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HCV on the Rise Among Women Giving Birth
Between 2009 and 2014, hepatitis C virus (HCV) infection among women giving birth rose 89%, from 1.8 to 3.4 per live births, according to a study published in Morbidity and Mortality Weekly Report. The researchers say, geographically, the increase in maternal HCV infection mirrors increases in HCV incidence among adults. The highest infection rate was in West Virginia, which had 22.6 per 1,000 live births. Next was Tennessee with 10.1. State infection rates varied widely: Hawaii had the lowest rate, of 0.7.
In Tennessee, the prevalence of maternal HCV infection increased 163%, from 3.8 per 1,000 in 2009 to 10 in 2014. But even among the 95 Tennessee counties, rates varied substantially. The highest rates were in the 52 Appalachian counties. Campbell County had 78 per 1,000 births. Compared with women in urban areas, pregnant women from rural areas had triple the odds of HCV infection. The rise in infection among pregnant women coincides with the rises in heroin and prescription opioid epidemics, which also disproportionately affect rural populations.
Analyzing the Tennessee births, researchers found that the odds of HCV infection were about 5 times higher among women who smoked cigarettes during pregnancy. Concurrent infections were another serious risk factor, with hepatitis B virus infection boosting the odds of HCV infection by nearly 17 times.
HCV infection is a growing—but modifiable—threat among pregnant women, the researchers say. The rise in infection is “particularly concerning,” in light of recent research that has found poor follow-up of HCV-exposed infants. The researchers cite a Philadelphia study that found only 16% of HCV-exposed infants were appropriately followed. That could mean that infected infants are going undetected, the researchers say. The rate of transmission from mothers to infants is estimated at 6%; it’s important for exposed infants to be followed for evidence of seroconversion. But anti-HCV antibody tests can’t be completed until 18 months because passively acquired maternal antibodies can persist. Testing for HCV ribonucleic acid can be performed earlier.
The CDC and the American College of Obstetricians and Gynecologists recommend selective screening of pregnant women at high risk for HCV infection, particularly those with a history of injection drug use or long-term hemodialysis.
Between 2009 and 2014, hepatitis C virus (HCV) infection among women giving birth rose 89%, from 1.8 to 3.4 per live births, according to a study published in Morbidity and Mortality Weekly Report. The researchers say, geographically, the increase in maternal HCV infection mirrors increases in HCV incidence among adults. The highest infection rate was in West Virginia, which had 22.6 per 1,000 live births. Next was Tennessee with 10.1. State infection rates varied widely: Hawaii had the lowest rate, of 0.7.
In Tennessee, the prevalence of maternal HCV infection increased 163%, from 3.8 per 1,000 in 2009 to 10 in 2014. But even among the 95 Tennessee counties, rates varied substantially. The highest rates were in the 52 Appalachian counties. Campbell County had 78 per 1,000 births. Compared with women in urban areas, pregnant women from rural areas had triple the odds of HCV infection. The rise in infection among pregnant women coincides with the rises in heroin and prescription opioid epidemics, which also disproportionately affect rural populations.
Analyzing the Tennessee births, researchers found that the odds of HCV infection were about 5 times higher among women who smoked cigarettes during pregnancy. Concurrent infections were another serious risk factor, with hepatitis B virus infection boosting the odds of HCV infection by nearly 17 times.
HCV infection is a growing—but modifiable—threat among pregnant women, the researchers say. The rise in infection is “particularly concerning,” in light of recent research that has found poor follow-up of HCV-exposed infants. The researchers cite a Philadelphia study that found only 16% of HCV-exposed infants were appropriately followed. That could mean that infected infants are going undetected, the researchers say. The rate of transmission from mothers to infants is estimated at 6%; it’s important for exposed infants to be followed for evidence of seroconversion. But anti-HCV antibody tests can’t be completed until 18 months because passively acquired maternal antibodies can persist. Testing for HCV ribonucleic acid can be performed earlier.
The CDC and the American College of Obstetricians and Gynecologists recommend selective screening of pregnant women at high risk for HCV infection, particularly those with a history of injection drug use or long-term hemodialysis.
Between 2009 and 2014, hepatitis C virus (HCV) infection among women giving birth rose 89%, from 1.8 to 3.4 per live births, according to a study published in Morbidity and Mortality Weekly Report. The researchers say, geographically, the increase in maternal HCV infection mirrors increases in HCV incidence among adults. The highest infection rate was in West Virginia, which had 22.6 per 1,000 live births. Next was Tennessee with 10.1. State infection rates varied widely: Hawaii had the lowest rate, of 0.7.
In Tennessee, the prevalence of maternal HCV infection increased 163%, from 3.8 per 1,000 in 2009 to 10 in 2014. But even among the 95 Tennessee counties, rates varied substantially. The highest rates were in the 52 Appalachian counties. Campbell County had 78 per 1,000 births. Compared with women in urban areas, pregnant women from rural areas had triple the odds of HCV infection. The rise in infection among pregnant women coincides with the rises in heroin and prescription opioid epidemics, which also disproportionately affect rural populations.
Analyzing the Tennessee births, researchers found that the odds of HCV infection were about 5 times higher among women who smoked cigarettes during pregnancy. Concurrent infections were another serious risk factor, with hepatitis B virus infection boosting the odds of HCV infection by nearly 17 times.
HCV infection is a growing—but modifiable—threat among pregnant women, the researchers say. The rise in infection is “particularly concerning,” in light of recent research that has found poor follow-up of HCV-exposed infants. The researchers cite a Philadelphia study that found only 16% of HCV-exposed infants were appropriately followed. That could mean that infected infants are going undetected, the researchers say. The rate of transmission from mothers to infants is estimated at 6%; it’s important for exposed infants to be followed for evidence of seroconversion. But anti-HCV antibody tests can’t be completed until 18 months because passively acquired maternal antibodies can persist. Testing for HCV ribonucleic acid can be performed earlier.
The CDC and the American College of Obstetricians and Gynecologists recommend selective screening of pregnant women at high risk for HCV infection, particularly those with a history of injection drug use or long-term hemodialysis.
Treatment of low bone density or osteoporosis to prevent fractures in men and women
Osteoporosis is defined by a clinically diagnosed fragility fracture or a bone mineral density (BMD) of at least 2.5 SD below the mean for young female adults, usually measured by dual-energy x-ray absorptiometry. Risk factors include age, female sex, post-menopause, hypogonadism or premature ovarian failure, history of cigarette smoking or alcohol consumption (3 or more drinks daily), rheumatoid arthritis, or medications including glucocorticoids, anticoagulants, anticonvulsants, and aromatase inhibitors.
This guideline update focuses on treatment with bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid) and denosumab. Denosumab, a human monoclonal antibody against RANK-ligand, approved by the Food and Drug Administration for treatment of osteoporosis, has been added to the list of allowed medications since publication of the 2008 guideline. Several therapies have been excluded from the update, including calcitonin, which is no longer widely used for osteoporosis treatment, and etidronate and pamidronate, neither of which are FDA-approved for the prevention of fractures or treatment of osteoporosis. It should be noted that the evidence continues to be insufficient regarding the effectiveness of therapies to prevent fractures or to treat osteoporosis in men.
Bisphosphonates are associated with mild upper GI symptoms, atypical subtrochanteric fracture, and rare osteonecrosis of the jaw. There is no significant association between bisphosphonate use and total cardiovascular adverse events. Evidence is insufficient to associate bisphosphonates with increased cancer risk. Zoledronic acid is associated with atrial fibrillation, arthritis/arthralgias, headaches, hypocalcemia, influenza-like symptoms, and an increased incidence of uveitis/episcleritis. Denosumab is associated with mild upper GI symptoms, rash/eczema, and cellulitis.
While in the past additional medications were recommended for osteoporosis, the current guidelines recommend against using raloxifene, ibandronate, teriparatide, menopausal estrogen therapy, or menopausal estrogen plus progesterone therapy for first-line pharmacologic treatment.
The overall effect of calcium, vitamin D, or exercise alone on fracture risk is uncertain. Calcium and vitamin D may be added to treatment regimens, as a majority of trials with bisphosphonate therapy added this supplementation. Dosages should be considered because excessive dosing has been associated with hypercalcemia. Although previous data suggested an association between calcium supplementation and increased risk for myocardial infarction, moderate-quality evidence shows no association, though there is a risk of kidney stones.
Recommendation: Women who have osteoporosis and receive pharmacologic treatment should be treated for 5 years (weak recommendation; low-quality evidence). The evidence to determine the length of treatment is not strong, so recommendation is an extrapolation from existing evidence. High-risk patients may benefit from more than 5 years of treatment. Data suggests that patients treated with alendronate who had preexisting fractures or those with a BMD of –2.5 or less after 5 years of initial therapy may benefit from continued treatment, because these patients experienced a decreased incidence of new clinical vertebral fractures.
Recommendation: Pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture can be offered to men who have clinically recognized osteoporosis (weak recommendation, low-quality evidence). No evidence suggests that outcomes associated with pharmacologic treatment would differ between men and women if based on similar BMDs.
Recommendation: Bone density monitoring is not recommended during the 5-year pharmacologic treatment period for osteoporosis in women (weak recommendation, low-quality evidence). Data showed that most women with normal dual-energy x-ray absorptiometry scores did not progress to osteoporosis within 15 years. Data also does not support monitoring BMD during the initial 5 years of treatment in patients taking pharmacologic agents to treat osteoporosis. Several studies showed that women treated with antiresorptive treatment benefited from reduced fractures with treatment even if BMD did not increase.
Only 10% of women with normal or mild osteopenia develop osteoporosis within 15 years; 10% of women with moderate osteopenia develop osteoporosis within 5 years, and 10% of women with advanced osteopenia develop osteoporosis within 1 year.
Recommendation: The decision about whether to treat osteopenic women older then 65 years of age who are at a high risk for fracture should be based on a discussion of with the patient about their risk of fracture and the risk and benefits of treatment. Clinicians can use their judgment regarding the qualitative risk for fracture, or a validated tool such as the FRAX tool that gives 10-year risk of any major osteoporotic fracture and of hip fracture. The FRAX site recommends consideration of treatment for individuals with low bone mass (T-score between –1.0 and –2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture of at least 3% or a 10-year probability of a major osteoporosis-related fracture greater than 20%.
Bottom line:
Clinicians should offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk of hip and vertebral fractures in women who have known osteoporosis diagnosed as a T score less than –2.5 or those with a fragility fracture. Pharmacologic therapy should be used for 5 years; however, high risk patients may benefit from longer treatment. There is no benefit to bone density monitoring during the 5-year pharmacologic treatment period. In addition, bisphosphonates should be considered in men who have clinically recognized osteoporosis.
Reference:
Qaseem, A, Forciea, MA, McLean RM, Denberg TD. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Int Med. 2017;166(11):818-39.
Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Meizinger is a second year resident in the Family Medicine Residency Program at Abington Jefferson Health.
Osteoporosis is defined by a clinically diagnosed fragility fracture or a bone mineral density (BMD) of at least 2.5 SD below the mean for young female adults, usually measured by dual-energy x-ray absorptiometry. Risk factors include age, female sex, post-menopause, hypogonadism or premature ovarian failure, history of cigarette smoking or alcohol consumption (3 or more drinks daily), rheumatoid arthritis, or medications including glucocorticoids, anticoagulants, anticonvulsants, and aromatase inhibitors.
This guideline update focuses on treatment with bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid) and denosumab. Denosumab, a human monoclonal antibody against RANK-ligand, approved by the Food and Drug Administration for treatment of osteoporosis, has been added to the list of allowed medications since publication of the 2008 guideline. Several therapies have been excluded from the update, including calcitonin, which is no longer widely used for osteoporosis treatment, and etidronate and pamidronate, neither of which are FDA-approved for the prevention of fractures or treatment of osteoporosis. It should be noted that the evidence continues to be insufficient regarding the effectiveness of therapies to prevent fractures or to treat osteoporosis in men.
Bisphosphonates are associated with mild upper GI symptoms, atypical subtrochanteric fracture, and rare osteonecrosis of the jaw. There is no significant association between bisphosphonate use and total cardiovascular adverse events. Evidence is insufficient to associate bisphosphonates with increased cancer risk. Zoledronic acid is associated with atrial fibrillation, arthritis/arthralgias, headaches, hypocalcemia, influenza-like symptoms, and an increased incidence of uveitis/episcleritis. Denosumab is associated with mild upper GI symptoms, rash/eczema, and cellulitis.
While in the past additional medications were recommended for osteoporosis, the current guidelines recommend against using raloxifene, ibandronate, teriparatide, menopausal estrogen therapy, or menopausal estrogen plus progesterone therapy for first-line pharmacologic treatment.
The overall effect of calcium, vitamin D, or exercise alone on fracture risk is uncertain. Calcium and vitamin D may be added to treatment regimens, as a majority of trials with bisphosphonate therapy added this supplementation. Dosages should be considered because excessive dosing has been associated with hypercalcemia. Although previous data suggested an association between calcium supplementation and increased risk for myocardial infarction, moderate-quality evidence shows no association, though there is a risk of kidney stones.
Recommendation: Women who have osteoporosis and receive pharmacologic treatment should be treated for 5 years (weak recommendation; low-quality evidence). The evidence to determine the length of treatment is not strong, so recommendation is an extrapolation from existing evidence. High-risk patients may benefit from more than 5 years of treatment. Data suggests that patients treated with alendronate who had preexisting fractures or those with a BMD of –2.5 or less after 5 years of initial therapy may benefit from continued treatment, because these patients experienced a decreased incidence of new clinical vertebral fractures.
Recommendation: Pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture can be offered to men who have clinically recognized osteoporosis (weak recommendation, low-quality evidence). No evidence suggests that outcomes associated with pharmacologic treatment would differ between men and women if based on similar BMDs.
Recommendation: Bone density monitoring is not recommended during the 5-year pharmacologic treatment period for osteoporosis in women (weak recommendation, low-quality evidence). Data showed that most women with normal dual-energy x-ray absorptiometry scores did not progress to osteoporosis within 15 years. Data also does not support monitoring BMD during the initial 5 years of treatment in patients taking pharmacologic agents to treat osteoporosis. Several studies showed that women treated with antiresorptive treatment benefited from reduced fractures with treatment even if BMD did not increase.
Only 10% of women with normal or mild osteopenia develop osteoporosis within 15 years; 10% of women with moderate osteopenia develop osteoporosis within 5 years, and 10% of women with advanced osteopenia develop osteoporosis within 1 year.
Recommendation: The decision about whether to treat osteopenic women older then 65 years of age who are at a high risk for fracture should be based on a discussion of with the patient about their risk of fracture and the risk and benefits of treatment. Clinicians can use their judgment regarding the qualitative risk for fracture, or a validated tool such as the FRAX tool that gives 10-year risk of any major osteoporotic fracture and of hip fracture. The FRAX site recommends consideration of treatment for individuals with low bone mass (T-score between –1.0 and –2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture of at least 3% or a 10-year probability of a major osteoporosis-related fracture greater than 20%.
Bottom line:
Clinicians should offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk of hip and vertebral fractures in women who have known osteoporosis diagnosed as a T score less than –2.5 or those with a fragility fracture. Pharmacologic therapy should be used for 5 years; however, high risk patients may benefit from longer treatment. There is no benefit to bone density monitoring during the 5-year pharmacologic treatment period. In addition, bisphosphonates should be considered in men who have clinically recognized osteoporosis.
Reference:
Qaseem, A, Forciea, MA, McLean RM, Denberg TD. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Int Med. 2017;166(11):818-39.
Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Meizinger is a second year resident in the Family Medicine Residency Program at Abington Jefferson Health.
Osteoporosis is defined by a clinically diagnosed fragility fracture or a bone mineral density (BMD) of at least 2.5 SD below the mean for young female adults, usually measured by dual-energy x-ray absorptiometry. Risk factors include age, female sex, post-menopause, hypogonadism or premature ovarian failure, history of cigarette smoking or alcohol consumption (3 or more drinks daily), rheumatoid arthritis, or medications including glucocorticoids, anticoagulants, anticonvulsants, and aromatase inhibitors.
This guideline update focuses on treatment with bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid) and denosumab. Denosumab, a human monoclonal antibody against RANK-ligand, approved by the Food and Drug Administration for treatment of osteoporosis, has been added to the list of allowed medications since publication of the 2008 guideline. Several therapies have been excluded from the update, including calcitonin, which is no longer widely used for osteoporosis treatment, and etidronate and pamidronate, neither of which are FDA-approved for the prevention of fractures or treatment of osteoporosis. It should be noted that the evidence continues to be insufficient regarding the effectiveness of therapies to prevent fractures or to treat osteoporosis in men.
Bisphosphonates are associated with mild upper GI symptoms, atypical subtrochanteric fracture, and rare osteonecrosis of the jaw. There is no significant association between bisphosphonate use and total cardiovascular adverse events. Evidence is insufficient to associate bisphosphonates with increased cancer risk. Zoledronic acid is associated with atrial fibrillation, arthritis/arthralgias, headaches, hypocalcemia, influenza-like symptoms, and an increased incidence of uveitis/episcleritis. Denosumab is associated with mild upper GI symptoms, rash/eczema, and cellulitis.
While in the past additional medications were recommended for osteoporosis, the current guidelines recommend against using raloxifene, ibandronate, teriparatide, menopausal estrogen therapy, or menopausal estrogen plus progesterone therapy for first-line pharmacologic treatment.
The overall effect of calcium, vitamin D, or exercise alone on fracture risk is uncertain. Calcium and vitamin D may be added to treatment regimens, as a majority of trials with bisphosphonate therapy added this supplementation. Dosages should be considered because excessive dosing has been associated with hypercalcemia. Although previous data suggested an association between calcium supplementation and increased risk for myocardial infarction, moderate-quality evidence shows no association, though there is a risk of kidney stones.
Recommendation: Women who have osteoporosis and receive pharmacologic treatment should be treated for 5 years (weak recommendation; low-quality evidence). The evidence to determine the length of treatment is not strong, so recommendation is an extrapolation from existing evidence. High-risk patients may benefit from more than 5 years of treatment. Data suggests that patients treated with alendronate who had preexisting fractures or those with a BMD of –2.5 or less after 5 years of initial therapy may benefit from continued treatment, because these patients experienced a decreased incidence of new clinical vertebral fractures.
Recommendation: Pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture can be offered to men who have clinically recognized osteoporosis (weak recommendation, low-quality evidence). No evidence suggests that outcomes associated with pharmacologic treatment would differ between men and women if based on similar BMDs.
Recommendation: Bone density monitoring is not recommended during the 5-year pharmacologic treatment period for osteoporosis in women (weak recommendation, low-quality evidence). Data showed that most women with normal dual-energy x-ray absorptiometry scores did not progress to osteoporosis within 15 years. Data also does not support monitoring BMD during the initial 5 years of treatment in patients taking pharmacologic agents to treat osteoporosis. Several studies showed that women treated with antiresorptive treatment benefited from reduced fractures with treatment even if BMD did not increase.
Only 10% of women with normal or mild osteopenia develop osteoporosis within 15 years; 10% of women with moderate osteopenia develop osteoporosis within 5 years, and 10% of women with advanced osteopenia develop osteoporosis within 1 year.
Recommendation: The decision about whether to treat osteopenic women older then 65 years of age who are at a high risk for fracture should be based on a discussion of with the patient about their risk of fracture and the risk and benefits of treatment. Clinicians can use their judgment regarding the qualitative risk for fracture, or a validated tool such as the FRAX tool that gives 10-year risk of any major osteoporotic fracture and of hip fracture. The FRAX site recommends consideration of treatment for individuals with low bone mass (T-score between –1.0 and –2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture of at least 3% or a 10-year probability of a major osteoporosis-related fracture greater than 20%.
Bottom line:
Clinicians should offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk of hip and vertebral fractures in women who have known osteoporosis diagnosed as a T score less than –2.5 or those with a fragility fracture. Pharmacologic therapy should be used for 5 years; however, high risk patients may benefit from longer treatment. There is no benefit to bone density monitoring during the 5-year pharmacologic treatment period. In addition, bisphosphonates should be considered in men who have clinically recognized osteoporosis.
Reference:
Qaseem, A, Forciea, MA, McLean RM, Denberg TD. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Int Med. 2017;166(11):818-39.
Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Meizinger is a second year resident in the Family Medicine Residency Program at Abington Jefferson Health.
TB meningitis cases in U.S. are fewer but more complicated
BOSTON – The number of cases of meningitis caused by tuberculosis has fallen dramatically in the United States in recent decades as TB itself has become less common, according to findings from a study presented at the annual meeting of the American Academy of Neurology.
However, these findings from patient hospitalizations during 1993-2013 in the Nationwide Inpatient Sample database also indicate that neurologic complications from TB meningitis are on the rise.
The findings suggest that neurologists need to become involved whenever a patient with TB shows signs of neurologic problems, said study lead author Alexander E. Merkler, MD, of Cornell University, New York, in an interview. “They’re at high risk, and some complications can be life threatening.”
According to Dr. Merkler, TB meningitis occurs when a patient’s case of TB invades the meninges surrounding the brain. “It can lead to seizures, stroke, hydrocephalus, and death,” he said at the meeting.
TB meningitis can affect anyone with TB, he said, but those who are immunocompromised and those with diabetes are especially vulnerable.
For their current study, Dr. Merkler and his associates used the Nationwide Inpatient Sample database to track patients hospitalized in the United States with TB meningitis from 1993 to 2013. They found 16,196 new cases over the 20-year period and uncovered a dramatic decrease in the rate of hospitalizations: The incidence fell from 6.2 to 1.9 hospitalizations per million people (rate difference, 4.3; 95% confidence interval, 2.1-6.5; P less than .001), and mortality during index hospitalization fell from 17.6% (95% CI, 12.0%-23.2%) to 7.6%, (95% CI, 2.2%-13.0%).
Dr. Merkler said that mortality appears to have declined as TB itself has become less common. According to the Centers for Disease Control and Prevention, the number of reported TB cases nationally was 9,557 in 2015, a rate of 3.0 cases per 100,000 persons. The total number of annual cases fell each year from 1993 to 2014, the CDC reported, although the rate leveled off at around 3.0/100,000 from 2013 to 2015.
“The fewer people have lung TB, the less they’ll have it going into meningitis and the brain,” Dr. Merkler said. “In terms of mortality, it is going down because we have better supportive care. We’re better at keeping these patients alive and giving them antibiotics sooner.”
However, the study found that the rates of the following complications in hospitalized TB meningitis patients rose over the 20-year period:
• Hydrocephalus, from 2.3% (95% confidence interval, 0.5%-4.2%) to 5.4% (95% CI, 2.3%-10.0%).
• Seizure, from 2.9% (95% CI, 0.3%-5.4%) to 14.1% (95% CI, 7.3%-21.0%).
• Stroke, from 2.9% (95% CI, 0.6%-5.3%) to 13.0% (95% CI, 6.3%-19.8%).
• Vision and hearing impairment, from 8.2% (95% CI, 4.8%-11.6%) to 10.9% (95% CI, 4.1%-17.6%), and from 1.1% (95% CI, 0.0%-2.3%) to 3.3% (95% CI, 0.0%-6.9%), respectively.
Dr. Merkler said it’s not clear why these rates are going up, but it may be because patients have more complications as a result of living longer. Another theory is that a form of drug-resistant TB is boosting the level of these complications, Dr. Merkler said, but he’s skeptical of that idea: “I don’t know why drug resistance would lead to more neurological complications.”
The study was funded by the National Institute of Neurological Disorders and Stroke and the Michael Goldberg Stroke Research Fund. Dr. Merkler reported no relevant financial disclosures.
BOSTON – The number of cases of meningitis caused by tuberculosis has fallen dramatically in the United States in recent decades as TB itself has become less common, according to findings from a study presented at the annual meeting of the American Academy of Neurology.
However, these findings from patient hospitalizations during 1993-2013 in the Nationwide Inpatient Sample database also indicate that neurologic complications from TB meningitis are on the rise.
The findings suggest that neurologists need to become involved whenever a patient with TB shows signs of neurologic problems, said study lead author Alexander E. Merkler, MD, of Cornell University, New York, in an interview. “They’re at high risk, and some complications can be life threatening.”
According to Dr. Merkler, TB meningitis occurs when a patient’s case of TB invades the meninges surrounding the brain. “It can lead to seizures, stroke, hydrocephalus, and death,” he said at the meeting.
TB meningitis can affect anyone with TB, he said, but those who are immunocompromised and those with diabetes are especially vulnerable.
For their current study, Dr. Merkler and his associates used the Nationwide Inpatient Sample database to track patients hospitalized in the United States with TB meningitis from 1993 to 2013. They found 16,196 new cases over the 20-year period and uncovered a dramatic decrease in the rate of hospitalizations: The incidence fell from 6.2 to 1.9 hospitalizations per million people (rate difference, 4.3; 95% confidence interval, 2.1-6.5; P less than .001), and mortality during index hospitalization fell from 17.6% (95% CI, 12.0%-23.2%) to 7.6%, (95% CI, 2.2%-13.0%).
Dr. Merkler said that mortality appears to have declined as TB itself has become less common. According to the Centers for Disease Control and Prevention, the number of reported TB cases nationally was 9,557 in 2015, a rate of 3.0 cases per 100,000 persons. The total number of annual cases fell each year from 1993 to 2014, the CDC reported, although the rate leveled off at around 3.0/100,000 from 2013 to 2015.
“The fewer people have lung TB, the less they’ll have it going into meningitis and the brain,” Dr. Merkler said. “In terms of mortality, it is going down because we have better supportive care. We’re better at keeping these patients alive and giving them antibiotics sooner.”
However, the study found that the rates of the following complications in hospitalized TB meningitis patients rose over the 20-year period:
• Hydrocephalus, from 2.3% (95% confidence interval, 0.5%-4.2%) to 5.4% (95% CI, 2.3%-10.0%).
• Seizure, from 2.9% (95% CI, 0.3%-5.4%) to 14.1% (95% CI, 7.3%-21.0%).
• Stroke, from 2.9% (95% CI, 0.6%-5.3%) to 13.0% (95% CI, 6.3%-19.8%).
• Vision and hearing impairment, from 8.2% (95% CI, 4.8%-11.6%) to 10.9% (95% CI, 4.1%-17.6%), and from 1.1% (95% CI, 0.0%-2.3%) to 3.3% (95% CI, 0.0%-6.9%), respectively.
Dr. Merkler said it’s not clear why these rates are going up, but it may be because patients have more complications as a result of living longer. Another theory is that a form of drug-resistant TB is boosting the level of these complications, Dr. Merkler said, but he’s skeptical of that idea: “I don’t know why drug resistance would lead to more neurological complications.”
The study was funded by the National Institute of Neurological Disorders and Stroke and the Michael Goldberg Stroke Research Fund. Dr. Merkler reported no relevant financial disclosures.
BOSTON – The number of cases of meningitis caused by tuberculosis has fallen dramatically in the United States in recent decades as TB itself has become less common, according to findings from a study presented at the annual meeting of the American Academy of Neurology.
However, these findings from patient hospitalizations during 1993-2013 in the Nationwide Inpatient Sample database also indicate that neurologic complications from TB meningitis are on the rise.
The findings suggest that neurologists need to become involved whenever a patient with TB shows signs of neurologic problems, said study lead author Alexander E. Merkler, MD, of Cornell University, New York, in an interview. “They’re at high risk, and some complications can be life threatening.”
According to Dr. Merkler, TB meningitis occurs when a patient’s case of TB invades the meninges surrounding the brain. “It can lead to seizures, stroke, hydrocephalus, and death,” he said at the meeting.
TB meningitis can affect anyone with TB, he said, but those who are immunocompromised and those with diabetes are especially vulnerable.
For their current study, Dr. Merkler and his associates used the Nationwide Inpatient Sample database to track patients hospitalized in the United States with TB meningitis from 1993 to 2013. They found 16,196 new cases over the 20-year period and uncovered a dramatic decrease in the rate of hospitalizations: The incidence fell from 6.2 to 1.9 hospitalizations per million people (rate difference, 4.3; 95% confidence interval, 2.1-6.5; P less than .001), and mortality during index hospitalization fell from 17.6% (95% CI, 12.0%-23.2%) to 7.6%, (95% CI, 2.2%-13.0%).
Dr. Merkler said that mortality appears to have declined as TB itself has become less common. According to the Centers for Disease Control and Prevention, the number of reported TB cases nationally was 9,557 in 2015, a rate of 3.0 cases per 100,000 persons. The total number of annual cases fell each year from 1993 to 2014, the CDC reported, although the rate leveled off at around 3.0/100,000 from 2013 to 2015.
“The fewer people have lung TB, the less they’ll have it going into meningitis and the brain,” Dr. Merkler said. “In terms of mortality, it is going down because we have better supportive care. We’re better at keeping these patients alive and giving them antibiotics sooner.”
However, the study found that the rates of the following complications in hospitalized TB meningitis patients rose over the 20-year period:
• Hydrocephalus, from 2.3% (95% confidence interval, 0.5%-4.2%) to 5.4% (95% CI, 2.3%-10.0%).
• Seizure, from 2.9% (95% CI, 0.3%-5.4%) to 14.1% (95% CI, 7.3%-21.0%).
• Stroke, from 2.9% (95% CI, 0.6%-5.3%) to 13.0% (95% CI, 6.3%-19.8%).
• Vision and hearing impairment, from 8.2% (95% CI, 4.8%-11.6%) to 10.9% (95% CI, 4.1%-17.6%), and from 1.1% (95% CI, 0.0%-2.3%) to 3.3% (95% CI, 0.0%-6.9%), respectively.
Dr. Merkler said it’s not clear why these rates are going up, but it may be because patients have more complications as a result of living longer. Another theory is that a form of drug-resistant TB is boosting the level of these complications, Dr. Merkler said, but he’s skeptical of that idea: “I don’t know why drug resistance would lead to more neurological complications.”
The study was funded by the National Institute of Neurological Disorders and Stroke and the Michael Goldberg Stroke Research Fund. Dr. Merkler reported no relevant financial disclosures.
AT AAN 2017
Key clinical point:
Major finding: The rate of TB meningitis hospitalizations fell from 6.2 to 1.9 per million people (rate difference, 4.3; 95% CI, 2.1-6.5; P less than .001).
Data source: The Nationwide Inpatient Sample database, which revealed 16,196 new cases of TB meningitis from 1993 to 2013.
Disclosures: The study was funded by the National Institute of Neurological Disorders and Stroke and the Michael Goldberg Stroke Research Fund. Dr. Merkler reported no relevant financial disclosures.
Nurses help more rheumatic disease patients get vaccinated
MADRID – A nurse-led program successfully increased the uptake of pneumococcal vaccination among patients with chronic inflammatory rheumatic diseases in a single-center study.
From the start to the end of a 4-month evaluation period, the rate of vaccination of at-risk patients increased from 17.1% (13/76) to 77.6% (59/76; P less than .001).
It is well known that patients with inflammatory rheumatic diseases, such as systemic lupus erythematous (SLE) and systemic vasculitis, are at high risk for contracting pneumococcal disease, reported Tiphaine Goulenok, MD, of Bichat Hospital, Paris, at the European Congress of Rheumatology. This is particularly the case if they are receiving immunosuppressive treatments.
Although French national guidelines were introduced in 2011 that recommend that such patients routinely receive pneumococcal vaccination, the vaccination rate is often lower than is desirable, Dr. Goulenok observed at a press briefing. Her prior research suggests that only 16.2% of patients with an indication for the PCV13 vaccine actually received it.
In the current study, 126 patients with inflammatory rheumatic diseases were consecutively recruited and seen at the day unit of Bichat Hospital. Of these patients, 76 were candidates for pneumococcal vaccination because they were receiving steroids or other immunosuppressive drugs. Of these patients, 13 were already vaccinated, and, of the 63 who were not, nurses correctly identified 56 (88.9%) who needed to be vaccinated, of whom 46 agreed and 10 refused.
“We found a low rate of pneumococcal vaccination among patients,” said Dr. Goulenok, “but, thanks to high screening by the nurses, vaccination coverage was increased and the nurse-led vaccination program was very efficient”.
Robert Landewé, MD, who chaired the press briefing, observed that, despite being in an “era of guidelines,” ways of successfully implementing them in practice remained a challenge. The nurse-led program appeared to be one way to increase pneumococcal vaccination uptake, but perhaps other ways need to be sought, especially as there may be substantial resistance to vaccination among patients, he said.
“Patients are sometimes more afraid of the consequences of vaccination than [of] the disease that is prevented by vaccination,” said Dr. Landewé, who is professor of rheumatology at the Academic Medical Center in Amsterdam (the Netherlands).
Dr. Goulenok and Dr. Landewé reported no disclosures.
MADRID – A nurse-led program successfully increased the uptake of pneumococcal vaccination among patients with chronic inflammatory rheumatic diseases in a single-center study.
From the start to the end of a 4-month evaluation period, the rate of vaccination of at-risk patients increased from 17.1% (13/76) to 77.6% (59/76; P less than .001).
It is well known that patients with inflammatory rheumatic diseases, such as systemic lupus erythematous (SLE) and systemic vasculitis, are at high risk for contracting pneumococcal disease, reported Tiphaine Goulenok, MD, of Bichat Hospital, Paris, at the European Congress of Rheumatology. This is particularly the case if they are receiving immunosuppressive treatments.
Although French national guidelines were introduced in 2011 that recommend that such patients routinely receive pneumococcal vaccination, the vaccination rate is often lower than is desirable, Dr. Goulenok observed at a press briefing. Her prior research suggests that only 16.2% of patients with an indication for the PCV13 vaccine actually received it.
In the current study, 126 patients with inflammatory rheumatic diseases were consecutively recruited and seen at the day unit of Bichat Hospital. Of these patients, 76 were candidates for pneumococcal vaccination because they were receiving steroids or other immunosuppressive drugs. Of these patients, 13 were already vaccinated, and, of the 63 who were not, nurses correctly identified 56 (88.9%) who needed to be vaccinated, of whom 46 agreed and 10 refused.
“We found a low rate of pneumococcal vaccination among patients,” said Dr. Goulenok, “but, thanks to high screening by the nurses, vaccination coverage was increased and the nurse-led vaccination program was very efficient”.
Robert Landewé, MD, who chaired the press briefing, observed that, despite being in an “era of guidelines,” ways of successfully implementing them in practice remained a challenge. The nurse-led program appeared to be one way to increase pneumococcal vaccination uptake, but perhaps other ways need to be sought, especially as there may be substantial resistance to vaccination among patients, he said.
“Patients are sometimes more afraid of the consequences of vaccination than [of] the disease that is prevented by vaccination,” said Dr. Landewé, who is professor of rheumatology at the Academic Medical Center in Amsterdam (the Netherlands).
Dr. Goulenok and Dr. Landewé reported no disclosures.
MADRID – A nurse-led program successfully increased the uptake of pneumococcal vaccination among patients with chronic inflammatory rheumatic diseases in a single-center study.
From the start to the end of a 4-month evaluation period, the rate of vaccination of at-risk patients increased from 17.1% (13/76) to 77.6% (59/76; P less than .001).
It is well known that patients with inflammatory rheumatic diseases, such as systemic lupus erythematous (SLE) and systemic vasculitis, are at high risk for contracting pneumococcal disease, reported Tiphaine Goulenok, MD, of Bichat Hospital, Paris, at the European Congress of Rheumatology. This is particularly the case if they are receiving immunosuppressive treatments.
Although French national guidelines were introduced in 2011 that recommend that such patients routinely receive pneumococcal vaccination, the vaccination rate is often lower than is desirable, Dr. Goulenok observed at a press briefing. Her prior research suggests that only 16.2% of patients with an indication for the PCV13 vaccine actually received it.
In the current study, 126 patients with inflammatory rheumatic diseases were consecutively recruited and seen at the day unit of Bichat Hospital. Of these patients, 76 were candidates for pneumococcal vaccination because they were receiving steroids or other immunosuppressive drugs. Of these patients, 13 were already vaccinated, and, of the 63 who were not, nurses correctly identified 56 (88.9%) who needed to be vaccinated, of whom 46 agreed and 10 refused.
“We found a low rate of pneumococcal vaccination among patients,” said Dr. Goulenok, “but, thanks to high screening by the nurses, vaccination coverage was increased and the nurse-led vaccination program was very efficient”.
Robert Landewé, MD, who chaired the press briefing, observed that, despite being in an “era of guidelines,” ways of successfully implementing them in practice remained a challenge. The nurse-led program appeared to be one way to increase pneumococcal vaccination uptake, but perhaps other ways need to be sought, especially as there may be substantial resistance to vaccination among patients, he said.
“Patients are sometimes more afraid of the consequences of vaccination than [of] the disease that is prevented by vaccination,” said Dr. Landewé, who is professor of rheumatology at the Academic Medical Center in Amsterdam (the Netherlands).
Dr. Goulenok and Dr. Landewé reported no disclosures.
AT THE EULAR 2017 CONGRESS
Key clinical point: A nurse-led program increased the uptake of a guideline-recommended vaccination in patients with chronic inflammatory rheumatic diseases.
Major finding: The pre- and postintervention pneumococcal vaccination rates were 17.1% (13/76) and 77.6% (59/76) of at-risk patients (P less than .001).
Data source: A 4-month, prospective pilot study of 126 consecutively recruited patients with chronic inflammatory rheumatic diseases.
Disclosures: The presenter and commentator had no disclosures to report.
New Center of Excellence to Lead Research of “Signature Wounds”
Take a brand-new research facility, then add a neighboring U.S. Army base with one of the largest veteran populations of any health care network and a world-class team of researchers—that’s a “recipe for success,” says Dr. Michael Russell, director of the VA Center of Excellence for Research on Returning War Veterans in Waco, Texas.
The 53,000-square-foot center is designed to conduct state-of-the-art research on mental health problems associated with PTSD and TBI, “signature wounds” of conflicts in Afghanistan and the Middle East. The flagship study is named Project MAVEREX. Researchers will examine whether the inability of the regions in injured brains to communicate with one another worsens behavior outcomes. Using “cutting-edge data analysis techniques,” they hope to characterize the effects of TBI on brain structure and function “with very high precision,” says Dr. Evan Gordon, a cognitive neuroscientist working on MAVEREX.
The Center of Excellence is on the campus of the historic Doris Miller VAMC. The facility has space for 75 staff members and faculty as well as 25 trainees. It features multiple examination rooms, observation rooms, electrocardiography, electroencephalography, a 3 Tesla MRI, a transcranial magnetic stimulation suite, and a custom-built laboratory wing.
Take a brand-new research facility, then add a neighboring U.S. Army base with one of the largest veteran populations of any health care network and a world-class team of researchers—that’s a “recipe for success,” says Dr. Michael Russell, director of the VA Center of Excellence for Research on Returning War Veterans in Waco, Texas.
The 53,000-square-foot center is designed to conduct state-of-the-art research on mental health problems associated with PTSD and TBI, “signature wounds” of conflicts in Afghanistan and the Middle East. The flagship study is named Project MAVEREX. Researchers will examine whether the inability of the regions in injured brains to communicate with one another worsens behavior outcomes. Using “cutting-edge data analysis techniques,” they hope to characterize the effects of TBI on brain structure and function “with very high precision,” says Dr. Evan Gordon, a cognitive neuroscientist working on MAVEREX.
The Center of Excellence is on the campus of the historic Doris Miller VAMC. The facility has space for 75 staff members and faculty as well as 25 trainees. It features multiple examination rooms, observation rooms, electrocardiography, electroencephalography, a 3 Tesla MRI, a transcranial magnetic stimulation suite, and a custom-built laboratory wing.
Take a brand-new research facility, then add a neighboring U.S. Army base with one of the largest veteran populations of any health care network and a world-class team of researchers—that’s a “recipe for success,” says Dr. Michael Russell, director of the VA Center of Excellence for Research on Returning War Veterans in Waco, Texas.
The 53,000-square-foot center is designed to conduct state-of-the-art research on mental health problems associated with PTSD and TBI, “signature wounds” of conflicts in Afghanistan and the Middle East. The flagship study is named Project MAVEREX. Researchers will examine whether the inability of the regions in injured brains to communicate with one another worsens behavior outcomes. Using “cutting-edge data analysis techniques,” they hope to characterize the effects of TBI on brain structure and function “with very high precision,” says Dr. Evan Gordon, a cognitive neuroscientist working on MAVEREX.
The Center of Excellence is on the campus of the historic Doris Miller VAMC. The facility has space for 75 staff members and faculty as well as 25 trainees. It features multiple examination rooms, observation rooms, electrocardiography, electroencephalography, a 3 Tesla MRI, a transcranial magnetic stimulation suite, and a custom-built laboratory wing.
Ibrutinib/buparlisib looks good for relapsed mantle cell lymphoma
LUGANO, SWITZERLAND – A combination of the Bruton’s tyrosine kinase (BTK) ibrutinib (Imbruvica) and the pan-phosphoinositide 3-kinase (PI3K) inhibitor buparlisib showed clinical activity superior to that of single-agent ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL).
In a phase I/IB dose escalation study and expansion cohort testing the combination in patients with diffuse large B cell lymphoma (DLBCL), follicular lymphoma, and MCL, the overall response rate (ORR) among patients with MCL was 100%, consisting of complete responses (CR) in 8 of 11 patients, and partial responses (PR) in 3 patients, reported Connie Lee Batlevi, MD, of Memorial Sloan Kettering Cancer Center in New York.
In contrast, the response rate to ibrutinib monotherapy among patients with relapsed MCL is around 20%, she said.
Preclinical studies have demonstrated synergism between BTK inhibitors and PI3K inhibitors in B-cell non-Hodgkin lymphoma (NHL), prompting the investigators to look into the combination in patients with relapsed or refractory DLBCL, follicular lymphoma (FL), and MCL.
They enrolled 25 patients (9 with DLBCL, 5 with FL, and 11 with MCL). The patients received escalating doses of once daily ibrutinib and buparlisib in three dose levels (ibrutinib 420-560 mg; buparlisib 80-100 mg). Dose level 3, consisting of ibrutinib 560 mg and buparlisib 100 mg, was selected for dose expansion based on one of six patients developing a dose-limiting toxicity.
Using the Lugano Response Criteria, the overall ORR (all histologies) was 52%. Among nine patients with DLBCL, the ORR was 11%, with one CR and no PR. Among five patients with FL, the ORR was 20%, consisting of one CR and no PR.
Among 11 patients with MCL, however, the ORR was far more impressive, at 100%, including eight CR and three PR. No patients with MCL had either stable or progressive disease.
Under the RECIL (International Working Group) criteria, the ORR was 48% including one CR each for DLBCL and FL, and eight CR and two PR for patients with MCL.
In the safety analysis, there were two dose-limiting toxicities in the lowest and highest dose groups, but none at dose level 2 (ibrutinib 560 mg and buparlisib 80 mg).
Grade 3 or greater adverse events occurred in 63% of patients. The most common events were hyperglycemia and rash in 19% each, and diarrhea, anorexia, and neurologic changes in 11% each,
The grade 3 neurologic changes included depression, agitation, mood swings, confusion and memory impairment, all of which resolved after buparlisib was withdrawn.
Dr. Batlevi showed scans of two patients with representative clinical responses in MCL. One 55-year-old man with blastoid MCL who had relapsed 18 months after frontline therapy with ofatumumab and bendamustine had near total clearance of lesions after two cycles of ibrutinib and buparlisib. He remains in CR after 12 months on the combination.
A second patient, a 77-year-old man with MCL that relapsed 10 years after R-CHOP and rituximab maintenance followed by autologous stem cell transplant, showed a complete response upon restaging after two cycles of ibrutinib/buparlisib.
The investigators are currently enrolling patients for phase IB expansions, with the goal of better estimating the safety and efficacy of the combination.
Memorial Sloan Kettering Cancer Center sponsored the study, with support from Janssen and Novartis. Dr. Batlevi reported no conflicts of interest.
LUGANO, SWITZERLAND – A combination of the Bruton’s tyrosine kinase (BTK) ibrutinib (Imbruvica) and the pan-phosphoinositide 3-kinase (PI3K) inhibitor buparlisib showed clinical activity superior to that of single-agent ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL).
In a phase I/IB dose escalation study and expansion cohort testing the combination in patients with diffuse large B cell lymphoma (DLBCL), follicular lymphoma, and MCL, the overall response rate (ORR) among patients with MCL was 100%, consisting of complete responses (CR) in 8 of 11 patients, and partial responses (PR) in 3 patients, reported Connie Lee Batlevi, MD, of Memorial Sloan Kettering Cancer Center in New York.
In contrast, the response rate to ibrutinib monotherapy among patients with relapsed MCL is around 20%, she said.
Preclinical studies have demonstrated synergism between BTK inhibitors and PI3K inhibitors in B-cell non-Hodgkin lymphoma (NHL), prompting the investigators to look into the combination in patients with relapsed or refractory DLBCL, follicular lymphoma (FL), and MCL.
They enrolled 25 patients (9 with DLBCL, 5 with FL, and 11 with MCL). The patients received escalating doses of once daily ibrutinib and buparlisib in three dose levels (ibrutinib 420-560 mg; buparlisib 80-100 mg). Dose level 3, consisting of ibrutinib 560 mg and buparlisib 100 mg, was selected for dose expansion based on one of six patients developing a dose-limiting toxicity.
Using the Lugano Response Criteria, the overall ORR (all histologies) was 52%. Among nine patients with DLBCL, the ORR was 11%, with one CR and no PR. Among five patients with FL, the ORR was 20%, consisting of one CR and no PR.
Among 11 patients with MCL, however, the ORR was far more impressive, at 100%, including eight CR and three PR. No patients with MCL had either stable or progressive disease.
Under the RECIL (International Working Group) criteria, the ORR was 48% including one CR each for DLBCL and FL, and eight CR and two PR for patients with MCL.
In the safety analysis, there were two dose-limiting toxicities in the lowest and highest dose groups, but none at dose level 2 (ibrutinib 560 mg and buparlisib 80 mg).
Grade 3 or greater adverse events occurred in 63% of patients. The most common events were hyperglycemia and rash in 19% each, and diarrhea, anorexia, and neurologic changes in 11% each,
The grade 3 neurologic changes included depression, agitation, mood swings, confusion and memory impairment, all of which resolved after buparlisib was withdrawn.
Dr. Batlevi showed scans of two patients with representative clinical responses in MCL. One 55-year-old man with blastoid MCL who had relapsed 18 months after frontline therapy with ofatumumab and bendamustine had near total clearance of lesions after two cycles of ibrutinib and buparlisib. He remains in CR after 12 months on the combination.
A second patient, a 77-year-old man with MCL that relapsed 10 years after R-CHOP and rituximab maintenance followed by autologous stem cell transplant, showed a complete response upon restaging after two cycles of ibrutinib/buparlisib.
The investigators are currently enrolling patients for phase IB expansions, with the goal of better estimating the safety and efficacy of the combination.
Memorial Sloan Kettering Cancer Center sponsored the study, with support from Janssen and Novartis. Dr. Batlevi reported no conflicts of interest.
LUGANO, SWITZERLAND – A combination of the Bruton’s tyrosine kinase (BTK) ibrutinib (Imbruvica) and the pan-phosphoinositide 3-kinase (PI3K) inhibitor buparlisib showed clinical activity superior to that of single-agent ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL).
In a phase I/IB dose escalation study and expansion cohort testing the combination in patients with diffuse large B cell lymphoma (DLBCL), follicular lymphoma, and MCL, the overall response rate (ORR) among patients with MCL was 100%, consisting of complete responses (CR) in 8 of 11 patients, and partial responses (PR) in 3 patients, reported Connie Lee Batlevi, MD, of Memorial Sloan Kettering Cancer Center in New York.
In contrast, the response rate to ibrutinib monotherapy among patients with relapsed MCL is around 20%, she said.
Preclinical studies have demonstrated synergism between BTK inhibitors and PI3K inhibitors in B-cell non-Hodgkin lymphoma (NHL), prompting the investigators to look into the combination in patients with relapsed or refractory DLBCL, follicular lymphoma (FL), and MCL.
They enrolled 25 patients (9 with DLBCL, 5 with FL, and 11 with MCL). The patients received escalating doses of once daily ibrutinib and buparlisib in three dose levels (ibrutinib 420-560 mg; buparlisib 80-100 mg). Dose level 3, consisting of ibrutinib 560 mg and buparlisib 100 mg, was selected for dose expansion based on one of six patients developing a dose-limiting toxicity.
Using the Lugano Response Criteria, the overall ORR (all histologies) was 52%. Among nine patients with DLBCL, the ORR was 11%, with one CR and no PR. Among five patients with FL, the ORR was 20%, consisting of one CR and no PR.
Among 11 patients with MCL, however, the ORR was far more impressive, at 100%, including eight CR and three PR. No patients with MCL had either stable or progressive disease.
Under the RECIL (International Working Group) criteria, the ORR was 48% including one CR each for DLBCL and FL, and eight CR and two PR for patients with MCL.
In the safety analysis, there were two dose-limiting toxicities in the lowest and highest dose groups, but none at dose level 2 (ibrutinib 560 mg and buparlisib 80 mg).
Grade 3 or greater adverse events occurred in 63% of patients. The most common events were hyperglycemia and rash in 19% each, and diarrhea, anorexia, and neurologic changes in 11% each,
The grade 3 neurologic changes included depression, agitation, mood swings, confusion and memory impairment, all of which resolved after buparlisib was withdrawn.
Dr. Batlevi showed scans of two patients with representative clinical responses in MCL. One 55-year-old man with blastoid MCL who had relapsed 18 months after frontline therapy with ofatumumab and bendamustine had near total clearance of lesions after two cycles of ibrutinib and buparlisib. He remains in CR after 12 months on the combination.
A second patient, a 77-year-old man with MCL that relapsed 10 years after R-CHOP and rituximab maintenance followed by autologous stem cell transplant, showed a complete response upon restaging after two cycles of ibrutinib/buparlisib.
The investigators are currently enrolling patients for phase IB expansions, with the goal of better estimating the safety and efficacy of the combination.
Memorial Sloan Kettering Cancer Center sponsored the study, with support from Janssen and Novartis. Dr. Batlevi reported no conflicts of interest.
AT 14-ICML
Key clinical point: The combination of ibrutinib and buparlisib showed efficacy against mantle cell lymphoma in a dose-escalation and safety study,
Major finding: The overall response rate to the combination among 11 patients with relapsed MCL was 100%.
Data source: Open label phase I/IB study of 25 patients with B-cell lymphomas.
Disclosures: Memorial Sloan Kettering Cancer Center sponsored the study, with support from Janssen and Novartis. Dr. Batlevi reported no conflicts of interest.
Genetic Information May Hold Key to Multiple-Substance Addiction
The Million Veteran Program (MVP) is now the largest genomic database in the world, with more than 550,000 veterans enrolled. Researchers have been mining the data for a variety of studies, including studies to examine the genetic risk factors for chronic use of alcohol, tobacco, and opioids.
Most people who smoke or use drugs also drink alcohol, and changes in one behavior are likely to be associated with changes in the others, according to researchers from the VA Connecticut Healthcare System and the Corporal Michael J. Crescenz VAMC. That likelihood suggests a shared genetic risk for multiple-substance use, but to date, studies on the subject have been limited by the small size of the available samples, the researchers say. The MVP is providing a unique opportunity to analyze massive amounts of longitudinal data to discover potential genetic links.
The answers also may provide opportunities for treatment and prevention. For example, it may be possible to reduce the use of multiple harmful substances simultaneously with more than 1 medication.
The first target in this “ambitious effort,” the researchers say, is heavy drinking. They’re using data from the Veterans Aging Cohort Study and from the AUDIT-C, a self-report questionnaire given annually to veterans, which quantifies recent drinking. The researchers plan to validate their initial findings, already published, and then combine that information with the genotype information from the MVP to identify novel genetic predictors of heavy drinking.
The researchers have begun to use a similar approach to study chronic opioid use and smoking. Ultimately, they plan to integrate all the findings to yield genetic profiles for multisubstance use.
The Million Veteran Program (MVP) is now the largest genomic database in the world, with more than 550,000 veterans enrolled. Researchers have been mining the data for a variety of studies, including studies to examine the genetic risk factors for chronic use of alcohol, tobacco, and opioids.
Most people who smoke or use drugs also drink alcohol, and changes in one behavior are likely to be associated with changes in the others, according to researchers from the VA Connecticut Healthcare System and the Corporal Michael J. Crescenz VAMC. That likelihood suggests a shared genetic risk for multiple-substance use, but to date, studies on the subject have been limited by the small size of the available samples, the researchers say. The MVP is providing a unique opportunity to analyze massive amounts of longitudinal data to discover potential genetic links.
The answers also may provide opportunities for treatment and prevention. For example, it may be possible to reduce the use of multiple harmful substances simultaneously with more than 1 medication.
The first target in this “ambitious effort,” the researchers say, is heavy drinking. They’re using data from the Veterans Aging Cohort Study and from the AUDIT-C, a self-report questionnaire given annually to veterans, which quantifies recent drinking. The researchers plan to validate their initial findings, already published, and then combine that information with the genotype information from the MVP to identify novel genetic predictors of heavy drinking.
The researchers have begun to use a similar approach to study chronic opioid use and smoking. Ultimately, they plan to integrate all the findings to yield genetic profiles for multisubstance use.
The Million Veteran Program (MVP) is now the largest genomic database in the world, with more than 550,000 veterans enrolled. Researchers have been mining the data for a variety of studies, including studies to examine the genetic risk factors for chronic use of alcohol, tobacco, and opioids.
Most people who smoke or use drugs also drink alcohol, and changes in one behavior are likely to be associated with changes in the others, according to researchers from the VA Connecticut Healthcare System and the Corporal Michael J. Crescenz VAMC. That likelihood suggests a shared genetic risk for multiple-substance use, but to date, studies on the subject have been limited by the small size of the available samples, the researchers say. The MVP is providing a unique opportunity to analyze massive amounts of longitudinal data to discover potential genetic links.
The answers also may provide opportunities for treatment and prevention. For example, it may be possible to reduce the use of multiple harmful substances simultaneously with more than 1 medication.
The first target in this “ambitious effort,” the researchers say, is heavy drinking. They’re using data from the Veterans Aging Cohort Study and from the AUDIT-C, a self-report questionnaire given annually to veterans, which quantifies recent drinking. The researchers plan to validate their initial findings, already published, and then combine that information with the genotype information from the MVP to identify novel genetic predictors of heavy drinking.
The researchers have begun to use a similar approach to study chronic opioid use and smoking. Ultimately, they plan to integrate all the findings to yield genetic profiles for multisubstance use.
Pregnant Patient Develops a Rare Case of Multiple Sclerosis
Pregnancy is generally found to offer a respite from multiple sclerosis (MS). Pregnant women rarely develop MS or to have relapses. But in a unique and challenging case, a woman in her 14th week of her second pregnancy developed signs and symptoms of tumefactive multiple sclerosis (TMS), a rare subtype of MS. The TMS was only one of several unexpected clinical puzzles, according to the clinicians reporting on the case.
The patient, who had been healthy, was admitted with acute onset of paresthesias and word-finding difficulty. She had just had a long drive from Florida, and the the clinicians first assumed that she was fatigued from the trip and from the pregnancy. A magnetic resonance imaging (MRI) scan of the brain, however, suggested an ischemic event.
While hospitalized, the patient’s condition rapidly worsened. More scan and test findings proved consistent with TMS. A repeat MRI scan showed interval progression with a growing tumefactive demyelinating lesion (TDL) with diffuse surrounding edema and new periventricular signal changes. Although rare, TDLs often represent fulminant forms of MS, the clinicians note. Because the lesions mimic strokes, tumors, and abscesses, diagnosis is difficult. Moreover, the gadolinium (which was avoided because it can cause birth defects) might have helped them visualize lesions sooner.
The patient was started on high-dose IV methylprednisolone and plasma exchange, but the response was mild. The poor response to both treatment modalities is infrequent in TMS, the clinicians say—yet another unforeseen obstacle.
In addition to counseling the patient about the usual protective effects of pregnancy, her clinicians counseled her “extensively” about natalizumab and the possible beneficial effects of disease-modifying therapies. But the patient made the difficult decision to terminate the pregnancy, in part because she felt it was better to focus on her existing child rather than on caring for 2 young children while having a chronic progressive disease with uncertain recovery.
Another surprise was in store. Within 12 hours after an uncomplicated dilatation and curettage, the patient was able to move her right arm. That “drastic improvement” was followed by moderate improvement in her right leg. Her “paradoxical” improvement after the termination might indicate a “different from expected” hormonal influence in the pathogenesis of TMS, the clinicians say, but more likely represents a delayed corroborating effect of steroids and plasma exchange.
In the following weeks, the patient’s recovery was “satisfying” with gradual improvement and partial return of expressive language. Eighteen months later, the patient was clinically stable on natalizumab.
Source:
Pakneshan S, Bernitsas E. BMJ Case Rep. 2017. pii: bcr-2017-219534.
doi: 10.1136/bcr-2017-219534.
Pregnancy is generally found to offer a respite from multiple sclerosis (MS). Pregnant women rarely develop MS or to have relapses. But in a unique and challenging case, a woman in her 14th week of her second pregnancy developed signs and symptoms of tumefactive multiple sclerosis (TMS), a rare subtype of MS. The TMS was only one of several unexpected clinical puzzles, according to the clinicians reporting on the case.
The patient, who had been healthy, was admitted with acute onset of paresthesias and word-finding difficulty. She had just had a long drive from Florida, and the the clinicians first assumed that she was fatigued from the trip and from the pregnancy. A magnetic resonance imaging (MRI) scan of the brain, however, suggested an ischemic event.
While hospitalized, the patient’s condition rapidly worsened. More scan and test findings proved consistent with TMS. A repeat MRI scan showed interval progression with a growing tumefactive demyelinating lesion (TDL) with diffuse surrounding edema and new periventricular signal changes. Although rare, TDLs often represent fulminant forms of MS, the clinicians note. Because the lesions mimic strokes, tumors, and abscesses, diagnosis is difficult. Moreover, the gadolinium (which was avoided because it can cause birth defects) might have helped them visualize lesions sooner.
The patient was started on high-dose IV methylprednisolone and plasma exchange, but the response was mild. The poor response to both treatment modalities is infrequent in TMS, the clinicians say—yet another unforeseen obstacle.
In addition to counseling the patient about the usual protective effects of pregnancy, her clinicians counseled her “extensively” about natalizumab and the possible beneficial effects of disease-modifying therapies. But the patient made the difficult decision to terminate the pregnancy, in part because she felt it was better to focus on her existing child rather than on caring for 2 young children while having a chronic progressive disease with uncertain recovery.
Another surprise was in store. Within 12 hours after an uncomplicated dilatation and curettage, the patient was able to move her right arm. That “drastic improvement” was followed by moderate improvement in her right leg. Her “paradoxical” improvement after the termination might indicate a “different from expected” hormonal influence in the pathogenesis of TMS, the clinicians say, but more likely represents a delayed corroborating effect of steroids and plasma exchange.
In the following weeks, the patient’s recovery was “satisfying” with gradual improvement and partial return of expressive language. Eighteen months later, the patient was clinically stable on natalizumab.
Source:
Pakneshan S, Bernitsas E. BMJ Case Rep. 2017. pii: bcr-2017-219534.
doi: 10.1136/bcr-2017-219534.
Pregnancy is generally found to offer a respite from multiple sclerosis (MS). Pregnant women rarely develop MS or to have relapses. But in a unique and challenging case, a woman in her 14th week of her second pregnancy developed signs and symptoms of tumefactive multiple sclerosis (TMS), a rare subtype of MS. The TMS was only one of several unexpected clinical puzzles, according to the clinicians reporting on the case.
The patient, who had been healthy, was admitted with acute onset of paresthesias and word-finding difficulty. She had just had a long drive from Florida, and the the clinicians first assumed that she was fatigued from the trip and from the pregnancy. A magnetic resonance imaging (MRI) scan of the brain, however, suggested an ischemic event.
While hospitalized, the patient’s condition rapidly worsened. More scan and test findings proved consistent with TMS. A repeat MRI scan showed interval progression with a growing tumefactive demyelinating lesion (TDL) with diffuse surrounding edema and new periventricular signal changes. Although rare, TDLs often represent fulminant forms of MS, the clinicians note. Because the lesions mimic strokes, tumors, and abscesses, diagnosis is difficult. Moreover, the gadolinium (which was avoided because it can cause birth defects) might have helped them visualize lesions sooner.
The patient was started on high-dose IV methylprednisolone and plasma exchange, but the response was mild. The poor response to both treatment modalities is infrequent in TMS, the clinicians say—yet another unforeseen obstacle.
In addition to counseling the patient about the usual protective effects of pregnancy, her clinicians counseled her “extensively” about natalizumab and the possible beneficial effects of disease-modifying therapies. But the patient made the difficult decision to terminate the pregnancy, in part because she felt it was better to focus on her existing child rather than on caring for 2 young children while having a chronic progressive disease with uncertain recovery.
Another surprise was in store. Within 12 hours after an uncomplicated dilatation and curettage, the patient was able to move her right arm. That “drastic improvement” was followed by moderate improvement in her right leg. Her “paradoxical” improvement after the termination might indicate a “different from expected” hormonal influence in the pathogenesis of TMS, the clinicians say, but more likely represents a delayed corroborating effect of steroids and plasma exchange.
In the following weeks, the patient’s recovery was “satisfying” with gradual improvement and partial return of expressive language. Eighteen months later, the patient was clinically stable on natalizumab.
Source:
Pakneshan S, Bernitsas E. BMJ Case Rep. 2017. pii: bcr-2017-219534.
doi: 10.1136/bcr-2017-219534.
Pembrolizumab + rituximab boost response rates in relapsed follicular lymphoma
LUGANO, SWITZERLAND – A novel combination of the anti-programmed death 1 (PD-1) checkpoint inhibitor pembrolizumab (Keytruda) and the anti-CD20 monoclonal antibody rituximab was associated with a high overall response rate (ORR) in patients with relapsed follicular lymphoma in a phase II clinical trial.
Among 20 patients evaluable for efficacy, the overall response rate to the combination was 65%, including 50% complete responses (CR) reported Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Follicular lymphoma is probably one of the best examples of targeting the immune system and also one of the earliest examples. Over the last few years we’ve learned a great deal about the different mechanisms of not only negative impact on infiltrating T cells, but also immune escape and T-cell exhaustion,” she said at the International Conference on Malignant Lymphoma.
Although biopsies of follicular lymphoma tumors have demonstrated infiltration of anti-tumor T cells, these cells are typically impeded by immune checkpoints, including PD-1 and its ligand (PD-L1).
The use of anti-PD-1 checkpoint inhibitors such as pembrolizumab has been shown to enhance the function of antitumor T cells in follicular lymphoma, and blocking PD-1 on natural killer cells enhances the antibody-dependent cell-mediated cytotoxicity of the natural killer cells, she said.
Because rituximab, a mainstay of therapy for non-Hodgkin lymphomas, induces antibody-dependent cell-mediated cytotoxicity, the investigators reasoned that combining it with pembrolizumab would simultaneously and synergistically stimulate activation of innate and adaptive immunity.
They designed a phase II, single-arm study in 30 patients with relapsed follicular lymphoma following one or more prior lines of therapy. The patients also had to have rituximab-sensitive disease, defined as a complete response (CR) or partial response lasting for at least 6 months following the most recent rituximab-containing therapy.
The patients were treated with rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1, and pembrolizumab 200 mg IV every 3 weeks for up to 16 cycles starting on day 2 of cycle 1.
The investigators expected that the combination would improve ORR, the primary endpoint, to at least 60%, compared with 40% for historical controls treated with repeat courses of rituximab.
At the data cutoff for the interim analysis, 32 patients had been enrolled, 30 were evaluable for safety, and 20 for efficacy after a median follow-up of 8.2 months.
Among the 20 patients (median age 64) in the efficacy analysis, 10 (50%) had a CR, and 3 (15%) had a partial response, for an ORR of 65%. Three additional patients had stable disease, and four had disease progression as best responses.
Among the patients with CRs, the duration of response ranged from nearly 275 days to more than 600 days.
“This does appear to be durable, and it is time dependent in terms of response. We did see early response, and we also saw deepening of response over time,” Dr. Nastoupil said.
Four patients were discontinued from the study because of immune-related adverse events. All four patients had achieved a CR at the time of study removal, and all four have ongoing CRs.
Among the 30 patients evaluable for safety, there were no grade 4 adverse events, no deaths, and few grade 3 events. Most events were grade 1 or 2, and included fatigue, eye pain/blurred vision/watery eye, nausea and vomiting, diarrhea dyspnea, rash, cough, and lymphopenia.
The investigators also looked at potential biomarkers for response, including PD-L1 expression in tumors prior to treatment. They found in samples from three patients who went on to achieve CRs that PD-L1 expression in tumor cells was low, ranging from 0% to 8%, suggesting that PD-L1 expression may not be necessary to generate a response with the combination.
They then looked at the association between CD8-positive T effector cells and responses in 12 patients, and found that patients with higher levels of expression had better ORR and CR rates.
“These interim results warrant further investigation of this combination in follicular lymphoma, and an expansion to include patients with refractory follicular lymphoma is planned,” Dr. Nastoupil concluded.
The Leukemia & Lymphoma Society supported the study. Dr Nastoupil has disclosed consulting fees from Celgene and contracted research for Abbvie, Janssen, and TG Therapeutics.
LUGANO, SWITZERLAND – A novel combination of the anti-programmed death 1 (PD-1) checkpoint inhibitor pembrolizumab (Keytruda) and the anti-CD20 monoclonal antibody rituximab was associated with a high overall response rate (ORR) in patients with relapsed follicular lymphoma in a phase II clinical trial.
Among 20 patients evaluable for efficacy, the overall response rate to the combination was 65%, including 50% complete responses (CR) reported Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Follicular lymphoma is probably one of the best examples of targeting the immune system and also one of the earliest examples. Over the last few years we’ve learned a great deal about the different mechanisms of not only negative impact on infiltrating T cells, but also immune escape and T-cell exhaustion,” she said at the International Conference on Malignant Lymphoma.
Although biopsies of follicular lymphoma tumors have demonstrated infiltration of anti-tumor T cells, these cells are typically impeded by immune checkpoints, including PD-1 and its ligand (PD-L1).
The use of anti-PD-1 checkpoint inhibitors such as pembrolizumab has been shown to enhance the function of antitumor T cells in follicular lymphoma, and blocking PD-1 on natural killer cells enhances the antibody-dependent cell-mediated cytotoxicity of the natural killer cells, she said.
Because rituximab, a mainstay of therapy for non-Hodgkin lymphomas, induces antibody-dependent cell-mediated cytotoxicity, the investigators reasoned that combining it with pembrolizumab would simultaneously and synergistically stimulate activation of innate and adaptive immunity.
They designed a phase II, single-arm study in 30 patients with relapsed follicular lymphoma following one or more prior lines of therapy. The patients also had to have rituximab-sensitive disease, defined as a complete response (CR) or partial response lasting for at least 6 months following the most recent rituximab-containing therapy.
The patients were treated with rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1, and pembrolizumab 200 mg IV every 3 weeks for up to 16 cycles starting on day 2 of cycle 1.
The investigators expected that the combination would improve ORR, the primary endpoint, to at least 60%, compared with 40% for historical controls treated with repeat courses of rituximab.
At the data cutoff for the interim analysis, 32 patients had been enrolled, 30 were evaluable for safety, and 20 for efficacy after a median follow-up of 8.2 months.
Among the 20 patients (median age 64) in the efficacy analysis, 10 (50%) had a CR, and 3 (15%) had a partial response, for an ORR of 65%. Three additional patients had stable disease, and four had disease progression as best responses.
Among the patients with CRs, the duration of response ranged from nearly 275 days to more than 600 days.
“This does appear to be durable, and it is time dependent in terms of response. We did see early response, and we also saw deepening of response over time,” Dr. Nastoupil said.
Four patients were discontinued from the study because of immune-related adverse events. All four patients had achieved a CR at the time of study removal, and all four have ongoing CRs.
Among the 30 patients evaluable for safety, there were no grade 4 adverse events, no deaths, and few grade 3 events. Most events were grade 1 or 2, and included fatigue, eye pain/blurred vision/watery eye, nausea and vomiting, diarrhea dyspnea, rash, cough, and lymphopenia.
The investigators also looked at potential biomarkers for response, including PD-L1 expression in tumors prior to treatment. They found in samples from three patients who went on to achieve CRs that PD-L1 expression in tumor cells was low, ranging from 0% to 8%, suggesting that PD-L1 expression may not be necessary to generate a response with the combination.
They then looked at the association between CD8-positive T effector cells and responses in 12 patients, and found that patients with higher levels of expression had better ORR and CR rates.
“These interim results warrant further investigation of this combination in follicular lymphoma, and an expansion to include patients with refractory follicular lymphoma is planned,” Dr. Nastoupil concluded.
The Leukemia & Lymphoma Society supported the study. Dr Nastoupil has disclosed consulting fees from Celgene and contracted research for Abbvie, Janssen, and TG Therapeutics.
LUGANO, SWITZERLAND – A novel combination of the anti-programmed death 1 (PD-1) checkpoint inhibitor pembrolizumab (Keytruda) and the anti-CD20 monoclonal antibody rituximab was associated with a high overall response rate (ORR) in patients with relapsed follicular lymphoma in a phase II clinical trial.
Among 20 patients evaluable for efficacy, the overall response rate to the combination was 65%, including 50% complete responses (CR) reported Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Follicular lymphoma is probably one of the best examples of targeting the immune system and also one of the earliest examples. Over the last few years we’ve learned a great deal about the different mechanisms of not only negative impact on infiltrating T cells, but also immune escape and T-cell exhaustion,” she said at the International Conference on Malignant Lymphoma.
Although biopsies of follicular lymphoma tumors have demonstrated infiltration of anti-tumor T cells, these cells are typically impeded by immune checkpoints, including PD-1 and its ligand (PD-L1).
The use of anti-PD-1 checkpoint inhibitors such as pembrolizumab has been shown to enhance the function of antitumor T cells in follicular lymphoma, and blocking PD-1 on natural killer cells enhances the antibody-dependent cell-mediated cytotoxicity of the natural killer cells, she said.
Because rituximab, a mainstay of therapy for non-Hodgkin lymphomas, induces antibody-dependent cell-mediated cytotoxicity, the investigators reasoned that combining it with pembrolizumab would simultaneously and synergistically stimulate activation of innate and adaptive immunity.
They designed a phase II, single-arm study in 30 patients with relapsed follicular lymphoma following one or more prior lines of therapy. The patients also had to have rituximab-sensitive disease, defined as a complete response (CR) or partial response lasting for at least 6 months following the most recent rituximab-containing therapy.
The patients were treated with rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1, and pembrolizumab 200 mg IV every 3 weeks for up to 16 cycles starting on day 2 of cycle 1.
The investigators expected that the combination would improve ORR, the primary endpoint, to at least 60%, compared with 40% for historical controls treated with repeat courses of rituximab.
At the data cutoff for the interim analysis, 32 patients had been enrolled, 30 were evaluable for safety, and 20 for efficacy after a median follow-up of 8.2 months.
Among the 20 patients (median age 64) in the efficacy analysis, 10 (50%) had a CR, and 3 (15%) had a partial response, for an ORR of 65%. Three additional patients had stable disease, and four had disease progression as best responses.
Among the patients with CRs, the duration of response ranged from nearly 275 days to more than 600 days.
“This does appear to be durable, and it is time dependent in terms of response. We did see early response, and we also saw deepening of response over time,” Dr. Nastoupil said.
Four patients were discontinued from the study because of immune-related adverse events. All four patients had achieved a CR at the time of study removal, and all four have ongoing CRs.
Among the 30 patients evaluable for safety, there were no grade 4 adverse events, no deaths, and few grade 3 events. Most events were grade 1 or 2, and included fatigue, eye pain/blurred vision/watery eye, nausea and vomiting, diarrhea dyspnea, rash, cough, and lymphopenia.
The investigators also looked at potential biomarkers for response, including PD-L1 expression in tumors prior to treatment. They found in samples from three patients who went on to achieve CRs that PD-L1 expression in tumor cells was low, ranging from 0% to 8%, suggesting that PD-L1 expression may not be necessary to generate a response with the combination.
They then looked at the association between CD8-positive T effector cells and responses in 12 patients, and found that patients with higher levels of expression had better ORR and CR rates.
“These interim results warrant further investigation of this combination in follicular lymphoma, and an expansion to include patients with refractory follicular lymphoma is planned,” Dr. Nastoupil concluded.
The Leukemia & Lymphoma Society supported the study. Dr Nastoupil has disclosed consulting fees from Celgene and contracted research for Abbvie, Janssen, and TG Therapeutics.
AT 14-ICML
Key clinical point: The combination of pembrolizumab and rituximab increased responses compared with repeat rituximab in patients with relapsed follicular lymphoma.
Major finding: The overall response rate with the combination was 65%, including 50% complete responses.
Data source: Open-label, phase II, single-arm study in 32 patients with relapsed follicular lymphoma (20 for efficacy, 30 for safety analysis).
Disclosures: The Leukemia & Lymphoma Society supported the study. Dr Nastoupil has disclosed consulting fees from Celgene and contracted research for Abbvie, Janssen, and TG Therapeutics.
What Does the Accountability Act Mean for VA Employees?
On Friday June 23, President Trump signed into law the VA Accountability and Whistleblower Protection Act, which established a revised disciplinary system for VA employees who are accused of poor performance or misconduct and protects those who report them. The bill amends Title 38 of the U.S. Code, adding VA employees to the list of those that the VA Secretary can remove if necessary. The act speeds up the termination and suspension processes for civil servants. The VA also claims that the bill will shorten the process of hiring new administrators. Still unclear is what this bill means for VA health care providers.
VA employees are protected under both Title 5 and Title 38 of the U.S. code. Title 5 governs the employment of all federal civil servants. Title 38 specifically governs the employment of VA employees in certain health care fields. Both titles specify processes for termination, demotion, or suspension and an appeals process.
Critics, including VA Secretary David J. Shulkin, MD, have complained that the previous civil service protections were time consuming and made it difficult to penalize or remove problem employees. Supporters insist that Title 5 and Title 38 protected the rights of good employees and whistleblowers from unfair workplace retaliation.
Under the new law, the VA Secretary can more easily remove, demote, or suspend any employee who warrants a penalty, including executives and supervisors. Although many of the Title 5 and Title 38 protections still cover VA employees, there are several notable changes.
What’s changing for VA employees?
- Time line: The act shortens time between the initial report, employee notification, Secretary’s decision, and appeal request/decision.
- Standard of proof: Previously, the standard of proof for misconduct was “preponderance of evidence.” The new bill lowers this standard to “supported by substantial evidence.” Changing the standard of proof effectively means that the Secretary will need to present less evidence of wrongdoing/negligence for the employee to be removed, demoted, or suspended.
- Appeals: Employees may still appeal removal, demotion, or suspension decisions, but rather than going through the Disciplinary Appeals Board, the Merit Systems Protection Board will hear appeals. Appeals must be filed within 10 days of the Secretary’s final decision. Additionally, administrative judges are instructed to uphold the decision of the Secretary if the evidence meets the “substantial evidence” standard. Administrative judges are prohibited from reducing the penalty.
Analysis
Although these changes are meant to increase the accountability of health care providers in the VA, there are several other legal implications for VA employees. Ultimately, the bill gives the VA Secretary more discretion. Whether this is a good or bad change is open to debate. Even though the bill easily passed in both the House of Representatives and the Senate, some lawmakers remain skeptical because the act increases the power of the Secretary and limits due process for VA employees. Under the new law, VA employees will have less time to prepare their defense and be held to a lower standard of proof, which will make it easier to remove VA employees from their jobs.
The Fifth Amendment of the U.S. Constitution guarantees that all Americans shall not be “deprived of life, liberty, or property, without due process of law.” Furthermore, due process rights increase when the limitations on ones’ rights are greater; this is why the burden of proof falls on the prosecution and why the standard of proof is “beyond a reasonable doubt” in criminal cases, because the rights that are at risk are liberty and, in some cases, life.
Due process is particularly important for civil servants because they are employed by the federal government. The rights to property are at risk of being limited if they are to be removed, demoted, or suspended from their jobs. The VA Accountability and Whistleblower Protection Act limits the due process of VA civil servants. However, it also is important to highlight that under this law, the VA Secretary has the right to remove, demote, or suspend any person who threatens the function and service of the VA or endangers veterans. In other words, while the VA employee’s due process may have decreased, it has increased for those whose lives depend on their service.
On Friday June 23, President Trump signed into law the VA Accountability and Whistleblower Protection Act, which established a revised disciplinary system for VA employees who are accused of poor performance or misconduct and protects those who report them. The bill amends Title 38 of the U.S. Code, adding VA employees to the list of those that the VA Secretary can remove if necessary. The act speeds up the termination and suspension processes for civil servants. The VA also claims that the bill will shorten the process of hiring new administrators. Still unclear is what this bill means for VA health care providers.
VA employees are protected under both Title 5 and Title 38 of the U.S. code. Title 5 governs the employment of all federal civil servants. Title 38 specifically governs the employment of VA employees in certain health care fields. Both titles specify processes for termination, demotion, or suspension and an appeals process.
Critics, including VA Secretary David J. Shulkin, MD, have complained that the previous civil service protections were time consuming and made it difficult to penalize or remove problem employees. Supporters insist that Title 5 and Title 38 protected the rights of good employees and whistleblowers from unfair workplace retaliation.
Under the new law, the VA Secretary can more easily remove, demote, or suspend any employee who warrants a penalty, including executives and supervisors. Although many of the Title 5 and Title 38 protections still cover VA employees, there are several notable changes.
What’s changing for VA employees?
- Time line: The act shortens time between the initial report, employee notification, Secretary’s decision, and appeal request/decision.
- Standard of proof: Previously, the standard of proof for misconduct was “preponderance of evidence.” The new bill lowers this standard to “supported by substantial evidence.” Changing the standard of proof effectively means that the Secretary will need to present less evidence of wrongdoing/negligence for the employee to be removed, demoted, or suspended.
- Appeals: Employees may still appeal removal, demotion, or suspension decisions, but rather than going through the Disciplinary Appeals Board, the Merit Systems Protection Board will hear appeals. Appeals must be filed within 10 days of the Secretary’s final decision. Additionally, administrative judges are instructed to uphold the decision of the Secretary if the evidence meets the “substantial evidence” standard. Administrative judges are prohibited from reducing the penalty.
Analysis
Although these changes are meant to increase the accountability of health care providers in the VA, there are several other legal implications for VA employees. Ultimately, the bill gives the VA Secretary more discretion. Whether this is a good or bad change is open to debate. Even though the bill easily passed in both the House of Representatives and the Senate, some lawmakers remain skeptical because the act increases the power of the Secretary and limits due process for VA employees. Under the new law, VA employees will have less time to prepare their defense and be held to a lower standard of proof, which will make it easier to remove VA employees from their jobs.
The Fifth Amendment of the U.S. Constitution guarantees that all Americans shall not be “deprived of life, liberty, or property, without due process of law.” Furthermore, due process rights increase when the limitations on ones’ rights are greater; this is why the burden of proof falls on the prosecution and why the standard of proof is “beyond a reasonable doubt” in criminal cases, because the rights that are at risk are liberty and, in some cases, life.
Due process is particularly important for civil servants because they are employed by the federal government. The rights to property are at risk of being limited if they are to be removed, demoted, or suspended from their jobs. The VA Accountability and Whistleblower Protection Act limits the due process of VA civil servants. However, it also is important to highlight that under this law, the VA Secretary has the right to remove, demote, or suspend any person who threatens the function and service of the VA or endangers veterans. In other words, while the VA employee’s due process may have decreased, it has increased for those whose lives depend on their service.
On Friday June 23, President Trump signed into law the VA Accountability and Whistleblower Protection Act, which established a revised disciplinary system for VA employees who are accused of poor performance or misconduct and protects those who report them. The bill amends Title 38 of the U.S. Code, adding VA employees to the list of those that the VA Secretary can remove if necessary. The act speeds up the termination and suspension processes for civil servants. The VA also claims that the bill will shorten the process of hiring new administrators. Still unclear is what this bill means for VA health care providers.
VA employees are protected under both Title 5 and Title 38 of the U.S. code. Title 5 governs the employment of all federal civil servants. Title 38 specifically governs the employment of VA employees in certain health care fields. Both titles specify processes for termination, demotion, or suspension and an appeals process.
Critics, including VA Secretary David J. Shulkin, MD, have complained that the previous civil service protections were time consuming and made it difficult to penalize or remove problem employees. Supporters insist that Title 5 and Title 38 protected the rights of good employees and whistleblowers from unfair workplace retaliation.
Under the new law, the VA Secretary can more easily remove, demote, or suspend any employee who warrants a penalty, including executives and supervisors. Although many of the Title 5 and Title 38 protections still cover VA employees, there are several notable changes.
What’s changing for VA employees?
- Time line: The act shortens time between the initial report, employee notification, Secretary’s decision, and appeal request/decision.
- Standard of proof: Previously, the standard of proof for misconduct was “preponderance of evidence.” The new bill lowers this standard to “supported by substantial evidence.” Changing the standard of proof effectively means that the Secretary will need to present less evidence of wrongdoing/negligence for the employee to be removed, demoted, or suspended.
- Appeals: Employees may still appeal removal, demotion, or suspension decisions, but rather than going through the Disciplinary Appeals Board, the Merit Systems Protection Board will hear appeals. Appeals must be filed within 10 days of the Secretary’s final decision. Additionally, administrative judges are instructed to uphold the decision of the Secretary if the evidence meets the “substantial evidence” standard. Administrative judges are prohibited from reducing the penalty.
Analysis
Although these changes are meant to increase the accountability of health care providers in the VA, there are several other legal implications for VA employees. Ultimately, the bill gives the VA Secretary more discretion. Whether this is a good or bad change is open to debate. Even though the bill easily passed in both the House of Representatives and the Senate, some lawmakers remain skeptical because the act increases the power of the Secretary and limits due process for VA employees. Under the new law, VA employees will have less time to prepare their defense and be held to a lower standard of proof, which will make it easier to remove VA employees from their jobs.
The Fifth Amendment of the U.S. Constitution guarantees that all Americans shall not be “deprived of life, liberty, or property, without due process of law.” Furthermore, due process rights increase when the limitations on ones’ rights are greater; this is why the burden of proof falls on the prosecution and why the standard of proof is “beyond a reasonable doubt” in criminal cases, because the rights that are at risk are liberty and, in some cases, life.
Due process is particularly important for civil servants because they are employed by the federal government. The rights to property are at risk of being limited if they are to be removed, demoted, or suspended from their jobs. The VA Accountability and Whistleblower Protection Act limits the due process of VA civil servants. However, it also is important to highlight that under this law, the VA Secretary has the right to remove, demote, or suspend any person who threatens the function and service of the VA or endangers veterans. In other words, while the VA employee’s due process may have decreased, it has increased for those whose lives depend on their service.