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Antipsychotic shows benefit for Alzheimer’s agitation
SAN FRANCISCO – In a widely anticipated report,
Members of a panel of dementia specialists here at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference said that the results were encouraging. But they also noted that the available data make it difficult to understand the impact of the drug on the day-to-day life on patients.
“I’d like to be able to translate that into something else to understand the risk benefit calculus,” said neurologist and neuroscientist Alireza Atri, MD, PhD, of Banner Sun Health Research Institute in Phoenix. “How does it affect the patients themselves, their quality of life, and the family members and their burden?”
Currently, there’s no Food and Drug Administration–approved treatment for agitation in AD.
In 2015, the FDA approved brexpiprazole, an oral medication, as a treatment for schizophrenia and an adjunctive treatment for major depressive disorder (MDD). It is an expensive drug with an average retail price per GoodRx of $1,582 per month, and no generic is available.
Researchers released the results of a trio of phase 3 clinical trials at CTAD that examined various doses of brexpiprazole. The results of the first two trials had been released earlier in 2018.
Three trials
All trials were multicenter, 12-week, randomized, double-blind and placebo-controlled.
Study participants were aged 55-90 years, had probable AD diagnoses, and had agitation per various scales. The average age in the groups was 74 years, 56.0%-61.7% were women, and 94.3%-98.1% were White.
The first trial examined two fixed doses (1 mg/d, n = 137; and 2 mg/d, n = 140) or placebo (n = 136). “The study initially included a 0.5 mg/day arm,” the researchers reported, “which was removed in a protocol amendment, and patients randomized to that arm were not included in efficacy analyses.”
The second trial looked at a flexible dose (0.5-2 mg/d, n = 133) or placebo (n = 137).
In a CTAD presentation, Nanco Hefting of Lundbeck, a codeveloper of the drug, said that the researchers learned from the first two trials that 2 mg/d might be an appropriate dose, and the FDA recommended they also examine 3 mg/day. As a result, the third trial examined two fixed doses (2 mg/d, n = 75; 3 mg/d, n = 153; or placebo, n = 117).
In the third trial, both the placebo and drug groups improved per a measurement of agitation; those in the drug group improved somewhat more.
The mean change in baseline on the Cohen-Mansfield Agitation Inventory scale – the primary endpoint – was –5.32 for the 2-mg/d and 3-mg/d groups vs. placebo (P = .0026); the score in the placebo group fell by about 18 and by about 22 in the drug group.
The key secondary endpoint was an improvement from baseline to week 12 in the Clinical Global Impression–Severity (CGI-S) score related to agitation. Compared with the placebo group, this score was –0.27 in the drug group (P = .0078). Both scores hovered around –1.0.
Safety data show the percentage of treatment-emergent events ranged from 45.9% in the placebo group to 49.0%-56.8% for brexpiprazole in the three trials. The percentage of these events leading to discontinuation was 6.3% among those receiving the drug and 3.4% in the placebo group.
University of Exeter dementia researcher Clive Ballard, MD, MB ChB, one of the panelists who discussed the research after the CTAD presentation, praised the trials as “well-conducted” and said that he was pleased that subjects in institutions were included. “It’s not an easy environment to do trials in. They should be really commended for doing for doing that.”
But he echoed fellow panelist Dr. Atri by noting that more data are needed to understand how well the drug works. “I would like to see the effect sizes and a little bit more detail to understand the clinical meaningfulness of that level of benefit.”
What’s next? A spokeswoman for Otsuka, a codeveloper of brexpiprazole, said that it hopes to hear in 2023 about a supplemental new drug application that was filed in November 2022.
Otsuka and Lundbeck funded the research. Mr. Hefting is an employee of Lundbeck, and several other authors work for Lundbeck or Otsuka. The single non-employee author reports various disclosures. Disclosures for Dr. Atri and Dr. Ballard were not provided.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – In a widely anticipated report,
Members of a panel of dementia specialists here at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference said that the results were encouraging. But they also noted that the available data make it difficult to understand the impact of the drug on the day-to-day life on patients.
“I’d like to be able to translate that into something else to understand the risk benefit calculus,” said neurologist and neuroscientist Alireza Atri, MD, PhD, of Banner Sun Health Research Institute in Phoenix. “How does it affect the patients themselves, their quality of life, and the family members and their burden?”
Currently, there’s no Food and Drug Administration–approved treatment for agitation in AD.
In 2015, the FDA approved brexpiprazole, an oral medication, as a treatment for schizophrenia and an adjunctive treatment for major depressive disorder (MDD). It is an expensive drug with an average retail price per GoodRx of $1,582 per month, and no generic is available.
Researchers released the results of a trio of phase 3 clinical trials at CTAD that examined various doses of brexpiprazole. The results of the first two trials had been released earlier in 2018.
Three trials
All trials were multicenter, 12-week, randomized, double-blind and placebo-controlled.
Study participants were aged 55-90 years, had probable AD diagnoses, and had agitation per various scales. The average age in the groups was 74 years, 56.0%-61.7% were women, and 94.3%-98.1% were White.
The first trial examined two fixed doses (1 mg/d, n = 137; and 2 mg/d, n = 140) or placebo (n = 136). “The study initially included a 0.5 mg/day arm,” the researchers reported, “which was removed in a protocol amendment, and patients randomized to that arm were not included in efficacy analyses.”
The second trial looked at a flexible dose (0.5-2 mg/d, n = 133) or placebo (n = 137).
In a CTAD presentation, Nanco Hefting of Lundbeck, a codeveloper of the drug, said that the researchers learned from the first two trials that 2 mg/d might be an appropriate dose, and the FDA recommended they also examine 3 mg/day. As a result, the third trial examined two fixed doses (2 mg/d, n = 75; 3 mg/d, n = 153; or placebo, n = 117).
In the third trial, both the placebo and drug groups improved per a measurement of agitation; those in the drug group improved somewhat more.
The mean change in baseline on the Cohen-Mansfield Agitation Inventory scale – the primary endpoint – was –5.32 for the 2-mg/d and 3-mg/d groups vs. placebo (P = .0026); the score in the placebo group fell by about 18 and by about 22 in the drug group.
The key secondary endpoint was an improvement from baseline to week 12 in the Clinical Global Impression–Severity (CGI-S) score related to agitation. Compared with the placebo group, this score was –0.27 in the drug group (P = .0078). Both scores hovered around –1.0.
Safety data show the percentage of treatment-emergent events ranged from 45.9% in the placebo group to 49.0%-56.8% for brexpiprazole in the three trials. The percentage of these events leading to discontinuation was 6.3% among those receiving the drug and 3.4% in the placebo group.
University of Exeter dementia researcher Clive Ballard, MD, MB ChB, one of the panelists who discussed the research after the CTAD presentation, praised the trials as “well-conducted” and said that he was pleased that subjects in institutions were included. “It’s not an easy environment to do trials in. They should be really commended for doing for doing that.”
But he echoed fellow panelist Dr. Atri by noting that more data are needed to understand how well the drug works. “I would like to see the effect sizes and a little bit more detail to understand the clinical meaningfulness of that level of benefit.”
What’s next? A spokeswoman for Otsuka, a codeveloper of brexpiprazole, said that it hopes to hear in 2023 about a supplemental new drug application that was filed in November 2022.
Otsuka and Lundbeck funded the research. Mr. Hefting is an employee of Lundbeck, and several other authors work for Lundbeck or Otsuka. The single non-employee author reports various disclosures. Disclosures for Dr. Atri and Dr. Ballard were not provided.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – In a widely anticipated report,
Members of a panel of dementia specialists here at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference said that the results were encouraging. But they also noted that the available data make it difficult to understand the impact of the drug on the day-to-day life on patients.
“I’d like to be able to translate that into something else to understand the risk benefit calculus,” said neurologist and neuroscientist Alireza Atri, MD, PhD, of Banner Sun Health Research Institute in Phoenix. “How does it affect the patients themselves, their quality of life, and the family members and their burden?”
Currently, there’s no Food and Drug Administration–approved treatment for agitation in AD.
In 2015, the FDA approved brexpiprazole, an oral medication, as a treatment for schizophrenia and an adjunctive treatment for major depressive disorder (MDD). It is an expensive drug with an average retail price per GoodRx of $1,582 per month, and no generic is available.
Researchers released the results of a trio of phase 3 clinical trials at CTAD that examined various doses of brexpiprazole. The results of the first two trials had been released earlier in 2018.
Three trials
All trials were multicenter, 12-week, randomized, double-blind and placebo-controlled.
Study participants were aged 55-90 years, had probable AD diagnoses, and had agitation per various scales. The average age in the groups was 74 years, 56.0%-61.7% were women, and 94.3%-98.1% were White.
The first trial examined two fixed doses (1 mg/d, n = 137; and 2 mg/d, n = 140) or placebo (n = 136). “The study initially included a 0.5 mg/day arm,” the researchers reported, “which was removed in a protocol amendment, and patients randomized to that arm were not included in efficacy analyses.”
The second trial looked at a flexible dose (0.5-2 mg/d, n = 133) or placebo (n = 137).
In a CTAD presentation, Nanco Hefting of Lundbeck, a codeveloper of the drug, said that the researchers learned from the first two trials that 2 mg/d might be an appropriate dose, and the FDA recommended they also examine 3 mg/day. As a result, the third trial examined two fixed doses (2 mg/d, n = 75; 3 mg/d, n = 153; or placebo, n = 117).
In the third trial, both the placebo and drug groups improved per a measurement of agitation; those in the drug group improved somewhat more.
The mean change in baseline on the Cohen-Mansfield Agitation Inventory scale – the primary endpoint – was –5.32 for the 2-mg/d and 3-mg/d groups vs. placebo (P = .0026); the score in the placebo group fell by about 18 and by about 22 in the drug group.
The key secondary endpoint was an improvement from baseline to week 12 in the Clinical Global Impression–Severity (CGI-S) score related to agitation. Compared with the placebo group, this score was –0.27 in the drug group (P = .0078). Both scores hovered around –1.0.
Safety data show the percentage of treatment-emergent events ranged from 45.9% in the placebo group to 49.0%-56.8% for brexpiprazole in the three trials. The percentage of these events leading to discontinuation was 6.3% among those receiving the drug and 3.4% in the placebo group.
University of Exeter dementia researcher Clive Ballard, MD, MB ChB, one of the panelists who discussed the research after the CTAD presentation, praised the trials as “well-conducted” and said that he was pleased that subjects in institutions were included. “It’s not an easy environment to do trials in. They should be really commended for doing for doing that.”
But he echoed fellow panelist Dr. Atri by noting that more data are needed to understand how well the drug works. “I would like to see the effect sizes and a little bit more detail to understand the clinical meaningfulness of that level of benefit.”
What’s next? A spokeswoman for Otsuka, a codeveloper of brexpiprazole, said that it hopes to hear in 2023 about a supplemental new drug application that was filed in November 2022.
Otsuka and Lundbeck funded the research. Mr. Hefting is an employee of Lundbeck, and several other authors work for Lundbeck or Otsuka. The single non-employee author reports various disclosures. Disclosures for Dr. Atri and Dr. Ballard were not provided.
A version of this article first appeared on Medscape.com.
AT CTAD 2022
Study: Formula-fed extreme preemies need more iron
NEW ORLEANS –
“We were surprised that, despite actually receiving more iron in total each day on average, the formula-fed infants were significantly more iron deficient than breast-fed babies. This is the opposite of what one would expect,” study lead author Grace Power, a medical student at Dalhousie University, Halifax, N.S., said in an interview. She presented the results at the annual meeting of the American Society of Hematology.
According to Ms. Power, there’s limited research into how breastfeeding and formula feeding affect iron levels in preterm infants – especially those born extremely early, between 23 and 30 weeks’ gestation.
“This kind of research is important because preterm infants are highly susceptible to iron deficiency for a number of reasons,” she said. “Iron deficiency early in life is associated with developmental and behavioral problems later on in life. That association still stands, even if the iron deficiency is corrected, so prevention is key in this population. Knowing more about how feeding type affects iron status can help us learn about ways to prevent iron deficiency in these infants in the future.”
For the study, researchers retrospectively analyzed data about all preterm infants (< 31 weeks gestation) in Nova Scotia from 2005 to 2018. Of the 392 infants in this group (55.75% male; average age, about 5 months), 285 were fed with iron-rich formula (mean intake, 1.66 mg/kg per day), and 107 were fully or partially breast fed. The two groups were similar in terms of traits such as mean birth weight and gestational age.
The formula-fed infants were more likely to develop iron deficiency (ID, 36.8%) than the breast-fed infants (20.6%; P = .002). “Mean gestational age and birth weight were both lower in the ID group. The ID group also had a higher percentage of infants born less than 1,100 g (P = .01). More babies in the ID group received at least one blood transfusion,” the researchers reported. “ID infants had a higher daily formula intake, daily iron intake from formula, and total daily iron intake combined from formula and supplements.”
Why is there such a gap between formula-fed infants and breast-fed infants? The researchers speculated that infants absorb less iron from formula versus breast milk, possibly because of the presence of lactoferrin in breast milk.
The researchers also wondered whether physicians may pull back on iron supplementation in infants who undergo blood transfusions out of fear of the risk of iron overload, which Ms. Power said can cause infection and poor growth. By doing so, they may inadvertently deprive the babies of their need for iron.
“We don’t want clinicians to assume an infant doesn’t need iron supplementation just because they’ve received a blood transfusion,” she said.
As for an overall message from the research, Ms. Power said clinicians “should be aware that formula feeding can put infants at risk for iron deficiency and consider this when making decisions about supplementation.” And she noted that guidelines from the American Academy of Pediatrics and Canadian Pediatric Society don’t highlight the importance of iron supplementation in formula-fed, very preterm infants.
In an interview, University of Michigan pediatrician Michael K. Georgieff, MD, who has studied iron supplementation, said the study’s primary findings are surprising, although it makes sense that infants with lower gestational age and birth weight would suffer from more ID. Blood transfusion can indeed raise iron levels, but it’s important to consider that these infants may already have low levels of iron.
Dr. Georgieff advised colleagues to understand the potential for various nutritional deficiencies in preterm infants well beyond the first few weeks. When the babies are handed off to other clinicians such as pediatricians, they should undergo nutritional screening at 6 months, not at a year.
Dalhousie University funded the study. The study authors and Dr. Georgieff have no disclosures.
NEW ORLEANS –
“We were surprised that, despite actually receiving more iron in total each day on average, the formula-fed infants were significantly more iron deficient than breast-fed babies. This is the opposite of what one would expect,” study lead author Grace Power, a medical student at Dalhousie University, Halifax, N.S., said in an interview. She presented the results at the annual meeting of the American Society of Hematology.
According to Ms. Power, there’s limited research into how breastfeeding and formula feeding affect iron levels in preterm infants – especially those born extremely early, between 23 and 30 weeks’ gestation.
“This kind of research is important because preterm infants are highly susceptible to iron deficiency for a number of reasons,” she said. “Iron deficiency early in life is associated with developmental and behavioral problems later on in life. That association still stands, even if the iron deficiency is corrected, so prevention is key in this population. Knowing more about how feeding type affects iron status can help us learn about ways to prevent iron deficiency in these infants in the future.”
For the study, researchers retrospectively analyzed data about all preterm infants (< 31 weeks gestation) in Nova Scotia from 2005 to 2018. Of the 392 infants in this group (55.75% male; average age, about 5 months), 285 were fed with iron-rich formula (mean intake, 1.66 mg/kg per day), and 107 were fully or partially breast fed. The two groups were similar in terms of traits such as mean birth weight and gestational age.
The formula-fed infants were more likely to develop iron deficiency (ID, 36.8%) than the breast-fed infants (20.6%; P = .002). “Mean gestational age and birth weight were both lower in the ID group. The ID group also had a higher percentage of infants born less than 1,100 g (P = .01). More babies in the ID group received at least one blood transfusion,” the researchers reported. “ID infants had a higher daily formula intake, daily iron intake from formula, and total daily iron intake combined from formula and supplements.”
Why is there such a gap between formula-fed infants and breast-fed infants? The researchers speculated that infants absorb less iron from formula versus breast milk, possibly because of the presence of lactoferrin in breast milk.
The researchers also wondered whether physicians may pull back on iron supplementation in infants who undergo blood transfusions out of fear of the risk of iron overload, which Ms. Power said can cause infection and poor growth. By doing so, they may inadvertently deprive the babies of their need for iron.
“We don’t want clinicians to assume an infant doesn’t need iron supplementation just because they’ve received a blood transfusion,” she said.
As for an overall message from the research, Ms. Power said clinicians “should be aware that formula feeding can put infants at risk for iron deficiency and consider this when making decisions about supplementation.” And she noted that guidelines from the American Academy of Pediatrics and Canadian Pediatric Society don’t highlight the importance of iron supplementation in formula-fed, very preterm infants.
In an interview, University of Michigan pediatrician Michael K. Georgieff, MD, who has studied iron supplementation, said the study’s primary findings are surprising, although it makes sense that infants with lower gestational age and birth weight would suffer from more ID. Blood transfusion can indeed raise iron levels, but it’s important to consider that these infants may already have low levels of iron.
Dr. Georgieff advised colleagues to understand the potential for various nutritional deficiencies in preterm infants well beyond the first few weeks. When the babies are handed off to other clinicians such as pediatricians, they should undergo nutritional screening at 6 months, not at a year.
Dalhousie University funded the study. The study authors and Dr. Georgieff have no disclosures.
NEW ORLEANS –
“We were surprised that, despite actually receiving more iron in total each day on average, the formula-fed infants were significantly more iron deficient than breast-fed babies. This is the opposite of what one would expect,” study lead author Grace Power, a medical student at Dalhousie University, Halifax, N.S., said in an interview. She presented the results at the annual meeting of the American Society of Hematology.
According to Ms. Power, there’s limited research into how breastfeeding and formula feeding affect iron levels in preterm infants – especially those born extremely early, between 23 and 30 weeks’ gestation.
“This kind of research is important because preterm infants are highly susceptible to iron deficiency for a number of reasons,” she said. “Iron deficiency early in life is associated with developmental and behavioral problems later on in life. That association still stands, even if the iron deficiency is corrected, so prevention is key in this population. Knowing more about how feeding type affects iron status can help us learn about ways to prevent iron deficiency in these infants in the future.”
For the study, researchers retrospectively analyzed data about all preterm infants (< 31 weeks gestation) in Nova Scotia from 2005 to 2018. Of the 392 infants in this group (55.75% male; average age, about 5 months), 285 were fed with iron-rich formula (mean intake, 1.66 mg/kg per day), and 107 were fully or partially breast fed. The two groups were similar in terms of traits such as mean birth weight and gestational age.
The formula-fed infants were more likely to develop iron deficiency (ID, 36.8%) than the breast-fed infants (20.6%; P = .002). “Mean gestational age and birth weight were both lower in the ID group. The ID group also had a higher percentage of infants born less than 1,100 g (P = .01). More babies in the ID group received at least one blood transfusion,” the researchers reported. “ID infants had a higher daily formula intake, daily iron intake from formula, and total daily iron intake combined from formula and supplements.”
Why is there such a gap between formula-fed infants and breast-fed infants? The researchers speculated that infants absorb less iron from formula versus breast milk, possibly because of the presence of lactoferrin in breast milk.
The researchers also wondered whether physicians may pull back on iron supplementation in infants who undergo blood transfusions out of fear of the risk of iron overload, which Ms. Power said can cause infection and poor growth. By doing so, they may inadvertently deprive the babies of their need for iron.
“We don’t want clinicians to assume an infant doesn’t need iron supplementation just because they’ve received a blood transfusion,” she said.
As for an overall message from the research, Ms. Power said clinicians “should be aware that formula feeding can put infants at risk for iron deficiency and consider this when making decisions about supplementation.” And she noted that guidelines from the American Academy of Pediatrics and Canadian Pediatric Society don’t highlight the importance of iron supplementation in formula-fed, very preterm infants.
In an interview, University of Michigan pediatrician Michael K. Georgieff, MD, who has studied iron supplementation, said the study’s primary findings are surprising, although it makes sense that infants with lower gestational age and birth weight would suffer from more ID. Blood transfusion can indeed raise iron levels, but it’s important to consider that these infants may already have low levels of iron.
Dr. Georgieff advised colleagues to understand the potential for various nutritional deficiencies in preterm infants well beyond the first few weeks. When the babies are handed off to other clinicians such as pediatricians, they should undergo nutritional screening at 6 months, not at a year.
Dalhousie University funded the study. The study authors and Dr. Georgieff have no disclosures.
AT ASH 2022
ITP: Biologic beat placebo, but few patients improved
NEW ORLEANS –
Nevertheless, “efgartigimod demonstrated a strong clinical benefit,” said hematologist/oncologist and study lead author Catherine M. Broome, MD, of Georgetown University, Washington, in an interview about the findings presented at the annual meeting of the American Society of Hematology.
“The data showed statistically significant and clinically meaningful improvement in platelet counts over placebo, a fast and robust platelet count improvement over placebo, and the confirmed ability for every-other-week dosing, as well as a favorable safety and tolerability profile, consistent with previous clinical trials,” she said.
In ITP, according to the National Organization for Rare Disorders, “the patient’s immune system tags their own platelets as ‘foreign,’ leading their B lymphocytes and plasma cells to produce self-reactive antiplatelet antibodies that attach to platelet surface.”
The prevalence of ITP among adults in the United States is 9.5 per 100,000, NORD says. Children are also affected, but they usually recover. An estimated 60% of adults recover within 3 years.
Treatment options include corticosteroids and intravenous immunoglobulin.
“There are a relatively large number of current treatments, and they tend to work well for most patients. However, there are a minority of patients who do not respond to or tolerate current therapies and would benefit from new treatment options,” said hematologist Adam C. Cuker, MD, MS, of Penn Medicine, Philadelphia, in an interview. He is chair of ASH’s Committee on Quality.
For the new industry-funded ADVANCE study, researchers recruited patients with long-standing, persistent/chronic ITP (an average of two platelet counts of < 30×109/L).
Subjects were randomized 2:1 to receive 10 mg/kg of efgartigimod weekly – or response-dependent doses after the first 4 weeks – or placebo for 24 weeks. There were 86 patients in the intervention group and 45 in the placebo group. Overall, 60 were male and 71 were female; 107 were under 65; 121 were White and 8 were Asian. Details about the others were not provided.
Subjects were allowed to take several other drugs such as oral corticosteroids, and oral thrombopoietin receptor agonists other than romiplostim.
Per the primary endpoint, 17/78 (21.8%) reached a sustained response, defined as platelet counts ≥ 50×109/L in ≥ four of six visits between weeks 19 and 24 without intercurrent events, such as rescue therapy at week 12 or later. In the placebo group, 2/40 reached this response (5.0%; P = .0316).
“The primary endpoint was a high bar to achieve,” Dr. Broome said. “This was a difficult-to-treat patient population heavily pretreated and refractory to other treatments: 68.6% of patients in the efgartigimod arm had received three or more prior ITP treatments.”
She added that “subgroup analyses – including prior ITP therapy, time since diagnosis, baseline platelet count and age/region demographics – of patients who achieved the primary endpoint all favored efgartigimod over placebo.”
Side effects were extremely common among both the drug and placebo groups, and serious adverse events were common in the placebo group. No deaths were reported.
Efgartigimod, a neonatal Fc receptor blocker, is an extremely expensive drug that is Food and Drug Administration approved for some cases of generalized myasthenia gravis. According to a report in Neurology earlier this year, company statements listed its price as $855,400 a year; the report questioned its cost-effectiveness.
In response to a query about price, Luc Truyen, MD, PhD, chief medical officer of drug manufacturer Argenx, declined to talk about cost – a sensitive topic for pharmaceutical companies. “It is too early to discuss pricing and access as no regulatory submission or discussion has occurred,” Dr. Truyen said.
Penn Medicine’s Dr. Cuker, who is familiar with the study findings, said the primary endpoint results are not very impressive. “That said, it should be borne in mind that the patients enrolled in the trial tended to be heavily pretreated and refractory patients,” he said.
As for adverse effects, he said the drug “appears to be safe and well tolerated. The biggest theoretical concern with this class of drugs is an increased risk of infection due to lowering of IgG levels.”
It would be helpful to have trials that directly compare second-line therapies in ITP, he added. “Unfortunately, no such trials exist, and pharmaceutical companies would not be motivated to conduct them.”
For now, he said, off-label use of efgartigimod “may be reasonable, but only in rare situations where other approved and better established ITP treatments have been exhausted.”
What’s next? According to Dr. Broome, another trial is currently evaluating efgartigimod for the treatment of primary ITP, with top-line data expected in the second half of 2023.
The study was funded by Argenx. Dr. Broome discloses honoraria from Alexion, Argenx, Apellis, and Sano. Dr. Truyen’s disclosures weren’t available. Dr. Cuker has no disclosures.
NEW ORLEANS –
Nevertheless, “efgartigimod demonstrated a strong clinical benefit,” said hematologist/oncologist and study lead author Catherine M. Broome, MD, of Georgetown University, Washington, in an interview about the findings presented at the annual meeting of the American Society of Hematology.
“The data showed statistically significant and clinically meaningful improvement in platelet counts over placebo, a fast and robust platelet count improvement over placebo, and the confirmed ability for every-other-week dosing, as well as a favorable safety and tolerability profile, consistent with previous clinical trials,” she said.
In ITP, according to the National Organization for Rare Disorders, “the patient’s immune system tags their own platelets as ‘foreign,’ leading their B lymphocytes and plasma cells to produce self-reactive antiplatelet antibodies that attach to platelet surface.”
The prevalence of ITP among adults in the United States is 9.5 per 100,000, NORD says. Children are also affected, but they usually recover. An estimated 60% of adults recover within 3 years.
Treatment options include corticosteroids and intravenous immunoglobulin.
“There are a relatively large number of current treatments, and they tend to work well for most patients. However, there are a minority of patients who do not respond to or tolerate current therapies and would benefit from new treatment options,” said hematologist Adam C. Cuker, MD, MS, of Penn Medicine, Philadelphia, in an interview. He is chair of ASH’s Committee on Quality.
For the new industry-funded ADVANCE study, researchers recruited patients with long-standing, persistent/chronic ITP (an average of two platelet counts of < 30×109/L).
Subjects were randomized 2:1 to receive 10 mg/kg of efgartigimod weekly – or response-dependent doses after the first 4 weeks – or placebo for 24 weeks. There were 86 patients in the intervention group and 45 in the placebo group. Overall, 60 were male and 71 were female; 107 were under 65; 121 were White and 8 were Asian. Details about the others were not provided.
Subjects were allowed to take several other drugs such as oral corticosteroids, and oral thrombopoietin receptor agonists other than romiplostim.
Per the primary endpoint, 17/78 (21.8%) reached a sustained response, defined as platelet counts ≥ 50×109/L in ≥ four of six visits between weeks 19 and 24 without intercurrent events, such as rescue therapy at week 12 or later. In the placebo group, 2/40 reached this response (5.0%; P = .0316).
“The primary endpoint was a high bar to achieve,” Dr. Broome said. “This was a difficult-to-treat patient population heavily pretreated and refractory to other treatments: 68.6% of patients in the efgartigimod arm had received three or more prior ITP treatments.”
She added that “subgroup analyses – including prior ITP therapy, time since diagnosis, baseline platelet count and age/region demographics – of patients who achieved the primary endpoint all favored efgartigimod over placebo.”
Side effects were extremely common among both the drug and placebo groups, and serious adverse events were common in the placebo group. No deaths were reported.
Efgartigimod, a neonatal Fc receptor blocker, is an extremely expensive drug that is Food and Drug Administration approved for some cases of generalized myasthenia gravis. According to a report in Neurology earlier this year, company statements listed its price as $855,400 a year; the report questioned its cost-effectiveness.
In response to a query about price, Luc Truyen, MD, PhD, chief medical officer of drug manufacturer Argenx, declined to talk about cost – a sensitive topic for pharmaceutical companies. “It is too early to discuss pricing and access as no regulatory submission or discussion has occurred,” Dr. Truyen said.
Penn Medicine’s Dr. Cuker, who is familiar with the study findings, said the primary endpoint results are not very impressive. “That said, it should be borne in mind that the patients enrolled in the trial tended to be heavily pretreated and refractory patients,” he said.
As for adverse effects, he said the drug “appears to be safe and well tolerated. The biggest theoretical concern with this class of drugs is an increased risk of infection due to lowering of IgG levels.”
It would be helpful to have trials that directly compare second-line therapies in ITP, he added. “Unfortunately, no such trials exist, and pharmaceutical companies would not be motivated to conduct them.”
For now, he said, off-label use of efgartigimod “may be reasonable, but only in rare situations where other approved and better established ITP treatments have been exhausted.”
What’s next? According to Dr. Broome, another trial is currently evaluating efgartigimod for the treatment of primary ITP, with top-line data expected in the second half of 2023.
The study was funded by Argenx. Dr. Broome discloses honoraria from Alexion, Argenx, Apellis, and Sano. Dr. Truyen’s disclosures weren’t available. Dr. Cuker has no disclosures.
NEW ORLEANS –
Nevertheless, “efgartigimod demonstrated a strong clinical benefit,” said hematologist/oncologist and study lead author Catherine M. Broome, MD, of Georgetown University, Washington, in an interview about the findings presented at the annual meeting of the American Society of Hematology.
“The data showed statistically significant and clinically meaningful improvement in platelet counts over placebo, a fast and robust platelet count improvement over placebo, and the confirmed ability for every-other-week dosing, as well as a favorable safety and tolerability profile, consistent with previous clinical trials,” she said.
In ITP, according to the National Organization for Rare Disorders, “the patient’s immune system tags their own platelets as ‘foreign,’ leading their B lymphocytes and plasma cells to produce self-reactive antiplatelet antibodies that attach to platelet surface.”
The prevalence of ITP among adults in the United States is 9.5 per 100,000, NORD says. Children are also affected, but they usually recover. An estimated 60% of adults recover within 3 years.
Treatment options include corticosteroids and intravenous immunoglobulin.
“There are a relatively large number of current treatments, and they tend to work well for most patients. However, there are a minority of patients who do not respond to or tolerate current therapies and would benefit from new treatment options,” said hematologist Adam C. Cuker, MD, MS, of Penn Medicine, Philadelphia, in an interview. He is chair of ASH’s Committee on Quality.
For the new industry-funded ADVANCE study, researchers recruited patients with long-standing, persistent/chronic ITP (an average of two platelet counts of < 30×109/L).
Subjects were randomized 2:1 to receive 10 mg/kg of efgartigimod weekly – or response-dependent doses after the first 4 weeks – or placebo for 24 weeks. There were 86 patients in the intervention group and 45 in the placebo group. Overall, 60 were male and 71 were female; 107 were under 65; 121 were White and 8 were Asian. Details about the others were not provided.
Subjects were allowed to take several other drugs such as oral corticosteroids, and oral thrombopoietin receptor agonists other than romiplostim.
Per the primary endpoint, 17/78 (21.8%) reached a sustained response, defined as platelet counts ≥ 50×109/L in ≥ four of six visits between weeks 19 and 24 without intercurrent events, such as rescue therapy at week 12 or later. In the placebo group, 2/40 reached this response (5.0%; P = .0316).
“The primary endpoint was a high bar to achieve,” Dr. Broome said. “This was a difficult-to-treat patient population heavily pretreated and refractory to other treatments: 68.6% of patients in the efgartigimod arm had received three or more prior ITP treatments.”
She added that “subgroup analyses – including prior ITP therapy, time since diagnosis, baseline platelet count and age/region demographics – of patients who achieved the primary endpoint all favored efgartigimod over placebo.”
Side effects were extremely common among both the drug and placebo groups, and serious adverse events were common in the placebo group. No deaths were reported.
Efgartigimod, a neonatal Fc receptor blocker, is an extremely expensive drug that is Food and Drug Administration approved for some cases of generalized myasthenia gravis. According to a report in Neurology earlier this year, company statements listed its price as $855,400 a year; the report questioned its cost-effectiveness.
In response to a query about price, Luc Truyen, MD, PhD, chief medical officer of drug manufacturer Argenx, declined to talk about cost – a sensitive topic for pharmaceutical companies. “It is too early to discuss pricing and access as no regulatory submission or discussion has occurred,” Dr. Truyen said.
Penn Medicine’s Dr. Cuker, who is familiar with the study findings, said the primary endpoint results are not very impressive. “That said, it should be borne in mind that the patients enrolled in the trial tended to be heavily pretreated and refractory patients,” he said.
As for adverse effects, he said the drug “appears to be safe and well tolerated. The biggest theoretical concern with this class of drugs is an increased risk of infection due to lowering of IgG levels.”
It would be helpful to have trials that directly compare second-line therapies in ITP, he added. “Unfortunately, no such trials exist, and pharmaceutical companies would not be motivated to conduct them.”
For now, he said, off-label use of efgartigimod “may be reasonable, but only in rare situations where other approved and better established ITP treatments have been exhausted.”
What’s next? According to Dr. Broome, another trial is currently evaluating efgartigimod for the treatment of primary ITP, with top-line data expected in the second half of 2023.
The study was funded by Argenx. Dr. Broome discloses honoraria from Alexion, Argenx, Apellis, and Sano. Dr. Truyen’s disclosures weren’t available. Dr. Cuker has no disclosures.
AT ASH 2022
MCL: Ibrutinib could become the ‘new standard’
First-line patients fared well on ibrutinib, a Bruton’s tyrosine kinase inhibitor, according to the findings.
“Based on the results so far ... at least for the majority of patients, ibrutinib early will become the new standard,” said study lead author Martin Dreyling, MD, associate professor of medicine at Ludwig Maximilian University (LMU) Munich. Dr. Dreyling spoke in a news briefing and at a separate presentation at the annual meeting of the American Society of Hematology. “It might well be that specific subsets of patients may benefit from autologous transplant.”
MCL is a rare form of non-Hodgkin’s lymphoma that strikes cells in the mantle zone of lymph nodes. It is usually diagnosed in older men and often presents at an advanced stage. Multiple available treatments include rituximab/bendamustine, CAR-T cell therapy, stem cell transplants, and Bruton’s tyrosine kinase inhibitors. Ibrutinib is approved by the Food and Drug Administration only for refractory/relapsed cases, however.
Dr. Dreyling was a pioneer in confirming benefit from stem-cell transplants for MCL. “However,” he said, “no one likes autologous transplant because it also has side effects.”
For the new open-label study, Dr. Dreyling and colleagues in the European MCL Network in 2016 began recruiting patients with newly diagnosed, advanced stage II-IV MCL. The patients were younger than 65.
The subjects were randomly assigned to three trial arms: Standard treatment (high-dose cytarabine followed by autologous stem cell transplant and rituximab maintenance, n = 288), the standard treatment plus ibrutinib (n = 292), and ibrutinib without stem cell transplant (n = 290). The median age was 57, and 76% of patients were male.
The primary endpoint was failure-free survival at 31 months. Standard therapy was not superior to the ibrutinib without transplant group (72% vs. 86%, respectively, P = .9979). However, standard therapy with ibrutinib was superior to the standard therapy group (88% vs. 72%, respectively, P = .0008). The researchers haven’t finished their analysis of standard therapy with ibrutinib vs. ibrutinib without transplant.
Subjects in the standard therapy plus ibrutinib arm had more grade 3-5 adverse events than did the standard therapy and ibrutinib without transplant groups: Neutropenia, 44%, 17%, and 23%, respectively; leukopenia, 4%, 2%, and 2%; febrile neutropenia, 6%, 3%, and 3%; infections and infestations, 25%, 13%, and 19%; and cardiac disorders, 3%, 1%, 4%. P values were not provided.
In an interview, Ohio State University hematologist Narendranath Epperla, MD, MS, who was not involved in the study, said that this research reflects efforts to understand how novel agents such as ibrutinib and cellular therapies fit into MCL treatment. “We are trying to incorporate them in the frontline setting with either chemo backbone or with other targeted agents to improve outcomes and minimize toxicity. We are also trying to understand in whom auto-HCT can be precluded.”
The results of the new study appear promising, Dr. Epperla said, but he questioned the primary endpoint (failure-free survival instead of progress-free survival) and the short duration of the trial.
“I would like to see how the patients with high-risk features such as TP53 mutation, complex cytogenetics, and blastoid/pleomorphic variants did on the three arms,” Dr. Epperla said. “And I would like to see longer follow-up data before adapting this – [addition] of ibrutinib to the chemotherapy backbone without auto-HCT – into clinical practice.”
What’s next? Dr. Dreyling said that upcoming data will provide further insight into ibrutinib vs. stem-cell transplantation. And “within the next half year or so,” he said, “there will be a next generation of studies challenging chemotherapy overall in mantle cell lymphoma and substituting targeted treatment, hopefully achieving much better tolerability.”
Funding information was not provided. Dr. Dreyling disclosed ties with Lilly/Loxo, AstraZeneca, Novartis, Amgen, Roche, Janssen, Gilead/Kite, BMS/Celgene, Bayer, Abbvie, and Beigene. The other study authors reported various disclosures. Dr. Epperla disclosed a relationship with Pharmacyclics.
First-line patients fared well on ibrutinib, a Bruton’s tyrosine kinase inhibitor, according to the findings.
“Based on the results so far ... at least for the majority of patients, ibrutinib early will become the new standard,” said study lead author Martin Dreyling, MD, associate professor of medicine at Ludwig Maximilian University (LMU) Munich. Dr. Dreyling spoke in a news briefing and at a separate presentation at the annual meeting of the American Society of Hematology. “It might well be that specific subsets of patients may benefit from autologous transplant.”
MCL is a rare form of non-Hodgkin’s lymphoma that strikes cells in the mantle zone of lymph nodes. It is usually diagnosed in older men and often presents at an advanced stage. Multiple available treatments include rituximab/bendamustine, CAR-T cell therapy, stem cell transplants, and Bruton’s tyrosine kinase inhibitors. Ibrutinib is approved by the Food and Drug Administration only for refractory/relapsed cases, however.
Dr. Dreyling was a pioneer in confirming benefit from stem-cell transplants for MCL. “However,” he said, “no one likes autologous transplant because it also has side effects.”
For the new open-label study, Dr. Dreyling and colleagues in the European MCL Network in 2016 began recruiting patients with newly diagnosed, advanced stage II-IV MCL. The patients were younger than 65.
The subjects were randomly assigned to three trial arms: Standard treatment (high-dose cytarabine followed by autologous stem cell transplant and rituximab maintenance, n = 288), the standard treatment plus ibrutinib (n = 292), and ibrutinib without stem cell transplant (n = 290). The median age was 57, and 76% of patients were male.
The primary endpoint was failure-free survival at 31 months. Standard therapy was not superior to the ibrutinib without transplant group (72% vs. 86%, respectively, P = .9979). However, standard therapy with ibrutinib was superior to the standard therapy group (88% vs. 72%, respectively, P = .0008). The researchers haven’t finished their analysis of standard therapy with ibrutinib vs. ibrutinib without transplant.
Subjects in the standard therapy plus ibrutinib arm had more grade 3-5 adverse events than did the standard therapy and ibrutinib without transplant groups: Neutropenia, 44%, 17%, and 23%, respectively; leukopenia, 4%, 2%, and 2%; febrile neutropenia, 6%, 3%, and 3%; infections and infestations, 25%, 13%, and 19%; and cardiac disorders, 3%, 1%, 4%. P values were not provided.
In an interview, Ohio State University hematologist Narendranath Epperla, MD, MS, who was not involved in the study, said that this research reflects efforts to understand how novel agents such as ibrutinib and cellular therapies fit into MCL treatment. “We are trying to incorporate them in the frontline setting with either chemo backbone or with other targeted agents to improve outcomes and minimize toxicity. We are also trying to understand in whom auto-HCT can be precluded.”
The results of the new study appear promising, Dr. Epperla said, but he questioned the primary endpoint (failure-free survival instead of progress-free survival) and the short duration of the trial.
“I would like to see how the patients with high-risk features such as TP53 mutation, complex cytogenetics, and blastoid/pleomorphic variants did on the three arms,” Dr. Epperla said. “And I would like to see longer follow-up data before adapting this – [addition] of ibrutinib to the chemotherapy backbone without auto-HCT – into clinical practice.”
What’s next? Dr. Dreyling said that upcoming data will provide further insight into ibrutinib vs. stem-cell transplantation. And “within the next half year or so,” he said, “there will be a next generation of studies challenging chemotherapy overall in mantle cell lymphoma and substituting targeted treatment, hopefully achieving much better tolerability.”
Funding information was not provided. Dr. Dreyling disclosed ties with Lilly/Loxo, AstraZeneca, Novartis, Amgen, Roche, Janssen, Gilead/Kite, BMS/Celgene, Bayer, Abbvie, and Beigene. The other study authors reported various disclosures. Dr. Epperla disclosed a relationship with Pharmacyclics.
First-line patients fared well on ibrutinib, a Bruton’s tyrosine kinase inhibitor, according to the findings.
“Based on the results so far ... at least for the majority of patients, ibrutinib early will become the new standard,” said study lead author Martin Dreyling, MD, associate professor of medicine at Ludwig Maximilian University (LMU) Munich. Dr. Dreyling spoke in a news briefing and at a separate presentation at the annual meeting of the American Society of Hematology. “It might well be that specific subsets of patients may benefit from autologous transplant.”
MCL is a rare form of non-Hodgkin’s lymphoma that strikes cells in the mantle zone of lymph nodes. It is usually diagnosed in older men and often presents at an advanced stage. Multiple available treatments include rituximab/bendamustine, CAR-T cell therapy, stem cell transplants, and Bruton’s tyrosine kinase inhibitors. Ibrutinib is approved by the Food and Drug Administration only for refractory/relapsed cases, however.
Dr. Dreyling was a pioneer in confirming benefit from stem-cell transplants for MCL. “However,” he said, “no one likes autologous transplant because it also has side effects.”
For the new open-label study, Dr. Dreyling and colleagues in the European MCL Network in 2016 began recruiting patients with newly diagnosed, advanced stage II-IV MCL. The patients were younger than 65.
The subjects were randomly assigned to three trial arms: Standard treatment (high-dose cytarabine followed by autologous stem cell transplant and rituximab maintenance, n = 288), the standard treatment plus ibrutinib (n = 292), and ibrutinib without stem cell transplant (n = 290). The median age was 57, and 76% of patients were male.
The primary endpoint was failure-free survival at 31 months. Standard therapy was not superior to the ibrutinib without transplant group (72% vs. 86%, respectively, P = .9979). However, standard therapy with ibrutinib was superior to the standard therapy group (88% vs. 72%, respectively, P = .0008). The researchers haven’t finished their analysis of standard therapy with ibrutinib vs. ibrutinib without transplant.
Subjects in the standard therapy plus ibrutinib arm had more grade 3-5 adverse events than did the standard therapy and ibrutinib without transplant groups: Neutropenia, 44%, 17%, and 23%, respectively; leukopenia, 4%, 2%, and 2%; febrile neutropenia, 6%, 3%, and 3%; infections and infestations, 25%, 13%, and 19%; and cardiac disorders, 3%, 1%, 4%. P values were not provided.
In an interview, Ohio State University hematologist Narendranath Epperla, MD, MS, who was not involved in the study, said that this research reflects efforts to understand how novel agents such as ibrutinib and cellular therapies fit into MCL treatment. “We are trying to incorporate them in the frontline setting with either chemo backbone or with other targeted agents to improve outcomes and minimize toxicity. We are also trying to understand in whom auto-HCT can be precluded.”
The results of the new study appear promising, Dr. Epperla said, but he questioned the primary endpoint (failure-free survival instead of progress-free survival) and the short duration of the trial.
“I would like to see how the patients with high-risk features such as TP53 mutation, complex cytogenetics, and blastoid/pleomorphic variants did on the three arms,” Dr. Epperla said. “And I would like to see longer follow-up data before adapting this – [addition] of ibrutinib to the chemotherapy backbone without auto-HCT – into clinical practice.”
What’s next? Dr. Dreyling said that upcoming data will provide further insight into ibrutinib vs. stem-cell transplantation. And “within the next half year or so,” he said, “there will be a next generation of studies challenging chemotherapy overall in mantle cell lymphoma and substituting targeted treatment, hopefully achieving much better tolerability.”
Funding information was not provided. Dr. Dreyling disclosed ties with Lilly/Loxo, AstraZeneca, Novartis, Amgen, Roche, Janssen, Gilead/Kite, BMS/Celgene, Bayer, Abbvie, and Beigene. The other study authors reported various disclosures. Dr. Epperla disclosed a relationship with Pharmacyclics.
AT ASH 2022
SSRI tied to improved cognition in comorbid depression, dementia
The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.
“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.
“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.
However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.
“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.
Potential neurotransmission modulator
Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”
The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.
Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.
The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.
In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.
“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.
“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.
More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.
For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”
A third of patients had drug-related treatment-emergent adverse events.
Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.
Small trial, open-label design
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”
She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.
The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.
A version of this article first appeared on Medscape.com.
The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.
“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.
“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.
However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.
“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.
Potential neurotransmission modulator
Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”
The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.
Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.
The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.
In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.
“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.
“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.
More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.
For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”
A third of patients had drug-related treatment-emergent adverse events.
Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.
Small trial, open-label design
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”
She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.
The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.
A version of this article first appeared on Medscape.com.
The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.
“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.
“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.
However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.
“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.
Potential neurotransmission modulator
Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”
The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.
Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.
The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.
In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.
“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.
“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.
More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.
For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”
A third of patients had drug-related treatment-emergent adverse events.
Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.
Small trial, open-label design
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”
She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.
The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.
A version of this article first appeared on Medscape.com.
FROM CTAD 2022
Melanoma mortality rates fell in 2010s as new therapies took hold
, a new study finds, although the dip appeared to stabilize over the next 2 years.
“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”
The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”
New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.
The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.
Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.
“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”
But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”
In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”
Which treatments are making the biggest difference? “It is difficult to say, but it’s likely immunotherapy because some patients on these medications have durable responses for many years,” Dr. Adamson said. “Studies are ongoing to figure out just how much more life some patients may expect after treatment.”
He added that “while this study did not evaluate mortality trends by race or ethnicity, it is important to note that the sharp decline in melanoma mortality rates is exclusively among non-Hispanic White Americans.”
Dermatologist David Polsky, MD, PhD, professor of dermatologic oncology at New York (N.Y.) University, said in an interview that the findings reflect extraordinary progress in melanoma treatment. “Historically, only 10% of metastatic melanoma patients would live 5 years. And now 30% to 50% of metastatic patients are living 5 years. That’s amazing to me,” said Dr. Polsky, who coauthored the 2020 report cited by Dr. Adamson.
A few years ago, Dr. Polsky added, he talked to an oncologist about how life at her clinic had changed as a result of new melanoma treatments. “She said, ‘My clinic has gotten really crowded. It used to be that patients died in a span of about a year and a half, and I would turn over my patient population. Now all those patients are still alive, and I’m getting new patients.’”
The study was funded by the University of Toledo College of Medicine and Life Sciences. One author reported receiving honoraria from Boston Healthcare Associates and research funding from Bayer, ImmunoVaccine, and the Ludwig Institute for Cancer Research. Dr. Polsky disclosed relationships with Merck (advisory board) and Novartis and Bristol Myers Squibb (consulting). Dr. Adamson disclosed he is web editor and associate editor at JAMA Dermatology.
, a new study finds, although the dip appeared to stabilize over the next 2 years.
“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”
The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”
New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.
The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.
Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.
“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”
But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”
In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”
Which treatments are making the biggest difference? “It is difficult to say, but it’s likely immunotherapy because some patients on these medications have durable responses for many years,” Dr. Adamson said. “Studies are ongoing to figure out just how much more life some patients may expect after treatment.”
He added that “while this study did not evaluate mortality trends by race or ethnicity, it is important to note that the sharp decline in melanoma mortality rates is exclusively among non-Hispanic White Americans.”
Dermatologist David Polsky, MD, PhD, professor of dermatologic oncology at New York (N.Y.) University, said in an interview that the findings reflect extraordinary progress in melanoma treatment. “Historically, only 10% of metastatic melanoma patients would live 5 years. And now 30% to 50% of metastatic patients are living 5 years. That’s amazing to me,” said Dr. Polsky, who coauthored the 2020 report cited by Dr. Adamson.
A few years ago, Dr. Polsky added, he talked to an oncologist about how life at her clinic had changed as a result of new melanoma treatments. “She said, ‘My clinic has gotten really crowded. It used to be that patients died in a span of about a year and a half, and I would turn over my patient population. Now all those patients are still alive, and I’m getting new patients.’”
The study was funded by the University of Toledo College of Medicine and Life Sciences. One author reported receiving honoraria from Boston Healthcare Associates and research funding from Bayer, ImmunoVaccine, and the Ludwig Institute for Cancer Research. Dr. Polsky disclosed relationships with Merck (advisory board) and Novartis and Bristol Myers Squibb (consulting). Dr. Adamson disclosed he is web editor and associate editor at JAMA Dermatology.
, a new study finds, although the dip appeared to stabilize over the next 2 years.
“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”
The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”
New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.
The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.
Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.
“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”
But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”
In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”
Which treatments are making the biggest difference? “It is difficult to say, but it’s likely immunotherapy because some patients on these medications have durable responses for many years,” Dr. Adamson said. “Studies are ongoing to figure out just how much more life some patients may expect after treatment.”
He added that “while this study did not evaluate mortality trends by race or ethnicity, it is important to note that the sharp decline in melanoma mortality rates is exclusively among non-Hispanic White Americans.”
Dermatologist David Polsky, MD, PhD, professor of dermatologic oncology at New York (N.Y.) University, said in an interview that the findings reflect extraordinary progress in melanoma treatment. “Historically, only 10% of metastatic melanoma patients would live 5 years. And now 30% to 50% of metastatic patients are living 5 years. That’s amazing to me,” said Dr. Polsky, who coauthored the 2020 report cited by Dr. Adamson.
A few years ago, Dr. Polsky added, he talked to an oncologist about how life at her clinic had changed as a result of new melanoma treatments. “She said, ‘My clinic has gotten really crowded. It used to be that patients died in a span of about a year and a half, and I would turn over my patient population. Now all those patients are still alive, and I’m getting new patients.’”
The study was funded by the University of Toledo College of Medicine and Life Sciences. One author reported receiving honoraria from Boston Healthcare Associates and research funding from Bayer, ImmunoVaccine, and the Ludwig Institute for Cancer Research. Dr. Polsky disclosed relationships with Merck (advisory board) and Novartis and Bristol Myers Squibb (consulting). Dr. Adamson disclosed he is web editor and associate editor at JAMA Dermatology.
FROM JAMA NETWORK OPEN
Post-transplant diet: Gruel no longer rules
NEW ORLEANS – A new Italian study yields more evidence that stem-cell transplant patients need not lose their appetites along with their immune systems. Low-bacterial, gruel-like diets, once the mainstay of immunity-lowering surgeries, don’t actually provide any protection against infections, researchers reported.
University of Miami hematologist Mikkael A. Sekeres, MD, MS, expressed delight to hear these findings.
“Around the world, we should eliminate these silly neutropenic diets, let people eat what they want, and give them a much better quality of life while they’re in the hospital,” said Dr. Sekeres, moderator of the news briefing where these research results were discussed at the annual meeting of the American Society of Hematology.
In recent decades, physicians and nutritionists have questioned the value of low-bacterial/neutropenic menus, designed to protect people with compromised immune systems from germs in food. These diets can be quite strict, outlawing food such as deli, processed, and cured meats; yogurt; hummus; strawberries and raspberries; lettuce; raw nuts; certain kinds of seafood; and herbs and spices such as pepper, unless they were cooked. Patients may be urged to avoid salad bars, buffets, and potlucks.
MD Anderson Cancer Center pediatrician Karen Moody, MD, MS, who has studied the diet, said in an interview that the diet has been around since the 1970s, despite a lack of evidence supporting it. “Cancer patients often suffer from treatment-related side effects that affect taste, appetite, and tolerance of food,” she said. “Further restricting food options in this population can be burdensome and reduce diet-related satisfaction.”
For the new multi-center, phase 3 study, researchers led by hematology resident Federico Stella, MD, of the University of Milan, randomly assigned consecutive adult patients undergoing hematopoietic stem cells transplantation or high-dose induction chemotherapy to either a low-bacterial diet (n = 224) or a non-restrictive diet (n = 224).
The low-bacterial diet emphasized food cooked to at least 176 degrees Fahrenheit and thick-skinned fruit. Raw fruits/vegetables, yogurt, honey, cold cuts and sausages, and raw fish and meat were forbidden.
The two groups were similar in age (median = 56 years), gender (about 57% male), and reason for admission (97% stem-cell transplants and 3% high-dose chemotherapy). The plan was to follow the patients for 100 days (stem-cell transplant recipients) or 30 days (high-dose chemotherapy patients).
No statistically significant differences between the group were found in the rates of infections of higher than Grade 2 (per CTCAE 4.0): These infections occurred in 38 (34%) of those on the low-bacterial diet and 44 (39%) of those on the non-restrictive diet (P = 0.5).
There were also no statistically significant differences in rates of fever of unknown origin (P = 0.2), sepsis (P = 0.5), and gastrointestinal infection (P = 0.7).
The findings show that the “use of a restrictive diet is an unnecessary burden for our patients’ quality of life,” said study lead author Dr. Stella at the news briefing.
Dr. Sekeres, the news briefing moderator, noted that the findings reflect his own suspicions about the worthlessness of the low-bacterial diet. “I’ve never seen a patient die of an infection that was foodborne. So years ago, when I was still in Cleveland, I eliminated the neutropenic diet on the leukemia floor. That did face a lot of resistance, as you can imagine. There were decades of people saying we should do this.”
Now, Dr. Sekeres said, he feels validated. “I love this study because it formalizes what I thought was true,” he said.
Dr. Moody said it’s difficult to evaluate the study since it’s in abstract form, and details are limited. “However,” she said, “the sample size, study design, and outcomes appear very appropriate, and I think most likely the full-length study will provide additional evidence to support abandonment of the low-microbial diet in transplant patients.”
Also, Dr. Moody said, the study “replicates the same findings of other prospective randomized trials of this diet that say it confers no protection from infection and has no identified health benefit whatsoever. Bottom line? This diet has burden without benefit.”
Moving forward, she said, “we need a lot more research on diet in general for cancer patients. Recently, there is a lot more interest in this topic. I think we are going to learn a lot in the next few decades about the relationship between diet, epigenetics, the microbiome, and various cancer-related health issues.”
No study funding was reported. Dr. Stella reports no disclosures, and other authors report various relationships with industry. Dr. Moody reports no disclosures, and disclosures for Dr. Sekeres were not available.
NEW ORLEANS – A new Italian study yields more evidence that stem-cell transplant patients need not lose their appetites along with their immune systems. Low-bacterial, gruel-like diets, once the mainstay of immunity-lowering surgeries, don’t actually provide any protection against infections, researchers reported.
University of Miami hematologist Mikkael A. Sekeres, MD, MS, expressed delight to hear these findings.
“Around the world, we should eliminate these silly neutropenic diets, let people eat what they want, and give them a much better quality of life while they’re in the hospital,” said Dr. Sekeres, moderator of the news briefing where these research results were discussed at the annual meeting of the American Society of Hematology.
In recent decades, physicians and nutritionists have questioned the value of low-bacterial/neutropenic menus, designed to protect people with compromised immune systems from germs in food. These diets can be quite strict, outlawing food such as deli, processed, and cured meats; yogurt; hummus; strawberries and raspberries; lettuce; raw nuts; certain kinds of seafood; and herbs and spices such as pepper, unless they were cooked. Patients may be urged to avoid salad bars, buffets, and potlucks.
MD Anderson Cancer Center pediatrician Karen Moody, MD, MS, who has studied the diet, said in an interview that the diet has been around since the 1970s, despite a lack of evidence supporting it. “Cancer patients often suffer from treatment-related side effects that affect taste, appetite, and tolerance of food,” she said. “Further restricting food options in this population can be burdensome and reduce diet-related satisfaction.”
For the new multi-center, phase 3 study, researchers led by hematology resident Federico Stella, MD, of the University of Milan, randomly assigned consecutive adult patients undergoing hematopoietic stem cells transplantation or high-dose induction chemotherapy to either a low-bacterial diet (n = 224) or a non-restrictive diet (n = 224).
The low-bacterial diet emphasized food cooked to at least 176 degrees Fahrenheit and thick-skinned fruit. Raw fruits/vegetables, yogurt, honey, cold cuts and sausages, and raw fish and meat were forbidden.
The two groups were similar in age (median = 56 years), gender (about 57% male), and reason for admission (97% stem-cell transplants and 3% high-dose chemotherapy). The plan was to follow the patients for 100 days (stem-cell transplant recipients) or 30 days (high-dose chemotherapy patients).
No statistically significant differences between the group were found in the rates of infections of higher than Grade 2 (per CTCAE 4.0): These infections occurred in 38 (34%) of those on the low-bacterial diet and 44 (39%) of those on the non-restrictive diet (P = 0.5).
There were also no statistically significant differences in rates of fever of unknown origin (P = 0.2), sepsis (P = 0.5), and gastrointestinal infection (P = 0.7).
The findings show that the “use of a restrictive diet is an unnecessary burden for our patients’ quality of life,” said study lead author Dr. Stella at the news briefing.
Dr. Sekeres, the news briefing moderator, noted that the findings reflect his own suspicions about the worthlessness of the low-bacterial diet. “I’ve never seen a patient die of an infection that was foodborne. So years ago, when I was still in Cleveland, I eliminated the neutropenic diet on the leukemia floor. That did face a lot of resistance, as you can imagine. There were decades of people saying we should do this.”
Now, Dr. Sekeres said, he feels validated. “I love this study because it formalizes what I thought was true,” he said.
Dr. Moody said it’s difficult to evaluate the study since it’s in abstract form, and details are limited. “However,” she said, “the sample size, study design, and outcomes appear very appropriate, and I think most likely the full-length study will provide additional evidence to support abandonment of the low-microbial diet in transplant patients.”
Also, Dr. Moody said, the study “replicates the same findings of other prospective randomized trials of this diet that say it confers no protection from infection and has no identified health benefit whatsoever. Bottom line? This diet has burden without benefit.”
Moving forward, she said, “we need a lot more research on diet in general for cancer patients. Recently, there is a lot more interest in this topic. I think we are going to learn a lot in the next few decades about the relationship between diet, epigenetics, the microbiome, and various cancer-related health issues.”
No study funding was reported. Dr. Stella reports no disclosures, and other authors report various relationships with industry. Dr. Moody reports no disclosures, and disclosures for Dr. Sekeres were not available.
NEW ORLEANS – A new Italian study yields more evidence that stem-cell transplant patients need not lose their appetites along with their immune systems. Low-bacterial, gruel-like diets, once the mainstay of immunity-lowering surgeries, don’t actually provide any protection against infections, researchers reported.
University of Miami hematologist Mikkael A. Sekeres, MD, MS, expressed delight to hear these findings.
“Around the world, we should eliminate these silly neutropenic diets, let people eat what they want, and give them a much better quality of life while they’re in the hospital,” said Dr. Sekeres, moderator of the news briefing where these research results were discussed at the annual meeting of the American Society of Hematology.
In recent decades, physicians and nutritionists have questioned the value of low-bacterial/neutropenic menus, designed to protect people with compromised immune systems from germs in food. These diets can be quite strict, outlawing food such as deli, processed, and cured meats; yogurt; hummus; strawberries and raspberries; lettuce; raw nuts; certain kinds of seafood; and herbs and spices such as pepper, unless they were cooked. Patients may be urged to avoid salad bars, buffets, and potlucks.
MD Anderson Cancer Center pediatrician Karen Moody, MD, MS, who has studied the diet, said in an interview that the diet has been around since the 1970s, despite a lack of evidence supporting it. “Cancer patients often suffer from treatment-related side effects that affect taste, appetite, and tolerance of food,” she said. “Further restricting food options in this population can be burdensome and reduce diet-related satisfaction.”
For the new multi-center, phase 3 study, researchers led by hematology resident Federico Stella, MD, of the University of Milan, randomly assigned consecutive adult patients undergoing hematopoietic stem cells transplantation or high-dose induction chemotherapy to either a low-bacterial diet (n = 224) or a non-restrictive diet (n = 224).
The low-bacterial diet emphasized food cooked to at least 176 degrees Fahrenheit and thick-skinned fruit. Raw fruits/vegetables, yogurt, honey, cold cuts and sausages, and raw fish and meat were forbidden.
The two groups were similar in age (median = 56 years), gender (about 57% male), and reason for admission (97% stem-cell transplants and 3% high-dose chemotherapy). The plan was to follow the patients for 100 days (stem-cell transplant recipients) or 30 days (high-dose chemotherapy patients).
No statistically significant differences between the group were found in the rates of infections of higher than Grade 2 (per CTCAE 4.0): These infections occurred in 38 (34%) of those on the low-bacterial diet and 44 (39%) of those on the non-restrictive diet (P = 0.5).
There were also no statistically significant differences in rates of fever of unknown origin (P = 0.2), sepsis (P = 0.5), and gastrointestinal infection (P = 0.7).
The findings show that the “use of a restrictive diet is an unnecessary burden for our patients’ quality of life,” said study lead author Dr. Stella at the news briefing.
Dr. Sekeres, the news briefing moderator, noted that the findings reflect his own suspicions about the worthlessness of the low-bacterial diet. “I’ve never seen a patient die of an infection that was foodborne. So years ago, when I was still in Cleveland, I eliminated the neutropenic diet on the leukemia floor. That did face a lot of resistance, as you can imagine. There were decades of people saying we should do this.”
Now, Dr. Sekeres said, he feels validated. “I love this study because it formalizes what I thought was true,” he said.
Dr. Moody said it’s difficult to evaluate the study since it’s in abstract form, and details are limited. “However,” she said, “the sample size, study design, and outcomes appear very appropriate, and I think most likely the full-length study will provide additional evidence to support abandonment of the low-microbial diet in transplant patients.”
Also, Dr. Moody said, the study “replicates the same findings of other prospective randomized trials of this diet that say it confers no protection from infection and has no identified health benefit whatsoever. Bottom line? This diet has burden without benefit.”
Moving forward, she said, “we need a lot more research on diet in general for cancer patients. Recently, there is a lot more interest in this topic. I think we are going to learn a lot in the next few decades about the relationship between diet, epigenetics, the microbiome, and various cancer-related health issues.”
No study funding was reported. Dr. Stella reports no disclosures, and other authors report various relationships with industry. Dr. Moody reports no disclosures, and disclosures for Dr. Sekeres were not available.
AT ASH 2022
For minorities with PE: Less advanced treatment, more mortality
NEW ORLEANS –
According to the research, released at the annual meeting of the American Society of Hematology, the biggest disparities affected Asian/Pacific Islander patients with PE. While they were the least likely among ethnic groups to be hospitalized for PE, the odds were 53% higher that they’d die in the hospital (adjusted odds ratio, 1.53; 95% confidence interval, 1.32-1.78), and 24% lower that they would get advanced therapies (aOR, 0.76; 95% CI, 0.59-0.98, P values not provided in this study).
“The findings really raise the importance of this research area and call for vigorous future research to try to better identify why we see these patterns and then come up with solutions to solve them,” said hematologist and study coauthor Mary Cushman, MD, of the University of Vermont, Burlington, at an ASH news briefing.
As Dr. Cushman noted, details about disparities in PE care are limited. It’s known that “Black people have a twofold greater mortality from pulmonary embolism compared to other groups, and this is a persistently observed disparity over many years,” she said. However, “little is known about the relationships of social determinants with treatment and course of pulmonary embolism,” she added.
The researchers used data from the Nationwide Inpatient Sample to track 1.1 million U.S. hospitalized patients with PE from 2016 to 2018. PE was the primary diagnosis in 615,570 patients (54.8%), and 66,570 (5.9%) had high-risk PE.
Among ethnic groups, hospitalization rates “differed pretty dramatically,” Dr. Cushman said. The researchers found that Blacks had the highest rate of PE hospitalization (20.1 per 10,000 person-years; 95% CI, 20.0-20.2), followed by Whites (13.1 per 10,000 person-years; 95% CI, 13.1-13.2), Hispanics (6.0 per 10,000 person-years; 95% CI, 5.9-6.1), Native Americans (5.6 per 10,000 person-years, 95% CI, 5.4-5.7) and Asians/Pacific Islanders (3.0 per 10,000 person-years; 95% CI, 2.9-3.1). Overall, the rate was 14.9/10,000 person-years.
With regard to treatment, therapies defined by the researchers as advanced – systemic thrombolysis, catheter-directed therapy, surgical embolectomy, and venoarterial extracorporeal membrane oxygenation – were also less commonly used in treating ethnic minorities.
These treatments were used in 5.5% of all patients, and 19% of those with high-risk PE. After adjusting for nearly 20 factors such as age, sex, and place of residence, researchers found that the odds that a patient would receive advanced treatment were lower in Blacks (aOR, 0.87; 95% CI, 0.81-0.92) and Asians/Pacific Islanders (aOR, 0.76; 95% CI, 0.59-0.98) compared with Whites. The differences in Hispanics and Native Americans were not statistically significant.
As for insurance, those with Medicare and Medicaid were less likely to get advanced treatment vs. those with private insurance (aOR, 0.73; 95% CI, 0.69-0.77 and aOR, 0.68; 95% CI, 0.63-0.74, respectively). Differences among income levels were not statistically significant.
In the hospital, 6.4% of patients with PE died, as did 50% of those with high-risk PE. There was no statistically significant difference in death rates overall between Whites and Blacks or Native Americans. However, Asians/Pacific Islanders had a much higher death rate (aOR, 1.53; 95% CI, 1.32-1.78), as did Hispanics (aOR, 1.10; 95% CI, 1.00-1.22).
Why are Asians/Pacific Islanders at such high risk of death? Dr. Cushman noted that, while their hospitalization rate is low, they are especially likely to present with high-risk PE.
The difference in death rates between patients with Medicare/Medicaid insurance and those with private insurance was not statistically significant. Neither was the difference in death rates among income groups vs. the highest quartile with one exception: The lowest quartile (aOR, 1.09; 95% CI, 1.02-1.17).
As for the reasons for the higher risks among various groups, Dr. Cushman said there are several possible theories. “It could be due to differences in awareness of PE symptoms: They don’t know how ill they are, so they present later in the course. Or they might have less trust in the system, which might lead to delayed care. Or it could be that they have misdiagnosis of PE symptoms when they present initially.”
Alternatively, she noted, the differences “could be rooted in structural racism and other social determinants of health that weren’t measured, such as education level and quality of education.”
In an interview, Dr. Cushman expressed the hope that “clinicians will think about these findings in terms of how they take care of patients and try their best to recognize any unconscious biases that might creep into their approach. In addition, as a society we need more education of the general public about PE. Some of our findings might be caused by delayed care due to lack of recognition of a need to seek care.”
In an interview, University of Pittsburgh vascular surgeon Rabih Chaer, MD, MSc, who didn’t take part in the study, said it relies on a "large dataset which offers valuable information but with limited granularity and follow-up. This limits the accurate categorization of PE severity, as well as comorbidities, all of which impact outcomes and survival.”
For example, Dr. Chaer said, PE treatments can be limited in some patients due to their comorbidities that cause bleeding risk. Still, Dr. Chaer said the findings mesh with his own research that has shown racial disparities in PE treatment and outcomes, including a 2021 study. "While we did not see a difference by race in in-hospital mortality, Black patients hospitalized with PE are younger with a higher severity of disease compared with White patients,” he said. "Although Black patients are less likely to receive an intervention overall, this differed depending on PE severity with higher risk of intervention only for life-threatening PE." And a 2022 study found that “patients with PE from deprived neighborhoods have worse survival beyond the index [first] admission and were more likely to suffer from cardiovascular or PE-related causes of death in the first year after the index pulmonary embolism,” he said.
Dr. Chaer noted that his research team “is actively working on the next steps beyond identifying the fact that there are racial disparities in PE treatment and outcomes. We are fortunate to have access to a large granular database with long-term follow up and are currently reviewing the medical record details to identify causes for disparities and potential solutions.”
Dr. Cushman received funding from the National Institutes of Health. Other study authors report various disclosures. Dr. Chaer has no disclosures.
NEW ORLEANS –
According to the research, released at the annual meeting of the American Society of Hematology, the biggest disparities affected Asian/Pacific Islander patients with PE. While they were the least likely among ethnic groups to be hospitalized for PE, the odds were 53% higher that they’d die in the hospital (adjusted odds ratio, 1.53; 95% confidence interval, 1.32-1.78), and 24% lower that they would get advanced therapies (aOR, 0.76; 95% CI, 0.59-0.98, P values not provided in this study).
“The findings really raise the importance of this research area and call for vigorous future research to try to better identify why we see these patterns and then come up with solutions to solve them,” said hematologist and study coauthor Mary Cushman, MD, of the University of Vermont, Burlington, at an ASH news briefing.
As Dr. Cushman noted, details about disparities in PE care are limited. It’s known that “Black people have a twofold greater mortality from pulmonary embolism compared to other groups, and this is a persistently observed disparity over many years,” she said. However, “little is known about the relationships of social determinants with treatment and course of pulmonary embolism,” she added.
The researchers used data from the Nationwide Inpatient Sample to track 1.1 million U.S. hospitalized patients with PE from 2016 to 2018. PE was the primary diagnosis in 615,570 patients (54.8%), and 66,570 (5.9%) had high-risk PE.
Among ethnic groups, hospitalization rates “differed pretty dramatically,” Dr. Cushman said. The researchers found that Blacks had the highest rate of PE hospitalization (20.1 per 10,000 person-years; 95% CI, 20.0-20.2), followed by Whites (13.1 per 10,000 person-years; 95% CI, 13.1-13.2), Hispanics (6.0 per 10,000 person-years; 95% CI, 5.9-6.1), Native Americans (5.6 per 10,000 person-years, 95% CI, 5.4-5.7) and Asians/Pacific Islanders (3.0 per 10,000 person-years; 95% CI, 2.9-3.1). Overall, the rate was 14.9/10,000 person-years.
With regard to treatment, therapies defined by the researchers as advanced – systemic thrombolysis, catheter-directed therapy, surgical embolectomy, and venoarterial extracorporeal membrane oxygenation – were also less commonly used in treating ethnic minorities.
These treatments were used in 5.5% of all patients, and 19% of those with high-risk PE. After adjusting for nearly 20 factors such as age, sex, and place of residence, researchers found that the odds that a patient would receive advanced treatment were lower in Blacks (aOR, 0.87; 95% CI, 0.81-0.92) and Asians/Pacific Islanders (aOR, 0.76; 95% CI, 0.59-0.98) compared with Whites. The differences in Hispanics and Native Americans were not statistically significant.
As for insurance, those with Medicare and Medicaid were less likely to get advanced treatment vs. those with private insurance (aOR, 0.73; 95% CI, 0.69-0.77 and aOR, 0.68; 95% CI, 0.63-0.74, respectively). Differences among income levels were not statistically significant.
In the hospital, 6.4% of patients with PE died, as did 50% of those with high-risk PE. There was no statistically significant difference in death rates overall between Whites and Blacks or Native Americans. However, Asians/Pacific Islanders had a much higher death rate (aOR, 1.53; 95% CI, 1.32-1.78), as did Hispanics (aOR, 1.10; 95% CI, 1.00-1.22).
Why are Asians/Pacific Islanders at such high risk of death? Dr. Cushman noted that, while their hospitalization rate is low, they are especially likely to present with high-risk PE.
The difference in death rates between patients with Medicare/Medicaid insurance and those with private insurance was not statistically significant. Neither was the difference in death rates among income groups vs. the highest quartile with one exception: The lowest quartile (aOR, 1.09; 95% CI, 1.02-1.17).
As for the reasons for the higher risks among various groups, Dr. Cushman said there are several possible theories. “It could be due to differences in awareness of PE symptoms: They don’t know how ill they are, so they present later in the course. Or they might have less trust in the system, which might lead to delayed care. Or it could be that they have misdiagnosis of PE symptoms when they present initially.”
Alternatively, she noted, the differences “could be rooted in structural racism and other social determinants of health that weren’t measured, such as education level and quality of education.”
In an interview, Dr. Cushman expressed the hope that “clinicians will think about these findings in terms of how they take care of patients and try their best to recognize any unconscious biases that might creep into their approach. In addition, as a society we need more education of the general public about PE. Some of our findings might be caused by delayed care due to lack of recognition of a need to seek care.”
In an interview, University of Pittsburgh vascular surgeon Rabih Chaer, MD, MSc, who didn’t take part in the study, said it relies on a "large dataset which offers valuable information but with limited granularity and follow-up. This limits the accurate categorization of PE severity, as well as comorbidities, all of which impact outcomes and survival.”
For example, Dr. Chaer said, PE treatments can be limited in some patients due to their comorbidities that cause bleeding risk. Still, Dr. Chaer said the findings mesh with his own research that has shown racial disparities in PE treatment and outcomes, including a 2021 study. "While we did not see a difference by race in in-hospital mortality, Black patients hospitalized with PE are younger with a higher severity of disease compared with White patients,” he said. "Although Black patients are less likely to receive an intervention overall, this differed depending on PE severity with higher risk of intervention only for life-threatening PE." And a 2022 study found that “patients with PE from deprived neighborhoods have worse survival beyond the index [first] admission and were more likely to suffer from cardiovascular or PE-related causes of death in the first year after the index pulmonary embolism,” he said.
Dr. Chaer noted that his research team “is actively working on the next steps beyond identifying the fact that there are racial disparities in PE treatment and outcomes. We are fortunate to have access to a large granular database with long-term follow up and are currently reviewing the medical record details to identify causes for disparities and potential solutions.”
Dr. Cushman received funding from the National Institutes of Health. Other study authors report various disclosures. Dr. Chaer has no disclosures.
NEW ORLEANS –
According to the research, released at the annual meeting of the American Society of Hematology, the biggest disparities affected Asian/Pacific Islander patients with PE. While they were the least likely among ethnic groups to be hospitalized for PE, the odds were 53% higher that they’d die in the hospital (adjusted odds ratio, 1.53; 95% confidence interval, 1.32-1.78), and 24% lower that they would get advanced therapies (aOR, 0.76; 95% CI, 0.59-0.98, P values not provided in this study).
“The findings really raise the importance of this research area and call for vigorous future research to try to better identify why we see these patterns and then come up with solutions to solve them,” said hematologist and study coauthor Mary Cushman, MD, of the University of Vermont, Burlington, at an ASH news briefing.
As Dr. Cushman noted, details about disparities in PE care are limited. It’s known that “Black people have a twofold greater mortality from pulmonary embolism compared to other groups, and this is a persistently observed disparity over many years,” she said. However, “little is known about the relationships of social determinants with treatment and course of pulmonary embolism,” she added.
The researchers used data from the Nationwide Inpatient Sample to track 1.1 million U.S. hospitalized patients with PE from 2016 to 2018. PE was the primary diagnosis in 615,570 patients (54.8%), and 66,570 (5.9%) had high-risk PE.
Among ethnic groups, hospitalization rates “differed pretty dramatically,” Dr. Cushman said. The researchers found that Blacks had the highest rate of PE hospitalization (20.1 per 10,000 person-years; 95% CI, 20.0-20.2), followed by Whites (13.1 per 10,000 person-years; 95% CI, 13.1-13.2), Hispanics (6.0 per 10,000 person-years; 95% CI, 5.9-6.1), Native Americans (5.6 per 10,000 person-years, 95% CI, 5.4-5.7) and Asians/Pacific Islanders (3.0 per 10,000 person-years; 95% CI, 2.9-3.1). Overall, the rate was 14.9/10,000 person-years.
With regard to treatment, therapies defined by the researchers as advanced – systemic thrombolysis, catheter-directed therapy, surgical embolectomy, and venoarterial extracorporeal membrane oxygenation – were also less commonly used in treating ethnic minorities.
These treatments were used in 5.5% of all patients, and 19% of those with high-risk PE. After adjusting for nearly 20 factors such as age, sex, and place of residence, researchers found that the odds that a patient would receive advanced treatment were lower in Blacks (aOR, 0.87; 95% CI, 0.81-0.92) and Asians/Pacific Islanders (aOR, 0.76; 95% CI, 0.59-0.98) compared with Whites. The differences in Hispanics and Native Americans were not statistically significant.
As for insurance, those with Medicare and Medicaid were less likely to get advanced treatment vs. those with private insurance (aOR, 0.73; 95% CI, 0.69-0.77 and aOR, 0.68; 95% CI, 0.63-0.74, respectively). Differences among income levels were not statistically significant.
In the hospital, 6.4% of patients with PE died, as did 50% of those with high-risk PE. There was no statistically significant difference in death rates overall between Whites and Blacks or Native Americans. However, Asians/Pacific Islanders had a much higher death rate (aOR, 1.53; 95% CI, 1.32-1.78), as did Hispanics (aOR, 1.10; 95% CI, 1.00-1.22).
Why are Asians/Pacific Islanders at such high risk of death? Dr. Cushman noted that, while their hospitalization rate is low, they are especially likely to present with high-risk PE.
The difference in death rates between patients with Medicare/Medicaid insurance and those with private insurance was not statistically significant. Neither was the difference in death rates among income groups vs. the highest quartile with one exception: The lowest quartile (aOR, 1.09; 95% CI, 1.02-1.17).
As for the reasons for the higher risks among various groups, Dr. Cushman said there are several possible theories. “It could be due to differences in awareness of PE symptoms: They don’t know how ill they are, so they present later in the course. Or they might have less trust in the system, which might lead to delayed care. Or it could be that they have misdiagnosis of PE symptoms when they present initially.”
Alternatively, she noted, the differences “could be rooted in structural racism and other social determinants of health that weren’t measured, such as education level and quality of education.”
In an interview, Dr. Cushman expressed the hope that “clinicians will think about these findings in terms of how they take care of patients and try their best to recognize any unconscious biases that might creep into their approach. In addition, as a society we need more education of the general public about PE. Some of our findings might be caused by delayed care due to lack of recognition of a need to seek care.”
In an interview, University of Pittsburgh vascular surgeon Rabih Chaer, MD, MSc, who didn’t take part in the study, said it relies on a "large dataset which offers valuable information but with limited granularity and follow-up. This limits the accurate categorization of PE severity, as well as comorbidities, all of which impact outcomes and survival.”
For example, Dr. Chaer said, PE treatments can be limited in some patients due to their comorbidities that cause bleeding risk. Still, Dr. Chaer said the findings mesh with his own research that has shown racial disparities in PE treatment and outcomes, including a 2021 study. "While we did not see a difference by race in in-hospital mortality, Black patients hospitalized with PE are younger with a higher severity of disease compared with White patients,” he said. "Although Black patients are less likely to receive an intervention overall, this differed depending on PE severity with higher risk of intervention only for life-threatening PE." And a 2022 study found that “patients with PE from deprived neighborhoods have worse survival beyond the index [first] admission and were more likely to suffer from cardiovascular or PE-related causes of death in the first year after the index pulmonary embolism,” he said.
Dr. Chaer noted that his research team “is actively working on the next steps beyond identifying the fact that there are racial disparities in PE treatment and outcomes. We are fortunate to have access to a large granular database with long-term follow up and are currently reviewing the medical record details to identify causes for disparities and potential solutions.”
Dr. Cushman received funding from the National Institutes of Health. Other study authors report various disclosures. Dr. Chaer has no disclosures.
AT ASH 2022
High cost and demand for old cancer drug sparks crisis
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
‘Modest’ benefit for lecanemab in Alzheimer’s disease, but adverse events are common
SAN FRANCISCO –
In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a recent news report linked a second death to the drug.
Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” wrote Christopher H. van Dyck, MD, Yale University, New Haven, Conn., and colleagues.
The full trial findings were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, with simultaneous publication on Nov. 29 in the New England Journal of Medicine.
Complications in the field
The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by this news organization at that time.
The Food and Drug Administration is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.
For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1,795 patients aged 50-90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets amyloid beta (A-beta) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).
The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1,734 participants, with 859 receiving lecanemab and 875 receiving placebo.
The primary endpoint was the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab versus 1.66 for placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; P < .001).
As Dr. van Dyck noted in his presentation at the CTAD meting, this represents a 27% slowing of the decline in the lecanemab group.
The published findings do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group versus placebo include the Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (mean difference, –1.44; 95% CI, –2.27 to –0.61), the Alzheimer’s Disease Composite Score (mean difference, –0.05; 95% CI, –.074 to –.027,), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2-2.8; all, P < .001).
Overall, Dr. van Dyck said, “Lecanemab met the primary and secondary endpoints versus placebo at 18 months, with highly significant differences starting at 6 months.”
In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, –59.1 centiloids; 95% CI, –62.6 to –55.6).
“Lecanemab has high selectivity for soluble aggregated species of A-beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species,” the researchers wrote.
Concerning AE data
With respect to AEs, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, according to a report in the journal Science published Nov. 27, a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”
The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Researchers summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”
In a CTAD presentation, study coauthor Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. “Causality with lecanemab is a little difficult ...,” he said. “Patients on anticoagulation might need further consideration.”
In the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and in 11.3% of the placebo group, leading to discontinuation 2.9% of the time, the investigators reported.
They added that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs. 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs. 9%, respectively); amyloid-related imaging abnormalities with edema or effusions (12.6% vs. 1.7%); headache (11.1% vs. 8.1%); and falls (10.4% vs. 9.6%).
In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and 0.1% of the placebo group.
Cautious optimism
In separate interviews, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.
Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said.
However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.
Still, “this could be a valuable adjunct to the armamentarium we have,” which includes interventions such as lifestyle changes, he said.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a “modest” effect on cognition.
However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal – fully reversing cognitive decline.
Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is “growing evidence” that some antiamyloid therapies, “especially lecanemab and donanemab” have shown promising results.
“Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain,” said Dr. Weiner, professor of radiology, medicine, and neurology at the University of California, San Francisco.
“There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments,” he added.
Rave reviews from the Alzheimer’s Association
In a statement, the Alzheimer’s Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease ...” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”
The association, which is a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the two reported deaths.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. Dr. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are fully listed in the original article.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO –
In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a recent news report linked a second death to the drug.
Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” wrote Christopher H. van Dyck, MD, Yale University, New Haven, Conn., and colleagues.
The full trial findings were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, with simultaneous publication on Nov. 29 in the New England Journal of Medicine.
Complications in the field
The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by this news organization at that time.
The Food and Drug Administration is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.
For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1,795 patients aged 50-90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets amyloid beta (A-beta) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).
The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1,734 participants, with 859 receiving lecanemab and 875 receiving placebo.
The primary endpoint was the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab versus 1.66 for placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; P < .001).
As Dr. van Dyck noted in his presentation at the CTAD meting, this represents a 27% slowing of the decline in the lecanemab group.
The published findings do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group versus placebo include the Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (mean difference, –1.44; 95% CI, –2.27 to –0.61), the Alzheimer’s Disease Composite Score (mean difference, –0.05; 95% CI, –.074 to –.027,), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2-2.8; all, P < .001).
Overall, Dr. van Dyck said, “Lecanemab met the primary and secondary endpoints versus placebo at 18 months, with highly significant differences starting at 6 months.”
In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, –59.1 centiloids; 95% CI, –62.6 to –55.6).
“Lecanemab has high selectivity for soluble aggregated species of A-beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species,” the researchers wrote.
Concerning AE data
With respect to AEs, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, according to a report in the journal Science published Nov. 27, a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”
The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Researchers summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”
In a CTAD presentation, study coauthor Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. “Causality with lecanemab is a little difficult ...,” he said. “Patients on anticoagulation might need further consideration.”
In the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and in 11.3% of the placebo group, leading to discontinuation 2.9% of the time, the investigators reported.
They added that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs. 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs. 9%, respectively); amyloid-related imaging abnormalities with edema or effusions (12.6% vs. 1.7%); headache (11.1% vs. 8.1%); and falls (10.4% vs. 9.6%).
In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and 0.1% of the placebo group.
Cautious optimism
In separate interviews, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.
Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said.
However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.
Still, “this could be a valuable adjunct to the armamentarium we have,” which includes interventions such as lifestyle changes, he said.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a “modest” effect on cognition.
However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal – fully reversing cognitive decline.
Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is “growing evidence” that some antiamyloid therapies, “especially lecanemab and donanemab” have shown promising results.
“Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain,” said Dr. Weiner, professor of radiology, medicine, and neurology at the University of California, San Francisco.
“There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments,” he added.
Rave reviews from the Alzheimer’s Association
In a statement, the Alzheimer’s Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease ...” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”
The association, which is a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the two reported deaths.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. Dr. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are fully listed in the original article.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO –
In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a recent news report linked a second death to the drug.
Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” wrote Christopher H. van Dyck, MD, Yale University, New Haven, Conn., and colleagues.
The full trial findings were presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, with simultaneous publication on Nov. 29 in the New England Journal of Medicine.
Complications in the field
The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by this news organization at that time.
The Food and Drug Administration is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.
For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1,795 patients aged 50-90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets amyloid beta (A-beta) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).
The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1,734 participants, with 859 receiving lecanemab and 875 receiving placebo.
The primary endpoint was the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab versus 1.66 for placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; P < .001).
As Dr. van Dyck noted in his presentation at the CTAD meting, this represents a 27% slowing of the decline in the lecanemab group.
The published findings do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group versus placebo include the Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (mean difference, –1.44; 95% CI, –2.27 to –0.61), the Alzheimer’s Disease Composite Score (mean difference, –0.05; 95% CI, –.074 to –.027,), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2-2.8; all, P < .001).
Overall, Dr. van Dyck said, “Lecanemab met the primary and secondary endpoints versus placebo at 18 months, with highly significant differences starting at 6 months.”
In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, –59.1 centiloids; 95% CI, –62.6 to –55.6).
“Lecanemab has high selectivity for soluble aggregated species of A-beta as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species,” the researchers wrote.
Concerning AE data
With respect to AEs, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, according to a report in the journal Science published Nov. 27, a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”
The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Researchers summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”
In a CTAD presentation, study coauthor Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. “Causality with lecanemab is a little difficult ...,” he said. “Patients on anticoagulation might need further consideration.”
In the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and in 11.3% of the placebo group, leading to discontinuation 2.9% of the time, the investigators reported.
They added that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs. 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs. 9%, respectively); amyloid-related imaging abnormalities with edema or effusions (12.6% vs. 1.7%); headache (11.1% vs. 8.1%); and falls (10.4% vs. 9.6%).
In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and 0.1% of the placebo group.
Cautious optimism
In separate interviews, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.
Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said.
However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.
Still, “this could be a valuable adjunct to the armamentarium we have,” which includes interventions such as lifestyle changes, he said.
Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a “modest” effect on cognition.
However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal – fully reversing cognitive decline.
Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is “growing evidence” that some antiamyloid therapies, “especially lecanemab and donanemab” have shown promising results.
“Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain,” said Dr. Weiner, professor of radiology, medicine, and neurology at the University of California, San Francisco.
“There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments,” he added.
Rave reviews from the Alzheimer’s Association
In a statement, the Alzheimer’s Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease ...” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”
The association, which is a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the two reported deaths.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. Dr. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are fully listed in the original article.
A version of this article first appeared on Medscape.com.
AT CTAD 2022