccination. While there are data suggesting that cancer patients are at higher risk, they are a bit murky, in part because cancer patients are a heterogeneous group. For example, there are data suggesting that lung and blood cancer patients fare worse. There is also a suggestion that, like in the general population, COVID risk in cancer patients remains driven by comorbidities.

It is likely, then, that personalized risk factors such as type of cancer therapy, site of disease, and comorbidities will shape individual choices about vaccination among cancer patients.

A version of this article first appeared on Medscape.com.

Earlier this week, Medscape spoke with Nora Disis, MD, about vaccinating cancer patients. Disis is a medical oncologist and director of both the Institute of Translational Health Sciences and the Cancer Vaccine Institute, the University of Washington, Seattle, Washington. As editor-in-chief of JAMA Oncology, she has watched COVID-19 developments in the oncology community over the past year.

Here are a few themes that Disis said oncologists should be aware of as vaccines eventually begin reaching cancer patients.

We should expect cancer patients to respond to vaccines. Historically, some believed that cancer patients would be unable to mount an immune response to vaccines. Data on other viral vaccines have shown otherwise. For example, there has been a long history of studies of flu vaccination in cancer patients, and in general, those vaccines confer protection. Likewise for pneumococcal vaccine, which, generally speaking, cancer patients should receive.

Special cases may include hematologic malignancies in which the immune system has been destroyed and profound immunosuppression occurs. Data on immunization during this immunosuppressed period are scarce, but what data are available suggest that once cancer patients are through this immunosuppressed period, they can be vaccinated successfully.

The type of vaccine will probably be important for cancer patients. Currently, there are 61 coronavirus vaccines in human clinical trials, and 17 have reached the final stages of testing. At least 85 preclinical vaccines are under active investigation in animals.

Both the Pfizer-BioNTech and Moderna COVID vaccines are mRNA type. There are many other types, including protein-based vaccines, viral vector vaccines based on adenoviruses, and inactivated or attenuated coronavirus vaccines.

The latter vaccines, particularly attenuated live virus vaccines, may not be a good choice for cancer patients. Especially in those with rapidly progressing disease or on chemotherapy, attenuated live viruses may cause a low-grade infection.

Incidentally, the technology used in the genetic, or mRNA, vaccines developed by both Pfizer-BioNTech and Moderna was initially developed for fighting cancer, and studies have shown that patients can generate immune responses to cancer-associated proteins with this type of vaccine.

These genetic vaccines could turn out to be the most effective for cancer patients, especially those with solid tumors.

Our understanding is very limited right now. Neither the Pfizer-BioNTech nor the Moderna early data discuss cancer patients. Two of the most important questions for cancer patients are dosing and booster scheduling. Potential defects in lymphocyte function among cancer patients may require unique initial dosing and booster schedules. In terms of timing, it is unclear how active therapy might affect a patient’s immune response to vaccination and whether vaccines should be timed with therapy cycles.

Vaccine access may depend on whether cancer patients are viewed as a vulnerable population. Those at higher risk for severe COVID-19 clearly have a greater need for vaccination. While there are data suggesting that cancer patients are at higher risk, they are a bit murky, in part because cancer patients are a heterogeneous group. For example, there are data suggesting that lung and blood cancer patients fare worse. There is also a suggestion that, like in the general population, COVID risk in cancer patients remains driven by comorbidities.

It is likely, then, that personalized risk factors such as type of cancer therapy, site of disease, and comorbidities will shape individual choices about vaccination among cancer patients.

A version of this article first appeared on Medscape.com.

Rare cancers, though individually rare by definition, impose a tremendous burden on adult and pediatric patient populations, especially when considering hematological cancers. In this Rare Diseases Report: Cancers, we bring you the latest information on new and ongoing developments in the treatment of some of these cancers through interviews with frontline researchers in the field.

In this issue:

• Survey reveals special impact of COVID-19 on patients with rare disorders
• New agents boost survival – and complexity – in chronic lymphocytic leukemia
• Targeted therapies may alter the landscape of MCL treatment
• Will CAR T push beyond lymphoma? There’s no guarantee

Read Now

Rare cancers, though individually rare by definition, impose a tremendous burden on adult and pediatric patient populations, especially when considering hematological cancers. In this Rare Diseases Report: Cancers, we bring you the latest information on new and ongoing developments in the treatment of some of these cancers through interviews with frontline researchers in the field.

In this issue:

• Survey reveals special impact of COVID-19 on patients with rare disorders
• New agents boost survival – and complexity – in chronic lymphocytic leukemia
• Targeted therapies may alter the landscape of MCL treatment
• Will CAR T push beyond lymphoma? There’s no guarantee

Read Now

Rare cancers, though individually rare by definition, impose a tremendous burden on adult and pediatric patient populations, especially when considering hematological cancers. In this Rare Diseases Report: Cancers, we bring you the latest information on new and ongoing developments in the treatment of some of these cancers through interviews with frontline researchers in the field.

In this issue:

• Survey reveals special impact of COVID-19 on patients with rare disorders
• New agents boost survival – and complexity – in chronic lymphocytic leukemia
• Targeted therapies may alter the landscape of MCL treatment
• Will CAR T push beyond lymphoma? There’s no guarantee

Read Now

More than 2 decades on, adult survivors of childhood Hodgkin lymphoma report significantly more neurocognitive impairment than their siblings, but the differences may be related to risk factors in adulthood rather than to treatment in childhood, investigators say.

Among adults with a history of childhood Hodgkin lymphoma and their siblings as controls, the survivors reported significantly worse functioning than their brothers or sisters in four domains of neurocognitive functioning.

In multivariate analysis, however, while sex, race, activity level and smoking status were all significant predictors for worse neurocognitive impairment, there were no significant associations between chemotherapy drugs or chest radiation and neurocognitive impairment, said Annalynn M. Williams, PhD, from St. Jude Children’s Research Hospital in Memphis.

“Hodgkin lymphoma is the most common cancer diagnosed in adolescents, and for many years we’ve had high cure rates, resulting in a growing population of survivors who are now, unfortunately, at an increased risk for cardiovascular, respiratory, endocrine and neurologic late morbidity. The neurocognitive morbidity in this population, however, is unknown,” she said in oral abstract presented at the annual meeting of the American Society of Hematology.
 

Survivors and sibs

To better characterize the potential late neurocognitive effects of intensive Hodgkin lymphoma therapy in childhood, Dr. Williams and colleagues polled survivors of childhood Hodgkin lymphoma and randomly selected sibling controls who were participants in the Childhood Cancer Survivor Study (CCSS).

Participants were asked to complete questionnaires regarding four domains of neurocognitive impairment: task efficiency, emotional regulation, organization, and memory. The investigators defined impairment in each domain as a score lower than that of the 90th percentile of community controls from the St. Jude Lifetime Cohort.

A total of 1,564 survivors and 725 controls completed the questionnaires and were included in the study.

The median age at follow-up was slightly higher among survivors, at 37 versus 32 years. The median age at diagnosis was 14, and the median time since diagnosis was 23 years.

In all, 10.8% of survivors reported impaired task efficiency, compared with 7.7% of controls. Problems with emotional regulation were reported by 16.6% of survivors versus 11.5% of siblings, and difficulties with organization and memory were reported by 12.1% versus10.3%, and 8.1% versus 5.7%, respectively.

In a model adjusted for age, sex, and race, the relative risks for neurocognitive impairment among survivors versus siblings, were as follows: task efficiency (RR,1.37); emotional regulation (RR, 1.56); organization (RR, 1.32); memory (RR, 1.72) (all significant by confidence interval).

In a model adjusted for sex, race, smoking status, exercise, age, time since diagnosis, and treatment exposures, risk factors for neurocognitive impairment among survivors included female versus male sex (significant for emotional regulation and memory deficits); non-White versus White (significant for task efficiency); former smoker versus never (significant for all domains except organization); current smoker versus never (significant for task efficiency and emotional regulation); and meeting Centers for Disease Control and Prevention exercise criteria versus not (negatively significant for task efficiency and organization); (P < .05 for all above comparisons).

However, in a model adjusted for relapse, second malignancy, treatment exposures, age, sex, race, time since diagnosis, smoking status and physical activity, only relapse or second malignancy – surrogates for additional treatment exposures – were significantly associated with neurocognitive impairment, and then only in the domain of task efficiency.

Chronic conditions significantly associated with risk for impairment included cardiovascular disease (significant across all domains), respiratory comorbidities (significant for task efficiency), endocrine disorders (significant for task efficiency), and neurologic disorders (significant in all domains except organization).

“While these analyses give us a sense of the presence of neurocognitive impairment in a large sample of Hodgkin lymphoma survivors from across the U.S., these analyses are limited by the self-reported nature of the data,” Dr. Williams acknowledged.

“Because survivors self-report impairments, these likely represent overt, symptomatic neurocognitive impairments. Many more survivors may experience more subtle neurocognitive impairments, and additional research with objective measures of both chronic health conditions and neurocognitive functioning are warranted,” she added.
 

Smoking gun?

In the question-and-answer session following the presentation, session comoderator Pallawi Torka, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., who was not involved in the research, commented that the finding regarding a link between current and former smoking as risk factors for neurocognitive impairment was “intriguing.”

“Do you think that smoking is a cause or an effect of having that impairment in childhood survivors of Hodgkin lymphoma?” she asked.

“That’s a great question, and actually one we have spent a great deal of time discussing, and we’re still trying to tease that apart. We’re still not really sure where that association is coming from,” Dr. Williams replied.

She noted that, in a different sample of CCSS participants from whom biospecimens were collected, the investigators plan to see whether smoking drives inflammation and oxidative stress mechanisms that may be contributing to neurocognitive impairment, or whether smoking is a coping mechanism related to anxiety and depression, which have also been seen in survivors.

Kara Kelly, MD, a pediatric oncologist at Roswell Park, commented that some survivors report symptoms of cognitive dysfunction shortly after treatment, and asked whether there might be a relationship to Hodgkin-specific factors such as B symptoms, in which cytokine-mediated inflammation may play a role.

Dr. Williams said that, “unfortunately, in CCSS these survivors had to be at least 5 years from diagnosis, but in many cases were recruited years after their diagnosis and treatment, so we don’t have data on B symptoms.”

The CCSS is funded by the National Cancer Institute. Dr. Williams, Dr. Palawi, and Dr. Kelly all reported no relevant conflicts of interest to disclose.

SOURCE: Williams AM et al. ASH 2020, Abstract 370.

More than 2 decades on, adult survivors of childhood Hodgkin lymphoma report significantly more neurocognitive impairment than their siblings, but the differences may be related to risk factors in adulthood rather than to treatment in childhood, investigators say.

Among adults with a history of childhood Hodgkin lymphoma and their siblings as controls, the survivors reported significantly worse functioning than their brothers or sisters in four domains of neurocognitive functioning.

In multivariate analysis, however, while sex, race, activity level and smoking status were all significant predictors for worse neurocognitive impairment, there were no significant associations between chemotherapy drugs or chest radiation and neurocognitive impairment, said Annalynn M. Williams, PhD, from St. Jude Children’s Research Hospital in Memphis.

“Hodgkin lymphoma is the most common cancer diagnosed in adolescents, and for many years we’ve had high cure rates, resulting in a growing population of survivors who are now, unfortunately, at an increased risk for cardiovascular, respiratory, endocrine and neurologic late morbidity. The neurocognitive morbidity in this population, however, is unknown,” she said in oral abstract presented at the annual meeting of the American Society of Hematology.
 

Survivors and sibs

To better characterize the potential late neurocognitive effects of intensive Hodgkin lymphoma therapy in childhood, Dr. Williams and colleagues polled survivors of childhood Hodgkin lymphoma and randomly selected sibling controls who were participants in the Childhood Cancer Survivor Study (CCSS).

Participants were asked to complete questionnaires regarding four domains of neurocognitive impairment: task efficiency, emotional regulation, organization, and memory. The investigators defined impairment in each domain as a score lower than that of the 90th percentile of community controls from the St. Jude Lifetime Cohort.

A total of 1,564 survivors and 725 controls completed the questionnaires and were included in the study.

The median age at follow-up was slightly higher among survivors, at 37 versus 32 years. The median age at diagnosis was 14, and the median time since diagnosis was 23 years.

In all, 10.8% of survivors reported impaired task efficiency, compared with 7.7% of controls. Problems with emotional regulation were reported by 16.6% of survivors versus 11.5% of siblings, and difficulties with organization and memory were reported by 12.1% versus10.3%, and 8.1% versus 5.7%, respectively.

In a model adjusted for age, sex, and race, the relative risks for neurocognitive impairment among survivors versus siblings, were as follows: task efficiency (RR,1.37); emotional regulation (RR, 1.56); organization (RR, 1.32); memory (RR, 1.72) (all significant by confidence interval).

In a model adjusted for sex, race, smoking status, exercise, age, time since diagnosis, and treatment exposures, risk factors for neurocognitive impairment among survivors included female versus male sex (significant for emotional regulation and memory deficits); non-White versus White (significant for task efficiency); former smoker versus never (significant for all domains except organization); current smoker versus never (significant for task efficiency and emotional regulation); and meeting Centers for Disease Control and Prevention exercise criteria versus not (negatively significant for task efficiency and organization); (P < .05 for all above comparisons).

However, in a model adjusted for relapse, second malignancy, treatment exposures, age, sex, race, time since diagnosis, smoking status and physical activity, only relapse or second malignancy – surrogates for additional treatment exposures – were significantly associated with neurocognitive impairment, and then only in the domain of task efficiency.

Chronic conditions significantly associated with risk for impairment included cardiovascular disease (significant across all domains), respiratory comorbidities (significant for task efficiency), endocrine disorders (significant for task efficiency), and neurologic disorders (significant in all domains except organization).

“While these analyses give us a sense of the presence of neurocognitive impairment in a large sample of Hodgkin lymphoma survivors from across the U.S., these analyses are limited by the self-reported nature of the data,” Dr. Williams acknowledged.

“Because survivors self-report impairments, these likely represent overt, symptomatic neurocognitive impairments. Many more survivors may experience more subtle neurocognitive impairments, and additional research with objective measures of both chronic health conditions and neurocognitive functioning are warranted,” she added.
 

Smoking gun?

In the question-and-answer session following the presentation, session comoderator Pallawi Torka, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., who was not involved in the research, commented that the finding regarding a link between current and former smoking as risk factors for neurocognitive impairment was “intriguing.”

“Do you think that smoking is a cause or an effect of having that impairment in childhood survivors of Hodgkin lymphoma?” she asked.

“That’s a great question, and actually one we have spent a great deal of time discussing, and we’re still trying to tease that apart. We’re still not really sure where that association is coming from,” Dr. Williams replied.

She noted that, in a different sample of CCSS participants from whom biospecimens were collected, the investigators plan to see whether smoking drives inflammation and oxidative stress mechanisms that may be contributing to neurocognitive impairment, or whether smoking is a coping mechanism related to anxiety and depression, which have also been seen in survivors.

Kara Kelly, MD, a pediatric oncologist at Roswell Park, commented that some survivors report symptoms of cognitive dysfunction shortly after treatment, and asked whether there might be a relationship to Hodgkin-specific factors such as B symptoms, in which cytokine-mediated inflammation may play a role.

Dr. Williams said that, “unfortunately, in CCSS these survivors had to be at least 5 years from diagnosis, but in many cases were recruited years after their diagnosis and treatment, so we don’t have data on B symptoms.”

The CCSS is funded by the National Cancer Institute. Dr. Williams, Dr. Palawi, and Dr. Kelly all reported no relevant conflicts of interest to disclose.

SOURCE: Williams AM et al. ASH 2020, Abstract 370.

More than 2 decades on, adult survivors of childhood Hodgkin lymphoma report significantly more neurocognitive impairment than their siblings, but the differences may be related to risk factors in adulthood rather than to treatment in childhood, investigators say.

Among adults with a history of childhood Hodgkin lymphoma and their siblings as controls, the survivors reported significantly worse functioning than their brothers or sisters in four domains of neurocognitive functioning.

In multivariate analysis, however, while sex, race, activity level and smoking status were all significant predictors for worse neurocognitive impairment, there were no significant associations between chemotherapy drugs or chest radiation and neurocognitive impairment, said Annalynn M. Williams, PhD, from St. Jude Children’s Research Hospital in Memphis.

“Hodgkin lymphoma is the most common cancer diagnosed in adolescents, and for many years we’ve had high cure rates, resulting in a growing population of survivors who are now, unfortunately, at an increased risk for cardiovascular, respiratory, endocrine and neurologic late morbidity. The neurocognitive morbidity in this population, however, is unknown,” she said in oral abstract presented at the annual meeting of the American Society of Hematology.
 

Survivors and sibs

To better characterize the potential late neurocognitive effects of intensive Hodgkin lymphoma therapy in childhood, Dr. Williams and colleagues polled survivors of childhood Hodgkin lymphoma and randomly selected sibling controls who were participants in the Childhood Cancer Survivor Study (CCSS).

Participants were asked to complete questionnaires regarding four domains of neurocognitive impairment: task efficiency, emotional regulation, organization, and memory. The investigators defined impairment in each domain as a score lower than that of the 90th percentile of community controls from the St. Jude Lifetime Cohort.

A total of 1,564 survivors and 725 controls completed the questionnaires and were included in the study.

The median age at follow-up was slightly higher among survivors, at 37 versus 32 years. The median age at diagnosis was 14, and the median time since diagnosis was 23 years.

In all, 10.8% of survivors reported impaired task efficiency, compared with 7.7% of controls. Problems with emotional regulation were reported by 16.6% of survivors versus 11.5% of siblings, and difficulties with organization and memory were reported by 12.1% versus10.3%, and 8.1% versus 5.7%, respectively.

In a model adjusted for age, sex, and race, the relative risks for neurocognitive impairment among survivors versus siblings, were as follows: task efficiency (RR,1.37); emotional regulation (RR, 1.56); organization (RR, 1.32); memory (RR, 1.72) (all significant by confidence interval).

In a model adjusted for sex, race, smoking status, exercise, age, time since diagnosis, and treatment exposures, risk factors for neurocognitive impairment among survivors included female versus male sex (significant for emotional regulation and memory deficits); non-White versus White (significant for task efficiency); former smoker versus never (significant for all domains except organization); current smoker versus never (significant for task efficiency and emotional regulation); and meeting Centers for Disease Control and Prevention exercise criteria versus not (negatively significant for task efficiency and organization); (P < .05 for all above comparisons).

However, in a model adjusted for relapse, second malignancy, treatment exposures, age, sex, race, time since diagnosis, smoking status and physical activity, only relapse or second malignancy – surrogates for additional treatment exposures – were significantly associated with neurocognitive impairment, and then only in the domain of task efficiency.

Chronic conditions significantly associated with risk for impairment included cardiovascular disease (significant across all domains), respiratory comorbidities (significant for task efficiency), endocrine disorders (significant for task efficiency), and neurologic disorders (significant in all domains except organization).

“While these analyses give us a sense of the presence of neurocognitive impairment in a large sample of Hodgkin lymphoma survivors from across the U.S., these analyses are limited by the self-reported nature of the data,” Dr. Williams acknowledged.

“Because survivors self-report impairments, these likely represent overt, symptomatic neurocognitive impairments. Many more survivors may experience more subtle neurocognitive impairments, and additional research with objective measures of both chronic health conditions and neurocognitive functioning are warranted,” she added.
 

Smoking gun?

In the question-and-answer session following the presentation, session comoderator Pallawi Torka, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., who was not involved in the research, commented that the finding regarding a link between current and former smoking as risk factors for neurocognitive impairment was “intriguing.”

“Do you think that smoking is a cause or an effect of having that impairment in childhood survivors of Hodgkin lymphoma?” she asked.

“That’s a great question, and actually one we have spent a great deal of time discussing, and we’re still trying to tease that apart. We’re still not really sure where that association is coming from,” Dr. Williams replied.

She noted that, in a different sample of CCSS participants from whom biospecimens were collected, the investigators plan to see whether smoking drives inflammation and oxidative stress mechanisms that may be contributing to neurocognitive impairment, or whether smoking is a coping mechanism related to anxiety and depression, which have also been seen in survivors.

Kara Kelly, MD, a pediatric oncologist at Roswell Park, commented that some survivors report symptoms of cognitive dysfunction shortly after treatment, and asked whether there might be a relationship to Hodgkin-specific factors such as B symptoms, in which cytokine-mediated inflammation may play a role.

Dr. Williams said that, “unfortunately, in CCSS these survivors had to be at least 5 years from diagnosis, but in many cases were recruited years after their diagnosis and treatment, so we don’t have data on B symptoms.”

The CCSS is funded by the National Cancer Institute. Dr. Williams, Dr. Palawi, and Dr. Kelly all reported no relevant conflicts of interest to disclose.

SOURCE: Williams AM et al. ASH 2020, Abstract 370.

The Food and Drug Administration has approved setmelanotide (Imcivree, Rhythm Pharmaceuticals) for weight management in adults and children as young as 6 years with obesity because of proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing.

Individuals with these rare genetic causes of severe obesity have a normal weight at birth but develop persistent severe obesity within months because of insatiable hunger (hyperphagia). 

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved therapy for these disorders.

“Many patients and families who live with these diseases face an often-burdensome stigma associated with severe obesity. To manage this obesity and control disruptive food-seeking behavior, caregivers often lock cabinets and refrigerators and significantly limit social activities,” said Jennifer Miller, MD, a pediatric endocrinologist at University of Florida Health, Gainesville, in a press release issued by the company.

“This FDA approval marks an important turning point, providing a much needed therapy and supporting the use of genetic testing to identify and properly diagnose patients with these rare genetic diseases of obesity,” she noted.

David Meeker, MD, chair, president, and CEO of Rhythm Pharmaceuticals, added: “We are advancing a first-in-class, precision medicine that is designed to directly address the underlying cause of obesities driven by genetic deficits in the MC4R pathway.”

Setmelanotide was evaluated in two phase 3 clinical trials. In one trial, 80% of patients with obesity caused by POMC or PCSK1 deficiency achieved greater than 10% weight loss after 1 year of treatment.

In the other trial, 45.5% of patients with obesity caused by LEPR deficiency achieved greater than 10% weight loss with 1 year of treatment.

Results for the two trials were recently published in The Lancet Diabetes & Endocrinology and discussed at the ObesityWeek Interactive 2020 meeting.

Setmelanotide was generally well tolerated in both trials. The most common adverse events were injection-site reactions, skin hyperpigmentation, and nausea.

The drug label notes that disturbances in sexual arousal, depression, and suicidal ideation; skin pigmentation; and darkening of preexisting nevi may occur with setmelanotide treatment.

The drug label also notes a risk for serious adverse reactions because of benzyl alcohol preservative in neonates and low-birth-weight infants. Setmelanotide is not approved for use in neonates or infants.

The company expects the drug to be commercially available in the United States in the first quarter of 2021.

Setmelanotide for the treatment of obesity associated with rare genetic defects had FDA breakthrough therapy designation as well as orphan drug designation.

The company is also evaluating setmelanotide for reduction in hunger and body weight in a pivotal phase 3 trial in people living with Bardet-Biedl or Alström syndrome, and top-line data are due soon.

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration has approved setmelanotide (Imcivree, Rhythm Pharmaceuticals) for weight management in adults and children as young as 6 years with obesity because of proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing.

Individuals with these rare genetic causes of severe obesity have a normal weight at birth but develop persistent severe obesity within months because of insatiable hunger (hyperphagia). 

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved therapy for these disorders.

“Many patients and families who live with these diseases face an often-burdensome stigma associated with severe obesity. To manage this obesity and control disruptive food-seeking behavior, caregivers often lock cabinets and refrigerators and significantly limit social activities,” said Jennifer Miller, MD, a pediatric endocrinologist at University of Florida Health, Gainesville, in a press release issued by the company.

“This FDA approval marks an important turning point, providing a much needed therapy and supporting the use of genetic testing to identify and properly diagnose patients with these rare genetic diseases of obesity,” she noted.

David Meeker, MD, chair, president, and CEO of Rhythm Pharmaceuticals, added: “We are advancing a first-in-class, precision medicine that is designed to directly address the underlying cause of obesities driven by genetic deficits in the MC4R pathway.”

Setmelanotide was evaluated in two phase 3 clinical trials. In one trial, 80% of patients with obesity caused by POMC or PCSK1 deficiency achieved greater than 10% weight loss after 1 year of treatment.

In the other trial, 45.5% of patients with obesity caused by LEPR deficiency achieved greater than 10% weight loss with 1 year of treatment.

Results for the two trials were recently published in The Lancet Diabetes & Endocrinology and discussed at the ObesityWeek Interactive 2020 meeting.

Setmelanotide was generally well tolerated in both trials. The most common adverse events were injection-site reactions, skin hyperpigmentation, and nausea.

The drug label notes that disturbances in sexual arousal, depression, and suicidal ideation; skin pigmentation; and darkening of preexisting nevi may occur with setmelanotide treatment.

The drug label also notes a risk for serious adverse reactions because of benzyl alcohol preservative in neonates and low-birth-weight infants. Setmelanotide is not approved for use in neonates or infants.

The company expects the drug to be commercially available in the United States in the first quarter of 2021.

Setmelanotide for the treatment of obesity associated with rare genetic defects had FDA breakthrough therapy designation as well as orphan drug designation.

The company is also evaluating setmelanotide for reduction in hunger and body weight in a pivotal phase 3 trial in people living with Bardet-Biedl or Alström syndrome, and top-line data are due soon.

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration has approved setmelanotide (Imcivree, Rhythm Pharmaceuticals) for weight management in adults and children as young as 6 years with obesity because of proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing.

Individuals with these rare genetic causes of severe obesity have a normal weight at birth but develop persistent severe obesity within months because of insatiable hunger (hyperphagia). 

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved therapy for these disorders.

“Many patients and families who live with these diseases face an often-burdensome stigma associated with severe obesity. To manage this obesity and control disruptive food-seeking behavior, caregivers often lock cabinets and refrigerators and significantly limit social activities,” said Jennifer Miller, MD, a pediatric endocrinologist at University of Florida Health, Gainesville, in a press release issued by the company.

“This FDA approval marks an important turning point, providing a much needed therapy and supporting the use of genetic testing to identify and properly diagnose patients with these rare genetic diseases of obesity,” she noted.

David Meeker, MD, chair, president, and CEO of Rhythm Pharmaceuticals, added: “We are advancing a first-in-class, precision medicine that is designed to directly address the underlying cause of obesities driven by genetic deficits in the MC4R pathway.”

Setmelanotide was evaluated in two phase 3 clinical trials. In one trial, 80% of patients with obesity caused by POMC or PCSK1 deficiency achieved greater than 10% weight loss after 1 year of treatment.

In the other trial, 45.5% of patients with obesity caused by LEPR deficiency achieved greater than 10% weight loss with 1 year of treatment.

Results for the two trials were recently published in The Lancet Diabetes & Endocrinology and discussed at the ObesityWeek Interactive 2020 meeting.

Setmelanotide was generally well tolerated in both trials. The most common adverse events were injection-site reactions, skin hyperpigmentation, and nausea.

The drug label notes that disturbances in sexual arousal, depression, and suicidal ideation; skin pigmentation; and darkening of preexisting nevi may occur with setmelanotide treatment.

The drug label also notes a risk for serious adverse reactions because of benzyl alcohol preservative in neonates and low-birth-weight infants. Setmelanotide is not approved for use in neonates or infants.

The company expects the drug to be commercially available in the United States in the first quarter of 2021.

Setmelanotide for the treatment of obesity associated with rare genetic defects had FDA breakthrough therapy designation as well as orphan drug designation.

The company is also evaluating setmelanotide for reduction in hunger and body weight in a pivotal phase 3 trial in people living with Bardet-Biedl or Alström syndrome, and top-line data are due soon.

A version of this article originally appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Traditional delivery of palliative care to outpatients with cancer is associated with many challenges.

Telehealth can eliminate some of these challenges but comes with issues of its own, according to results of the REACH PC trial.

Jennifer S. Temel, MD, of Massachusetts General Hospital in Boston, discussed the use of telemedicine in palliative care, including results from REACH PC, during an educational session at the ASCO Virtual Quality Care Symposium 2020.

Dr. Temel noted that, for cancer patients, an in-person visit with a palliative care specialist can cost time, induce fatigue, and increase financial burden from transportation and parking expenses.

For caregivers and family, an in-person visit may necessitate absence from family and/or work, require complex scheduling to coordinate with other office visits, and result in additional transportation and/or parking expenses.

For health care systems, to have a dedicated palliative care clinic requires precious space and financial expenditures for office personnel and other resources.

These issues make it attractive to consider whether telehealth could be used for palliative care services.
 

Scarcity of palliative care specialists

In the United States, there is roughly 1 palliative care physician for every 20,000 older adults with a life-limiting illness, according to research published in Annual Review of Public Health in 2014.

In its 2019 state-by-state report card, the Center to Advance Palliative Care noted that only 72% of U.S. hospitals with 50 or more beds have a palliative care team.

For patients with serious illnesses and those who are socioeconomically or geographically disadvantaged, palliative care is often inaccessible.

Inefficiencies in the current system are an additional impediment. Palliative care specialists frequently see patients during a portion of the patient’s routine visit to subspecialty or primary care clinics. This limits the palliative care specialist’s ability to perform comprehensive assessments and provide patient-centered care efficiently.
 

Special considerations regarding telehealth for palliative care

As a specialty, palliative care involves interactions that could make the use of telehealth problematic. For example, conveyance of interest, warmth, and touch are challenging or impossible in a video format.

Palliative care specialists engage with patients regarding relatively serious topics such as prognosis and end-of-life preferences. There is uncertainty about how those discussions would be received by patients and their caregivers via video.

Furthermore, there are logistical impediments such as prescribing opioids with video or across state lines.

Despite these concerns, the ENABLE study showed that supplementing usual oncology care with weekly (transitioning to monthly) telephone-based educational palliative care produced higher quality of life and mood than did usual oncology care alone. These results were published in JAMA in 2009.
 

REACH PC study demonstrates feasibility of telehealth model

Dr. Temel described the ongoing REACH PC trial in which palliative care is delivered via video visits and compared with in-person palliative care for patients with advanced non–small cell lung cancer.

The primary aim of REACH PC is to determine whether telehealth palliative care is equivalent to traditional palliative care in improving quality of life as a supplement to routine oncology care.

Currently, REACH PC has enrolled 581 patients at its 20 sites, spanning a geographically diverse area. Just over half of patients approached about REACH PC agreed to enroll in it. Ultimately, 1,250 enrollees are sought.

Among patients who declined to participate, 7.6% indicated “discomfort with technology” as the reason. Most refusals were due to lack of interest in research (35.1%) and/or palliative care (22.9%).

Older adults were prominent among enrollees. More than 60% were older than 60 years of age, and more than one-third were older than 70 years.

Among patients who began the trial, there were slightly more withdrawals in the telehealth participants, in comparison with in-person participants (13.6% versus 9.1%).

When palliative care clinicians were queried about video visits, 64.3% said there were no challenges. This is comparable to the 65.5% of clinicians who had no challenges with in-person visits.

When problems occurred with video visits, they were most frequently technical (19.1%). Only 1.4% of clinicians reported difficulty addressing topics that felt uncomfortable over video, and 1.5% reported difficulty establishing rapport.

The success rates of video and in-person visits were similar. About 80% of visits accomplished planned goals.
 

‘Webside’ manner

Strategies such as reflective listening and summarizing what patients say (to verify an accurate understanding of the patient’s perspective) are key to successful palliative care visits, regardless of the setting.

For telehealth visits, Dr. Temel described techniques she defined as “webside manner,” to compensate for the inability of the clinician to touch a patient. These techniques include leaning in toward the camera, nodding, and pausing to be certain the patient has finished speaking before the clinician speaks again.
 

Is telehealth the future of palliative care?

I include myself among those oncologists who have voiced concern about moving from face-to-face to remote visits for complicated consultations such as those required for palliative care. Nonetheless, from the preliminary results of the REACH PC trial, it appears that telehealth could be a valuable tool.

To minimize differences between in-person and remote delivery of palliative care, practical strategies for ensuring rapport and facilitating a trusting relationship should be defined further and disseminated.

In addition, we need to be vigilant for widening inequities of care from rapid movement to the use of technology (i.e., an equity gap). In their telehealth experience during the COVID-19 pandemic, investigators at Houston Methodist Cancer Center found that patients declining virtual visits tended to be older, lower-income, and less likely to have commercial insurance. These results were recently published in JCO Oncology Practice.

For the foregoing reasons, hybrid systems for palliative care services will probably always be needed.

Going forward, we should heed the advice of Alvin Toffler in his book Future Shock. Mr. Toffler said, “The illiterate of the 21st century will not be those who cannot read and write, but those who cannot learn, unlearn, and relearn.”

The traditional model for delivering palliative care will almost certainly need to be reimagined and relearned.

Dr. Temel disclosed institutional research funding from Pfizer.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Traditional delivery of palliative care to outpatients with cancer is associated with many challenges.

Telehealth can eliminate some of these challenges but comes with issues of its own, according to results of the REACH PC trial.

Jennifer S. Temel, MD, of Massachusetts General Hospital in Boston, discussed the use of telemedicine in palliative care, including results from REACH PC, during an educational session at the ASCO Virtual Quality Care Symposium 2020.

Dr. Temel noted that, for cancer patients, an in-person visit with a palliative care specialist can cost time, induce fatigue, and increase financial burden from transportation and parking expenses.

For caregivers and family, an in-person visit may necessitate absence from family and/or work, require complex scheduling to coordinate with other office visits, and result in additional transportation and/or parking expenses.

For health care systems, to have a dedicated palliative care clinic requires precious space and financial expenditures for office personnel and other resources.

These issues make it attractive to consider whether telehealth could be used for palliative care services.
 

Scarcity of palliative care specialists

In the United States, there is roughly 1 palliative care physician for every 20,000 older adults with a life-limiting illness, according to research published in Annual Review of Public Health in 2014.

In its 2019 state-by-state report card, the Center to Advance Palliative Care noted that only 72% of U.S. hospitals with 50 or more beds have a palliative care team.

For patients with serious illnesses and those who are socioeconomically or geographically disadvantaged, palliative care is often inaccessible.

Inefficiencies in the current system are an additional impediment. Palliative care specialists frequently see patients during a portion of the patient’s routine visit to subspecialty or primary care clinics. This limits the palliative care specialist’s ability to perform comprehensive assessments and provide patient-centered care efficiently.
 

Special considerations regarding telehealth for palliative care

As a specialty, palliative care involves interactions that could make the use of telehealth problematic. For example, conveyance of interest, warmth, and touch are challenging or impossible in a video format.

Palliative care specialists engage with patients regarding relatively serious topics such as prognosis and end-of-life preferences. There is uncertainty about how those discussions would be received by patients and their caregivers via video.

Furthermore, there are logistical impediments such as prescribing opioids with video or across state lines.

Despite these concerns, the ENABLE study showed that supplementing usual oncology care with weekly (transitioning to monthly) telephone-based educational palliative care produced higher quality of life and mood than did usual oncology care alone. These results were published in JAMA in 2009.
 

REACH PC study demonstrates feasibility of telehealth model

Dr. Temel described the ongoing REACH PC trial in which palliative care is delivered via video visits and compared with in-person palliative care for patients with advanced non–small cell lung cancer.

The primary aim of REACH PC is to determine whether telehealth palliative care is equivalent to traditional palliative care in improving quality of life as a supplement to routine oncology care.

Currently, REACH PC has enrolled 581 patients at its 20 sites, spanning a geographically diverse area. Just over half of patients approached about REACH PC agreed to enroll in it. Ultimately, 1,250 enrollees are sought.

Among patients who declined to participate, 7.6% indicated “discomfort with technology” as the reason. Most refusals were due to lack of interest in research (35.1%) and/or palliative care (22.9%).

Older adults were prominent among enrollees. More than 60% were older than 60 years of age, and more than one-third were older than 70 years.

Among patients who began the trial, there were slightly more withdrawals in the telehealth participants, in comparison with in-person participants (13.6% versus 9.1%).

When palliative care clinicians were queried about video visits, 64.3% said there were no challenges. This is comparable to the 65.5% of clinicians who had no challenges with in-person visits.

When problems occurred with video visits, they were most frequently technical (19.1%). Only 1.4% of clinicians reported difficulty addressing topics that felt uncomfortable over video, and 1.5% reported difficulty establishing rapport.

The success rates of video and in-person visits were similar. About 80% of visits accomplished planned goals.
 

‘Webside’ manner

Strategies such as reflective listening and summarizing what patients say (to verify an accurate understanding of the patient’s perspective) are key to successful palliative care visits, regardless of the setting.

For telehealth visits, Dr. Temel described techniques she defined as “webside manner,” to compensate for the inability of the clinician to touch a patient. These techniques include leaning in toward the camera, nodding, and pausing to be certain the patient has finished speaking before the clinician speaks again.
 

Is telehealth the future of palliative care?

I include myself among those oncologists who have voiced concern about moving from face-to-face to remote visits for complicated consultations such as those required for palliative care. Nonetheless, from the preliminary results of the REACH PC trial, it appears that telehealth could be a valuable tool.

To minimize differences between in-person and remote delivery of palliative care, practical strategies for ensuring rapport and facilitating a trusting relationship should be defined further and disseminated.

In addition, we need to be vigilant for widening inequities of care from rapid movement to the use of technology (i.e., an equity gap). In their telehealth experience during the COVID-19 pandemic, investigators at Houston Methodist Cancer Center found that patients declining virtual visits tended to be older, lower-income, and less likely to have commercial insurance. These results were recently published in JCO Oncology Practice.

For the foregoing reasons, hybrid systems for palliative care services will probably always be needed.

Going forward, we should heed the advice of Alvin Toffler in his book Future Shock. Mr. Toffler said, “The illiterate of the 21st century will not be those who cannot read and write, but those who cannot learn, unlearn, and relearn.”

The traditional model for delivering palliative care will almost certainly need to be reimagined and relearned.

Dr. Temel disclosed institutional research funding from Pfizer.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Traditional delivery of palliative care to outpatients with cancer is associated with many challenges.

Telehealth can eliminate some of these challenges but comes with issues of its own, according to results of the REACH PC trial.

Jennifer S. Temel, MD, of Massachusetts General Hospital in Boston, discussed the use of telemedicine in palliative care, including results from REACH PC, during an educational session at the ASCO Virtual Quality Care Symposium 2020.

Dr. Temel noted that, for cancer patients, an in-person visit with a palliative care specialist can cost time, induce fatigue, and increase financial burden from transportation and parking expenses.

For caregivers and family, an in-person visit may necessitate absence from family and/or work, require complex scheduling to coordinate with other office visits, and result in additional transportation and/or parking expenses.

For health care systems, to have a dedicated palliative care clinic requires precious space and financial expenditures for office personnel and other resources.

These issues make it attractive to consider whether telehealth could be used for palliative care services.
 

Scarcity of palliative care specialists

In the United States, there is roughly 1 palliative care physician for every 20,000 older adults with a life-limiting illness, according to research published in Annual Review of Public Health in 2014.

In its 2019 state-by-state report card, the Center to Advance Palliative Care noted that only 72% of U.S. hospitals with 50 or more beds have a palliative care team.

For patients with serious illnesses and those who are socioeconomically or geographically disadvantaged, palliative care is often inaccessible.

Inefficiencies in the current system are an additional impediment. Palliative care specialists frequently see patients during a portion of the patient’s routine visit to subspecialty or primary care clinics. This limits the palliative care specialist’s ability to perform comprehensive assessments and provide patient-centered care efficiently.
 

Special considerations regarding telehealth for palliative care

As a specialty, palliative care involves interactions that could make the use of telehealth problematic. For example, conveyance of interest, warmth, and touch are challenging or impossible in a video format.

Palliative care specialists engage with patients regarding relatively serious topics such as prognosis and end-of-life preferences. There is uncertainty about how those discussions would be received by patients and their caregivers via video.

Furthermore, there are logistical impediments such as prescribing opioids with video or across state lines.

Despite these concerns, the ENABLE study showed that supplementing usual oncology care with weekly (transitioning to monthly) telephone-based educational palliative care produced higher quality of life and mood than did usual oncology care alone. These results were published in JAMA in 2009.
 

REACH PC study demonstrates feasibility of telehealth model

Dr. Temel described the ongoing REACH PC trial in which palliative care is delivered via video visits and compared with in-person palliative care for patients with advanced non–small cell lung cancer.

The primary aim of REACH PC is to determine whether telehealth palliative care is equivalent to traditional palliative care in improving quality of life as a supplement to routine oncology care.

Currently, REACH PC has enrolled 581 patients at its 20 sites, spanning a geographically diverse area. Just over half of patients approached about REACH PC agreed to enroll in it. Ultimately, 1,250 enrollees are sought.

Among patients who declined to participate, 7.6% indicated “discomfort with technology” as the reason. Most refusals were due to lack of interest in research (35.1%) and/or palliative care (22.9%).

Older adults were prominent among enrollees. More than 60% were older than 60 years of age, and more than one-third were older than 70 years.

Among patients who began the trial, there were slightly more withdrawals in the telehealth participants, in comparison with in-person participants (13.6% versus 9.1%).

When palliative care clinicians were queried about video visits, 64.3% said there were no challenges. This is comparable to the 65.5% of clinicians who had no challenges with in-person visits.

When problems occurred with video visits, they were most frequently technical (19.1%). Only 1.4% of clinicians reported difficulty addressing topics that felt uncomfortable over video, and 1.5% reported difficulty establishing rapport.

The success rates of video and in-person visits were similar. About 80% of visits accomplished planned goals.
 

‘Webside’ manner

Strategies such as reflective listening and summarizing what patients say (to verify an accurate understanding of the patient’s perspective) are key to successful palliative care visits, regardless of the setting.

For telehealth visits, Dr. Temel described techniques she defined as “webside manner,” to compensate for the inability of the clinician to touch a patient. These techniques include leaning in toward the camera, nodding, and pausing to be certain the patient has finished speaking before the clinician speaks again.
 

Is telehealth the future of palliative care?

I include myself among those oncologists who have voiced concern about moving from face-to-face to remote visits for complicated consultations such as those required for palliative care. Nonetheless, from the preliminary results of the REACH PC trial, it appears that telehealth could be a valuable tool.

To minimize differences between in-person and remote delivery of palliative care, practical strategies for ensuring rapport and facilitating a trusting relationship should be defined further and disseminated.

In addition, we need to be vigilant for widening inequities of care from rapid movement to the use of technology (i.e., an equity gap). In their telehealth experience during the COVID-19 pandemic, investigators at Houston Methodist Cancer Center found that patients declining virtual visits tended to be older, lower-income, and less likely to have commercial insurance. These results were recently published in JCO Oncology Practice.

For the foregoing reasons, hybrid systems for palliative care services will probably always be needed.

Going forward, we should heed the advice of Alvin Toffler in his book Future Shock. Mr. Toffler said, “The illiterate of the 21st century will not be those who cannot read and write, but those who cannot learn, unlearn, and relearn.”

The traditional model for delivering palliative care will almost certainly need to be reimagined and relearned.

Dr. Temel disclosed institutional research funding from Pfizer.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients with primary biliary cholangitis experienced rapid improvements in itch and quality of life after treatment with linerixibat in a randomized, placebo-controlled trial of the safety, efficacy, and tolerability of the small-molecule drug.

Moderate to severe pruritus “affects patients’ quality of life and is a huge burden for them,” said investigator Cynthia Levy, MD, from the University of Miami Health System.

“Finally having a medication that controls those symptoms is really important,” she said in an interview.

With a twice-daily mid-range dose of the drug for 12 weeks, patients with moderate to severe itch reported significantly less itch and better social and emotional quality of life, Dr. Levy reported at the Liver Meeting, where she presented findings from the phase 2 GLIMMER trial.

After a single-blind 4-week placebo run-in period for patients with itch scores of at least 4 on a 10-point rating scale, those with itch scores of at least 3 were then randomly assigned to one of five treatment regimens – once-daily linerixibat at doses of 20 mg, 90 mg, or 180 mg, or twice-daily doses of 40 mg or 90 mg – or to placebo.

After 12 weeks of treatment, all 147 participants once again received placebo for 4 weeks.

During the trial, participants recorded itch levels twice daily. The worst of these daily scores was averaged every 7 days to determine the mean worst daily itch.

The primary study endpoint was the change in worst daily itch from baseline after 12 weeks of treatment. Participants whose self-rated itch improved by 2 points on the 10-point scale were considered to have had a response to the drug.

Participants also completed the PBC-40, an instrument to measure quality of life in patients with primary biliary cholangitis, answering questions about itch and social and emotional status.

Reductions in worst daily itch from baseline to 12 weeks were steepest in the 40-mg twice-daily group, at 2.86 points, and in the 90-mg twice-daily group, at 2.25 points. In the placebo group, the mean decrease was 1.73 points.

During the subsequent 4 weeks of placebo, after treatment ended, the itch relief faded in all groups.

Scores on the PBC-40 itch domain improved significantly in every group, including placebo. However, only those in the twice-daily 40-mg group saw significant improvements on the social (P = .0016) and emotional (P = .0025) domains.
 

‘Between incremental and revolutionary’

The results are on a “kind of continuum between incremental and revolutionary,” said Jonathan A. Dranoff, MD, from the University of Arkansas for Medical Sciences, Little Rock, who was not involved in the study. “It doesn’t hit either extreme, but it’s the first new drug for this purpose in forever, which by itself is a good thing.”

The placebo effect suggests that “maybe the actual contribution of the noncognitive brain to pruritus is bigger than we thought, and that’s worth noting,” he added. Nevertheless, “the drug still appears to have effects that are statistically different from placebo.”

The placebo effect in itching studies is always high but tends to wane over time, said Dr. Levy. This trial had a 4-week placebo run-in period to allow that effect to fade somewhat, she explained.

About 10% of the study cohort experienced drug-related diarrhea, which was expected, and about 10% dropped out of the trial because of drug-related adverse events.

Linerixibat is an ileal sodium-dependent bile acid transporter inhibitor, so the gut has to deal with the excess bile acid fallout, but the diarrhea is likely manageable with antidiarrheals, said Dr. Levy.

It is unlikely that diarrhea will deter patients with severe itch from using an effective drug when other drugs have failed them. “These patients are consumed by itch most of the time,” said Dr. Dranoff. “I think for people who don’t regularly treat patients with primary biliary cholangitis, it’s one of the underappreciated aspects of the disease.”

The improvements in social and emotional quality of life seen with linerixibat are not only statistically significant, they are also clinically significant, said Dr. Levy. “We are really expecting this to impact the lives of our patients and are looking forward to phase 3.”

Dr. Levy disclosed support from GlaxoSmithKline. Dr. Dranoff disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Capillary malformation-arteriovenous malformation syndrome

Capillary Malformation-arteriovenous malformation syndrome (CM-AVM) is a rare vascular disorder characterized by the presence of capillary malformations with or without arteriovenous malformations, as well as arteriovenous fistulas (AVFs). CM-AVM is an autosomal dominant disorder.¹ CM-AVM type 1 is caused by mutations in the RASA1 gene, and CM-AVM type 2 is caused by mutations in the EPHB⁴ gene.² Approximately 70% of patients with RASA1-associated CM-AVM syndrome and 80% of patients with EPHB4-associated CM-AVM syndrome have an affected parent, while the remainder have de novo variants.¹

In patients with CM-AVM syndrome, CMs are often present at birth and more are typically acquired over time. CMs are characteristically 1-3 cm in diameter, round or oval, dull red or red-brown macules and patches with a blanched halo.³ Some CMs may be warm to touch indicating a possible underlying AVM or AVF.⁴ This can be confirmed by Doppler ultrasound, which would demonstrate increased arterial flow.⁴ CMs are most commonly located on the face and limbs and may present in isolation, but approximately one-third of patients have associated AVMs and AVFs.^1,5 These high-flow vascular malformations may be present in skin, muscle, bone, brain, and/or spine and may be asymptomatic or lead to serious sequelae, including bleeding, congestive heart failure, and neurologic complications, such as migraine headaches, seizures, or even stroke.⁵ Symptoms from intracranial and spinal high-flow lesions usually present in early childhood and affect approximately 7% of patients.³

The diagnosis of CM-AVM should be suspected in an individual with numerous characteristic CMs and may be supported by the presence of AVMs and AVFs, family history of CM-AVM, and/or identification of RASA1 or EPHB4 mutation by molecular genetic testing.^1,3 Although there are no consensus protocols for imaging CM-AVM patients, MRI of the brain and spine is recommended at diagnosis to identify underlying high-flow lesions.¹ This may allow for early treatment before the development of symptoms.¹ Any lesions identified on screening imaging may require regular surveillance, which is best determined by discussion with the radiologist.¹ Although there are no reports of patients with negative results on screening imaging who later develop AVMs or AVFs, there should be a low threshold for repeat imaging in patients who develop new symptoms or physical exam findings.^3,4

It has previously been suggested that the CMs in CM-AVM may actually represent early or small AVMs and pulsed-dye laser (PDL) treatment was not recommended because of concern for potential progression of lesions.⁴ However, a recent study demonstrated good response to PDL in patients with CM-AVM with no evidence of worsening or recurrence of lesions with long-term follow-up.⁶ Treatment of CMs that cause cosmetic concerns may be considered following discussion of risks and benefits with a dermatologist. Management of AVMs and AVFs requires a multidisciplinary team that, depending on location and symptoms of these features, may require the expertise of specialists such as neurosurgery, surgery, orthopedics, cardiology, and/or interventional radiology.¹

Given the suspicion for CM-AVM in our patient, further workup was completed. A skin biopsy was consistent with CM. Genetic testing with the Vascular Malformations Panel, Sequencing and Deletion/Duplication revealed a pathogenic variant in the RASA1 gene and a variant of unknown clinical significance in the TEK gene. Parental genetic testing for the RASA1 mutation was negative, supporting a de novo mutation in the patient. CNS imaging showed a small developmental venous malformation in the brain that neurosurgery did not think was clinically significant. At the most recent follow-up at age 8 years, our patient had developed a few new small CMs but was otherwise well.

Dr. Leszczynska is trained in pediatrics and is the current dermatology research fellow at the University of Texas at Austin. Ms. Croce is a dermatology-trained pediatric nurse practitioner and PhD student at the University of Texas at Austin School of Nursing. Dr. Diaz is chief of pediatric dermatology at Dell Children’s Medical Center, Austin, assistant professor of pediatrics and medicine (dermatology), and dermatology residency associate program director at University of Texas at Austin . The authors have no relevant conflicts of interest to disclose. Donna Bilu Martin, MD, is the editor of this column.


References

1. Bayrak-Toydemir P, Stevenson D. Capillary Malformation-Arteriovenous Malformation Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle: University of Washington, Seattle; February 22, 2011.

2.Yu J et al. Pediatr Dermatol. 2017 Sep;34(5):e227-30.

3. Orme CM et al. Pediatr Dermatol. 2013 Jul-Aug;30(4):409-15.

4. Weitz NA et al. Pediatr Dermatol. 2015 Jan-Feb;32(1):76-84.

5. Revencu N et al. Hum Mutat. 2013 Dec;34(12):1632-41.

6. Iznardo H et al. Pediatr Dermatol. 2020 Mar;37(2):342-44.
 

Capillary malformation-arteriovenous malformation syndrome

Capillary Malformation-arteriovenous malformation syndrome (CM-AVM) is a rare vascular disorder characterized by the presence of capillary malformations with or without arteriovenous malformations, as well as arteriovenous fistulas (AVFs). CM-AVM is an autosomal dominant disorder.¹ CM-AVM type 1 is caused by mutations in the RASA1 gene, and CM-AVM type 2 is caused by mutations in the EPHB⁴ gene.² Approximately 70% of patients with RASA1-associated CM-AVM syndrome and 80% of patients with EPHB4-associated CM-AVM syndrome have an affected parent, while the remainder have de novo variants.¹

In patients with CM-AVM syndrome, CMs are often present at birth and more are typically acquired over time. CMs are characteristically 1-3 cm in diameter, round or oval, dull red or red-brown macules and patches with a blanched halo.³ Some CMs may be warm to touch indicating a possible underlying AVM or AVF.⁴ This can be confirmed by Doppler ultrasound, which would demonstrate increased arterial flow.⁴ CMs are most commonly located on the face and limbs and may present in isolation, but approximately one-third of patients have associated AVMs and AVFs.^1,5 These high-flow vascular malformations may be present in skin, muscle, bone, brain, and/or spine and may be asymptomatic or lead to serious sequelae, including bleeding, congestive heart failure, and neurologic complications, such as migraine headaches, seizures, or even stroke.⁵ Symptoms from intracranial and spinal high-flow lesions usually present in early childhood and affect approximately 7% of patients.³

The diagnosis of CM-AVM should be suspected in an individual with numerous characteristic CMs and may be supported by the presence of AVMs and AVFs, family history of CM-AVM, and/or identification of RASA1 or EPHB4 mutation by molecular genetic testing.^1,3 Although there are no consensus protocols for imaging CM-AVM patients, MRI of the brain and spine is recommended at diagnosis to identify underlying high-flow lesions.¹ This may allow for early treatment before the development of symptoms.¹ Any lesions identified on screening imaging may require regular surveillance, which is best determined by discussion with the radiologist.¹ Although there are no reports of patients with negative results on screening imaging who later develop AVMs or AVFs, there should be a low threshold for repeat imaging in patients who develop new symptoms or physical exam findings.^3,4

It has previously been suggested that the CMs in CM-AVM may actually represent early or small AVMs and pulsed-dye laser (PDL) treatment was not recommended because of concern for potential progression of lesions.⁴ However, a recent study demonstrated good response to PDL in patients with CM-AVM with no evidence of worsening or recurrence of lesions with long-term follow-up.⁶ Treatment of CMs that cause cosmetic concerns may be considered following discussion of risks and benefits with a dermatologist. Management of AVMs and AVFs requires a multidisciplinary team that, depending on location and symptoms of these features, may require the expertise of specialists such as neurosurgery, surgery, orthopedics, cardiology, and/or interventional radiology.¹

Given the suspicion for CM-AVM in our patient, further workup was completed. A skin biopsy was consistent with CM. Genetic testing with the Vascular Malformations Panel, Sequencing and Deletion/Duplication revealed a pathogenic variant in the RASA1 gene and a variant of unknown clinical significance in the TEK gene. Parental genetic testing for the RASA1 mutation was negative, supporting a de novo mutation in the patient. CNS imaging showed a small developmental venous malformation in the brain that neurosurgery did not think was clinically significant. At the most recent follow-up at age 8 years, our patient had developed a few new small CMs but was otherwise well.

Dr. Leszczynska is trained in pediatrics and is the current dermatology research fellow at the University of Texas at Austin. Ms. Croce is a dermatology-trained pediatric nurse practitioner and PhD student at the University of Texas at Austin School of Nursing. Dr. Diaz is chief of pediatric dermatology at Dell Children’s Medical Center, Austin, assistant professor of pediatrics and medicine (dermatology), and dermatology residency associate program director at University of Texas at Austin . The authors have no relevant conflicts of interest to disclose. Donna Bilu Martin, MD, is the editor of this column.


References

1. Bayrak-Toydemir P, Stevenson D. Capillary Malformation-Arteriovenous Malformation Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle: University of Washington, Seattle; February 22, 2011.

2.Yu J et al. Pediatr Dermatol. 2017 Sep;34(5):e227-30.

3. Orme CM et al. Pediatr Dermatol. 2013 Jul-Aug;30(4):409-15.

4. Weitz NA et al. Pediatr Dermatol. 2015 Jan-Feb;32(1):76-84.

5. Revencu N et al. Hum Mutat. 2013 Dec;34(12):1632-41.

6. Iznardo H et al. Pediatr Dermatol. 2020 Mar;37(2):342-44.
 

Capillary malformation-arteriovenous malformation syndrome

Capillary Malformation-arteriovenous malformation syndrome (CM-AVM) is a rare vascular disorder characterized by the presence of capillary malformations with or without arteriovenous malformations, as well as arteriovenous fistulas (AVFs). CM-AVM is an autosomal dominant disorder.¹ CM-AVM type 1 is caused by mutations in the RASA1 gene, and CM-AVM type 2 is caused by mutations in the EPHB⁴ gene.² Approximately 70% of patients with RASA1-associated CM-AVM syndrome and 80% of patients with EPHB4-associated CM-AVM syndrome have an affected parent, while the remainder have de novo variants.¹

In patients with CM-AVM syndrome, CMs are often present at birth and more are typically acquired over time. CMs are characteristically 1-3 cm in diameter, round or oval, dull red or red-brown macules and patches with a blanched halo.³ Some CMs may be warm to touch indicating a possible underlying AVM or AVF.⁴ This can be confirmed by Doppler ultrasound, which would demonstrate increased arterial flow.⁴ CMs are most commonly located on the face and limbs and may present in isolation, but approximately one-third of patients have associated AVMs and AVFs.^1,5 These high-flow vascular malformations may be present in skin, muscle, bone, brain, and/or spine and may be asymptomatic or lead to serious sequelae, including bleeding, congestive heart failure, and neurologic complications, such as migraine headaches, seizures, or even stroke.⁵ Symptoms from intracranial and spinal high-flow lesions usually present in early childhood and affect approximately 7% of patients.³

The diagnosis of CM-AVM should be suspected in an individual with numerous characteristic CMs and may be supported by the presence of AVMs and AVFs, family history of CM-AVM, and/or identification of RASA1 or EPHB4 mutation by molecular genetic testing.^1,3 Although there are no consensus protocols for imaging CM-AVM patients, MRI of the brain and spine is recommended at diagnosis to identify underlying high-flow lesions.¹ This may allow for early treatment before the development of symptoms.¹ Any lesions identified on screening imaging may require regular surveillance, which is best determined by discussion with the radiologist.¹ Although there are no reports of patients with negative results on screening imaging who later develop AVMs or AVFs, there should be a low threshold for repeat imaging in patients who develop new symptoms or physical exam findings.^3,4

It has previously been suggested that the CMs in CM-AVM may actually represent early or small AVMs and pulsed-dye laser (PDL) treatment was not recommended because of concern for potential progression of lesions.⁴ However, a recent study demonstrated good response to PDL in patients with CM-AVM with no evidence of worsening or recurrence of lesions with long-term follow-up.⁶ Treatment of CMs that cause cosmetic concerns may be considered following discussion of risks and benefits with a dermatologist. Management of AVMs and AVFs requires a multidisciplinary team that, depending on location and symptoms of these features, may require the expertise of specialists such as neurosurgery, surgery, orthopedics, cardiology, and/or interventional radiology.¹

Given the suspicion for CM-AVM in our patient, further workup was completed. A skin biopsy was consistent with CM. Genetic testing with the Vascular Malformations Panel, Sequencing and Deletion/Duplication revealed a pathogenic variant in the RASA1 gene and a variant of unknown clinical significance in the TEK gene. Parental genetic testing for the RASA1 mutation was negative, supporting a de novo mutation in the patient. CNS imaging showed a small developmental venous malformation in the brain that neurosurgery did not think was clinically significant. At the most recent follow-up at age 8 years, our patient had developed a few new small CMs but was otherwise well.

Dr. Leszczynska is trained in pediatrics and is the current dermatology research fellow at the University of Texas at Austin. Ms. Croce is a dermatology-trained pediatric nurse practitioner and PhD student at the University of Texas at Austin School of Nursing. Dr. Diaz is chief of pediatric dermatology at Dell Children’s Medical Center, Austin, assistant professor of pediatrics and medicine (dermatology), and dermatology residency associate program director at University of Texas at Austin . The authors have no relevant conflicts of interest to disclose. Donna Bilu Martin, MD, is the editor of this column.


References

1. Bayrak-Toydemir P, Stevenson D. Capillary Malformation-Arteriovenous Malformation Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle: University of Washington, Seattle; February 22, 2011.

2.Yu J et al. Pediatr Dermatol. 2017 Sep;34(5):e227-30.

3. Orme CM et al. Pediatr Dermatol. 2013 Jul-Aug;30(4):409-15.

4. Weitz NA et al. Pediatr Dermatol. 2015 Jan-Feb;32(1):76-84.

5. Revencu N et al. Hum Mutat. 2013 Dec;34(12):1632-41.

6. Iznardo H et al. Pediatr Dermatol. 2020 Mar;37(2):342-44.
 

Survivors of Kawasaki disease remain at a higher long-term risk for cardiovascular events into young adulthood, including myocardial infarction, compared to people without the disease, new evidence reveals. The elevated risks emerged in survivors both with and without cardiovascular involvement at the time of initial diagnosis.

Overall risk of cardiovascular events was highest in the first year following Kawasaki disease diagnosis, and about 10 times greater than in healthy children, Cal Robinson, MD, said during a press conference at the virtual annual meeting of the American College of Rheumatology.

“The risk gradually decreased over time. However, even 10 years after diagnosis of their illness, they still had a 39% higher risk,” said study author Dr. Robinson, a PGY4 pediatric nephrology fellow at The Hospital for Sick Children in Toronto.

Dr. Robinson also put the numbers in perspective. “We fully acknowledged these are very rare events in children, especially healthy children, which is why we needed such a large cohort to study this. Interpret the numbers cautiously.”

In terms of patient and family counseling, “I would say children with Kawasaki disease have a higher risk of myocardial infarction, but the absolute risk is still low,” he added. For example, 16 Kawasaki disease survivors experienced a heart attack during follow-up, or 0.4% of the affected study population, compared to a rate of 0.1% among matched controls.

“These families are often very frightened after the initial Kawasaki disease diagnosis,” Dr. Robinson said. “We have to balance some discussion with what we know about Kawasaki disease without overly scaring or terrifying these families, who are already anxious.”

To quantify the incidence and timing of cardiovascular events and cardiac disease following diagnosis, Dr. Robinson and colleagues assessed large databases representing approximately 3 million children. They focused on children hospitalized with a Kawasaki disease diagnosis between 1995 and 2018. These children had a median length of stay of 3 days and 2.5% were admitted to critical care. The investigators matched his population 1:100 to unaffected children in Ontario.

Follow-up was up to 24 years (median, 11 years) in this retrospective, population-based cohort study.

Risks raised over a decade and beyond

Compared to matched controls, Kawasaki disease survivors had a higher risk for a cardiac event in the first year following diagnosis (adjusted hazard ratio, 11.65; 95% confidence interval, 10.34-13.13). The 1- to 5-year risk was lower (aHR, 3.35), a trend that continued between 5 and 10 years (aHR, 1.87) and as well as after more than 10 years (aHR, 1.39).

The risk of major adverse cardiac events (MACE, a composite of myocardial infarction, stroke, or cardiovascular death) was likewise highest in the first year after diagnosis (aHR, 3.27), followed by a 51% greater risk at 1-5 years, a 113% increased risk at 5-10 years, and a 17% elevated risk after 10 years.

The investigators compared the 144 Kawasaki disease survivors who experienced a coronary artery aneurysm (CAA) within 90 days of hospital admission to the 4,453 others who did not have a CAA. The risk for a composite cardiovascular event was elevated at each time point among those with a history of CAA, especially in the first year. The adjusted HR was 33.12 in the CAA group versus 10.44 in the non-CAA group.

“The most interesting finding of this study was that children with Kawasaki syndrome are at higher risk for composite cardiovascular events and major adverse cardiac events even if they were not diagnosed with coronary artery aneurysm,” session comoderator Shervin Assassi, MD, professor of medicine and director of division of rheumatology at the University of Texas Health Science Center at Houston, said when asked to comment.

Dr. Robinson and colleagues also looked at outcomes based on presence or absence of coronary involvement at the time of Kawasaki disease diagnosis. For example, among those with initial coronary involvement, 15% later experienced a cardiovascular event and 10% experienced a major cardiovascular event.

“However, we were specifically interested in looking at children without initial coronary involvement. In this group, we also found these children were at increased risk for cardiovascular events compared to children without Kawasaki disease,” Dr. Robinson said. He said the distinction is important because approximately 95% of children diagnosed with Kawasaki disease do not feature initial coronary involvement.

In terms of clinical care, “our data provides an early signal that Kawasaki disease survivors – including those without initial coronary involvement – may be at higher risk of cardiovascular events into early adulthood.”
 

A call for closer monitoring

“Based on our results, we find that Kawasaki disease survivors may benefit from additional follow-up and surveillance for cardiovascular disease risk factors, such as obesity, high blood pressure, and high cholesterol,” Dr. Robinson said. Early identification of heightened risk could allow physicians to more closely monitor this subgroup and emphasize potentially beneficial lifestyle modifications, including increasing physical activity, implementing a heart healthy diet, and avoiding smoking.

Mortality was not significantly different between groups. “Despite the risk of cardiac events we found, death was uncommon,” Dr. Robinson said. Among children with Kawasaki disease, 1 in 500 died during follow-up, so “the risk of death was actually lower than for children without Kawasaki disease.”

Similar findings of lower mortality have been reported in research out of Japan, he added during a plenary presentation at ACR 2020. Future research is warranted to evaluate this finding further, Dr. Robinson said.
 

Future plans

Going forward, the investigators plan to evaluate noncardiovascular outcomes in this patient population. They would also like to examine health care utilization following a diagnosis of Kawasaki disease “to better understand what kind of follow-up is happening now in Ontario,” Dr. Robinson said.

Another unanswered question is whether the cardiovascular events observed in the study stem from atherosclerotic disease or a different mechanism among survivors of Kawasaki disease.

The research was supported by a McMaster University Resident Research Grant, a Hamilton Health Sciences New Investigator Award, and Ontario’s Institute for Clinical Evaluative Sciences. Dr. Robinson had no relevant financial disclosures.

SOURCE: Robinson C et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0937.

Survivors of Kawasaki disease remain at a higher long-term risk for cardiovascular events into young adulthood, including myocardial infarction, compared to people without the disease, new evidence reveals. The elevated risks emerged in survivors both with and without cardiovascular involvement at the time of initial diagnosis.

Overall risk of cardiovascular events was highest in the first year following Kawasaki disease diagnosis, and about 10 times greater than in healthy children, Cal Robinson, MD, said during a press conference at the virtual annual meeting of the American College of Rheumatology.

“The risk gradually decreased over time. However, even 10 years after diagnosis of their illness, they still had a 39% higher risk,” said study author Dr. Robinson, a PGY4 pediatric nephrology fellow at The Hospital for Sick Children in Toronto.

Dr. Robinson also put the numbers in perspective. “We fully acknowledged these are very rare events in children, especially healthy children, which is why we needed such a large cohort to study this. Interpret the numbers cautiously.”

In terms of patient and family counseling, “I would say children with Kawasaki disease have a higher risk of myocardial infarction, but the absolute risk is still low,” he added. For example, 16 Kawasaki disease survivors experienced a heart attack during follow-up, or 0.4% of the affected study population, compared to a rate of 0.1% among matched controls.

“These families are often very frightened after the initial Kawasaki disease diagnosis,” Dr. Robinson said. “We have to balance some discussion with what we know about Kawasaki disease without overly scaring or terrifying these families, who are already anxious.”

To quantify the incidence and timing of cardiovascular events and cardiac disease following diagnosis, Dr. Robinson and colleagues assessed large databases representing approximately 3 million children. They focused on children hospitalized with a Kawasaki disease diagnosis between 1995 and 2018. These children had a median length of stay of 3 days and 2.5% were admitted to critical care. The investigators matched his population 1:100 to unaffected children in Ontario.

Follow-up was up to 24 years (median, 11 years) in this retrospective, population-based cohort study.

Risks raised over a decade and beyond

Compared to matched controls, Kawasaki disease survivors had a higher risk for a cardiac event in the first year following diagnosis (adjusted hazard ratio, 11.65; 95% confidence interval, 10.34-13.13). The 1- to 5-year risk was lower (aHR, 3.35), a trend that continued between 5 and 10 years (aHR, 1.87) and as well as after more than 10 years (aHR, 1.39).

The risk of major adverse cardiac events (MACE, a composite of myocardial infarction, stroke, or cardiovascular death) was likewise highest in the first year after diagnosis (aHR, 3.27), followed by a 51% greater risk at 1-5 years, a 113% increased risk at 5-10 years, and a 17% elevated risk after 10 years.

The investigators compared the 144 Kawasaki disease survivors who experienced a coronary artery aneurysm (CAA) within 90 days of hospital admission to the 4,453 others who did not have a CAA. The risk for a composite cardiovascular event was elevated at each time point among those with a history of CAA, especially in the first year. The adjusted HR was 33.12 in the CAA group versus 10.44 in the non-CAA group.

“The most interesting finding of this study was that children with Kawasaki syndrome are at higher risk for composite cardiovascular events and major adverse cardiac events even if they were not diagnosed with coronary artery aneurysm,” session comoderator Shervin Assassi, MD, professor of medicine and director of division of rheumatology at the University of Texas Health Science Center at Houston, said when asked to comment.

Dr. Robinson and colleagues also looked at outcomes based on presence or absence of coronary involvement at the time of Kawasaki disease diagnosis. For example, among those with initial coronary involvement, 15% later experienced a cardiovascular event and 10% experienced a major cardiovascular event.

“However, we were specifically interested in looking at children without initial coronary involvement. In this group, we also found these children were at increased risk for cardiovascular events compared to children without Kawasaki disease,” Dr. Robinson said. He said the distinction is important because approximately 95% of children diagnosed with Kawasaki disease do not feature initial coronary involvement.

In terms of clinical care, “our data provides an early signal that Kawasaki disease survivors – including those without initial coronary involvement – may be at higher risk of cardiovascular events into early adulthood.”
 

A call for closer monitoring

“Based on our results, we find that Kawasaki disease survivors may benefit from additional follow-up and surveillance for cardiovascular disease risk factors, such as obesity, high blood pressure, and high cholesterol,” Dr. Robinson said. Early identification of heightened risk could allow physicians to more closely monitor this subgroup and emphasize potentially beneficial lifestyle modifications, including increasing physical activity, implementing a heart healthy diet, and avoiding smoking.

Mortality was not significantly different between groups. “Despite the risk of cardiac events we found, death was uncommon,” Dr. Robinson said. Among children with Kawasaki disease, 1 in 500 died during follow-up, so “the risk of death was actually lower than for children without Kawasaki disease.”

Similar findings of lower mortality have been reported in research out of Japan, he added during a plenary presentation at ACR 2020. Future research is warranted to evaluate this finding further, Dr. Robinson said.
 

Future plans

Going forward, the investigators plan to evaluate noncardiovascular outcomes in this patient population. They would also like to examine health care utilization following a diagnosis of Kawasaki disease “to better understand what kind of follow-up is happening now in Ontario,” Dr. Robinson said.

Another unanswered question is whether the cardiovascular events observed in the study stem from atherosclerotic disease or a different mechanism among survivors of Kawasaki disease.

The research was supported by a McMaster University Resident Research Grant, a Hamilton Health Sciences New Investigator Award, and Ontario’s Institute for Clinical Evaluative Sciences. Dr. Robinson had no relevant financial disclosures.

SOURCE: Robinson C et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0937.

Survivors of Kawasaki disease remain at a higher long-term risk for cardiovascular events into young adulthood, including myocardial infarction, compared to people without the disease, new evidence reveals. The elevated risks emerged in survivors both with and without cardiovascular involvement at the time of initial diagnosis.

Overall risk of cardiovascular events was highest in the first year following Kawasaki disease diagnosis, and about 10 times greater than in healthy children, Cal Robinson, MD, said during a press conference at the virtual annual meeting of the American College of Rheumatology.

“The risk gradually decreased over time. However, even 10 years after diagnosis of their illness, they still had a 39% higher risk,” said study author Dr. Robinson, a PGY4 pediatric nephrology fellow at The Hospital for Sick Children in Toronto.

Dr. Robinson also put the numbers in perspective. “We fully acknowledged these are very rare events in children, especially healthy children, which is why we needed such a large cohort to study this. Interpret the numbers cautiously.”

In terms of patient and family counseling, “I would say children with Kawasaki disease have a higher risk of myocardial infarction, but the absolute risk is still low,” he added. For example, 16 Kawasaki disease survivors experienced a heart attack during follow-up, or 0.4% of the affected study population, compared to a rate of 0.1% among matched controls.

“These families are often very frightened after the initial Kawasaki disease diagnosis,” Dr. Robinson said. “We have to balance some discussion with what we know about Kawasaki disease without overly scaring or terrifying these families, who are already anxious.”

To quantify the incidence and timing of cardiovascular events and cardiac disease following diagnosis, Dr. Robinson and colleagues assessed large databases representing approximately 3 million children. They focused on children hospitalized with a Kawasaki disease diagnosis between 1995 and 2018. These children had a median length of stay of 3 days and 2.5% were admitted to critical care. The investigators matched his population 1:100 to unaffected children in Ontario.

Follow-up was up to 24 years (median, 11 years) in this retrospective, population-based cohort study.

Risks raised over a decade and beyond

Compared to matched controls, Kawasaki disease survivors had a higher risk for a cardiac event in the first year following diagnosis (adjusted hazard ratio, 11.65; 95% confidence interval, 10.34-13.13). The 1- to 5-year risk was lower (aHR, 3.35), a trend that continued between 5 and 10 years (aHR, 1.87) and as well as after more than 10 years (aHR, 1.39).

The risk of major adverse cardiac events (MACE, a composite of myocardial infarction, stroke, or cardiovascular death) was likewise highest in the first year after diagnosis (aHR, 3.27), followed by a 51% greater risk at 1-5 years, a 113% increased risk at 5-10 years, and a 17% elevated risk after 10 years.

The investigators compared the 144 Kawasaki disease survivors who experienced a coronary artery aneurysm (CAA) within 90 days of hospital admission to the 4,453 others who did not have a CAA. The risk for a composite cardiovascular event was elevated at each time point among those with a history of CAA, especially in the first year. The adjusted HR was 33.12 in the CAA group versus 10.44 in the non-CAA group.

“The most interesting finding of this study was that children with Kawasaki syndrome are at higher risk for composite cardiovascular events and major adverse cardiac events even if they were not diagnosed with coronary artery aneurysm,” session comoderator Shervin Assassi, MD, professor of medicine and director of division of rheumatology at the University of Texas Health Science Center at Houston, said when asked to comment.

Dr. Robinson and colleagues also looked at outcomes based on presence or absence of coronary involvement at the time of Kawasaki disease diagnosis. For example, among those with initial coronary involvement, 15% later experienced a cardiovascular event and 10% experienced a major cardiovascular event.

“However, we were specifically interested in looking at children without initial coronary involvement. In this group, we also found these children were at increased risk for cardiovascular events compared to children without Kawasaki disease,” Dr. Robinson said. He said the distinction is important because approximately 95% of children diagnosed with Kawasaki disease do not feature initial coronary involvement.

In terms of clinical care, “our data provides an early signal that Kawasaki disease survivors – including those without initial coronary involvement – may be at higher risk of cardiovascular events into early adulthood.”
 

A call for closer monitoring

“Based on our results, we find that Kawasaki disease survivors may benefit from additional follow-up and surveillance for cardiovascular disease risk factors, such as obesity, high blood pressure, and high cholesterol,” Dr. Robinson said. Early identification of heightened risk could allow physicians to more closely monitor this subgroup and emphasize potentially beneficial lifestyle modifications, including increasing physical activity, implementing a heart healthy diet, and avoiding smoking.

Mortality was not significantly different between groups. “Despite the risk of cardiac events we found, death was uncommon,” Dr. Robinson said. Among children with Kawasaki disease, 1 in 500 died during follow-up, so “the risk of death was actually lower than for children without Kawasaki disease.”

Similar findings of lower mortality have been reported in research out of Japan, he added during a plenary presentation at ACR 2020. Future research is warranted to evaluate this finding further, Dr. Robinson said.
 

Future plans

Going forward, the investigators plan to evaluate noncardiovascular outcomes in this patient population. They would also like to examine health care utilization following a diagnosis of Kawasaki disease “to better understand what kind of follow-up is happening now in Ontario,” Dr. Robinson said.

Another unanswered question is whether the cardiovascular events observed in the study stem from atherosclerotic disease or a different mechanism among survivors of Kawasaki disease.

The research was supported by a McMaster University Resident Research Grant, a Hamilton Health Sciences New Investigator Award, and Ontario’s Institute for Clinical Evaluative Sciences. Dr. Robinson had no relevant financial disclosures.

SOURCE: Robinson C et al. Arthritis Rheumatol. 2020;72(suppl 10): Abstract 0937.

A gene-replacement therapy called AT132 significantly decreases dependence on a ventilator among children with X-linked myotubular myopathy, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.

belchonock/Thinkstock

The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.

X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
 

The ASPIRO trial

Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.

Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 10¹⁴ vg/kg of AAT132, 3 × 10¹⁴ vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.

The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
 

Treatment improved respiratory function

As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.

Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.

Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 10¹⁴ vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 10¹⁴ vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.

In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH₂O for the low-dose group, 46.1 cmH₂O for the high-dose group, and −8.0 cmH₂O for controls.

Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.

Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
 

Deaths under investigation

In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.

“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.

Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.

[email protected]

SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.

A gene-replacement therapy called AT132 significantly decreases dependence on a ventilator among children with X-linked myotubular myopathy, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.

belchonock/Thinkstock

The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.

X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
 

The ASPIRO trial

Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.

Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 10¹⁴ vg/kg of AAT132, 3 × 10¹⁴ vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.

The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
 

Treatment improved respiratory function

As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.

Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.

Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 10¹⁴ vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 10¹⁴ vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.

In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH₂O for the low-dose group, 46.1 cmH₂O for the high-dose group, and −8.0 cmH₂O for controls.

Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.

Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
 

Deaths under investigation

In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.

“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.

Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.

[email protected]

SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.

A gene-replacement therapy called AT132 significantly decreases dependence on a ventilator among children with X-linked myotubular myopathy, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.

belchonock/Thinkstock

The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.

X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
 

The ASPIRO trial

Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.

Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 10¹⁴ vg/kg of AAT132, 3 × 10¹⁴ vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.

The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
 

Treatment improved respiratory function

As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.

Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.

Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 10¹⁴ vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 10¹⁴ vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.

In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH₂O for the low-dose group, 46.1 cmH₂O for the high-dose group, and −8.0 cmH₂O for controls.

Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.

Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
 

Deaths under investigation

In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.

“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.

Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.

[email protected]

SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.