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Trends in the management of pulmonary embolism
One of the newest trends in pulmonary embolism management is treatment of cancer associated venous thromboembolism (VTE) which encompasses deep vein thrombosis (DVT) and PE. Following the clinical management of cancer-associated venous thromboembolism in the hospital, direct oral anticoagulant therapy at discharge is your starting point, except in cases of intact luminal cancers, Scott Kaatz, DO, MSc, FACP, SFHM, said during SHM Converge, the annual conference of the Society of Hospital Medicine.
Dr. Kaatz, of the division of hospital medicine at Henry Ford Hospital, Detroit, based his remarks on emerging recommendations from leading medical societies on the topic, as well as a one-page algorithm from the Anticoagulation Forum that can be accessed at https://acforum-excellence.org/Resource-Center/resource_files/1638-2020-11-30-121425.pdf.
For the short-term treatment of VTE (3-6 months) for patients with active cancer, the American Society of Hematology guideline panel suggests direct oral anticoagulants, such as apixaban, edoxaban, or rivaroxaban, over low-molecular-weight heparin (LMWH) – a conditional recommendation based on low certainty in the evidence of effects.
Dr. Kaatz also discussed the latest recommendations regarding length of VTE treatment. After completion of primary treatment for patients with DVT and/or PE provoked by a chronic risk factor such as a surgery, pregnancy, or having a leg in a cast, the ASH guideline panel suggests indefinite antithrombotic therapy over stopping anticoagulation. “On the other hand, patients with DVT and/or PE provoked by a transient factor typically do not require antithrombotic therapy after completion of primary treatment,” said Dr. Kaatz, who is also a clinical professor of medicine at Wayne State University, Detroit.
After completion of primary treatment for patients with unprovoked DVT and/or PE, the ASH guideline panel suggests indefinite antithrombotic therapy over stopping anticoagulation. “The recommendation does not apply to patients who have a high risk for bleeding complications,” he noted.
Transient or reversible risk factors should be also considered in length of VTE treatment. For example, according to guidelines from the European Society of Cardiology, the estimated risk for long-term VTE recurrence is high (defined as greater than 8% per year) for patients with active cancer, for patients with one or more previous episodes of VTE in the absence of a major transient or reversible factor, and for those with antiphospholipid antibody syndrome.
Dr. Kaatz also highlighted recommendations for the acute treatment of intermediate risk, or submassive PE. The ESC guidelines state that if anticoagulation is initiated parenterally, LMWH or fondaparinux is recommended over unfractionated heparin (UFH) for most patients. “The reason for that is, one drug-use evaluation study found that, after 24 hours using UFH, only about 24% of patients had reached their therapeutic goal,” Dr. Kaatz said. Guidelines for intermediate risk patients from ASH recommend anticoagulation as your starting point, while thrombolysis is reasonable to consider for submassive PE and low risk for bleeding in selected younger patients or for patients at high risk for decompensation because of concomitant cardiopulmonary disease. “The bleeding rates get much higher in patients over age 65,” he said.
Another resource Dr. Kaatz mentioned is the Pulmonary Embolism Response Team (PERT) Consortium, which was developed after initial efforts of a multidisciplinary team of physicians at Massachusetts General Hospital. The first PERT sought to coordinate and expedite the treatment of pulmonary embolus with a team of physicians from a variety of specialties. In 2019 the PERT Consortium published guidelines on the diagnosis, treatment, and follow-up of acute PE. “It includes detailed algorithms that are a little different from the ASH and ESC guidelines,” Dr. Kaatz said.
Dr. Kaatz disclosed that he is a consultant for Janssen, Pfizer, Portola/Alexion, Bristol-Myers Squibb, Novartis, and CSL Behring. He has also received research funding from Janssen, Bristol-Myers Squibb, and Osmosis. He also holds board positions with the AC Forum and the National Blood Clot Alliance Medical and Scientific Advisory Board.
One of the newest trends in pulmonary embolism management is treatment of cancer associated venous thromboembolism (VTE) which encompasses deep vein thrombosis (DVT) and PE. Following the clinical management of cancer-associated venous thromboembolism in the hospital, direct oral anticoagulant therapy at discharge is your starting point, except in cases of intact luminal cancers, Scott Kaatz, DO, MSc, FACP, SFHM, said during SHM Converge, the annual conference of the Society of Hospital Medicine.
Dr. Kaatz, of the division of hospital medicine at Henry Ford Hospital, Detroit, based his remarks on emerging recommendations from leading medical societies on the topic, as well as a one-page algorithm from the Anticoagulation Forum that can be accessed at https://acforum-excellence.org/Resource-Center/resource_files/1638-2020-11-30-121425.pdf.
For the short-term treatment of VTE (3-6 months) for patients with active cancer, the American Society of Hematology guideline panel suggests direct oral anticoagulants, such as apixaban, edoxaban, or rivaroxaban, over low-molecular-weight heparin (LMWH) – a conditional recommendation based on low certainty in the evidence of effects.
Dr. Kaatz also discussed the latest recommendations regarding length of VTE treatment. After completion of primary treatment for patients with DVT and/or PE provoked by a chronic risk factor such as a surgery, pregnancy, or having a leg in a cast, the ASH guideline panel suggests indefinite antithrombotic therapy over stopping anticoagulation. “On the other hand, patients with DVT and/or PE provoked by a transient factor typically do not require antithrombotic therapy after completion of primary treatment,” said Dr. Kaatz, who is also a clinical professor of medicine at Wayne State University, Detroit.
After completion of primary treatment for patients with unprovoked DVT and/or PE, the ASH guideline panel suggests indefinite antithrombotic therapy over stopping anticoagulation. “The recommendation does not apply to patients who have a high risk for bleeding complications,” he noted.
Transient or reversible risk factors should be also considered in length of VTE treatment. For example, according to guidelines from the European Society of Cardiology, the estimated risk for long-term VTE recurrence is high (defined as greater than 8% per year) for patients with active cancer, for patients with one or more previous episodes of VTE in the absence of a major transient or reversible factor, and for those with antiphospholipid antibody syndrome.
Dr. Kaatz also highlighted recommendations for the acute treatment of intermediate risk, or submassive PE. The ESC guidelines state that if anticoagulation is initiated parenterally, LMWH or fondaparinux is recommended over unfractionated heparin (UFH) for most patients. “The reason for that is, one drug-use evaluation study found that, after 24 hours using UFH, only about 24% of patients had reached their therapeutic goal,” Dr. Kaatz said. Guidelines for intermediate risk patients from ASH recommend anticoagulation as your starting point, while thrombolysis is reasonable to consider for submassive PE and low risk for bleeding in selected younger patients or for patients at high risk for decompensation because of concomitant cardiopulmonary disease. “The bleeding rates get much higher in patients over age 65,” he said.
Another resource Dr. Kaatz mentioned is the Pulmonary Embolism Response Team (PERT) Consortium, which was developed after initial efforts of a multidisciplinary team of physicians at Massachusetts General Hospital. The first PERT sought to coordinate and expedite the treatment of pulmonary embolus with a team of physicians from a variety of specialties. In 2019 the PERT Consortium published guidelines on the diagnosis, treatment, and follow-up of acute PE. “It includes detailed algorithms that are a little different from the ASH and ESC guidelines,” Dr. Kaatz said.
Dr. Kaatz disclosed that he is a consultant for Janssen, Pfizer, Portola/Alexion, Bristol-Myers Squibb, Novartis, and CSL Behring. He has also received research funding from Janssen, Bristol-Myers Squibb, and Osmosis. He also holds board positions with the AC Forum and the National Blood Clot Alliance Medical and Scientific Advisory Board.
One of the newest trends in pulmonary embolism management is treatment of cancer associated venous thromboembolism (VTE) which encompasses deep vein thrombosis (DVT) and PE. Following the clinical management of cancer-associated venous thromboembolism in the hospital, direct oral anticoagulant therapy at discharge is your starting point, except in cases of intact luminal cancers, Scott Kaatz, DO, MSc, FACP, SFHM, said during SHM Converge, the annual conference of the Society of Hospital Medicine.
Dr. Kaatz, of the division of hospital medicine at Henry Ford Hospital, Detroit, based his remarks on emerging recommendations from leading medical societies on the topic, as well as a one-page algorithm from the Anticoagulation Forum that can be accessed at https://acforum-excellence.org/Resource-Center/resource_files/1638-2020-11-30-121425.pdf.
For the short-term treatment of VTE (3-6 months) for patients with active cancer, the American Society of Hematology guideline panel suggests direct oral anticoagulants, such as apixaban, edoxaban, or rivaroxaban, over low-molecular-weight heparin (LMWH) – a conditional recommendation based on low certainty in the evidence of effects.
Dr. Kaatz also discussed the latest recommendations regarding length of VTE treatment. After completion of primary treatment for patients with DVT and/or PE provoked by a chronic risk factor such as a surgery, pregnancy, or having a leg in a cast, the ASH guideline panel suggests indefinite antithrombotic therapy over stopping anticoagulation. “On the other hand, patients with DVT and/or PE provoked by a transient factor typically do not require antithrombotic therapy after completion of primary treatment,” said Dr. Kaatz, who is also a clinical professor of medicine at Wayne State University, Detroit.
After completion of primary treatment for patients with unprovoked DVT and/or PE, the ASH guideline panel suggests indefinite antithrombotic therapy over stopping anticoagulation. “The recommendation does not apply to patients who have a high risk for bleeding complications,” he noted.
Transient or reversible risk factors should be also considered in length of VTE treatment. For example, according to guidelines from the European Society of Cardiology, the estimated risk for long-term VTE recurrence is high (defined as greater than 8% per year) for patients with active cancer, for patients with one or more previous episodes of VTE in the absence of a major transient or reversible factor, and for those with antiphospholipid antibody syndrome.
Dr. Kaatz also highlighted recommendations for the acute treatment of intermediate risk, or submassive PE. The ESC guidelines state that if anticoagulation is initiated parenterally, LMWH or fondaparinux is recommended over unfractionated heparin (UFH) for most patients. “The reason for that is, one drug-use evaluation study found that, after 24 hours using UFH, only about 24% of patients had reached their therapeutic goal,” Dr. Kaatz said. Guidelines for intermediate risk patients from ASH recommend anticoagulation as your starting point, while thrombolysis is reasonable to consider for submassive PE and low risk for bleeding in selected younger patients or for patients at high risk for decompensation because of concomitant cardiopulmonary disease. “The bleeding rates get much higher in patients over age 65,” he said.
Another resource Dr. Kaatz mentioned is the Pulmonary Embolism Response Team (PERT) Consortium, which was developed after initial efforts of a multidisciplinary team of physicians at Massachusetts General Hospital. The first PERT sought to coordinate and expedite the treatment of pulmonary embolus with a team of physicians from a variety of specialties. In 2019 the PERT Consortium published guidelines on the diagnosis, treatment, and follow-up of acute PE. “It includes detailed algorithms that are a little different from the ASH and ESC guidelines,” Dr. Kaatz said.
Dr. Kaatz disclosed that he is a consultant for Janssen, Pfizer, Portola/Alexion, Bristol-Myers Squibb, Novartis, and CSL Behring. He has also received research funding from Janssen, Bristol-Myers Squibb, and Osmosis. He also holds board positions with the AC Forum and the National Blood Clot Alliance Medical and Scientific Advisory Board.
FROM SHM CONVERGE 2021
Pediatric cancer survivors at risk for opioid misuse
Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.
Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.
Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.
“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.
“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
Database review
Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).
They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).
They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).
They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.
In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).
Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).
Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.
Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.
Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
Opioids pre- and posttreatment?
“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.
Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.
The researchers plan to investigate this question in future studies, Dr. Ji replied.
They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.
Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.
Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.
Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.
“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.
“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
Database review
Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).
They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).
They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).
They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.
In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).
Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).
Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.
Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.
Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
Opioids pre- and posttreatment?
“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.
Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.
The researchers plan to investigate this question in future studies, Dr. Ji replied.
They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.
Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.
Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.
Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.
“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.
“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
Database review
Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).
They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).
They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).
They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.
In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).
Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).
Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.
Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.
Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
Opioids pre- and posttreatment?
“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.
Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.
The researchers plan to investigate this question in future studies, Dr. Ji replied.
They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.
FROM 2021 ASPHO CONFERENCE
High variability found in studies assessing hemophilia-related pain
Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.
The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.
The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.
Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
Conflicting results
Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.
All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.
Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.
The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.
“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.
The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.
Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.
The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.
The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.
Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
Conflicting results
Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.
All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.
Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.
The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.
“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.
The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.
Chronic pain is a common condition among people with hemophilia and is associated with joint deterioration because of repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain because of hemophilia and to analyze its interference in the lives of patients, according to Ana Cristina Paredes, a PhD student at the University of Minho, Braga, Portugal, and colleagues.
The manuscripts included in the study, which was published online in the Journal of Pain, were mostly observational, cross-sectional studies and one prospective investigation, published between 2009 and 2019.
The issue of pain is particularly important among people with hemophilia, as many adult patients suffer from distinct degrees of arthropathy and associated chronic pain, due to the lifelong occurrence of hemarthrosis, the authors noted. In an important distinction, according to the authors, people with hemophilia may therefore experience both acute pain during bleeds and chronic pain caused by joint deterioration. Acute pain ceases with the resolution of the bleeding episode, but the chronic pain is significantly more challenging, since it persists in time and may trigger changes in the nervous system, leading to peripheral or central sensitization.
Data in the assessed studies were collected from a variety of sources: hemophilia centers, online surveys, by mail, or through a national database, with return rates ranging from 29.2% to 98%. Overall, these studies comprised 4,772 adults, with individual sample sizes ranging from 21 to 2,253 patients, the authors added.
Conflicting results
Overall, there was a widely varying prevalence of hemophilia-related chronic pain reported across studies. Additionally, methodologies and sample characteristics varied widely. The meta-analyses revealed high heterogeneity between studies, and, therefore, pooled prevalence estimates values must be interpreted with caution, the authors stated.
All of the 11 selected studies included for meta-analysis and review reported on the prevalence of chronic pain caused by hemophilia. Chronic pain was assessed using direct questions developed by the authors in eight studies and using the European Haemophilia Therapy Standardization Board definition in three studies. The prevalence for global samples ranged widely from 17% to 84%.
Although there was high heterogeneity, the random-effects meta-analysis including all studies demonstrated a pooled prevalence of 46% of patients reporting chronic pain. Subgroup analyses of studies including all disease severities (mild, moderate, and severe; seven studies) revealed a pooled prevalence of 48%, but also with high heterogeneity. Looking at severe patients only (six studies), the chronic pain prevalence ranged from 33% to 86.4%, with a pooled prevalence of 53% and high heterogeneity, the authors added.
The wide disparity of the chronic pain prevalence seen across the studies is likely because of the fact that some investigations inquired about pain without distinguishing between acute (hemarthrosis-related) or chronic (arthropathy-related) pain, and without clarifying if the only focus is pain caused by hemophilia, or including all causes of pain complaints, according to the researchers.
“Concerning hemophilia-related chronic pain interference, it is striking that the existing literature does not distinguish between the impact of acute or chronic pain. Such a distinction is needed and should be made in future studies to ensure accurate accounts of hemophilia-related pain and to fully understand its interference according to the type of pain (acute vs. chronic). This information is relevant to promote targeted and effective treatment approaches,” the researchers concluded.
The research was supported by a Novo Nordisk HERO Research Grant 2015, the Portuguese Foundation for Science and Technology, and the Foundation for Science and Technology in Portugal. The authors declared they had no conflicts of interest.
FROM THE JOURNAL OF PAIN
AHA guidance on blood clots linked to COVID-19 vaccine
A newly released report is offering guidance concerning rare conditions associated with COVID-19 as well as vaccines against the virus.
The report was released April 29, 2021, by the American Heart Association/American Stroke Association Stroke Council Leadership in answer to the decision April 23 by the Centers for Disease Control and Prevention and the Food and Drug Administration to lift an earlier “pause” in administration of the Johnson & Johnson (Janssen) vaccine.
That pause had been put in place after reports were received of a possible association between the J&J vaccine and cerebral venous sinus thrombosis (CVST) and thrombosis-thrombocytopenia syndrome (TTS, blood clots plus low blood platelets). CVST and TTS were also linked to patients in Europe and Canada who received the AstraZeneca COVID-19 vaccine.
However, the new report noted that these conditions are very rare.
“The risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine,” lead author Karen L. Furie, MD, chair of the department of neurology at Brown University, Providence, R.I., said in a press release.
“The public can be reassured by the CDC’s and FDA’s investigation and these statistics – the likelihood of developing CVST after a COVID-19 vaccine is extremely low,” said Dr. Furie, adding that the authors “urge all adults to receive any of the approved COVID-19 vaccines.”
The new guidance, which was published online April 29, 2021, in Stroke, discusses signs and symptoms of CVST and TTS, as well as vaccine-induced immune thrombotic thrombocytopenia (VITT). It also recommends best options for treating these conditions.
Assessing 81 million patients
In their analysis, the investigators assessed a database of 59 health care organizations and 81 million patients, 98% of whom were in the United States.
Of almost 514,000 patients diagnosed with COVID-19 between January 2020 and March 2021, 20 also received a diagnosis of CVST.
Among about 490,000 adults who received either the Pfizer or Moderna vaccines, there were no diagnosed cases of thrombocytopenia.
Dr. Furie reiterated that CVST blood clots “are very rare adverse events,” but recommended that any patient in the ED with a suspected clot should be screened immediately to determine if they received a COVID vaccine during the previous few weeks.
For those who have recently received the COVID-19 vaccine, a suspected clot should be treated with nonheparin anticoagulants, Dr. Furie said.
“No heparin products in any dose should be given for suspected CVST, TTS, or VITT. With the right treatment, most patients can have a full recovery,” she added. The report includes additional, detailed treatment recommendations if one of these conditions are suspected.
Rare events
The authors noted that cases of TTS/VITT occurred up to 2.5 weeks after receiving the J&J vaccine in the United States and up to 3.5 weeks after receiving the AstraZeneca vaccine in Europe.
An April 23 report from the CDC and FDA noted that, out of almost 7 million adults who received the J&J vaccine, the agencies investigated only 15 reported cases of TTS.
An April 7 report from the European Medicines Agency noted that, out of more than 25 million people who received the AstraZeneca vaccine in the European Union, it found 62 cases of CVST.
A statement put out by the American Heart Association/American Stroke Association urges “everyone to receive a COVID-19 vaccine” as soon as possible.
“We are confident the benefits of vaccination far exceed the very small, rare risks,” the organizations said. “The risks of vaccination are also far smaller than the risk of COVID-19 and its potentially fatal consequences.”
A version of this article first appeared on Medscape.com.
A newly released report is offering guidance concerning rare conditions associated with COVID-19 as well as vaccines against the virus.
The report was released April 29, 2021, by the American Heart Association/American Stroke Association Stroke Council Leadership in answer to the decision April 23 by the Centers for Disease Control and Prevention and the Food and Drug Administration to lift an earlier “pause” in administration of the Johnson & Johnson (Janssen) vaccine.
That pause had been put in place after reports were received of a possible association between the J&J vaccine and cerebral venous sinus thrombosis (CVST) and thrombosis-thrombocytopenia syndrome (TTS, blood clots plus low blood platelets). CVST and TTS were also linked to patients in Europe and Canada who received the AstraZeneca COVID-19 vaccine.
However, the new report noted that these conditions are very rare.
“The risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine,” lead author Karen L. Furie, MD, chair of the department of neurology at Brown University, Providence, R.I., said in a press release.
“The public can be reassured by the CDC’s and FDA’s investigation and these statistics – the likelihood of developing CVST after a COVID-19 vaccine is extremely low,” said Dr. Furie, adding that the authors “urge all adults to receive any of the approved COVID-19 vaccines.”
The new guidance, which was published online April 29, 2021, in Stroke, discusses signs and symptoms of CVST and TTS, as well as vaccine-induced immune thrombotic thrombocytopenia (VITT). It also recommends best options for treating these conditions.
Assessing 81 million patients
In their analysis, the investigators assessed a database of 59 health care organizations and 81 million patients, 98% of whom were in the United States.
Of almost 514,000 patients diagnosed with COVID-19 between January 2020 and March 2021, 20 also received a diagnosis of CVST.
Among about 490,000 adults who received either the Pfizer or Moderna vaccines, there were no diagnosed cases of thrombocytopenia.
Dr. Furie reiterated that CVST blood clots “are very rare adverse events,” but recommended that any patient in the ED with a suspected clot should be screened immediately to determine if they received a COVID vaccine during the previous few weeks.
For those who have recently received the COVID-19 vaccine, a suspected clot should be treated with nonheparin anticoagulants, Dr. Furie said.
“No heparin products in any dose should be given for suspected CVST, TTS, or VITT. With the right treatment, most patients can have a full recovery,” she added. The report includes additional, detailed treatment recommendations if one of these conditions are suspected.
Rare events
The authors noted that cases of TTS/VITT occurred up to 2.5 weeks after receiving the J&J vaccine in the United States and up to 3.5 weeks after receiving the AstraZeneca vaccine in Europe.
An April 23 report from the CDC and FDA noted that, out of almost 7 million adults who received the J&J vaccine, the agencies investigated only 15 reported cases of TTS.
An April 7 report from the European Medicines Agency noted that, out of more than 25 million people who received the AstraZeneca vaccine in the European Union, it found 62 cases of CVST.
A statement put out by the American Heart Association/American Stroke Association urges “everyone to receive a COVID-19 vaccine” as soon as possible.
“We are confident the benefits of vaccination far exceed the very small, rare risks,” the organizations said. “The risks of vaccination are also far smaller than the risk of COVID-19 and its potentially fatal consequences.”
A version of this article first appeared on Medscape.com.
A newly released report is offering guidance concerning rare conditions associated with COVID-19 as well as vaccines against the virus.
The report was released April 29, 2021, by the American Heart Association/American Stroke Association Stroke Council Leadership in answer to the decision April 23 by the Centers for Disease Control and Prevention and the Food and Drug Administration to lift an earlier “pause” in administration of the Johnson & Johnson (Janssen) vaccine.
That pause had been put in place after reports were received of a possible association between the J&J vaccine and cerebral venous sinus thrombosis (CVST) and thrombosis-thrombocytopenia syndrome (TTS, blood clots plus low blood platelets). CVST and TTS were also linked to patients in Europe and Canada who received the AstraZeneca COVID-19 vaccine.
However, the new report noted that these conditions are very rare.
“The risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine,” lead author Karen L. Furie, MD, chair of the department of neurology at Brown University, Providence, R.I., said in a press release.
“The public can be reassured by the CDC’s and FDA’s investigation and these statistics – the likelihood of developing CVST after a COVID-19 vaccine is extremely low,” said Dr. Furie, adding that the authors “urge all adults to receive any of the approved COVID-19 vaccines.”
The new guidance, which was published online April 29, 2021, in Stroke, discusses signs and symptoms of CVST and TTS, as well as vaccine-induced immune thrombotic thrombocytopenia (VITT). It also recommends best options for treating these conditions.
Assessing 81 million patients
In their analysis, the investigators assessed a database of 59 health care organizations and 81 million patients, 98% of whom were in the United States.
Of almost 514,000 patients diagnosed with COVID-19 between January 2020 and March 2021, 20 also received a diagnosis of CVST.
Among about 490,000 adults who received either the Pfizer or Moderna vaccines, there were no diagnosed cases of thrombocytopenia.
Dr. Furie reiterated that CVST blood clots “are very rare adverse events,” but recommended that any patient in the ED with a suspected clot should be screened immediately to determine if they received a COVID vaccine during the previous few weeks.
For those who have recently received the COVID-19 vaccine, a suspected clot should be treated with nonheparin anticoagulants, Dr. Furie said.
“No heparin products in any dose should be given for suspected CVST, TTS, or VITT. With the right treatment, most patients can have a full recovery,” she added. The report includes additional, detailed treatment recommendations if one of these conditions are suspected.
Rare events
The authors noted that cases of TTS/VITT occurred up to 2.5 weeks after receiving the J&J vaccine in the United States and up to 3.5 weeks after receiving the AstraZeneca vaccine in Europe.
An April 23 report from the CDC and FDA noted that, out of almost 7 million adults who received the J&J vaccine, the agencies investigated only 15 reported cases of TTS.
An April 7 report from the European Medicines Agency noted that, out of more than 25 million people who received the AstraZeneca vaccine in the European Union, it found 62 cases of CVST.
A statement put out by the American Heart Association/American Stroke Association urges “everyone to receive a COVID-19 vaccine” as soon as possible.
“We are confident the benefits of vaccination far exceed the very small, rare risks,” the organizations said. “The risks of vaccination are also far smaller than the risk of COVID-19 and its potentially fatal consequences.”
A version of this article first appeared on Medscape.com.
Commentary: Functional assessment developed for older adults with sickle cell disease
As individuals with sickle cell disease (SCD) are living longer than ever before there is a greater need to focus on maintaining and improving function and independence in this growing population. In the general population, impairments in functional measures such as usual gait speed, grip strength, Timed Up and Go, and cognition are associated with adverse health outcomes such as falls, fractures, loss of independence, and death.
Adults with SCD experience multiple complications such as avascular necrosis of the joints, retinopathy, and strokes that lead to functional limitations similar to those experienced by geriatric populations. However, functional assessments are not routinely performed during clinic visits with older adults with SCD.
In order to address this gap in care, my colleagues and I developed the first functional assessment for older adults with SCD, called the Sickle Cell Disease Functional Assessment (SCD-FA). This assessment will allow providers to evaluate the capabilities and vulnerabilities of older adults with SCD.
We assessed the feasibility of administering the SCD-FA in a prospective cohort pilot study. We enrolled 40 adults with SCD (20 older adults aged at least 50 years and 20 younger adults aged 18-49 years as a comparison group). All participants were assessed at steady-state.
For the SCD-FA, we selected geriatric assessment measures across seven domains: functional status, comorbid medical conditions, psychological state, social support, nutritional status, cognition, and medications. Several of these measures were previously validated in an oncology geriatric assessment and enriched with additional physical and cognitive measures to evaluate conditions at the intersection of SCD and geriatrics.
In September 2020, we published a protocol describing the methods and rationale for selecting measures for the SCD-FA in Pilot and Feasibility Studies.1 The preliminary data was presented at the annual meeting of the American Society of Hematology in December 2020 and was included in the annual Hematology and Aging Poster Walk.
The results of this pilot study showed that the SCD-FA is feasible (91% of participants who consented completed the SCD-FA), acceptable (95% reported the length as appropriate and had no difficulty understanding the measures), and safe with no adverse events.2 On physical performance testing, both younger and older participants had results consistent with accelerated aging with a functional age at least 20-30 years older than their chronological age.2
The majority of the participants (63%) had a usual gait speed slower than the speed required to safely cross the street at an intersection, and 25% had a gait speed slower than 1 m/s, which has been associated with increased mortality in the general population.3,4
Benefits to management
The SCD-FA can improve management of adults with SCD by:
- Characterizing their capabilities and physiological age, identifying individuals at high risk for functional decline and death early identifying targets for interventions that have been successful in geriatrics,5 assessing risk of toxicity from curative therapies, and evaluating functional response to SCD-specific therapies.
The SCD-FA provides a framework for developing exercise interventions to target functional impairments. This work supports our goal of improving the quality of life and longevity for people with SCD.
Dr. Oyedeji is a senior hematology Fellow at the department of medicine, division of hematology, Duke University, Durham, N.C. She reported that she has no conflicts of interest.
References
1. Pilot Feasibility Stud. 2020;6:131.
2. Blood. 2020;136(Supplement 1):26-7.
3. J Rehabil Res Dev. 2005;42(4):535-46.
4. JAMA. 2011;305(1):50-8.
5. South Med J. 1994;87(5):S83-7.
As individuals with sickle cell disease (SCD) are living longer than ever before there is a greater need to focus on maintaining and improving function and independence in this growing population. In the general population, impairments in functional measures such as usual gait speed, grip strength, Timed Up and Go, and cognition are associated with adverse health outcomes such as falls, fractures, loss of independence, and death.
Adults with SCD experience multiple complications such as avascular necrosis of the joints, retinopathy, and strokes that lead to functional limitations similar to those experienced by geriatric populations. However, functional assessments are not routinely performed during clinic visits with older adults with SCD.
In order to address this gap in care, my colleagues and I developed the first functional assessment for older adults with SCD, called the Sickle Cell Disease Functional Assessment (SCD-FA). This assessment will allow providers to evaluate the capabilities and vulnerabilities of older adults with SCD.
We assessed the feasibility of administering the SCD-FA in a prospective cohort pilot study. We enrolled 40 adults with SCD (20 older adults aged at least 50 years and 20 younger adults aged 18-49 years as a comparison group). All participants were assessed at steady-state.
For the SCD-FA, we selected geriatric assessment measures across seven domains: functional status, comorbid medical conditions, psychological state, social support, nutritional status, cognition, and medications. Several of these measures were previously validated in an oncology geriatric assessment and enriched with additional physical and cognitive measures to evaluate conditions at the intersection of SCD and geriatrics.
In September 2020, we published a protocol describing the methods and rationale for selecting measures for the SCD-FA in Pilot and Feasibility Studies.1 The preliminary data was presented at the annual meeting of the American Society of Hematology in December 2020 and was included in the annual Hematology and Aging Poster Walk.
The results of this pilot study showed that the SCD-FA is feasible (91% of participants who consented completed the SCD-FA), acceptable (95% reported the length as appropriate and had no difficulty understanding the measures), and safe with no adverse events.2 On physical performance testing, both younger and older participants had results consistent with accelerated aging with a functional age at least 20-30 years older than their chronological age.2
The majority of the participants (63%) had a usual gait speed slower than the speed required to safely cross the street at an intersection, and 25% had a gait speed slower than 1 m/s, which has been associated with increased mortality in the general population.3,4
Benefits to management
The SCD-FA can improve management of adults with SCD by:
- Characterizing their capabilities and physiological age, identifying individuals at high risk for functional decline and death early identifying targets for interventions that have been successful in geriatrics,5 assessing risk of toxicity from curative therapies, and evaluating functional response to SCD-specific therapies.
The SCD-FA provides a framework for developing exercise interventions to target functional impairments. This work supports our goal of improving the quality of life and longevity for people with SCD.
Dr. Oyedeji is a senior hematology Fellow at the department of medicine, division of hematology, Duke University, Durham, N.C. She reported that she has no conflicts of interest.
References
1. Pilot Feasibility Stud. 2020;6:131.
2. Blood. 2020;136(Supplement 1):26-7.
3. J Rehabil Res Dev. 2005;42(4):535-46.
4. JAMA. 2011;305(1):50-8.
5. South Med J. 1994;87(5):S83-7.
As individuals with sickle cell disease (SCD) are living longer than ever before there is a greater need to focus on maintaining and improving function and independence in this growing population. In the general population, impairments in functional measures such as usual gait speed, grip strength, Timed Up and Go, and cognition are associated with adverse health outcomes such as falls, fractures, loss of independence, and death.
Adults with SCD experience multiple complications such as avascular necrosis of the joints, retinopathy, and strokes that lead to functional limitations similar to those experienced by geriatric populations. However, functional assessments are not routinely performed during clinic visits with older adults with SCD.
In order to address this gap in care, my colleagues and I developed the first functional assessment for older adults with SCD, called the Sickle Cell Disease Functional Assessment (SCD-FA). This assessment will allow providers to evaluate the capabilities and vulnerabilities of older adults with SCD.
We assessed the feasibility of administering the SCD-FA in a prospective cohort pilot study. We enrolled 40 adults with SCD (20 older adults aged at least 50 years and 20 younger adults aged 18-49 years as a comparison group). All participants were assessed at steady-state.
For the SCD-FA, we selected geriatric assessment measures across seven domains: functional status, comorbid medical conditions, psychological state, social support, nutritional status, cognition, and medications. Several of these measures were previously validated in an oncology geriatric assessment and enriched with additional physical and cognitive measures to evaluate conditions at the intersection of SCD and geriatrics.
In September 2020, we published a protocol describing the methods and rationale for selecting measures for the SCD-FA in Pilot and Feasibility Studies.1 The preliminary data was presented at the annual meeting of the American Society of Hematology in December 2020 and was included in the annual Hematology and Aging Poster Walk.
The results of this pilot study showed that the SCD-FA is feasible (91% of participants who consented completed the SCD-FA), acceptable (95% reported the length as appropriate and had no difficulty understanding the measures), and safe with no adverse events.2 On physical performance testing, both younger and older participants had results consistent with accelerated aging with a functional age at least 20-30 years older than their chronological age.2
The majority of the participants (63%) had a usual gait speed slower than the speed required to safely cross the street at an intersection, and 25% had a gait speed slower than 1 m/s, which has been associated with increased mortality in the general population.3,4
Benefits to management
The SCD-FA can improve management of adults with SCD by:
- Characterizing their capabilities and physiological age, identifying individuals at high risk for functional decline and death early identifying targets for interventions that have been successful in geriatrics,5 assessing risk of toxicity from curative therapies, and evaluating functional response to SCD-specific therapies.
The SCD-FA provides a framework for developing exercise interventions to target functional impairments. This work supports our goal of improving the quality of life and longevity for people with SCD.
Dr. Oyedeji is a senior hematology Fellow at the department of medicine, division of hematology, Duke University, Durham, N.C. She reported that she has no conflicts of interest.
References
1. Pilot Feasibility Stud. 2020;6:131.
2. Blood. 2020;136(Supplement 1):26-7.
3. J Rehabil Res Dev. 2005;42(4):535-46.
4. JAMA. 2011;305(1):50-8.
5. South Med J. 1994;87(5):S83-7.
Mitochondrial DNA predicts survival in pediatric acute myeloid leukemia
Mitochondrial DNA (mtDNA) copy number alterations are known to occur in acute myeloid leukemia (AML), however their biological significance has not been well studied. Pediatric AML has a distinct biology, different from adults, and with heterogeneous clinical outcomes, the biological basis of which are not well understood, according to researchers Shilpi Chaudhary, PhD, of the All India Institute of Medical Sciences, New Delhi, and colleagues.
Their analysis of 123 pediatric patients with AML found that mtDNA copy number was an independent predictor of aggressive disease, lower event-free survival, and overall survival, according to a report published in Mitochondrion.
In an attempt to find the biological factors involved in the increased mtDNA copy numbers and their effect on the development and aggressiveness of pediatric AML, the researchers studied the regulation and significance of mtDNA copy number in pediatric AML patients using quantitative real time–polymerase chain reaction, as well as in vitro studies. For patients, results were correlated with clinical outcomes.
Mitochondrial biogenesis genes (TFAM, POLG, POLRMT) and two regulator of mitochondrial biogenesis, MYC and PGC1A, were also assessed, according to Dr. Chaudhary and colleagues.
Predictive results
MtDNA copy number was significantly higher in patients, compared with controls (P < .001) and was found to be an independent predictor of aggressive disease (P = .006), lower event-free survival (P = .033), and overall survival (P = .007).
TFAM, POLG & POLRMT and ND3 were also found to be significantly up-regulated in patients, compared with controls as was the expression of the mitochondrial biogenesis regulator MYC (P < .001). However, correlation analysis showed that mtDNA copy number was not associated with the expression of these genes.
In contrast, PGC1A expression was not significantly different in patients, compared with controls overall, although there was a subset of patients whose PGC1A expression was extremely high, according to the researchers.
Importantly, however, in the subset of patients with high PGC1A expression (n = 28), mtDNA copy number had a positive correlation with PGC1A expression (P = .013). On the other hand, among patients with low MYC expression (n = 27), there was no correlation of mtDNA copy number with either PGC1A or MYC expression.
These results were corroborated in in vitro studies, where treatment with the inhibitor tigecycline led to a significant decrease in expression of MYC (P < .001), TFAM (P = .037) and ND3 (P = .010) but resulted in no significant change in mtDNA copy number (P = .23) or expression of PGC1A (P = .10).
Therapeutic candidate?
In contrast to the case of MYC, in vitro PGC1A inhibition significantly reduced mtDNA copy number in along with expression of TFAM and even expression of POLG and POLRMT at higher concentration.
“This observation is in line with our finding in patient samples as well that PGC1A expression positively correlated with mtDNA copy number, more so in patients with higher PGC1A expression,” the researchers stated.
“This makes it plausible to infer that PGC1A may have a possible role in enhancing mtDNA copy number in AML patients, likely independent of MYC,” they added. “Therefore, a strategy of designing therapeutics using already approved inhibitors targeting PGC1A may be an exciting area of therapeutic intervention.”
The authors reported that they have no competing financial conflicts of interests.
Mitochondrial DNA (mtDNA) copy number alterations are known to occur in acute myeloid leukemia (AML), however their biological significance has not been well studied. Pediatric AML has a distinct biology, different from adults, and with heterogeneous clinical outcomes, the biological basis of which are not well understood, according to researchers Shilpi Chaudhary, PhD, of the All India Institute of Medical Sciences, New Delhi, and colleagues.
Their analysis of 123 pediatric patients with AML found that mtDNA copy number was an independent predictor of aggressive disease, lower event-free survival, and overall survival, according to a report published in Mitochondrion.
In an attempt to find the biological factors involved in the increased mtDNA copy numbers and their effect on the development and aggressiveness of pediatric AML, the researchers studied the regulation and significance of mtDNA copy number in pediatric AML patients using quantitative real time–polymerase chain reaction, as well as in vitro studies. For patients, results were correlated with clinical outcomes.
Mitochondrial biogenesis genes (TFAM, POLG, POLRMT) and two regulator of mitochondrial biogenesis, MYC and PGC1A, were also assessed, according to Dr. Chaudhary and colleagues.
Predictive results
MtDNA copy number was significantly higher in patients, compared with controls (P < .001) and was found to be an independent predictor of aggressive disease (P = .006), lower event-free survival (P = .033), and overall survival (P = .007).
TFAM, POLG & POLRMT and ND3 were also found to be significantly up-regulated in patients, compared with controls as was the expression of the mitochondrial biogenesis regulator MYC (P < .001). However, correlation analysis showed that mtDNA copy number was not associated with the expression of these genes.
In contrast, PGC1A expression was not significantly different in patients, compared with controls overall, although there was a subset of patients whose PGC1A expression was extremely high, according to the researchers.
Importantly, however, in the subset of patients with high PGC1A expression (n = 28), mtDNA copy number had a positive correlation with PGC1A expression (P = .013). On the other hand, among patients with low MYC expression (n = 27), there was no correlation of mtDNA copy number with either PGC1A or MYC expression.
These results were corroborated in in vitro studies, where treatment with the inhibitor tigecycline led to a significant decrease in expression of MYC (P < .001), TFAM (P = .037) and ND3 (P = .010) but resulted in no significant change in mtDNA copy number (P = .23) or expression of PGC1A (P = .10).
Therapeutic candidate?
In contrast to the case of MYC, in vitro PGC1A inhibition significantly reduced mtDNA copy number in along with expression of TFAM and even expression of POLG and POLRMT at higher concentration.
“This observation is in line with our finding in patient samples as well that PGC1A expression positively correlated with mtDNA copy number, more so in patients with higher PGC1A expression,” the researchers stated.
“This makes it plausible to infer that PGC1A may have a possible role in enhancing mtDNA copy number in AML patients, likely independent of MYC,” they added. “Therefore, a strategy of designing therapeutics using already approved inhibitors targeting PGC1A may be an exciting area of therapeutic intervention.”
The authors reported that they have no competing financial conflicts of interests.
Mitochondrial DNA (mtDNA) copy number alterations are known to occur in acute myeloid leukemia (AML), however their biological significance has not been well studied. Pediatric AML has a distinct biology, different from adults, and with heterogeneous clinical outcomes, the biological basis of which are not well understood, according to researchers Shilpi Chaudhary, PhD, of the All India Institute of Medical Sciences, New Delhi, and colleagues.
Their analysis of 123 pediatric patients with AML found that mtDNA copy number was an independent predictor of aggressive disease, lower event-free survival, and overall survival, according to a report published in Mitochondrion.
In an attempt to find the biological factors involved in the increased mtDNA copy numbers and their effect on the development and aggressiveness of pediatric AML, the researchers studied the regulation and significance of mtDNA copy number in pediatric AML patients using quantitative real time–polymerase chain reaction, as well as in vitro studies. For patients, results were correlated with clinical outcomes.
Mitochondrial biogenesis genes (TFAM, POLG, POLRMT) and two regulator of mitochondrial biogenesis, MYC and PGC1A, were also assessed, according to Dr. Chaudhary and colleagues.
Predictive results
MtDNA copy number was significantly higher in patients, compared with controls (P < .001) and was found to be an independent predictor of aggressive disease (P = .006), lower event-free survival (P = .033), and overall survival (P = .007).
TFAM, POLG & POLRMT and ND3 were also found to be significantly up-regulated in patients, compared with controls as was the expression of the mitochondrial biogenesis regulator MYC (P < .001). However, correlation analysis showed that mtDNA copy number was not associated with the expression of these genes.
In contrast, PGC1A expression was not significantly different in patients, compared with controls overall, although there was a subset of patients whose PGC1A expression was extremely high, according to the researchers.
Importantly, however, in the subset of patients with high PGC1A expression (n = 28), mtDNA copy number had a positive correlation with PGC1A expression (P = .013). On the other hand, among patients with low MYC expression (n = 27), there was no correlation of mtDNA copy number with either PGC1A or MYC expression.
These results were corroborated in in vitro studies, where treatment with the inhibitor tigecycline led to a significant decrease in expression of MYC (P < .001), TFAM (P = .037) and ND3 (P = .010) but resulted in no significant change in mtDNA copy number (P = .23) or expression of PGC1A (P = .10).
Therapeutic candidate?
In contrast to the case of MYC, in vitro PGC1A inhibition significantly reduced mtDNA copy number in along with expression of TFAM and even expression of POLG and POLRMT at higher concentration.
“This observation is in line with our finding in patient samples as well that PGC1A expression positively correlated with mtDNA copy number, more so in patients with higher PGC1A expression,” the researchers stated.
“This makes it plausible to infer that PGC1A may have a possible role in enhancing mtDNA copy number in AML patients, likely independent of MYC,” they added. “Therefore, a strategy of designing therapeutics using already approved inhibitors targeting PGC1A may be an exciting area of therapeutic intervention.”
The authors reported that they have no competing financial conflicts of interests.
FROM MITOCHONDRION
Predicting outcomes in therapy-related AML
Therapy-related acute myeloid leukemia (t-AML) occurs as a complication of chemotherapy and/or radiotherapy for previous cancer or for nonmalignant disorders, with an estimated prevalence of 10%-15% of all AML cases, according to Ram Vasudevan Nampoothiri, MD, and colleagues at the Princess Margaret Cancer Center, University of Toronto.
Dr. Nampoothiri and colleagues performed a retrospective study of 68 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at their institution. They found significant predictors of reduced overall survival, including chromosomal rearrangements, induction regimens, donor type, patient performance status, and the type of graft-versus-host disease (GVHD) prophylaxis the patients received, as reported in Hematology/Oncology and Stem Cell Therapy.
Some populations benefit
Among the 68 patients studied, a total of 59.9% were women; and the median age was 56.5 years. All patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival, overall survival, and predictors of outcomes.
At 2 years, the cumulative incidence of relapse, nonrelapse mortality, relapse-free survival, and overall survival were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Overall, acute and chronic GVHD occurred in 39 (57.4%) and 23 (33.8%) patients, respectively, according to the researchers.
The significant predictors of reduced overall survival were the presence of the 11q23 chromosomal rearrangement (hazard ratio, 3.24), use of induction regimens other than fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or 7 + 3 (HR, 3.65), use of haploidentical donors (HR, 3.48), an Eastern Cooperative Oncology Group performance status of 2 or higher (HR, 5.83), and use of cyclosporine A–methotrexate as GVHD prophylaxis (HR, 2.41).
The researchers also found that a significant decrease in survival was seen with an increasing number of any of these prognostic factors.
A growing need
The incidence of t-AML is increasing because of longer life expectancy of the general population and also because of the improved survival of patients treated with chemotherapy and/or radiation for prior malignancies, according to the researchers.
They concluded that, even with this increasing prevalence and normally poor prognosis, “patients of t-AML having good-risk karyotypes, good performance status, and having HLA-matched donors have favorable outcomes after allo-HSCT.”
The authors reported that they had no competing financial interests.
Therapy-related acute myeloid leukemia (t-AML) occurs as a complication of chemotherapy and/or radiotherapy for previous cancer or for nonmalignant disorders, with an estimated prevalence of 10%-15% of all AML cases, according to Ram Vasudevan Nampoothiri, MD, and colleagues at the Princess Margaret Cancer Center, University of Toronto.
Dr. Nampoothiri and colleagues performed a retrospective study of 68 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at their institution. They found significant predictors of reduced overall survival, including chromosomal rearrangements, induction regimens, donor type, patient performance status, and the type of graft-versus-host disease (GVHD) prophylaxis the patients received, as reported in Hematology/Oncology and Stem Cell Therapy.
Some populations benefit
Among the 68 patients studied, a total of 59.9% were women; and the median age was 56.5 years. All patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival, overall survival, and predictors of outcomes.
At 2 years, the cumulative incidence of relapse, nonrelapse mortality, relapse-free survival, and overall survival were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Overall, acute and chronic GVHD occurred in 39 (57.4%) and 23 (33.8%) patients, respectively, according to the researchers.
The significant predictors of reduced overall survival were the presence of the 11q23 chromosomal rearrangement (hazard ratio, 3.24), use of induction regimens other than fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or 7 + 3 (HR, 3.65), use of haploidentical donors (HR, 3.48), an Eastern Cooperative Oncology Group performance status of 2 or higher (HR, 5.83), and use of cyclosporine A–methotrexate as GVHD prophylaxis (HR, 2.41).
The researchers also found that a significant decrease in survival was seen with an increasing number of any of these prognostic factors.
A growing need
The incidence of t-AML is increasing because of longer life expectancy of the general population and also because of the improved survival of patients treated with chemotherapy and/or radiation for prior malignancies, according to the researchers.
They concluded that, even with this increasing prevalence and normally poor prognosis, “patients of t-AML having good-risk karyotypes, good performance status, and having HLA-matched donors have favorable outcomes after allo-HSCT.”
The authors reported that they had no competing financial interests.
Therapy-related acute myeloid leukemia (t-AML) occurs as a complication of chemotherapy and/or radiotherapy for previous cancer or for nonmalignant disorders, with an estimated prevalence of 10%-15% of all AML cases, according to Ram Vasudevan Nampoothiri, MD, and colleagues at the Princess Margaret Cancer Center, University of Toronto.
Dr. Nampoothiri and colleagues performed a retrospective study of 68 patients with t-AML who underwent hematopoietic stem cell transplantation (HSCT) at their institution. They found significant predictors of reduced overall survival, including chromosomal rearrangements, induction regimens, donor type, patient performance status, and the type of graft-versus-host disease (GVHD) prophylaxis the patients received, as reported in Hematology/Oncology and Stem Cell Therapy.
Some populations benefit
Among the 68 patients studied, a total of 59.9% were women; and the median age was 56.5 years. All patients were analyzed for prior malignancy, therapy, time to diagnosis of t-AML, transplant details, relapse-free survival, overall survival, and predictors of outcomes.
At 2 years, the cumulative incidence of relapse, nonrelapse mortality, relapse-free survival, and overall survival were 17.9%, 34.5%, 47.6%, and 49.3%, respectively. Overall, acute and chronic GVHD occurred in 39 (57.4%) and 23 (33.8%) patients, respectively, according to the researchers.
The significant predictors of reduced overall survival were the presence of the 11q23 chromosomal rearrangement (hazard ratio, 3.24), use of induction regimens other than fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or 7 + 3 (HR, 3.65), use of haploidentical donors (HR, 3.48), an Eastern Cooperative Oncology Group performance status of 2 or higher (HR, 5.83), and use of cyclosporine A–methotrexate as GVHD prophylaxis (HR, 2.41).
The researchers also found that a significant decrease in survival was seen with an increasing number of any of these prognostic factors.
A growing need
The incidence of t-AML is increasing because of longer life expectancy of the general population and also because of the improved survival of patients treated with chemotherapy and/or radiation for prior malignancies, according to the researchers.
They concluded that, even with this increasing prevalence and normally poor prognosis, “patients of t-AML having good-risk karyotypes, good performance status, and having HLA-matched donors have favorable outcomes after allo-HSCT.”
The authors reported that they had no competing financial interests.
FROM HEMATOLOGY/ONCOLOGY AND STEM CELL THERAPY
Frontline brentuximab vedotin shows promise in high-risk pediatric Hodgkin lymphoma
A frontline treatment regimen including brentuximab vedotin (Bv) was well tolerated, was highly effective, and significantly reduced radiation exposure in pediatric patients with high-risk Hodgkin lymphoma, according to the results of an open-label, phase 2 trial.
Of 77 patients enrolled in the investigator-initiated, single-arm, multicenter trial, 27 (35%) achieved complete remission (CR) without radiation at the early response assessment (ERA) after two cycles of therapy, reported Monika L. Metzger, MD, of St. Jude Children’s Research Hospital, Memphis, Tenn. and colleagues. The report was published online in the Journal of Clinical Oncology.
The addition of Bv also resulted in superior event-free survival (97.4%) and overall survival (98.7%) at median follow-up of 3.4 years, compared with previously published pediatric trials, such as the HOD99 trial (EFS and OS of 80.8% and 96.5%, respectively), the authors noted.
Bv chemotherapy
Bv, a targeted anti-CD30 antibody-drug conjugate, received expanded Food and Drug Administration approval in March 2018 for frontline use in combination with chemotherapy in adults with stage III or IV classical Hodgkin lymphoma (HL). The current study is the first to include Bv as part of a chemotherapy regimen in the frontline setting for pediatric classical HL, the authors noted, adding that their primary aim was to reduce prescribed radiation thereby limiting late toxicities associated with radiation in this population.
Patients enrolled were children and adolescents aged 18 years and under with stage IIB, IIIB, or IV classical HL. Bv was used in place of vincristine in the standard OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) frontline regimen for pediatric HL.
The Bv-based chemotherapy regimen was well tolerated and mostly limited to low-grade nausea, vomiting, and constipation, and the most common adverse events were hematologic events occurring mainly during the first two cycles of chemotherapy.
“Notably, we observed a very low incidence of neuropathy (4%) by both clinician and patient report, and no participants required Bv dose reduction or discontinuation,” they wrote, explaining that neuropathy is more common with vincristine.
Radiation exposure
Residual node radiotherapy (RNRT) was delivered at a prescribed dose of 25.5 Gy in 17 fractions of 1.5 Gy, 2-4 weeks after completion of chemotherapy only to nodal sites that did not achieve a CR at the early response assessment (ERA) after two cycles of therapy.
“Patients treated with RNRT had significantly lower integral radiation dose compared with patients treated on HOD99 with [involved-field radiation therapy] (78.1 J vs. 249.6 J),” the authors wrote. “Doses to specific organs were also compared ... [t]he mean heart dose was reduced to 5.29 Gy from 16.9 Gy, and the mean thyroid dose was reduced to 4.46 Gy from 25.9 Gy.”
Women also had significantly less breast radiation exposure (mean of 3.21 Gy vs. 6.85 Gy in HOD99).
One irradiated patient experienced disease progression at the end of therapy, but remained disease free more than 6 years following salvage therapy, and one unexpected death occurred, the authors said.
“We have already reduced the use of radiation for low-risk Hodgkin lymphoma patients. In this study we’ve shown that it is also possible to either omit or reduce the extent of radiation for high-risk patients, using highly focal methods such as proton beam radiation or intensity modulated radiation,” co–senior author Matthew Krasin, MD, of St. Jude’s department of radiation oncology, stated in a press release.
Next steps
Co–senior author Melissa Hudson, MD, the St. Jude cancer survivorship division director, added that “[b]eing able to offer Hodgkin lymphoma patients a targeted therapy in the frontline setting is an exciting development.
“The favorable safety and toxicity profile of Bv in combination with chemotherapy for high-risk pediatric patients supports its prospective evaluation in a randomized trial,” the authors concluded, noting that “[l]onger follow-up is required to establish if this approach reduces risk of late-occurring toxicities such as second malignant neoplasms in this cohort of minimally irradiated patients.”
The study was sponsored by Seattle Genetics. The research at St. Jude was funded in part by grants from the National Cancer Institute and ALSAC (American Lebanese Syrian Associated Charities), St. Jude’s fundraising and awareness organization. Dr. Metzger reported research funding from Seattle Genetics. Dr. Krasin reported a consulting or advisory role for Debiopharm Group. Dr. Hudson reported a consulting or advisory role for Oncology Research Information Exchange Network, Princess Máxima Center.
A frontline treatment regimen including brentuximab vedotin (Bv) was well tolerated, was highly effective, and significantly reduced radiation exposure in pediatric patients with high-risk Hodgkin lymphoma, according to the results of an open-label, phase 2 trial.
Of 77 patients enrolled in the investigator-initiated, single-arm, multicenter trial, 27 (35%) achieved complete remission (CR) without radiation at the early response assessment (ERA) after two cycles of therapy, reported Monika L. Metzger, MD, of St. Jude Children’s Research Hospital, Memphis, Tenn. and colleagues. The report was published online in the Journal of Clinical Oncology.
The addition of Bv also resulted in superior event-free survival (97.4%) and overall survival (98.7%) at median follow-up of 3.4 years, compared with previously published pediatric trials, such as the HOD99 trial (EFS and OS of 80.8% and 96.5%, respectively), the authors noted.
Bv chemotherapy
Bv, a targeted anti-CD30 antibody-drug conjugate, received expanded Food and Drug Administration approval in March 2018 for frontline use in combination with chemotherapy in adults with stage III or IV classical Hodgkin lymphoma (HL). The current study is the first to include Bv as part of a chemotherapy regimen in the frontline setting for pediatric classical HL, the authors noted, adding that their primary aim was to reduce prescribed radiation thereby limiting late toxicities associated with radiation in this population.
Patients enrolled were children and adolescents aged 18 years and under with stage IIB, IIIB, or IV classical HL. Bv was used in place of vincristine in the standard OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) frontline regimen for pediatric HL.
The Bv-based chemotherapy regimen was well tolerated and mostly limited to low-grade nausea, vomiting, and constipation, and the most common adverse events were hematologic events occurring mainly during the first two cycles of chemotherapy.
“Notably, we observed a very low incidence of neuropathy (4%) by both clinician and patient report, and no participants required Bv dose reduction or discontinuation,” they wrote, explaining that neuropathy is more common with vincristine.
Radiation exposure
Residual node radiotherapy (RNRT) was delivered at a prescribed dose of 25.5 Gy in 17 fractions of 1.5 Gy, 2-4 weeks after completion of chemotherapy only to nodal sites that did not achieve a CR at the early response assessment (ERA) after two cycles of therapy.
“Patients treated with RNRT had significantly lower integral radiation dose compared with patients treated on HOD99 with [involved-field radiation therapy] (78.1 J vs. 249.6 J),” the authors wrote. “Doses to specific organs were also compared ... [t]he mean heart dose was reduced to 5.29 Gy from 16.9 Gy, and the mean thyroid dose was reduced to 4.46 Gy from 25.9 Gy.”
Women also had significantly less breast radiation exposure (mean of 3.21 Gy vs. 6.85 Gy in HOD99).
One irradiated patient experienced disease progression at the end of therapy, but remained disease free more than 6 years following salvage therapy, and one unexpected death occurred, the authors said.
“We have already reduced the use of radiation for low-risk Hodgkin lymphoma patients. In this study we’ve shown that it is also possible to either omit or reduce the extent of radiation for high-risk patients, using highly focal methods such as proton beam radiation or intensity modulated radiation,” co–senior author Matthew Krasin, MD, of St. Jude’s department of radiation oncology, stated in a press release.
Next steps
Co–senior author Melissa Hudson, MD, the St. Jude cancer survivorship division director, added that “[b]eing able to offer Hodgkin lymphoma patients a targeted therapy in the frontline setting is an exciting development.
“The favorable safety and toxicity profile of Bv in combination with chemotherapy for high-risk pediatric patients supports its prospective evaluation in a randomized trial,” the authors concluded, noting that “[l]onger follow-up is required to establish if this approach reduces risk of late-occurring toxicities such as second malignant neoplasms in this cohort of minimally irradiated patients.”
The study was sponsored by Seattle Genetics. The research at St. Jude was funded in part by grants from the National Cancer Institute and ALSAC (American Lebanese Syrian Associated Charities), St. Jude’s fundraising and awareness organization. Dr. Metzger reported research funding from Seattle Genetics. Dr. Krasin reported a consulting or advisory role for Debiopharm Group. Dr. Hudson reported a consulting or advisory role for Oncology Research Information Exchange Network, Princess Máxima Center.
A frontline treatment regimen including brentuximab vedotin (Bv) was well tolerated, was highly effective, and significantly reduced radiation exposure in pediatric patients with high-risk Hodgkin lymphoma, according to the results of an open-label, phase 2 trial.
Of 77 patients enrolled in the investigator-initiated, single-arm, multicenter trial, 27 (35%) achieved complete remission (CR) without radiation at the early response assessment (ERA) after two cycles of therapy, reported Monika L. Metzger, MD, of St. Jude Children’s Research Hospital, Memphis, Tenn. and colleagues. The report was published online in the Journal of Clinical Oncology.
The addition of Bv also resulted in superior event-free survival (97.4%) and overall survival (98.7%) at median follow-up of 3.4 years, compared with previously published pediatric trials, such as the HOD99 trial (EFS and OS of 80.8% and 96.5%, respectively), the authors noted.
Bv chemotherapy
Bv, a targeted anti-CD30 antibody-drug conjugate, received expanded Food and Drug Administration approval in March 2018 for frontline use in combination with chemotherapy in adults with stage III or IV classical Hodgkin lymphoma (HL). The current study is the first to include Bv as part of a chemotherapy regimen in the frontline setting for pediatric classical HL, the authors noted, adding that their primary aim was to reduce prescribed radiation thereby limiting late toxicities associated with radiation in this population.
Patients enrolled were children and adolescents aged 18 years and under with stage IIB, IIIB, or IV classical HL. Bv was used in place of vincristine in the standard OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) frontline regimen for pediatric HL.
The Bv-based chemotherapy regimen was well tolerated and mostly limited to low-grade nausea, vomiting, and constipation, and the most common adverse events were hematologic events occurring mainly during the first two cycles of chemotherapy.
“Notably, we observed a very low incidence of neuropathy (4%) by both clinician and patient report, and no participants required Bv dose reduction or discontinuation,” they wrote, explaining that neuropathy is more common with vincristine.
Radiation exposure
Residual node radiotherapy (RNRT) was delivered at a prescribed dose of 25.5 Gy in 17 fractions of 1.5 Gy, 2-4 weeks after completion of chemotherapy only to nodal sites that did not achieve a CR at the early response assessment (ERA) after two cycles of therapy.
“Patients treated with RNRT had significantly lower integral radiation dose compared with patients treated on HOD99 with [involved-field radiation therapy] (78.1 J vs. 249.6 J),” the authors wrote. “Doses to specific organs were also compared ... [t]he mean heart dose was reduced to 5.29 Gy from 16.9 Gy, and the mean thyroid dose was reduced to 4.46 Gy from 25.9 Gy.”
Women also had significantly less breast radiation exposure (mean of 3.21 Gy vs. 6.85 Gy in HOD99).
One irradiated patient experienced disease progression at the end of therapy, but remained disease free more than 6 years following salvage therapy, and one unexpected death occurred, the authors said.
“We have already reduced the use of radiation for low-risk Hodgkin lymphoma patients. In this study we’ve shown that it is also possible to either omit or reduce the extent of radiation for high-risk patients, using highly focal methods such as proton beam radiation or intensity modulated radiation,” co–senior author Matthew Krasin, MD, of St. Jude’s department of radiation oncology, stated in a press release.
Next steps
Co–senior author Melissa Hudson, MD, the St. Jude cancer survivorship division director, added that “[b]eing able to offer Hodgkin lymphoma patients a targeted therapy in the frontline setting is an exciting development.
“The favorable safety and toxicity profile of Bv in combination with chemotherapy for high-risk pediatric patients supports its prospective evaluation in a randomized trial,” the authors concluded, noting that “[l]onger follow-up is required to establish if this approach reduces risk of late-occurring toxicities such as second malignant neoplasms in this cohort of minimally irradiated patients.”
The study was sponsored by Seattle Genetics. The research at St. Jude was funded in part by grants from the National Cancer Institute and ALSAC (American Lebanese Syrian Associated Charities), St. Jude’s fundraising and awareness organization. Dr. Metzger reported research funding from Seattle Genetics. Dr. Krasin reported a consulting or advisory role for Debiopharm Group. Dr. Hudson reported a consulting or advisory role for Oncology Research Information Exchange Network, Princess Máxima Center.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
GENUINE improvements: Ublituximab plus ibrutinib for CLL
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
How some COVID-19 vaccines could cause rare blood clots
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.