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Researchers seek a way to predict cognitive deficits in children treated for ALL
Researchers are attempting to determine, early in the treatment process, which children with acute lymphoblastic leukemia (ALL) have an increased risk of neurocognitive deficits after chemotherapy.
The goal of the researchers’ project (5R01CA220568-02) is to determine if gene variants and biomarkers associated with oxidative stress, neuroinflammation, and folate physiology correlate with cognitive decline during and after chemotherapy. Ideally, certain variants and biomarkers will reveal patients who might benefit from interventions to prevent or even reverse cognitive deficits.
Peter D. Cole, MD, of Rutgers Cancer Institute, New Brunswick, N.J., and colleagues are conducting this research in patients from the DFCI-16-001 trial (NCT03020030). This multicenter, phase 3 study is enrolling patients (aged 1-21 years) with B- or T-cell ALL who then receive a multidrug chemotherapy regimen.
Dr. Cole and colleagues are analyzing a subset of patients from the trial, looking for relationships between chemotherapy-induced neurocognitive changes, gene variants, and changes in biomarkers detected in cerebrospinal fluid (CSF).
“We’re looking at a broad panel of target gene variants that are associated with either drug metabolism, defenses against oxidative stress, neuroinflammation, or folate physiology,” Dr. Cole said in an interview.
This includes variants Dr. Cole and colleagues identified in a previous, retrospective study of ALL survivors. The researchers found that survivors who were homozygous for NOS3 894T, had a variant SLCO2A1 G allele, or had at least one GSTP1 T allele were more likely to exhibit cognitive deficits (J Clin Oncol. 2015 Jul 1;33[19]:2205-11).
The researchers are also analyzing CSF samples, looking for changes in tau protein, homocysteine, homocysteic acid, the adenosylmethionine to adenosylhomocysteine ratio, and other biomarkers of oxidative stress, neuroinflammation, and folate physiology. The CSF is collected at five time points: the start of chemotherapy, day 18, the start of first consolidation, the end of first consolidation, and 7 weeks later in second consolidation.
Cognitive testing
While Dr. Cole is leading the genetic and biomarker analyses, Stephen A. Sands, PsyD, of Memorial Sloan Kettering Cancer Center in New York, is leading the cognitive testing.
The researchers are evaluating patients for cognitive decline using computerized tests from a company called Cogstate. The tests are designed to assess functions such as processing speed, attention, visual learning, and working memory. The tests are administered on an iPad and involve tasks like identifying features of playing cards and finding the correct way through a maze.
The patients – aged 3 years and older – undergo cognitive testing at six time points: baseline, which is any time between days 8 and 32 of induction (except within 72 hours after sedation or anesthesia); at first consolidation; the end of central nervous system therapy; 1 year into chemotherapy; the end of chemotherapy; and 1 year after chemotherapy ends.
In a prior study, Cogstate testing proved reliable for detecting neurocognitive changes in patients undergoing treatment for ALL (Support Care Cancer. 2017;25[2]:449-57). In the current study, the researchers are supplementing Cogstate test results with Wechsler IQ tests administered 1 year after patients complete chemotherapy.
Dr. Sands noted that Cogstate tests provide benefits over the Wechsler “paper-and-pencil” tests. One benefit is that Cogstate tests can be given more often without inducing practice effects (J Clin Exp Neuropsychol. 2006 Oct;28[7]:1095-112). Another is that Cogstate tests can be administered by anyone with a bachelor’s degree who has undergone the appropriate training, while Wechsler IQ tests must be given by psychologists.
Preliminary results
This research is ongoing, so it’s too early to announce any discoveries, but the study is moving along as planned.
“The preliminary data we have so far are demonstrating the validity of the study,” Dr. Cole said. “Things are going well. We’re able to do the cognitive testing and collect the samples that we need and ship them without losing the integrity of the samples.”
Dr. Sands noted that enrollment has been encouraging. As this is a substudy of DFCI-16-001, the researchers must obtain consent separately from the main study. Dr. Sands said about 89% of parents involved in the main study have agreed to enroll their children in the substudy.
Dr. Sands also said that early results from Cogstate testing have revealed patients who are experiencing cognitive decline during treatment. The researchers still have to determine if these results correlate with any biomarkers or gene variants.
Potential interventions
If the researchers can pinpoint patients at risk for cognitive deficits, the next step will be to investigate pharmacologic and behavioral interventions.
Dr. Cole said he is particularly interested in treatments that reduce oxidative stress, such as dextromethorphan and memantine. Dextromethorphan has been shown to resolve symptoms of methotrexate-induced neurotoxicity in patients (Pediatr Hematol Oncol. 2002 Jul-Aug;19[5]:319-27), and memantine reduced memory deficits in animals treated with methotrexate (Clin Cancer Res. 2013 Aug 15;19[16]:4446-54).
“Memantine hasn’t been used in kids with leukemia yet, but it’s something that I’d like to see brought to a clinical trial,” Dr. Cole said.
Dr. Sands pointed to other potential pharmacologic interventions, including the stimulants methylphenidate and modafinil. Both drugs have been shown to improve cognitive deficits in cancer survivors (J Clin Oncol. 2001 Mar 15;19[6]:1802-8; Cancer. 2009 Jun 15; 115[12]: 2605-16).
Computer-based cognitive training tools may be another option. One such tool, Lumosity, improved executive functions in a study of breast cancer survivors (Clin Breast Cancer. 2013 Aug;13[4]:299-306). Another tool, CogMed, improved working memory in survivors of brain tumors and ALL (Psychooncology. 2013 Aug; 22[8]: 1856-65).
Other behavioral interventions might include sleep hygiene and exercise. Sleep hygiene has been shown to improve cognitive function in childhood cancer survivors (Cancer. 2011 Jun 1;117[11]:2559-68), and a recent study revealed an association between exercise intolerance and negative neurocognitive outcomes in ALL survivors (Cancer. 2019 Oct 21. doi: 10.1002/cncr.32510).
“What we need to figure out is which children will respond to which interventions,” Dr. Sands said, adding that interventions will likely need to be combined.
“It’s not going to be one thing that will work for everybody,” he said. “It’s going to be: What packages of things will work for different people?”
Dr. Sands and Dr. Cole reported having no relevant financial disclosures.
Researchers are attempting to determine, early in the treatment process, which children with acute lymphoblastic leukemia (ALL) have an increased risk of neurocognitive deficits after chemotherapy.
The goal of the researchers’ project (5R01CA220568-02) is to determine if gene variants and biomarkers associated with oxidative stress, neuroinflammation, and folate physiology correlate with cognitive decline during and after chemotherapy. Ideally, certain variants and biomarkers will reveal patients who might benefit from interventions to prevent or even reverse cognitive deficits.
Peter D. Cole, MD, of Rutgers Cancer Institute, New Brunswick, N.J., and colleagues are conducting this research in patients from the DFCI-16-001 trial (NCT03020030). This multicenter, phase 3 study is enrolling patients (aged 1-21 years) with B- or T-cell ALL who then receive a multidrug chemotherapy regimen.
Dr. Cole and colleagues are analyzing a subset of patients from the trial, looking for relationships between chemotherapy-induced neurocognitive changes, gene variants, and changes in biomarkers detected in cerebrospinal fluid (CSF).
“We’re looking at a broad panel of target gene variants that are associated with either drug metabolism, defenses against oxidative stress, neuroinflammation, or folate physiology,” Dr. Cole said in an interview.
This includes variants Dr. Cole and colleagues identified in a previous, retrospective study of ALL survivors. The researchers found that survivors who were homozygous for NOS3 894T, had a variant SLCO2A1 G allele, or had at least one GSTP1 T allele were more likely to exhibit cognitive deficits (J Clin Oncol. 2015 Jul 1;33[19]:2205-11).
The researchers are also analyzing CSF samples, looking for changes in tau protein, homocysteine, homocysteic acid, the adenosylmethionine to adenosylhomocysteine ratio, and other biomarkers of oxidative stress, neuroinflammation, and folate physiology. The CSF is collected at five time points: the start of chemotherapy, day 18, the start of first consolidation, the end of first consolidation, and 7 weeks later in second consolidation.
Cognitive testing
While Dr. Cole is leading the genetic and biomarker analyses, Stephen A. Sands, PsyD, of Memorial Sloan Kettering Cancer Center in New York, is leading the cognitive testing.
The researchers are evaluating patients for cognitive decline using computerized tests from a company called Cogstate. The tests are designed to assess functions such as processing speed, attention, visual learning, and working memory. The tests are administered on an iPad and involve tasks like identifying features of playing cards and finding the correct way through a maze.
The patients – aged 3 years and older – undergo cognitive testing at six time points: baseline, which is any time between days 8 and 32 of induction (except within 72 hours after sedation or anesthesia); at first consolidation; the end of central nervous system therapy; 1 year into chemotherapy; the end of chemotherapy; and 1 year after chemotherapy ends.
In a prior study, Cogstate testing proved reliable for detecting neurocognitive changes in patients undergoing treatment for ALL (Support Care Cancer. 2017;25[2]:449-57). In the current study, the researchers are supplementing Cogstate test results with Wechsler IQ tests administered 1 year after patients complete chemotherapy.
Dr. Sands noted that Cogstate tests provide benefits over the Wechsler “paper-and-pencil” tests. One benefit is that Cogstate tests can be given more often without inducing practice effects (J Clin Exp Neuropsychol. 2006 Oct;28[7]:1095-112). Another is that Cogstate tests can be administered by anyone with a bachelor’s degree who has undergone the appropriate training, while Wechsler IQ tests must be given by psychologists.
Preliminary results
This research is ongoing, so it’s too early to announce any discoveries, but the study is moving along as planned.
“The preliminary data we have so far are demonstrating the validity of the study,” Dr. Cole said. “Things are going well. We’re able to do the cognitive testing and collect the samples that we need and ship them without losing the integrity of the samples.”
Dr. Sands noted that enrollment has been encouraging. As this is a substudy of DFCI-16-001, the researchers must obtain consent separately from the main study. Dr. Sands said about 89% of parents involved in the main study have agreed to enroll their children in the substudy.
Dr. Sands also said that early results from Cogstate testing have revealed patients who are experiencing cognitive decline during treatment. The researchers still have to determine if these results correlate with any biomarkers or gene variants.
Potential interventions
If the researchers can pinpoint patients at risk for cognitive deficits, the next step will be to investigate pharmacologic and behavioral interventions.
Dr. Cole said he is particularly interested in treatments that reduce oxidative stress, such as dextromethorphan and memantine. Dextromethorphan has been shown to resolve symptoms of methotrexate-induced neurotoxicity in patients (Pediatr Hematol Oncol. 2002 Jul-Aug;19[5]:319-27), and memantine reduced memory deficits in animals treated with methotrexate (Clin Cancer Res. 2013 Aug 15;19[16]:4446-54).
“Memantine hasn’t been used in kids with leukemia yet, but it’s something that I’d like to see brought to a clinical trial,” Dr. Cole said.
Dr. Sands pointed to other potential pharmacologic interventions, including the stimulants methylphenidate and modafinil. Both drugs have been shown to improve cognitive deficits in cancer survivors (J Clin Oncol. 2001 Mar 15;19[6]:1802-8; Cancer. 2009 Jun 15; 115[12]: 2605-16).
Computer-based cognitive training tools may be another option. One such tool, Lumosity, improved executive functions in a study of breast cancer survivors (Clin Breast Cancer. 2013 Aug;13[4]:299-306). Another tool, CogMed, improved working memory in survivors of brain tumors and ALL (Psychooncology. 2013 Aug; 22[8]: 1856-65).
Other behavioral interventions might include sleep hygiene and exercise. Sleep hygiene has been shown to improve cognitive function in childhood cancer survivors (Cancer. 2011 Jun 1;117[11]:2559-68), and a recent study revealed an association between exercise intolerance and negative neurocognitive outcomes in ALL survivors (Cancer. 2019 Oct 21. doi: 10.1002/cncr.32510).
“What we need to figure out is which children will respond to which interventions,” Dr. Sands said, adding that interventions will likely need to be combined.
“It’s not going to be one thing that will work for everybody,” he said. “It’s going to be: What packages of things will work for different people?”
Dr. Sands and Dr. Cole reported having no relevant financial disclosures.
Researchers are attempting to determine, early in the treatment process, which children with acute lymphoblastic leukemia (ALL) have an increased risk of neurocognitive deficits after chemotherapy.
The goal of the researchers’ project (5R01CA220568-02) is to determine if gene variants and biomarkers associated with oxidative stress, neuroinflammation, and folate physiology correlate with cognitive decline during and after chemotherapy. Ideally, certain variants and biomarkers will reveal patients who might benefit from interventions to prevent or even reverse cognitive deficits.
Peter D. Cole, MD, of Rutgers Cancer Institute, New Brunswick, N.J., and colleagues are conducting this research in patients from the DFCI-16-001 trial (NCT03020030). This multicenter, phase 3 study is enrolling patients (aged 1-21 years) with B- or T-cell ALL who then receive a multidrug chemotherapy regimen.
Dr. Cole and colleagues are analyzing a subset of patients from the trial, looking for relationships between chemotherapy-induced neurocognitive changes, gene variants, and changes in biomarkers detected in cerebrospinal fluid (CSF).
“We’re looking at a broad panel of target gene variants that are associated with either drug metabolism, defenses against oxidative stress, neuroinflammation, or folate physiology,” Dr. Cole said in an interview.
This includes variants Dr. Cole and colleagues identified in a previous, retrospective study of ALL survivors. The researchers found that survivors who were homozygous for NOS3 894T, had a variant SLCO2A1 G allele, or had at least one GSTP1 T allele were more likely to exhibit cognitive deficits (J Clin Oncol. 2015 Jul 1;33[19]:2205-11).
The researchers are also analyzing CSF samples, looking for changes in tau protein, homocysteine, homocysteic acid, the adenosylmethionine to adenosylhomocysteine ratio, and other biomarkers of oxidative stress, neuroinflammation, and folate physiology. The CSF is collected at five time points: the start of chemotherapy, day 18, the start of first consolidation, the end of first consolidation, and 7 weeks later in second consolidation.
Cognitive testing
While Dr. Cole is leading the genetic and biomarker analyses, Stephen A. Sands, PsyD, of Memorial Sloan Kettering Cancer Center in New York, is leading the cognitive testing.
The researchers are evaluating patients for cognitive decline using computerized tests from a company called Cogstate. The tests are designed to assess functions such as processing speed, attention, visual learning, and working memory. The tests are administered on an iPad and involve tasks like identifying features of playing cards and finding the correct way through a maze.
The patients – aged 3 years and older – undergo cognitive testing at six time points: baseline, which is any time between days 8 and 32 of induction (except within 72 hours after sedation or anesthesia); at first consolidation; the end of central nervous system therapy; 1 year into chemotherapy; the end of chemotherapy; and 1 year after chemotherapy ends.
In a prior study, Cogstate testing proved reliable for detecting neurocognitive changes in patients undergoing treatment for ALL (Support Care Cancer. 2017;25[2]:449-57). In the current study, the researchers are supplementing Cogstate test results with Wechsler IQ tests administered 1 year after patients complete chemotherapy.
Dr. Sands noted that Cogstate tests provide benefits over the Wechsler “paper-and-pencil” tests. One benefit is that Cogstate tests can be given more often without inducing practice effects (J Clin Exp Neuropsychol. 2006 Oct;28[7]:1095-112). Another is that Cogstate tests can be administered by anyone with a bachelor’s degree who has undergone the appropriate training, while Wechsler IQ tests must be given by psychologists.
Preliminary results
This research is ongoing, so it’s too early to announce any discoveries, but the study is moving along as planned.
“The preliminary data we have so far are demonstrating the validity of the study,” Dr. Cole said. “Things are going well. We’re able to do the cognitive testing and collect the samples that we need and ship them without losing the integrity of the samples.”
Dr. Sands noted that enrollment has been encouraging. As this is a substudy of DFCI-16-001, the researchers must obtain consent separately from the main study. Dr. Sands said about 89% of parents involved in the main study have agreed to enroll their children in the substudy.
Dr. Sands also said that early results from Cogstate testing have revealed patients who are experiencing cognitive decline during treatment. The researchers still have to determine if these results correlate with any biomarkers or gene variants.
Potential interventions
If the researchers can pinpoint patients at risk for cognitive deficits, the next step will be to investigate pharmacologic and behavioral interventions.
Dr. Cole said he is particularly interested in treatments that reduce oxidative stress, such as dextromethorphan and memantine. Dextromethorphan has been shown to resolve symptoms of methotrexate-induced neurotoxicity in patients (Pediatr Hematol Oncol. 2002 Jul-Aug;19[5]:319-27), and memantine reduced memory deficits in animals treated with methotrexate (Clin Cancer Res. 2013 Aug 15;19[16]:4446-54).
“Memantine hasn’t been used in kids with leukemia yet, but it’s something that I’d like to see brought to a clinical trial,” Dr. Cole said.
Dr. Sands pointed to other potential pharmacologic interventions, including the stimulants methylphenidate and modafinil. Both drugs have been shown to improve cognitive deficits in cancer survivors (J Clin Oncol. 2001 Mar 15;19[6]:1802-8; Cancer. 2009 Jun 15; 115[12]: 2605-16).
Computer-based cognitive training tools may be another option. One such tool, Lumosity, improved executive functions in a study of breast cancer survivors (Clin Breast Cancer. 2013 Aug;13[4]:299-306). Another tool, CogMed, improved working memory in survivors of brain tumors and ALL (Psychooncology. 2013 Aug; 22[8]: 1856-65).
Other behavioral interventions might include sleep hygiene and exercise. Sleep hygiene has been shown to improve cognitive function in childhood cancer survivors (Cancer. 2011 Jun 1;117[11]:2559-68), and a recent study revealed an association between exercise intolerance and negative neurocognitive outcomes in ALL survivors (Cancer. 2019 Oct 21. doi: 10.1002/cncr.32510).
“What we need to figure out is which children will respond to which interventions,” Dr. Sands said, adding that interventions will likely need to be combined.
“It’s not going to be one thing that will work for everybody,” he said. “It’s going to be: What packages of things will work for different people?”
Dr. Sands and Dr. Cole reported having no relevant financial disclosures.
Transfusion-related lung injury is on the rise in elderly patients
SAN ANTONIO – Although there has been a general decline in transfusion-related anaphylaxis and acute infections over time among hospitalized older adults in the United States, incidence rates for both transfusion-related acute lung injury and transfusion-associated circulatory overload have risen over the last decade, according to researchers from the Food and Drug Administration.
Mikhail Menis, PharmD, an epidemiologist at the FDA Center for Biologics Evaluation and Research (CBER) and colleagues queried large Medicare databases to assess trends in transfusion-related adverse events among adults aged 65 years and older.
The investigators saw “substantially higher risk of all outcomes among immunocompromised beneficiaries, which could be related to higher blood use of all blood components, especially platelets, underlying conditions such as malignancies, and treatments such as chemotherapy or radiation, which need further investigation,” Dr. Menis said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.
He reported data from a series of studies on four categories of transfusion-related events that may be life-threatening or fatal: transfusion-related anaphylaxis (TRA), transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and acute infection following transfusion (AIFT).
For each type of event, the researchers looked at overall incidence and the incidence by immune status, calendar year, blood components transfused, number of units transfused, age, sex, and race.
Anaphylaxis (TRA)
TRA may be caused by preformed immunoglobin E (IgE) antibodies to proteins in the plasma in transfused blood products or by preformed IgA antibodies in patients who are likely IgA deficient, Dr. Menis said.
The overall incidence of TRA among 8,833,817 inpatient transfusions stays for elderly beneficiaries from 2012 through 2018 was 7.1 per 100,000 stays. The rate was higher for immunocompromised patients, at 9.6, than it was among nonimmunocompromised patients, at 6.5.
The rates varied by every subgroup measured except immune status. Annual rates showed a downward trend, from 8.7 per 100,000 in 2012, to 5.1 in 2017 and 6.4 in 2018. The decline in occurrence may be caused by a decline in inpatient blood utilization during the study period, particularly among immunocompromised patients.
TRA rates increased with five or more units transfused. The risk was significantly reduced in the oldest group of patients versus the youngest (P less than .001), which supports the immune-based mechanism of action of anaphylaxis, Dr. Menis said.
They also found that TRA rates were substantially higher among patients who had received platelet and/or plasma transfusions, compared with patients who received only red blood cells (RBCs).
Additionally, risk for TRA was significantly higher among men than it was among women (9.3 vs. 5.4) and among white versus nonwhite patients (7.8 vs. 3.8).
The evidence suggested TRA cases are likely to be severe in this population, with inpatient mortality of 7.1%, and hospital stays of 7 days or longer in about 58% of cases, indicating the importance of TRA prevention, Dr. Menis said.
The investigators plan to perform multivariate regression analyses to assess potential risk factors, including underlying comorbidities and health histories for TRA occurrence for both the overall population and by immune status.
Acute lung injury (TRALI)
TRALI is a rare but serious adverse event, a clinical syndrome with onset within 6 hours of transfusion that presents as acute hypoxemia, respiratory distress, and noncardiogenic pulmonary edema.
Among 17,771,193 total inpatient transfusion stays, the overall incidence of TRALI was 33.2 per 100,000. The rate was 55.9 for immunocompromised patients versus 28.4 for nonimmunocompromised patients. The rate ratio was 2.0 (P less than .001).
The difference by immune status may be caused by higher blood utilizations with more units transfused per stay among immunocompromised patients, a higher incidence of prior transfusions among these patients, higher use of irradiated blood components that may lead to accumulation of proinflammatory mediators in blood products during storage, or underlying comorbidities.
The overall rate increased from 14.3 in 2007 to 56.4 in 2018. The rates increased proportionally among both immunocompromised and nonimmunocompromised patients.
As with TRA, the incidence of TRALI was higher in patients with five or more units transfused, while the incidence declined with age, likely caused by declining blood use and age-related changes in neutrophil function, Dr. Menis said.
TRALI rates were slightly higher among men than among women, as well as higher among white patients than among nonwhite patients.
Overall, TRALI rates were higher for patients who received platelets either alone or in combination with RBCs and/or plasma. The highest rates were among patients who received RBCs, plasma and platelets.
Dr. Menis called for studies to determine what effects the processing and storage of blood components may have on TRALI occurrence; he and his colleagues also are planning regression analyses to assess potential risk factors for this complication.
Circulatory overload (TACO)
TACO is one of the leading reported causes of transfusion-related fatalities in the U.S., with onset usually occurring within 6 hours of transfusion, presenting as acute respiratory distress with dyspnea, orthopnea, increased blood pressure, and cardiogenic pulmonary edema.
The overall incidence of TACO among hospitalized patients aged 65 years and older from 2011 through 2018 was 86.3 per 100,000 stays. The incidences were 128.3 in immunocompromised and 76.0 in nonimmunocompromised patients. The rate ratio for TACO in immunocompromised versus nonimmunocompromised patients was 1.70 (P less than .001).
Overall incidence rates of TACO rose from 62 per 100,000 stays in 2011 to 119.8 in 2018. As with other adverse events, incident rates rose with the number of units transfused.
Rates of TACO were significantly higher among women than they were among men (94.6 vs. 75.9 per 100,000; P less than .001), which could be caused by the higher mean age of women and/or a lower tolerance for increased blood volume from transfusion.
The study results also suggested that TACO and TRALI may coexist, based on evidence that 3.5% of all TACO stays also had diagnostic codes for TRALI. The frequency of co-occurrence of these two adverse events also increased over time, which may be caused by improved awareness, Dr. Menis said.
Infections (AIFT)
Acute infections following transfusion can lead to prolonged hospitalizations, sepsis, septic shock, and death. Those most at risk include elderly and immunocompromised patients because of high utilization of blood products, comorbidities, and decreased immune function.
Among 8,833,817 stays, the overall rate per 100,000 stays was 2.1. The rate for immunocompromised patients was 5.4, compared with 1.2 for nonimmunocompromised patients, for a rate ratio of 4.4 (P less than .001).
The incidence rate declined significantly (P = .03) over the study period, with the 3 latest years having the lowest rates.
Rates increased substantially among immunocompromised patients by the number of units transfused, but remained relatively stable among nonimmunocompromised patients.
Infection rates declined with age, from 2.7 per 100,000 stays for patients aged 65-68 years to 1.2 per 100,000 for those aged 85 years and older.
As with other adverse events, AIFT rates were likely related to the blood components transfused, with substantially higher rates for stays during which platelets were transfused either alone or with RBCs, compared with RBCs alone. This could be caused by the room-temperature storage of platelets and higher number of platelets units transfused, compared with RBCs alone, especially among immunocompromised patients.
In all, 51.9% of AIFT cases also had sepsis noted in the medical record, indicating high severity and emphasizing the importance of AIFT prevention, Dr. Menis said.
The studies were funded by the FDA, and Dr. Menis is an FDA employee. He reported having no conflicts of interest.
SAN ANTONIO – Although there has been a general decline in transfusion-related anaphylaxis and acute infections over time among hospitalized older adults in the United States, incidence rates for both transfusion-related acute lung injury and transfusion-associated circulatory overload have risen over the last decade, according to researchers from the Food and Drug Administration.
Mikhail Menis, PharmD, an epidemiologist at the FDA Center for Biologics Evaluation and Research (CBER) and colleagues queried large Medicare databases to assess trends in transfusion-related adverse events among adults aged 65 years and older.
The investigators saw “substantially higher risk of all outcomes among immunocompromised beneficiaries, which could be related to higher blood use of all blood components, especially platelets, underlying conditions such as malignancies, and treatments such as chemotherapy or radiation, which need further investigation,” Dr. Menis said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.
He reported data from a series of studies on four categories of transfusion-related events that may be life-threatening or fatal: transfusion-related anaphylaxis (TRA), transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and acute infection following transfusion (AIFT).
For each type of event, the researchers looked at overall incidence and the incidence by immune status, calendar year, blood components transfused, number of units transfused, age, sex, and race.
Anaphylaxis (TRA)
TRA may be caused by preformed immunoglobin E (IgE) antibodies to proteins in the plasma in transfused blood products or by preformed IgA antibodies in patients who are likely IgA deficient, Dr. Menis said.
The overall incidence of TRA among 8,833,817 inpatient transfusions stays for elderly beneficiaries from 2012 through 2018 was 7.1 per 100,000 stays. The rate was higher for immunocompromised patients, at 9.6, than it was among nonimmunocompromised patients, at 6.5.
The rates varied by every subgroup measured except immune status. Annual rates showed a downward trend, from 8.7 per 100,000 in 2012, to 5.1 in 2017 and 6.4 in 2018. The decline in occurrence may be caused by a decline in inpatient blood utilization during the study period, particularly among immunocompromised patients.
TRA rates increased with five or more units transfused. The risk was significantly reduced in the oldest group of patients versus the youngest (P less than .001), which supports the immune-based mechanism of action of anaphylaxis, Dr. Menis said.
They also found that TRA rates were substantially higher among patients who had received platelet and/or plasma transfusions, compared with patients who received only red blood cells (RBCs).
Additionally, risk for TRA was significantly higher among men than it was among women (9.3 vs. 5.4) and among white versus nonwhite patients (7.8 vs. 3.8).
The evidence suggested TRA cases are likely to be severe in this population, with inpatient mortality of 7.1%, and hospital stays of 7 days or longer in about 58% of cases, indicating the importance of TRA prevention, Dr. Menis said.
The investigators plan to perform multivariate regression analyses to assess potential risk factors, including underlying comorbidities and health histories for TRA occurrence for both the overall population and by immune status.
Acute lung injury (TRALI)
TRALI is a rare but serious adverse event, a clinical syndrome with onset within 6 hours of transfusion that presents as acute hypoxemia, respiratory distress, and noncardiogenic pulmonary edema.
Among 17,771,193 total inpatient transfusion stays, the overall incidence of TRALI was 33.2 per 100,000. The rate was 55.9 for immunocompromised patients versus 28.4 for nonimmunocompromised patients. The rate ratio was 2.0 (P less than .001).
The difference by immune status may be caused by higher blood utilizations with more units transfused per stay among immunocompromised patients, a higher incidence of prior transfusions among these patients, higher use of irradiated blood components that may lead to accumulation of proinflammatory mediators in blood products during storage, or underlying comorbidities.
The overall rate increased from 14.3 in 2007 to 56.4 in 2018. The rates increased proportionally among both immunocompromised and nonimmunocompromised patients.
As with TRA, the incidence of TRALI was higher in patients with five or more units transfused, while the incidence declined with age, likely caused by declining blood use and age-related changes in neutrophil function, Dr. Menis said.
TRALI rates were slightly higher among men than among women, as well as higher among white patients than among nonwhite patients.
Overall, TRALI rates were higher for patients who received platelets either alone or in combination with RBCs and/or plasma. The highest rates were among patients who received RBCs, plasma and platelets.
Dr. Menis called for studies to determine what effects the processing and storage of blood components may have on TRALI occurrence; he and his colleagues also are planning regression analyses to assess potential risk factors for this complication.
Circulatory overload (TACO)
TACO is one of the leading reported causes of transfusion-related fatalities in the U.S., with onset usually occurring within 6 hours of transfusion, presenting as acute respiratory distress with dyspnea, orthopnea, increased blood pressure, and cardiogenic pulmonary edema.
The overall incidence of TACO among hospitalized patients aged 65 years and older from 2011 through 2018 was 86.3 per 100,000 stays. The incidences were 128.3 in immunocompromised and 76.0 in nonimmunocompromised patients. The rate ratio for TACO in immunocompromised versus nonimmunocompromised patients was 1.70 (P less than .001).
Overall incidence rates of TACO rose from 62 per 100,000 stays in 2011 to 119.8 in 2018. As with other adverse events, incident rates rose with the number of units transfused.
Rates of TACO were significantly higher among women than they were among men (94.6 vs. 75.9 per 100,000; P less than .001), which could be caused by the higher mean age of women and/or a lower tolerance for increased blood volume from transfusion.
The study results also suggested that TACO and TRALI may coexist, based on evidence that 3.5% of all TACO stays also had diagnostic codes for TRALI. The frequency of co-occurrence of these two adverse events also increased over time, which may be caused by improved awareness, Dr. Menis said.
Infections (AIFT)
Acute infections following transfusion can lead to prolonged hospitalizations, sepsis, septic shock, and death. Those most at risk include elderly and immunocompromised patients because of high utilization of blood products, comorbidities, and decreased immune function.
Among 8,833,817 stays, the overall rate per 100,000 stays was 2.1. The rate for immunocompromised patients was 5.4, compared with 1.2 for nonimmunocompromised patients, for a rate ratio of 4.4 (P less than .001).
The incidence rate declined significantly (P = .03) over the study period, with the 3 latest years having the lowest rates.
Rates increased substantially among immunocompromised patients by the number of units transfused, but remained relatively stable among nonimmunocompromised patients.
Infection rates declined with age, from 2.7 per 100,000 stays for patients aged 65-68 years to 1.2 per 100,000 for those aged 85 years and older.
As with other adverse events, AIFT rates were likely related to the blood components transfused, with substantially higher rates for stays during which platelets were transfused either alone or with RBCs, compared with RBCs alone. This could be caused by the room-temperature storage of platelets and higher number of platelets units transfused, compared with RBCs alone, especially among immunocompromised patients.
In all, 51.9% of AIFT cases also had sepsis noted in the medical record, indicating high severity and emphasizing the importance of AIFT prevention, Dr. Menis said.
The studies were funded by the FDA, and Dr. Menis is an FDA employee. He reported having no conflicts of interest.
SAN ANTONIO – Although there has been a general decline in transfusion-related anaphylaxis and acute infections over time among hospitalized older adults in the United States, incidence rates for both transfusion-related acute lung injury and transfusion-associated circulatory overload have risen over the last decade, according to researchers from the Food and Drug Administration.
Mikhail Menis, PharmD, an epidemiologist at the FDA Center for Biologics Evaluation and Research (CBER) and colleagues queried large Medicare databases to assess trends in transfusion-related adverse events among adults aged 65 years and older.
The investigators saw “substantially higher risk of all outcomes among immunocompromised beneficiaries, which could be related to higher blood use of all blood components, especially platelets, underlying conditions such as malignancies, and treatments such as chemotherapy or radiation, which need further investigation,” Dr. Menis said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.
He reported data from a series of studies on four categories of transfusion-related events that may be life-threatening or fatal: transfusion-related anaphylaxis (TRA), transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and acute infection following transfusion (AIFT).
For each type of event, the researchers looked at overall incidence and the incidence by immune status, calendar year, blood components transfused, number of units transfused, age, sex, and race.
Anaphylaxis (TRA)
TRA may be caused by preformed immunoglobin E (IgE) antibodies to proteins in the plasma in transfused blood products or by preformed IgA antibodies in patients who are likely IgA deficient, Dr. Menis said.
The overall incidence of TRA among 8,833,817 inpatient transfusions stays for elderly beneficiaries from 2012 through 2018 was 7.1 per 100,000 stays. The rate was higher for immunocompromised patients, at 9.6, than it was among nonimmunocompromised patients, at 6.5.
The rates varied by every subgroup measured except immune status. Annual rates showed a downward trend, from 8.7 per 100,000 in 2012, to 5.1 in 2017 and 6.4 in 2018. The decline in occurrence may be caused by a decline in inpatient blood utilization during the study period, particularly among immunocompromised patients.
TRA rates increased with five or more units transfused. The risk was significantly reduced in the oldest group of patients versus the youngest (P less than .001), which supports the immune-based mechanism of action of anaphylaxis, Dr. Menis said.
They also found that TRA rates were substantially higher among patients who had received platelet and/or plasma transfusions, compared with patients who received only red blood cells (RBCs).
Additionally, risk for TRA was significantly higher among men than it was among women (9.3 vs. 5.4) and among white versus nonwhite patients (7.8 vs. 3.8).
The evidence suggested TRA cases are likely to be severe in this population, with inpatient mortality of 7.1%, and hospital stays of 7 days or longer in about 58% of cases, indicating the importance of TRA prevention, Dr. Menis said.
The investigators plan to perform multivariate regression analyses to assess potential risk factors, including underlying comorbidities and health histories for TRA occurrence for both the overall population and by immune status.
Acute lung injury (TRALI)
TRALI is a rare but serious adverse event, a clinical syndrome with onset within 6 hours of transfusion that presents as acute hypoxemia, respiratory distress, and noncardiogenic pulmonary edema.
Among 17,771,193 total inpatient transfusion stays, the overall incidence of TRALI was 33.2 per 100,000. The rate was 55.9 for immunocompromised patients versus 28.4 for nonimmunocompromised patients. The rate ratio was 2.0 (P less than .001).
The difference by immune status may be caused by higher blood utilizations with more units transfused per stay among immunocompromised patients, a higher incidence of prior transfusions among these patients, higher use of irradiated blood components that may lead to accumulation of proinflammatory mediators in blood products during storage, or underlying comorbidities.
The overall rate increased from 14.3 in 2007 to 56.4 in 2018. The rates increased proportionally among both immunocompromised and nonimmunocompromised patients.
As with TRA, the incidence of TRALI was higher in patients with five or more units transfused, while the incidence declined with age, likely caused by declining blood use and age-related changes in neutrophil function, Dr. Menis said.
TRALI rates were slightly higher among men than among women, as well as higher among white patients than among nonwhite patients.
Overall, TRALI rates were higher for patients who received platelets either alone or in combination with RBCs and/or plasma. The highest rates were among patients who received RBCs, plasma and platelets.
Dr. Menis called for studies to determine what effects the processing and storage of blood components may have on TRALI occurrence; he and his colleagues also are planning regression analyses to assess potential risk factors for this complication.
Circulatory overload (TACO)
TACO is one of the leading reported causes of transfusion-related fatalities in the U.S., with onset usually occurring within 6 hours of transfusion, presenting as acute respiratory distress with dyspnea, orthopnea, increased blood pressure, and cardiogenic pulmonary edema.
The overall incidence of TACO among hospitalized patients aged 65 years and older from 2011 through 2018 was 86.3 per 100,000 stays. The incidences were 128.3 in immunocompromised and 76.0 in nonimmunocompromised patients. The rate ratio for TACO in immunocompromised versus nonimmunocompromised patients was 1.70 (P less than .001).
Overall incidence rates of TACO rose from 62 per 100,000 stays in 2011 to 119.8 in 2018. As with other adverse events, incident rates rose with the number of units transfused.
Rates of TACO were significantly higher among women than they were among men (94.6 vs. 75.9 per 100,000; P less than .001), which could be caused by the higher mean age of women and/or a lower tolerance for increased blood volume from transfusion.
The study results also suggested that TACO and TRALI may coexist, based on evidence that 3.5% of all TACO stays also had diagnostic codes for TRALI. The frequency of co-occurrence of these two adverse events also increased over time, which may be caused by improved awareness, Dr. Menis said.
Infections (AIFT)
Acute infections following transfusion can lead to prolonged hospitalizations, sepsis, septic shock, and death. Those most at risk include elderly and immunocompromised patients because of high utilization of blood products, comorbidities, and decreased immune function.
Among 8,833,817 stays, the overall rate per 100,000 stays was 2.1. The rate for immunocompromised patients was 5.4, compared with 1.2 for nonimmunocompromised patients, for a rate ratio of 4.4 (P less than .001).
The incidence rate declined significantly (P = .03) over the study period, with the 3 latest years having the lowest rates.
Rates increased substantially among immunocompromised patients by the number of units transfused, but remained relatively stable among nonimmunocompromised patients.
Infection rates declined with age, from 2.7 per 100,000 stays for patients aged 65-68 years to 1.2 per 100,000 for those aged 85 years and older.
As with other adverse events, AIFT rates were likely related to the blood components transfused, with substantially higher rates for stays during which platelets were transfused either alone or with RBCs, compared with RBCs alone. This could be caused by the room-temperature storage of platelets and higher number of platelets units transfused, compared with RBCs alone, especially among immunocompromised patients.
In all, 51.9% of AIFT cases also had sepsis noted in the medical record, indicating high severity and emphasizing the importance of AIFT prevention, Dr. Menis said.
The studies were funded by the FDA, and Dr. Menis is an FDA employee. He reported having no conflicts of interest.
REPORTING FROM AABB 2019
Don’t miss neuromuscular complications of cancer immunotherapy
AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.
At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.
“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.
Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.
Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
CAR T-cell and dendritic cell vaccine therapies
Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.
CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).
Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.
The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.
Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
Immune checkpoint inhibitor toxicities
Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.
The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.
The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).
Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).
Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
Distinguishing features of neuromuscular immunotherapy-related adverse events
MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.
Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.
While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.
Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.
Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.
GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.
Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.
Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.
Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).
Dr Trevino had no disclosures.
AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.
At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.
“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.
Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.
Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
CAR T-cell and dendritic cell vaccine therapies
Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.
CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).
Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.
The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.
Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
Immune checkpoint inhibitor toxicities
Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.
The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.
The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).
Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).
Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
Distinguishing features of neuromuscular immunotherapy-related adverse events
MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.
Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.
While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.
Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.
Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.
GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.
Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.
Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.
Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).
Dr Trevino had no disclosures.
AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.
At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.
“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.
Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.
Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
CAR T-cell and dendritic cell vaccine therapies
Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.
CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).
Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.
The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.
Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
Immune checkpoint inhibitor toxicities
Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.
The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.
The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).
Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).
Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
Distinguishing features of neuromuscular immunotherapy-related adverse events
MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.
Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.
While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.
Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.
Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.
GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.
Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.
Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.
Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).
Dr Trevino had no disclosures.
EXPERT ANALYSIS FROM AANEM 2019
Armored CAR T cells elicit responses in NHL patients
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
REPORTING FROM SITC 2019
FDA approves anemia treatment for transfusion-dependent beta thalassemia patients
The Food and Drug Administration has approved the first treatment for anemia in adults with transfusion-dependent beta thalassemia.
Luspatercept-aamt (Reblozyl) is an erythroid maturation agent that reduced the transfusion burden for patients with beta thalassemia in the BELIEVE trial of 336 patients. In total, 21% of patients who received luspatercept-aamt achieved at least a 33% reduction in red blood cell transfusions, compared with 4.5% of patients who received placebo, according to the FDA.
Common side effects associated with luspatercept-aamt were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. Patients taking the agent should be monitored for thrombosis, the FDA advised.
Celgene, which makes luspatercept-aamt, said the agent would be available about 1 week following the FDA approval.
The FDA is also evaluating luspatercept-aamt as an anemia treatment in adults with very-low– to intermediate-risk myelodysplastic syndromes who have ring sideroblasts and require red blood cell transfusions. The agency is expected to take action on that application in April 2020.
The Food and Drug Administration has approved the first treatment for anemia in adults with transfusion-dependent beta thalassemia.
Luspatercept-aamt (Reblozyl) is an erythroid maturation agent that reduced the transfusion burden for patients with beta thalassemia in the BELIEVE trial of 336 patients. In total, 21% of patients who received luspatercept-aamt achieved at least a 33% reduction in red blood cell transfusions, compared with 4.5% of patients who received placebo, according to the FDA.
Common side effects associated with luspatercept-aamt were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. Patients taking the agent should be monitored for thrombosis, the FDA advised.
Celgene, which makes luspatercept-aamt, said the agent would be available about 1 week following the FDA approval.
The FDA is also evaluating luspatercept-aamt as an anemia treatment in adults with very-low– to intermediate-risk myelodysplastic syndromes who have ring sideroblasts and require red blood cell transfusions. The agency is expected to take action on that application in April 2020.
The Food and Drug Administration has approved the first treatment for anemia in adults with transfusion-dependent beta thalassemia.
Luspatercept-aamt (Reblozyl) is an erythroid maturation agent that reduced the transfusion burden for patients with beta thalassemia in the BELIEVE trial of 336 patients. In total, 21% of patients who received luspatercept-aamt achieved at least a 33% reduction in red blood cell transfusions, compared with 4.5% of patients who received placebo, according to the FDA.
Common side effects associated with luspatercept-aamt were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. Patients taking the agent should be monitored for thrombosis, the FDA advised.
Celgene, which makes luspatercept-aamt, said the agent would be available about 1 week following the FDA approval.
The FDA is also evaluating luspatercept-aamt as an anemia treatment in adults with very-low– to intermediate-risk myelodysplastic syndromes who have ring sideroblasts and require red blood cell transfusions. The agency is expected to take action on that application in April 2020.
U.S. deaths from preventable causes occur more often in rural areas
compared with the most urban counties during 2010-2017, according to study published in CDC’s Morbidity and Mortality Weekly Report.
These leading causes of death comprised heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke and accounted for approximately 1.7 million deaths or 61% of all deaths in 2017.
The study presents estimates, percentages, and annual percent changes for potentially excess deaths by urban-rural classification from heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke. Urban-rural categories were identified using the National Center for Health Statistics 2013 urban-rural classification scheme for counties.
The report’s main findings include the following statistics:
- In 2010, 28.7% of deaths from cancer in the most rural counties were potentially preventable, compared with 17.9% in the most urban counties. By 2017, 21.7% of cancer deaths in the most rural counties were potentially preventable, compared with 3.2% in the most urban counties.
- In 2010, 45.1% of deaths from heart disease in the most rural counties were potentially preventable, compared with 33.5% in the most urban counties. By 2017, 44.9% of deaths from heart disease in the most rural counties were potentially preventable, compared with 28.0% in the most urban counties.
- In 2010, 60.9% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 25.4% in the most urban counties. By 2017, 64.1% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 47.8% in the most urban counties.
- In 2010, 54.3% of deaths from chronic lower respiratory disease (such as COPD) in the most rural counties were potentially preventable, compared with 23.4% in the most urban counties. By 2017, 57.1% of deaths from chronic lower respiratory disease in the most rural counties were potentially preventable, compared with 13% in the most urban counties.
- In 2010, 41.6% of deaths from stroke in the most rural counties were potentially preventable, compared with 31.7% in most urban areas. By 2017, 37.8% of deaths from stroke in the most rural counties were potentially preventable, compared with 27.4% most urban counties.
“This report demonstrates the value of analyzing potentially excess deaths according to the six 2013 [National Center for Health Statistics] urban-rural county classifications. Reporting trends in potentially excess deaths over an 8-year period highlights differences over time, independent of traditional underlying structural, environmental, and genetic factors,” wrote Macarena C. Garcia, DrPH, and coauthors.
“Because of increasing percentages of potentially excess deaths in recent years for certain causes of death and certain demographic groups, these data can be used, with traditional rate comparisons, by public health practitioners who are involved in planning interventions. Comparing the findings in this report with data from tools such as the CDC Interactive Atlas of Heart Disease and Stroke might help identify the social determinants, health care infrastructures, and public policies that could increase or decrease numbers of deaths in specific nonmetropolitan areas,” they added.
The study authors did not disclose any potential conflicts of interest.
SOURCE: Garcia MC et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(10);1-11.
compared with the most urban counties during 2010-2017, according to study published in CDC’s Morbidity and Mortality Weekly Report.
These leading causes of death comprised heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke and accounted for approximately 1.7 million deaths or 61% of all deaths in 2017.
The study presents estimates, percentages, and annual percent changes for potentially excess deaths by urban-rural classification from heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke. Urban-rural categories were identified using the National Center for Health Statistics 2013 urban-rural classification scheme for counties.
The report’s main findings include the following statistics:
- In 2010, 28.7% of deaths from cancer in the most rural counties were potentially preventable, compared with 17.9% in the most urban counties. By 2017, 21.7% of cancer deaths in the most rural counties were potentially preventable, compared with 3.2% in the most urban counties.
- In 2010, 45.1% of deaths from heart disease in the most rural counties were potentially preventable, compared with 33.5% in the most urban counties. By 2017, 44.9% of deaths from heart disease in the most rural counties were potentially preventable, compared with 28.0% in the most urban counties.
- In 2010, 60.9% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 25.4% in the most urban counties. By 2017, 64.1% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 47.8% in the most urban counties.
- In 2010, 54.3% of deaths from chronic lower respiratory disease (such as COPD) in the most rural counties were potentially preventable, compared with 23.4% in the most urban counties. By 2017, 57.1% of deaths from chronic lower respiratory disease in the most rural counties were potentially preventable, compared with 13% in the most urban counties.
- In 2010, 41.6% of deaths from stroke in the most rural counties were potentially preventable, compared with 31.7% in most urban areas. By 2017, 37.8% of deaths from stroke in the most rural counties were potentially preventable, compared with 27.4% most urban counties.
“This report demonstrates the value of analyzing potentially excess deaths according to the six 2013 [National Center for Health Statistics] urban-rural county classifications. Reporting trends in potentially excess deaths over an 8-year period highlights differences over time, independent of traditional underlying structural, environmental, and genetic factors,” wrote Macarena C. Garcia, DrPH, and coauthors.
“Because of increasing percentages of potentially excess deaths in recent years for certain causes of death and certain demographic groups, these data can be used, with traditional rate comparisons, by public health practitioners who are involved in planning interventions. Comparing the findings in this report with data from tools such as the CDC Interactive Atlas of Heart Disease and Stroke might help identify the social determinants, health care infrastructures, and public policies that could increase or decrease numbers of deaths in specific nonmetropolitan areas,” they added.
The study authors did not disclose any potential conflicts of interest.
SOURCE: Garcia MC et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(10);1-11.
compared with the most urban counties during 2010-2017, according to study published in CDC’s Morbidity and Mortality Weekly Report.
These leading causes of death comprised heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke and accounted for approximately 1.7 million deaths or 61% of all deaths in 2017.
The study presents estimates, percentages, and annual percent changes for potentially excess deaths by urban-rural classification from heart disease, cancer, unintentional injury, chronic lower respiratory disease, and stroke. Urban-rural categories were identified using the National Center for Health Statistics 2013 urban-rural classification scheme for counties.
The report’s main findings include the following statistics:
- In 2010, 28.7% of deaths from cancer in the most rural counties were potentially preventable, compared with 17.9% in the most urban counties. By 2017, 21.7% of cancer deaths in the most rural counties were potentially preventable, compared with 3.2% in the most urban counties.
- In 2010, 45.1% of deaths from heart disease in the most rural counties were potentially preventable, compared with 33.5% in the most urban counties. By 2017, 44.9% of deaths from heart disease in the most rural counties were potentially preventable, compared with 28.0% in the most urban counties.
- In 2010, 60.9% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 25.4% in the most urban counties. By 2017, 64.1% of deaths from unintentional injury in the most rural counties were potentially preventable, compared with 47.8% in the most urban counties.
- In 2010, 54.3% of deaths from chronic lower respiratory disease (such as COPD) in the most rural counties were potentially preventable, compared with 23.4% in the most urban counties. By 2017, 57.1% of deaths from chronic lower respiratory disease in the most rural counties were potentially preventable, compared with 13% in the most urban counties.
- In 2010, 41.6% of deaths from stroke in the most rural counties were potentially preventable, compared with 31.7% in most urban areas. By 2017, 37.8% of deaths from stroke in the most rural counties were potentially preventable, compared with 27.4% most urban counties.
“This report demonstrates the value of analyzing potentially excess deaths according to the six 2013 [National Center for Health Statistics] urban-rural county classifications. Reporting trends in potentially excess deaths over an 8-year period highlights differences over time, independent of traditional underlying structural, environmental, and genetic factors,” wrote Macarena C. Garcia, DrPH, and coauthors.
“Because of increasing percentages of potentially excess deaths in recent years for certain causes of death and certain demographic groups, these data can be used, with traditional rate comparisons, by public health practitioners who are involved in planning interventions. Comparing the findings in this report with data from tools such as the CDC Interactive Atlas of Heart Disease and Stroke might help identify the social determinants, health care infrastructures, and public policies that could increase or decrease numbers of deaths in specific nonmetropolitan areas,” they added.
The study authors did not disclose any potential conflicts of interest.
SOURCE: Garcia MC et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(10);1-11.
Best practice alerts really can work
SAN ANTONIO – Clinicians don’t appear to mind too much when their red blood cell orders are flagged for review by a best practice alert system, and alert fatigue doesn’t seem to hamper patient blood management efforts, investigators in a single-center study reported.
At the Medical University of South Carolina, Charleston (MUSC), if clinicians order RBC transfusions for patients with hemoglobin levels over 7.0 g/dL or for patients who did not have a hemoglobin determination over the past 24 hours, they receive a best practice alert. They must acknowledge it and cancel the order, or override it and document a reason in the medical record.
Although approximately 70% of alerts were overridden, the reasons for the overrides “were consistent over time and appropriate,” reported Jerry E. Squires, MD, PhD, and colleagues from MUSC in a poster presentation at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.
The goal of the study was to find out if the effectiveness of the alert was wearing out after months of active use by clinicians. “Is it true that they’re clicking too much and they’re inundated with other [best practice alerts], and are they even paying attention?” said coauthor Heather Toeppner, RN, also from MUSC, in an interview. “All in all, we found that the alert is making a lasting impression in our institution,” she said.
Transfusion clinical decision support systems that produce automated alerts for clinicians can improve usage and reduce waste of RBCs, but whether the effect is sustained over time was unknown, Ms. Toeppner said, prompting the investigators to study the effect of the RBC best practice alert over 10 months.
As noted, the alert is triggered when providers order RBCs for patients with hemoglobin levels over 7.0 g/dL or when there is no record of a hemoglobin test in the chart within the past 24 hours. Before the alert is triggered, however, the system reviews the record and excludes alerts for patients with specific conditions, such as concurrent surgery or sickle cell disease.
The authors found that the alert was triggered an average of 195 times per month over the 10 months studied. On average, 16% of the alerts resulted in a cancellation of the RBC order, and 71% of alerts were overridden.
“Most importantly, there was no trend suggesting that either cancellation of the RBC order or overriding the alert became more frequent over time,” the investigators wrote. “Similarly, reasons for overriding the alert were consistent over time, with ‘preparation for an invasive procedure’ and ‘active bleeding’ being the most common reasons for overriding the alert (32% and 23% of all overrides, respectively).”
Other common reasons for overrides included tachycardia, shortness of breath, hypotension, onset of chest pain, and acute coronary syndrome.
Interestingly, but perhaps not surprisingly, they found that overrides dropped sharply and changed orders rose by the same magnitude in July, when new residents started their rotations.
The investigators wrote that the relatively small number of alerts may be attributable to their institution’s robust patient blood management program and the intentional exclusion of orders for patients with specific diagnostic codes, including intraoperative patients, those with sickle cell disease, and all patients aged younger than 18 years.
The study was internally funded. The authors reported having no conflicts of interest.
SAN ANTONIO – Clinicians don’t appear to mind too much when their red blood cell orders are flagged for review by a best practice alert system, and alert fatigue doesn’t seem to hamper patient blood management efforts, investigators in a single-center study reported.
At the Medical University of South Carolina, Charleston (MUSC), if clinicians order RBC transfusions for patients with hemoglobin levels over 7.0 g/dL or for patients who did not have a hemoglobin determination over the past 24 hours, they receive a best practice alert. They must acknowledge it and cancel the order, or override it and document a reason in the medical record.
Although approximately 70% of alerts were overridden, the reasons for the overrides “were consistent over time and appropriate,” reported Jerry E. Squires, MD, PhD, and colleagues from MUSC in a poster presentation at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.
The goal of the study was to find out if the effectiveness of the alert was wearing out after months of active use by clinicians. “Is it true that they’re clicking too much and they’re inundated with other [best practice alerts], and are they even paying attention?” said coauthor Heather Toeppner, RN, also from MUSC, in an interview. “All in all, we found that the alert is making a lasting impression in our institution,” she said.
Transfusion clinical decision support systems that produce automated alerts for clinicians can improve usage and reduce waste of RBCs, but whether the effect is sustained over time was unknown, Ms. Toeppner said, prompting the investigators to study the effect of the RBC best practice alert over 10 months.
As noted, the alert is triggered when providers order RBCs for patients with hemoglobin levels over 7.0 g/dL or when there is no record of a hemoglobin test in the chart within the past 24 hours. Before the alert is triggered, however, the system reviews the record and excludes alerts for patients with specific conditions, such as concurrent surgery or sickle cell disease.
The authors found that the alert was triggered an average of 195 times per month over the 10 months studied. On average, 16% of the alerts resulted in a cancellation of the RBC order, and 71% of alerts were overridden.
“Most importantly, there was no trend suggesting that either cancellation of the RBC order or overriding the alert became more frequent over time,” the investigators wrote. “Similarly, reasons for overriding the alert were consistent over time, with ‘preparation for an invasive procedure’ and ‘active bleeding’ being the most common reasons for overriding the alert (32% and 23% of all overrides, respectively).”
Other common reasons for overrides included tachycardia, shortness of breath, hypotension, onset of chest pain, and acute coronary syndrome.
Interestingly, but perhaps not surprisingly, they found that overrides dropped sharply and changed orders rose by the same magnitude in July, when new residents started their rotations.
The investigators wrote that the relatively small number of alerts may be attributable to their institution’s robust patient blood management program and the intentional exclusion of orders for patients with specific diagnostic codes, including intraoperative patients, those with sickle cell disease, and all patients aged younger than 18 years.
The study was internally funded. The authors reported having no conflicts of interest.
SAN ANTONIO – Clinicians don’t appear to mind too much when their red blood cell orders are flagged for review by a best practice alert system, and alert fatigue doesn’t seem to hamper patient blood management efforts, investigators in a single-center study reported.
At the Medical University of South Carolina, Charleston (MUSC), if clinicians order RBC transfusions for patients with hemoglobin levels over 7.0 g/dL or for patients who did not have a hemoglobin determination over the past 24 hours, they receive a best practice alert. They must acknowledge it and cancel the order, or override it and document a reason in the medical record.
Although approximately 70% of alerts were overridden, the reasons for the overrides “were consistent over time and appropriate,” reported Jerry E. Squires, MD, PhD, and colleagues from MUSC in a poster presentation at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.
The goal of the study was to find out if the effectiveness of the alert was wearing out after months of active use by clinicians. “Is it true that they’re clicking too much and they’re inundated with other [best practice alerts], and are they even paying attention?” said coauthor Heather Toeppner, RN, also from MUSC, in an interview. “All in all, we found that the alert is making a lasting impression in our institution,” she said.
Transfusion clinical decision support systems that produce automated alerts for clinicians can improve usage and reduce waste of RBCs, but whether the effect is sustained over time was unknown, Ms. Toeppner said, prompting the investigators to study the effect of the RBC best practice alert over 10 months.
As noted, the alert is triggered when providers order RBCs for patients with hemoglobin levels over 7.0 g/dL or when there is no record of a hemoglobin test in the chart within the past 24 hours. Before the alert is triggered, however, the system reviews the record and excludes alerts for patients with specific conditions, such as concurrent surgery or sickle cell disease.
The authors found that the alert was triggered an average of 195 times per month over the 10 months studied. On average, 16% of the alerts resulted in a cancellation of the RBC order, and 71% of alerts were overridden.
“Most importantly, there was no trend suggesting that either cancellation of the RBC order or overriding the alert became more frequent over time,” the investigators wrote. “Similarly, reasons for overriding the alert were consistent over time, with ‘preparation for an invasive procedure’ and ‘active bleeding’ being the most common reasons for overriding the alert (32% and 23% of all overrides, respectively).”
Other common reasons for overrides included tachycardia, shortness of breath, hypotension, onset of chest pain, and acute coronary syndrome.
Interestingly, but perhaps not surprisingly, they found that overrides dropped sharply and changed orders rose by the same magnitude in July, when new residents started their rotations.
The investigators wrote that the relatively small number of alerts may be attributable to their institution’s robust patient blood management program and the intentional exclusion of orders for patients with specific diagnostic codes, including intraoperative patients, those with sickle cell disease, and all patients aged younger than 18 years.
The study was internally funded. The authors reported having no conflicts of interest.
REPORTING FROM AABB 2019
Fresh RBCs offer no benefit over older cells in pediatric ICU
SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.
Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.
“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.
The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”
Is fresh really better?
The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.
Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.
Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.
The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.
There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.
The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.
There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).
Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.
Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.
Why no difference?
Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.
“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.
Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.
ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.
SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.
Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.
“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.
The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”
Is fresh really better?
The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.
Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.
Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.
The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.
There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.
The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.
There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).
Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.
Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.
Why no difference?
Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.
“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.
Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.
ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.
SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.
Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.
“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.
The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”
Is fresh really better?
The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.
Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.
Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.
The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.
There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.
The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.
There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).
Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.
Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.
Why no difference?
Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.
“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.
Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.
ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.
REPORTING FROM AABB 2019
Levofloxacin prophylaxis improves survival in newly diagnosed myeloma
Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.
The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.
The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.
Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.
At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.
After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).
With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).
“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.
One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.
“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.
The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.
SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.
Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.
The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.
The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.
Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.
At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.
After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).
With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).
“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.
One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.
“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.
The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.
SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.
Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.
The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.
The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.
Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.
At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.
After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).
With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).
“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.
One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.
“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.
The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.
SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.
FROM LANCET ONCOLOGY
Atraumatic splenic rupture in acute myeloid leukemia
A 50-year-old man with acute myeloid leukemia (AML) with a complex karyotype was admitted to the hospital with several days of dull, left-sided abdominal pain. His most recent bone marrow biopsy showed 30% blasts, and immunophenotyping was suggestive of persistent AML (CD13+, CD34+, CD117+, CD33+, CD7+, MPO–). He was on treatment with venetoclax and cytarabine after induction therapy had failed.
On admission, his heart rate was 101 beats per minute and his blood pressure was 122/85 mm Hg. Abdominal examination revealed mild distention, hepatomegaly, and previously known massive splenomegaly, with the splenic tip extending to the umbilicus, and mild tenderness.
Results of laboratory testing revealed persistent pancytopenia:
- Hemoglobin level 6.8 g/dL (reference range 13.0–17.0)
- Total white blood cell count 0.8 × 109/L (4.5–11.0)
- Platelet count 8 × 109/L (150–400).
The next day, he developed severe, acute-onset left-sided abdominal pain. A check of vital signs showed worsening sinus tachycardia at 132 beats per minute and a drop in blood pressure to 90/56 mm Hg. He had worsening diffuse abdominal tenderness with sluggish bowel sounds. His hemoglobin concentration was 6.4 g/dL and platelet count 12 × 109/L.
He received supportive transfusions of blood products. Surgical exploration was deemed risky, given his overall condition and severe thrombocytopenia. Splenic angiography showed no evidence of pseudoaneurysm or focal contrast extravasation. He underwent empiric embolization of the midsplenic artery, after which his hemodynamic status stabilized. He died 4 weeks later of acute respiratory failure from pneumonia.
SPLENIC RUPTURE IN AML
Atraumatic splenic rupture is rare but potentially life-threatening, especially if the diagnosis is delayed. Conditions that can cause splenomegaly and predispose to rupture include infection (infectious mononucleosis, malaria), malignant hematologic disorders (leukemia, lymphoma), other neoplasms, and amyloidosis.1
The literature includes a few reports of splenic rupture in patients with AML.2–4 The proposed mechanisms include bleeding from infarction sites or tumor foci, dysregulated hemostasis, and leukostasis.
The classic presentation of splenic rupture is acute-onset left-sided abdominal pain associated with hypotension and decreasing hemoglobin levels. CT of the abdomen is confirmatory, and resuscitation with crystalloids and blood products is a vital initial step in management. Choice of treatment depends on the patient’s surgical risk and hemodynamic status; options include conservative medical management, splenic artery embolization, and exploratory laparotomy.
In patients with AML and splenomegaly presenting with acute abdominal pain, clinicians need to be aware of this potential hematologic emergency.
- Renzulli P, Hostettler A, Schoepfer AM, Gloor B, Candinas D. Systematic review of atraumatic splenic rupture. Br J Surg 2009; 96(10):1114–1121. doi:10.1002/bjs.6737
- Gardner JA, Bao L, Ornstein DL. Spontaneous splenic rupture in acute myeloid leukemia with mixed-lineage leukemia gene rearrangement. Med Rep Case Stud 2016; 1:119. doi:10.4172/2572-5130.1000119
- Zeidan AM, Mitchell M, Khatri R, et al. Spontaneous splenic rupture during induction chemotherapy for acute myeloid leukemia. Leuk Lymphoma 2014; 55(1):209–212. doi:10.3109/10428194.2013.796060
- Fahmi Y, Elabbasi T, Khaiz D, et al. Splenic spontaneous rupture associated with acute myeloïd leukemia: report of a case and literature review. Surgery Curr Res 2014; 4:170. doi:10.4172/2161-1076.1000170
A 50-year-old man with acute myeloid leukemia (AML) with a complex karyotype was admitted to the hospital with several days of dull, left-sided abdominal pain. His most recent bone marrow biopsy showed 30% blasts, and immunophenotyping was suggestive of persistent AML (CD13+, CD34+, CD117+, CD33+, CD7+, MPO–). He was on treatment with venetoclax and cytarabine after induction therapy had failed.
On admission, his heart rate was 101 beats per minute and his blood pressure was 122/85 mm Hg. Abdominal examination revealed mild distention, hepatomegaly, and previously known massive splenomegaly, with the splenic tip extending to the umbilicus, and mild tenderness.
Results of laboratory testing revealed persistent pancytopenia:
- Hemoglobin level 6.8 g/dL (reference range 13.0–17.0)
- Total white blood cell count 0.8 × 109/L (4.5–11.0)
- Platelet count 8 × 109/L (150–400).
The next day, he developed severe, acute-onset left-sided abdominal pain. A check of vital signs showed worsening sinus tachycardia at 132 beats per minute and a drop in blood pressure to 90/56 mm Hg. He had worsening diffuse abdominal tenderness with sluggish bowel sounds. His hemoglobin concentration was 6.4 g/dL and platelet count 12 × 109/L.
He received supportive transfusions of blood products. Surgical exploration was deemed risky, given his overall condition and severe thrombocytopenia. Splenic angiography showed no evidence of pseudoaneurysm or focal contrast extravasation. He underwent empiric embolization of the midsplenic artery, after which his hemodynamic status stabilized. He died 4 weeks later of acute respiratory failure from pneumonia.
SPLENIC RUPTURE IN AML
Atraumatic splenic rupture is rare but potentially life-threatening, especially if the diagnosis is delayed. Conditions that can cause splenomegaly and predispose to rupture include infection (infectious mononucleosis, malaria), malignant hematologic disorders (leukemia, lymphoma), other neoplasms, and amyloidosis.1
The literature includes a few reports of splenic rupture in patients with AML.2–4 The proposed mechanisms include bleeding from infarction sites or tumor foci, dysregulated hemostasis, and leukostasis.
The classic presentation of splenic rupture is acute-onset left-sided abdominal pain associated with hypotension and decreasing hemoglobin levels. CT of the abdomen is confirmatory, and resuscitation with crystalloids and blood products is a vital initial step in management. Choice of treatment depends on the patient’s surgical risk and hemodynamic status; options include conservative medical management, splenic artery embolization, and exploratory laparotomy.
In patients with AML and splenomegaly presenting with acute abdominal pain, clinicians need to be aware of this potential hematologic emergency.
A 50-year-old man with acute myeloid leukemia (AML) with a complex karyotype was admitted to the hospital with several days of dull, left-sided abdominal pain. His most recent bone marrow biopsy showed 30% blasts, and immunophenotyping was suggestive of persistent AML (CD13+, CD34+, CD117+, CD33+, CD7+, MPO–). He was on treatment with venetoclax and cytarabine after induction therapy had failed.
On admission, his heart rate was 101 beats per minute and his blood pressure was 122/85 mm Hg. Abdominal examination revealed mild distention, hepatomegaly, and previously known massive splenomegaly, with the splenic tip extending to the umbilicus, and mild tenderness.
Results of laboratory testing revealed persistent pancytopenia:
- Hemoglobin level 6.8 g/dL (reference range 13.0–17.0)
- Total white blood cell count 0.8 × 109/L (4.5–11.0)
- Platelet count 8 × 109/L (150–400).
The next day, he developed severe, acute-onset left-sided abdominal pain. A check of vital signs showed worsening sinus tachycardia at 132 beats per minute and a drop in blood pressure to 90/56 mm Hg. He had worsening diffuse abdominal tenderness with sluggish bowel sounds. His hemoglobin concentration was 6.4 g/dL and platelet count 12 × 109/L.
He received supportive transfusions of blood products. Surgical exploration was deemed risky, given his overall condition and severe thrombocytopenia. Splenic angiography showed no evidence of pseudoaneurysm or focal contrast extravasation. He underwent empiric embolization of the midsplenic artery, after which his hemodynamic status stabilized. He died 4 weeks later of acute respiratory failure from pneumonia.
SPLENIC RUPTURE IN AML
Atraumatic splenic rupture is rare but potentially life-threatening, especially if the diagnosis is delayed. Conditions that can cause splenomegaly and predispose to rupture include infection (infectious mononucleosis, malaria), malignant hematologic disorders (leukemia, lymphoma), other neoplasms, and amyloidosis.1
The literature includes a few reports of splenic rupture in patients with AML.2–4 The proposed mechanisms include bleeding from infarction sites or tumor foci, dysregulated hemostasis, and leukostasis.
The classic presentation of splenic rupture is acute-onset left-sided abdominal pain associated with hypotension and decreasing hemoglobin levels. CT of the abdomen is confirmatory, and resuscitation with crystalloids and blood products is a vital initial step in management. Choice of treatment depends on the patient’s surgical risk and hemodynamic status; options include conservative medical management, splenic artery embolization, and exploratory laparotomy.
In patients with AML and splenomegaly presenting with acute abdominal pain, clinicians need to be aware of this potential hematologic emergency.
- Renzulli P, Hostettler A, Schoepfer AM, Gloor B, Candinas D. Systematic review of atraumatic splenic rupture. Br J Surg 2009; 96(10):1114–1121. doi:10.1002/bjs.6737
- Gardner JA, Bao L, Ornstein DL. Spontaneous splenic rupture in acute myeloid leukemia with mixed-lineage leukemia gene rearrangement. Med Rep Case Stud 2016; 1:119. doi:10.4172/2572-5130.1000119
- Zeidan AM, Mitchell M, Khatri R, et al. Spontaneous splenic rupture during induction chemotherapy for acute myeloid leukemia. Leuk Lymphoma 2014; 55(1):209–212. doi:10.3109/10428194.2013.796060
- Fahmi Y, Elabbasi T, Khaiz D, et al. Splenic spontaneous rupture associated with acute myeloïd leukemia: report of a case and literature review. Surgery Curr Res 2014; 4:170. doi:10.4172/2161-1076.1000170
- Renzulli P, Hostettler A, Schoepfer AM, Gloor B, Candinas D. Systematic review of atraumatic splenic rupture. Br J Surg 2009; 96(10):1114–1121. doi:10.1002/bjs.6737
- Gardner JA, Bao L, Ornstein DL. Spontaneous splenic rupture in acute myeloid leukemia with mixed-lineage leukemia gene rearrangement. Med Rep Case Stud 2016; 1:119. doi:10.4172/2572-5130.1000119
- Zeidan AM, Mitchell M, Khatri R, et al. Spontaneous splenic rupture during induction chemotherapy for acute myeloid leukemia. Leuk Lymphoma 2014; 55(1):209–212. doi:10.3109/10428194.2013.796060
- Fahmi Y, Elabbasi T, Khaiz D, et al. Splenic spontaneous rupture associated with acute myeloïd leukemia: report of a case and literature review. Surgery Curr Res 2014; 4:170. doi:10.4172/2161-1076.1000170
