Pharmacology

Dexamethasone can have a detrimental effect on survival in patients with glioblastoma who are receiving immunotherapy, according to a study published in Clinical Cancer Research.

Investigators found that baseline dexamethasone use was associated with poor overall survival (OS) in glioblastoma patients receiving anti–PD-1 or anti–PD-L1 therapy. In fact, in a multivariable analysis, baseline dexamethasone use was the strongest predictor of poor survival.

These results “support accumulating concerns that corticosteroids can be detrimental to immunotherapy for oncology patients,” wrote senior study author David Reardon, MD, of Dana-Farber Cancer Institute in Boston and colleagues.

The concerns are particularly relevant for glioblastoma patients because dexamethasone is a cornerstone of glioblastoma therapy, being used to reduce tumor-associated edema. Patients often receive dexamethasone early on and in significant doses for a protracted period of time to stay ahead of evolving symptoms.

However, the current study suggests dexamethasone and other corticosteroids may be contraindicated in glioblastoma patients on immunotherapy. Therefore, Dr. Reardon and colleagues recommended “careful evaluation of dexamethasone use” in these patients.

“If a glioblastoma patient requires corticosteroids, and they often do for debilitating symptoms, only use these drugs if the patient really needs them,” Dr. Reardon advised. “Start at a low dose and use the shortest treatment interval possible.”
 

Preclinical and clinical results

Dr. Reardon and colleagues initially evaluated the effects of dexamethasone when administered with PD-1 blockade and/or radiotherapy in an immunocompetent syngeneic mouse model.

Most mice that received anti–PD-1 monotherapy were cured, but the benefit of anti–PD-1 therapy was significantly diminished, in a dose-dependent manner, when dexamethasone was added.

At 100 days, the OS rate was about 76% in the anti–PD-1 monotherapy group, 47% when dexamethasone was given at 1 mg/kg, 31% with dexamethasone at 2.5 mg/kg, and 27% with dexamethasone at 10 mg/kg.

A mechanistic study, including analysis of immune cells in the spleen, showed that dexamethasone decreased intratumoral T cells and systemic levels of T cells, natural killer cells, and myeloid cells, while qualitatively impairing lymphocyte function. The mechanism of T-cell depletion included induction of apoptosis, which was noted as soon as 1 hour after the dexamethasone dose, Dr. Reardon said.

The researchers also evaluated 181 consecutive glioblastoma patients treated with PD-1– or PD-L1–targeted therapy. The study included a multivariable statistical analysis that accounted for age, performance status, extent of resection, size of tumor, bulk tumor burden, and MGMT promoter methylation status.

In an initial unadjusted analysis, baseline dexamethasone decreased the median OS to 8.1 months when it was given at less than 2 mg daily and 6.3 months when given at 2 mg or more daily. The median OS was 13.1 months for patients who did not receive dexamethasone.

After multivariable adjustment, baseline dexamethasone eliminated the survival benefit of immunotherapy, the researchers said. The hazard ratio was 2.16 (P = .003) when dexamethasone was given at less than 2 mg daily and 1.97 (P = .005) with dexamethasone at 2 mg or more daily, compared with no baseline dexamethasone.

In fact, the strongest negative risk factor for OS was the use of dexamethasone at initiation of checkpoint inhibitor therapy.
 

Implications: Use corticosteroids ‘very judiciously’

The results of this research suggest “corticosteroids can be detrimental when used along with checkpoint inhibitors,” Dr. Reardon said. He added that this effect could extend to other immunotherapies, such as vaccines, cellular therapies, and oncolytic viruses.

“We need to understand what is driving the inflammatory response,” Dr. Reardon said. “Other targets in the downstream pathway may be regulated to avoid the detrimental effect of corticosteroids.”

Ongoing prospective clinical trials need to build in whether concurrent use of corticosteroids leads to poorer outcomes, according to Dr. Reardon.

“We are validating this prospectively in ongoing clinical trials to evaluate differences in outcome in glioblastoma patients and exploring different types of immunotherapies,” he said.

Though questions remain, Dr. Reardon advises judicious use of corticosteroids or even substituting corticosteroids with bevacizumab in glioblastoma patients.

“If a glioblastoma patient develops debilitating symptoms due to swelling in the brain and is a candidate for immunotherapy, then consider using bevacizumab to avoid using corticosteroids,” Dr. Reardon said, adding that this is being tested prospectively in a clinical trial as well.

“We know corticosteroids have a host of side effects. An additional side effect may be limiting immune function in brain cancer patients and jeopardizing the potential benefits of immunotherapy going forward. I implore practicing oncologists to use corticosteroids very judiciously and as little as possible for as little time as possible,” Dr. Reardon said.

This research was funded by grants from the National Institutes of Health and support from various foundations and institutions. The researchers disclosed relationships with many pharmaceutical companies.

SOURCE: Iorgulescu JB et al. Clin Cancer Res. 2020 Nov 25. doi: 10.1158/1078-0432.CCR-20-2291.

Dexamethasone can have a detrimental effect on survival in patients with glioblastoma who are receiving immunotherapy, according to a study published in Clinical Cancer Research.

Investigators found that baseline dexamethasone use was associated with poor overall survival (OS) in glioblastoma patients receiving anti–PD-1 or anti–PD-L1 therapy. In fact, in a multivariable analysis, baseline dexamethasone use was the strongest predictor of poor survival.

These results “support accumulating concerns that corticosteroids can be detrimental to immunotherapy for oncology patients,” wrote senior study author David Reardon, MD, of Dana-Farber Cancer Institute in Boston and colleagues.

The concerns are particularly relevant for glioblastoma patients because dexamethasone is a cornerstone of glioblastoma therapy, being used to reduce tumor-associated edema. Patients often receive dexamethasone early on and in significant doses for a protracted period of time to stay ahead of evolving symptoms.

However, the current study suggests dexamethasone and other corticosteroids may be contraindicated in glioblastoma patients on immunotherapy. Therefore, Dr. Reardon and colleagues recommended “careful evaluation of dexamethasone use” in these patients.

“If a glioblastoma patient requires corticosteroids, and they often do for debilitating symptoms, only use these drugs if the patient really needs them,” Dr. Reardon advised. “Start at a low dose and use the shortest treatment interval possible.”
 

Preclinical and clinical results

Dr. Reardon and colleagues initially evaluated the effects of dexamethasone when administered with PD-1 blockade and/or radiotherapy in an immunocompetent syngeneic mouse model.

Most mice that received anti–PD-1 monotherapy were cured, but the benefit of anti–PD-1 therapy was significantly diminished, in a dose-dependent manner, when dexamethasone was added.

At 100 days, the OS rate was about 76% in the anti–PD-1 monotherapy group, 47% when dexamethasone was given at 1 mg/kg, 31% with dexamethasone at 2.5 mg/kg, and 27% with dexamethasone at 10 mg/kg.

A mechanistic study, including analysis of immune cells in the spleen, showed that dexamethasone decreased intratumoral T cells and systemic levels of T cells, natural killer cells, and myeloid cells, while qualitatively impairing lymphocyte function. The mechanism of T-cell depletion included induction of apoptosis, which was noted as soon as 1 hour after the dexamethasone dose, Dr. Reardon said.

The researchers also evaluated 181 consecutive glioblastoma patients treated with PD-1– or PD-L1–targeted therapy. The study included a multivariable statistical analysis that accounted for age, performance status, extent of resection, size of tumor, bulk tumor burden, and MGMT promoter methylation status.

In an initial unadjusted analysis, baseline dexamethasone decreased the median OS to 8.1 months when it was given at less than 2 mg daily and 6.3 months when given at 2 mg or more daily. The median OS was 13.1 months for patients who did not receive dexamethasone.

After multivariable adjustment, baseline dexamethasone eliminated the survival benefit of immunotherapy, the researchers said. The hazard ratio was 2.16 (P = .003) when dexamethasone was given at less than 2 mg daily and 1.97 (P = .005) with dexamethasone at 2 mg or more daily, compared with no baseline dexamethasone.

In fact, the strongest negative risk factor for OS was the use of dexamethasone at initiation of checkpoint inhibitor therapy.
 

Implications: Use corticosteroids ‘very judiciously’

The results of this research suggest “corticosteroids can be detrimental when used along with checkpoint inhibitors,” Dr. Reardon said. He added that this effect could extend to other immunotherapies, such as vaccines, cellular therapies, and oncolytic viruses.

“We need to understand what is driving the inflammatory response,” Dr. Reardon said. “Other targets in the downstream pathway may be regulated to avoid the detrimental effect of corticosteroids.”

Ongoing prospective clinical trials need to build in whether concurrent use of corticosteroids leads to poorer outcomes, according to Dr. Reardon.

“We are validating this prospectively in ongoing clinical trials to evaluate differences in outcome in glioblastoma patients and exploring different types of immunotherapies,” he said.

Though questions remain, Dr. Reardon advises judicious use of corticosteroids or even substituting corticosteroids with bevacizumab in glioblastoma patients.

“If a glioblastoma patient develops debilitating symptoms due to swelling in the brain and is a candidate for immunotherapy, then consider using bevacizumab to avoid using corticosteroids,” Dr. Reardon said, adding that this is being tested prospectively in a clinical trial as well.

“We know corticosteroids have a host of side effects. An additional side effect may be limiting immune function in brain cancer patients and jeopardizing the potential benefits of immunotherapy going forward. I implore practicing oncologists to use corticosteroids very judiciously and as little as possible for as little time as possible,” Dr. Reardon said.

This research was funded by grants from the National Institutes of Health and support from various foundations and institutions. The researchers disclosed relationships with many pharmaceutical companies.

SOURCE: Iorgulescu JB et al. Clin Cancer Res. 2020 Nov 25. doi: 10.1158/1078-0432.CCR-20-2291.

Dexamethasone can have a detrimental effect on survival in patients with glioblastoma who are receiving immunotherapy, according to a study published in Clinical Cancer Research.

Investigators found that baseline dexamethasone use was associated with poor overall survival (OS) in glioblastoma patients receiving anti–PD-1 or anti–PD-L1 therapy. In fact, in a multivariable analysis, baseline dexamethasone use was the strongest predictor of poor survival.

These results “support accumulating concerns that corticosteroids can be detrimental to immunotherapy for oncology patients,” wrote senior study author David Reardon, MD, of Dana-Farber Cancer Institute in Boston and colleagues.

The concerns are particularly relevant for glioblastoma patients because dexamethasone is a cornerstone of glioblastoma therapy, being used to reduce tumor-associated edema. Patients often receive dexamethasone early on and in significant doses for a protracted period of time to stay ahead of evolving symptoms.

However, the current study suggests dexamethasone and other corticosteroids may be contraindicated in glioblastoma patients on immunotherapy. Therefore, Dr. Reardon and colleagues recommended “careful evaluation of dexamethasone use” in these patients.

“If a glioblastoma patient requires corticosteroids, and they often do for debilitating symptoms, only use these drugs if the patient really needs them,” Dr. Reardon advised. “Start at a low dose and use the shortest treatment interval possible.”
 

Preclinical and clinical results

Dr. Reardon and colleagues initially evaluated the effects of dexamethasone when administered with PD-1 blockade and/or radiotherapy in an immunocompetent syngeneic mouse model.

Most mice that received anti–PD-1 monotherapy were cured, but the benefit of anti–PD-1 therapy was significantly diminished, in a dose-dependent manner, when dexamethasone was added.

At 100 days, the OS rate was about 76% in the anti–PD-1 monotherapy group, 47% when dexamethasone was given at 1 mg/kg, 31% with dexamethasone at 2.5 mg/kg, and 27% with dexamethasone at 10 mg/kg.

A mechanistic study, including analysis of immune cells in the spleen, showed that dexamethasone decreased intratumoral T cells and systemic levels of T cells, natural killer cells, and myeloid cells, while qualitatively impairing lymphocyte function. The mechanism of T-cell depletion included induction of apoptosis, which was noted as soon as 1 hour after the dexamethasone dose, Dr. Reardon said.

The researchers also evaluated 181 consecutive glioblastoma patients treated with PD-1– or PD-L1–targeted therapy. The study included a multivariable statistical analysis that accounted for age, performance status, extent of resection, size of tumor, bulk tumor burden, and MGMT promoter methylation status.

In an initial unadjusted analysis, baseline dexamethasone decreased the median OS to 8.1 months when it was given at less than 2 mg daily and 6.3 months when given at 2 mg or more daily. The median OS was 13.1 months for patients who did not receive dexamethasone.

After multivariable adjustment, baseline dexamethasone eliminated the survival benefit of immunotherapy, the researchers said. The hazard ratio was 2.16 (P = .003) when dexamethasone was given at less than 2 mg daily and 1.97 (P = .005) with dexamethasone at 2 mg or more daily, compared with no baseline dexamethasone.

In fact, the strongest negative risk factor for OS was the use of dexamethasone at initiation of checkpoint inhibitor therapy.
 

Implications: Use corticosteroids ‘very judiciously’

The results of this research suggest “corticosteroids can be detrimental when used along with checkpoint inhibitors,” Dr. Reardon said. He added that this effect could extend to other immunotherapies, such as vaccines, cellular therapies, and oncolytic viruses.

“We need to understand what is driving the inflammatory response,” Dr. Reardon said. “Other targets in the downstream pathway may be regulated to avoid the detrimental effect of corticosteroids.”

Ongoing prospective clinical trials need to build in whether concurrent use of corticosteroids leads to poorer outcomes, according to Dr. Reardon.

“We are validating this prospectively in ongoing clinical trials to evaluate differences in outcome in glioblastoma patients and exploring different types of immunotherapies,” he said.

Though questions remain, Dr. Reardon advises judicious use of corticosteroids or even substituting corticosteroids with bevacizumab in glioblastoma patients.

“If a glioblastoma patient develops debilitating symptoms due to swelling in the brain and is a candidate for immunotherapy, then consider using bevacizumab to avoid using corticosteroids,” Dr. Reardon said, adding that this is being tested prospectively in a clinical trial as well.

“We know corticosteroids have a host of side effects. An additional side effect may be limiting immune function in brain cancer patients and jeopardizing the potential benefits of immunotherapy going forward. I implore practicing oncologists to use corticosteroids very judiciously and as little as possible for as little time as possible,” Dr. Reardon said.

This research was funded by grants from the National Institutes of Health and support from various foundations and institutions. The researchers disclosed relationships with many pharmaceutical companies.

SOURCE: Iorgulescu JB et al. Clin Cancer Res. 2020 Nov 25. doi: 10.1158/1078-0432.CCR-20-2291.

Adults with inflammatory bowel disease were more likely to continue using vedolizumab, compared with anti–tumor necrosis factor (TNF) drugs over 3 years, based on data from a retrospective study of nearly 16,000 patients.

Patient persistence with prescribed therapy is essential to managing chronic inflammatory bowel disease (IBD), but data on the persistence of patients with treatments are limited, wrote Ulf Helwig, MD, of the Practice for Internal Medicine, Oldenburg, Germany, and colleagues. “With the advent of vedolizumab, physicians for the first time had the choice between biologicals with different modes of action,” they wrote.

In a study published in the Journal of Clinical Gastroenterology, the researchers used a national prescription database to identify 15,984 adults aged 18 years and older who were treatment-naive to biologics and received prescriptions between July 2014 and March 2017. Treatment persistence was defined as continuous treatment time of at least 90 days without prescription.

A total of 2,076 vedolizumab patients were matched with 2,076 adalimumab patients; 716 vedolizumab patients were matched with 716 golimumab patients; and 2,055 vedolizumab patients were matched with 2,055 infliximab patients.

Within 3 years after the first prescription, the overall persistence rates were 35.9% for vedolizumab, 27.8% for adalimumab, 20.7% for golimumab, and 29.8% for infliximab.

In matched-pair analysis, 35.2% of vedolizumab patients were persistent, compared with 28.9% of adalimumab patients over a 3-year period; the difference was statistically significant. In addition, 30.5% of vedolizumab patients persisted, compared with 25.4% of golimumab patients, also statistically significant. A matched-pair comparison between vedolizumab and infliximab (35.7% vs. 30.2%) was not statistically significant (P = 0.119).

In addition, vedolizumab patients were significantly less likely to discontinue therapy, compared with both adalimumab and golimumab patients, with hazard ratios of 0.86 and 0.60, respectively, in the matched pair analysis; discontinuation, compared with infliximab, was not statistically significant.

“Several reasons may account for significant rates of discontinuation reported for all biological treatments in IBD,” the researchers noted. “These comprise differences in health care systems in the concerned countries, including differences in availability of biologicals, access to reimbursed drugs, or different patient care settings,” they wrote.

The study findings were limited by several factors including the lack of data on specific IBD diagnoses, IBD severity, disease course, and dose escalation, they noted.

However, the study was strengthened by the large sample size and use of a real-world setting, they said.

“Further studies are needed to identify the reasons for persistence differences between vedolizumab and anti-TNF drugs,” they concluded.
 

Comparisons inform choices

“There are multiple biologic options for therapy of inflammatory bowel disease, and response to therapy tends to drop off over time in many patients for a variety of reasons including development of antibodies and escape from the mechanism of the action of the drug,” said Kim L. Isaacs, MD, of the University of North Carolina at Chapel Hill, in an interview.

“Intolerance or side effects of medication also may lead to discontinuation of therapy,” said Dr. Isaacs. “This trial looks at therapy discontinuation among four biologics used for inflammatory bowel disease over a 3-year period after initiation of therapy in patients who were previous biologically naive. Reasons for discontinuation cannot be assessed with this data set,” she noted. “There are very few comparative trials with the different biologic therapies in IBD. This trial is important because it compares the two distinct biologic mechanisms of action and continuation of therapy in biologically naive patients,” she said.

Dr. Isaacs said she was not surprised by the study findings. “Discontinuation of anti-TNF therapy was more common, compared to vedolizumab and golimumab. There was no statistical difference in terms of therapy discontinuation with infliximab,” she said. “In general, vedolizumab is felt to be less systemically immunosuppressant with targeting of white blood cell trafficking to the gut, whereas anti-TNF therapy is more systemically immunosuppressant and may be associated with more systemic side effects,” she explained.

The study design does not allow for comment on comparative efficacy, “although the findings are intriguing,” said Dr. Isaacs. “If the discontinuations were caused by lack of efficacy, the findings in this study may help in positioning biologic therapy in the biologic-naive patients,” she said.

The study is “a ‘real-world’ experiment that suggests there is a difference between different biologic therapies for inflammatory bowel disease,” said Dr. Isaacs. “More controlled comparative efficacy trials are needed that can look at reasons for drug discontinuation between different populations. To date, the VARSITY trial comparing vedolizumab to adalimumab in ulcerative colitis is the only published trial to do this,” she added.  

The study received no outside funding. Lead author Dr. Helwig disclosed lecture and consulting fees from AbbVie, Amgen, Biogen, Celltrion, Hexal, MSD, Ferring, Falk Foundation, Takeda, Mundipharma, Pfizer, Hospira, and Vifor Pharma. Dr. Isaacs disclosed serving on the Data and Safety Monitoring Board (DSMB) for Janssen.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

SOURCE: Helwig U et al. J Clin Gastroenterol. 2021 Jan. doi: 10.1097/MCG.0000000000001323

Story updated Jan. 5, 2021.

Adults with inflammatory bowel disease were more likely to continue using vedolizumab, compared with anti–tumor necrosis factor (TNF) drugs over 3 years, based on data from a retrospective study of nearly 16,000 patients.

Patient persistence with prescribed therapy is essential to managing chronic inflammatory bowel disease (IBD), but data on the persistence of patients with treatments are limited, wrote Ulf Helwig, MD, of the Practice for Internal Medicine, Oldenburg, Germany, and colleagues. “With the advent of vedolizumab, physicians for the first time had the choice between biologicals with different modes of action,” they wrote.

In a study published in the Journal of Clinical Gastroenterology, the researchers used a national prescription database to identify 15,984 adults aged 18 years and older who were treatment-naive to biologics and received prescriptions between July 2014 and March 2017. Treatment persistence was defined as continuous treatment time of at least 90 days without prescription.

A total of 2,076 vedolizumab patients were matched with 2,076 adalimumab patients; 716 vedolizumab patients were matched with 716 golimumab patients; and 2,055 vedolizumab patients were matched with 2,055 infliximab patients.

Within 3 years after the first prescription, the overall persistence rates were 35.9% for vedolizumab, 27.8% for adalimumab, 20.7% for golimumab, and 29.8% for infliximab.

In matched-pair analysis, 35.2% of vedolizumab patients were persistent, compared with 28.9% of adalimumab patients over a 3-year period; the difference was statistically significant. In addition, 30.5% of vedolizumab patients persisted, compared with 25.4% of golimumab patients, also statistically significant. A matched-pair comparison between vedolizumab and infliximab (35.7% vs. 30.2%) was not statistically significant (P = 0.119).

In addition, vedolizumab patients were significantly less likely to discontinue therapy, compared with both adalimumab and golimumab patients, with hazard ratios of 0.86 and 0.60, respectively, in the matched pair analysis; discontinuation, compared with infliximab, was not statistically significant.

“Several reasons may account for significant rates of discontinuation reported for all biological treatments in IBD,” the researchers noted. “These comprise differences in health care systems in the concerned countries, including differences in availability of biologicals, access to reimbursed drugs, or different patient care settings,” they wrote.

The study findings were limited by several factors including the lack of data on specific IBD diagnoses, IBD severity, disease course, and dose escalation, they noted.

However, the study was strengthened by the large sample size and use of a real-world setting, they said.

“Further studies are needed to identify the reasons for persistence differences between vedolizumab and anti-TNF drugs,” they concluded.
 

Comparisons inform choices

“There are multiple biologic options for therapy of inflammatory bowel disease, and response to therapy tends to drop off over time in many patients for a variety of reasons including development of antibodies and escape from the mechanism of the action of the drug,” said Kim L. Isaacs, MD, of the University of North Carolina at Chapel Hill, in an interview.

“Intolerance or side effects of medication also may lead to discontinuation of therapy,” said Dr. Isaacs. “This trial looks at therapy discontinuation among four biologics used for inflammatory bowel disease over a 3-year period after initiation of therapy in patients who were previous biologically naive. Reasons for discontinuation cannot be assessed with this data set,” she noted. “There are very few comparative trials with the different biologic therapies in IBD. This trial is important because it compares the two distinct biologic mechanisms of action and continuation of therapy in biologically naive patients,” she said.

Dr. Isaacs said she was not surprised by the study findings. “Discontinuation of anti-TNF therapy was more common, compared to vedolizumab and golimumab. There was no statistical difference in terms of therapy discontinuation with infliximab,” she said. “In general, vedolizumab is felt to be less systemically immunosuppressant with targeting of white blood cell trafficking to the gut, whereas anti-TNF therapy is more systemically immunosuppressant and may be associated with more systemic side effects,” she explained.

The study design does not allow for comment on comparative efficacy, “although the findings are intriguing,” said Dr. Isaacs. “If the discontinuations were caused by lack of efficacy, the findings in this study may help in positioning biologic therapy in the biologic-naive patients,” she said.

The study is “a ‘real-world’ experiment that suggests there is a difference between different biologic therapies for inflammatory bowel disease,” said Dr. Isaacs. “More controlled comparative efficacy trials are needed that can look at reasons for drug discontinuation between different populations. To date, the VARSITY trial comparing vedolizumab to adalimumab in ulcerative colitis is the only published trial to do this,” she added.  

The study received no outside funding. Lead author Dr. Helwig disclosed lecture and consulting fees from AbbVie, Amgen, Biogen, Celltrion, Hexal, MSD, Ferring, Falk Foundation, Takeda, Mundipharma, Pfizer, Hospira, and Vifor Pharma. Dr. Isaacs disclosed serving on the Data and Safety Monitoring Board (DSMB) for Janssen.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

SOURCE: Helwig U et al. J Clin Gastroenterol. 2021 Jan. doi: 10.1097/MCG.0000000000001323

Story updated Jan. 5, 2021.

Adults with inflammatory bowel disease were more likely to continue using vedolizumab, compared with anti–tumor necrosis factor (TNF) drugs over 3 years, based on data from a retrospective study of nearly 16,000 patients.

Patient persistence with prescribed therapy is essential to managing chronic inflammatory bowel disease (IBD), but data on the persistence of patients with treatments are limited, wrote Ulf Helwig, MD, of the Practice for Internal Medicine, Oldenburg, Germany, and colleagues. “With the advent of vedolizumab, physicians for the first time had the choice between biologicals with different modes of action,” they wrote.

In a study published in the Journal of Clinical Gastroenterology, the researchers used a national prescription database to identify 15,984 adults aged 18 years and older who were treatment-naive to biologics and received prescriptions between July 2014 and March 2017. Treatment persistence was defined as continuous treatment time of at least 90 days without prescription.

A total of 2,076 vedolizumab patients were matched with 2,076 adalimumab patients; 716 vedolizumab patients were matched with 716 golimumab patients; and 2,055 vedolizumab patients were matched with 2,055 infliximab patients.

Within 3 years after the first prescription, the overall persistence rates were 35.9% for vedolizumab, 27.8% for adalimumab, 20.7% for golimumab, and 29.8% for infliximab.

In matched-pair analysis, 35.2% of vedolizumab patients were persistent, compared with 28.9% of adalimumab patients over a 3-year period; the difference was statistically significant. In addition, 30.5% of vedolizumab patients persisted, compared with 25.4% of golimumab patients, also statistically significant. A matched-pair comparison between vedolizumab and infliximab (35.7% vs. 30.2%) was not statistically significant (P = 0.119).

In addition, vedolizumab patients were significantly less likely to discontinue therapy, compared with both adalimumab and golimumab patients, with hazard ratios of 0.86 and 0.60, respectively, in the matched pair analysis; discontinuation, compared with infliximab, was not statistically significant.

“Several reasons may account for significant rates of discontinuation reported for all biological treatments in IBD,” the researchers noted. “These comprise differences in health care systems in the concerned countries, including differences in availability of biologicals, access to reimbursed drugs, or different patient care settings,” they wrote.

The study findings were limited by several factors including the lack of data on specific IBD diagnoses, IBD severity, disease course, and dose escalation, they noted.

However, the study was strengthened by the large sample size and use of a real-world setting, they said.

“Further studies are needed to identify the reasons for persistence differences between vedolizumab and anti-TNF drugs,” they concluded.
 

Comparisons inform choices

“There are multiple biologic options for therapy of inflammatory bowel disease, and response to therapy tends to drop off over time in many patients for a variety of reasons including development of antibodies and escape from the mechanism of the action of the drug,” said Kim L. Isaacs, MD, of the University of North Carolina at Chapel Hill, in an interview.

“Intolerance or side effects of medication also may lead to discontinuation of therapy,” said Dr. Isaacs. “This trial looks at therapy discontinuation among four biologics used for inflammatory bowel disease over a 3-year period after initiation of therapy in patients who were previous biologically naive. Reasons for discontinuation cannot be assessed with this data set,” she noted. “There are very few comparative trials with the different biologic therapies in IBD. This trial is important because it compares the two distinct biologic mechanisms of action and continuation of therapy in biologically naive patients,” she said.

Dr. Isaacs said she was not surprised by the study findings. “Discontinuation of anti-TNF therapy was more common, compared to vedolizumab and golimumab. There was no statistical difference in terms of therapy discontinuation with infliximab,” she said. “In general, vedolizumab is felt to be less systemically immunosuppressant with targeting of white blood cell trafficking to the gut, whereas anti-TNF therapy is more systemically immunosuppressant and may be associated with more systemic side effects,” she explained.

The study design does not allow for comment on comparative efficacy, “although the findings are intriguing,” said Dr. Isaacs. “If the discontinuations were caused by lack of efficacy, the findings in this study may help in positioning biologic therapy in the biologic-naive patients,” she said.

The study is “a ‘real-world’ experiment that suggests there is a difference between different biologic therapies for inflammatory bowel disease,” said Dr. Isaacs. “More controlled comparative efficacy trials are needed that can look at reasons for drug discontinuation between different populations. To date, the VARSITY trial comparing vedolizumab to adalimumab in ulcerative colitis is the only published trial to do this,” she added.  

The study received no outside funding. Lead author Dr. Helwig disclosed lecture and consulting fees from AbbVie, Amgen, Biogen, Celltrion, Hexal, MSD, Ferring, Falk Foundation, Takeda, Mundipharma, Pfizer, Hospira, and Vifor Pharma. Dr. Isaacs disclosed serving on the Data and Safety Monitoring Board (DSMB) for Janssen.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

SOURCE: Helwig U et al. J Clin Gastroenterol. 2021 Jan. doi: 10.1097/MCG.0000000000001323

Story updated Jan. 5, 2021.

The US Food and Drug Administration (FDA) has approved osimertinib (Tagrisso) as the first adjuvant treatment for adults with early-stage non–small cell lung cancer (NSCLC) bearing EGFR exon 19 deletions or exon 21 L858R mutations.

Osimertinib was first approved in the US in 2018 for the first-line treatment of patients with metastatic EGFR-mutated NSCLC.

With this new indication, “patients may be treated with this targeted therapy in an earlier and potentially more curative stage of non-small cell lung cancer,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a news release.

The expanded indication is based on results of the ADAURA clinical trial, which compared osimertinib with placebo following complete resection of localized or locally advanced NSCLC with negative margins. 

In the trial, adjuvant osimertinib reduced the relative risk of disease recurrence or death by 83% in patients with stage II and IIIA disease (hazard ratio [HR], 0.17; 95% CI, 0.12 - 0.23; P < .0001).

Disease-free survival (DFS) in the overall trial population of patients with stage IB-IIIA disease showed osimertinib reduced the risk of disease recurrence or death by 80% (HR, 0.20; 95% CI, 0.15 - 0.27; P < .0001).

At 2 years, 89% of patients treated with the targeted agent remained alive and disease free vs 52% on placebo after surgery. The safety and tolerability of osimertinib in the adjuvant setting was consistent with previous trials in the metastatic setting.

The trial of 682 patients was unblinded early and halted on the recommendation of the independent data-monitoring committee, because of the efficacy of osimertinib.

“If I were on the committee, I would have done the same thing. These are extraordinary results,” study investigator Roy S. Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center, New Haven, Connecticut, said at a press briefing prior to the study presentation at the American Society of Clinical Oncology’s (ASCO) virtual scientific program last spring.

In a Medscape commentary, Mark Kris, MD, of Memorial Sloan Kettering Cancer Center in New York City, said the data with osimertinib in the adjuvant setting are “important and practice-changing.”

“The potential for this drug to improve outcomes has been there for a long time. This phase 3 randomized trial presented at the plenary session of ASCO showed a more than doubling of disease-free survival at 2 years. It shows that we can use therapies in the earlier stages of disease,” Kris noted.

“This approval dispels the notion that treatment is over after surgery and chemotherapy, as the ADAURA results show that Tagrisso can dramatically change the course of this disease,” Dave Fredrickson, executive vice president, AstraZeneca oncology business unit, said in a news release.

Osimertinib had orphan drug status and breakthrough therapy designation for treatment of EGFR mutation-positive NSCLC.

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

The US Food and Drug Administration (FDA) has approved osimertinib (Tagrisso) as the first adjuvant treatment for adults with early-stage non–small cell lung cancer (NSCLC) bearing EGFR exon 19 deletions or exon 21 L858R mutations.

Osimertinib was first approved in the US in 2018 for the first-line treatment of patients with metastatic EGFR-mutated NSCLC.

With this new indication, “patients may be treated with this targeted therapy in an earlier and potentially more curative stage of non-small cell lung cancer,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a news release.

The expanded indication is based on results of the ADAURA clinical trial, which compared osimertinib with placebo following complete resection of localized or locally advanced NSCLC with negative margins. 

In the trial, adjuvant osimertinib reduced the relative risk of disease recurrence or death by 83% in patients with stage II and IIIA disease (hazard ratio [HR], 0.17; 95% CI, 0.12 - 0.23; P < .0001).

Disease-free survival (DFS) in the overall trial population of patients with stage IB-IIIA disease showed osimertinib reduced the risk of disease recurrence or death by 80% (HR, 0.20; 95% CI, 0.15 - 0.27; P < .0001).

At 2 years, 89% of patients treated with the targeted agent remained alive and disease free vs 52% on placebo after surgery. The safety and tolerability of osimertinib in the adjuvant setting was consistent with previous trials in the metastatic setting.

The trial of 682 patients was unblinded early and halted on the recommendation of the independent data-monitoring committee, because of the efficacy of osimertinib.

“If I were on the committee, I would have done the same thing. These are extraordinary results,” study investigator Roy S. Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center, New Haven, Connecticut, said at a press briefing prior to the study presentation at the American Society of Clinical Oncology’s (ASCO) virtual scientific program last spring.

In a Medscape commentary, Mark Kris, MD, of Memorial Sloan Kettering Cancer Center in New York City, said the data with osimertinib in the adjuvant setting are “important and practice-changing.”

“The potential for this drug to improve outcomes has been there for a long time. This phase 3 randomized trial presented at the plenary session of ASCO showed a more than doubling of disease-free survival at 2 years. It shows that we can use therapies in the earlier stages of disease,” Kris noted.

“This approval dispels the notion that treatment is over after surgery and chemotherapy, as the ADAURA results show that Tagrisso can dramatically change the course of this disease,” Dave Fredrickson, executive vice president, AstraZeneca oncology business unit, said in a news release.

Osimertinib had orphan drug status and breakthrough therapy designation for treatment of EGFR mutation-positive NSCLC.

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

The US Food and Drug Administration (FDA) has approved osimertinib (Tagrisso) as the first adjuvant treatment for adults with early-stage non–small cell lung cancer (NSCLC) bearing EGFR exon 19 deletions or exon 21 L858R mutations.

Osimertinib was first approved in the US in 2018 for the first-line treatment of patients with metastatic EGFR-mutated NSCLC.

With this new indication, “patients may be treated with this targeted therapy in an earlier and potentially more curative stage of non-small cell lung cancer,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a news release.

The expanded indication is based on results of the ADAURA clinical trial, which compared osimertinib with placebo following complete resection of localized or locally advanced NSCLC with negative margins. 

In the trial, adjuvant osimertinib reduced the relative risk of disease recurrence or death by 83% in patients with stage II and IIIA disease (hazard ratio [HR], 0.17; 95% CI, 0.12 - 0.23; P < .0001).

Disease-free survival (DFS) in the overall trial population of patients with stage IB-IIIA disease showed osimertinib reduced the risk of disease recurrence or death by 80% (HR, 0.20; 95% CI, 0.15 - 0.27; P < .0001).

At 2 years, 89% of patients treated with the targeted agent remained alive and disease free vs 52% on placebo after surgery. The safety and tolerability of osimertinib in the adjuvant setting was consistent with previous trials in the metastatic setting.

The trial of 682 patients was unblinded early and halted on the recommendation of the independent data-monitoring committee, because of the efficacy of osimertinib.

“If I were on the committee, I would have done the same thing. These are extraordinary results,” study investigator Roy S. Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center, New Haven, Connecticut, said at a press briefing prior to the study presentation at the American Society of Clinical Oncology’s (ASCO) virtual scientific program last spring.

In a Medscape commentary, Mark Kris, MD, of Memorial Sloan Kettering Cancer Center in New York City, said the data with osimertinib in the adjuvant setting are “important and practice-changing.”

“The potential for this drug to improve outcomes has been there for a long time. This phase 3 randomized trial presented at the plenary session of ASCO showed a more than doubling of disease-free survival at 2 years. It shows that we can use therapies in the earlier stages of disease,” Kris noted.

“This approval dispels the notion that treatment is over after surgery and chemotherapy, as the ADAURA results show that Tagrisso can dramatically change the course of this disease,” Dave Fredrickson, executive vice president, AstraZeneca oncology business unit, said in a news release.

Osimertinib had orphan drug status and breakthrough therapy designation for treatment of EGFR mutation-positive NSCLC.

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

Cannabis is ineffective at alleviating depression in pregnant women undergoing opioid agonist therapy (OAT), new research shows.

RyanKing999/iStock/Getty Images

A study of more than 120 pregnant women undergoing treatment of opioid use disorder (OUD) showed that those who used cannabis to alleviate their depressive symptoms while undergoing OAT continued to have high depression scores at the end of opioid treatment.

In addition, depression scores improved for those who abstained from cannabis use after their first positive screen. Interestingly, cannabis use did not affect patient retention in treatment for OUD, the investigators note.

“To our knowledge, this is the first time looking at the impact of cannabis on the specific population of pregnant women with opioid use disorder, who are very vulnerable to depression,” lead author Abigail Richison, MD, University of Arkansas for Medical Sciences, Little Rock, said in an interview.

The findings were presented at the American Academy of Addiction Psychiatry (AAAP) 31st Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

A safer alternative?

Data from the National Survey on Drug Use and Health show that perinatal cannabis use increased by 62% between 2002 and 2014. Many women try to ameliorate their depression symptoms by using cannabis in the mistaken belief that it will help their depression, the investigators noted.

In addition, many women consider cannabis safer during pregnancy than prescribed medications for improving mood, said Dr. Richison. She said that cannabis does not alleviate depression and may even worsen it.

Dr. Richison noted that at her center, which has a women’s health program that treats pregnant women with OUDs, she was seeing a lot of patients who reported using cannabis to improve their mood.

“However, it didn’t seem like it was really helping, so I started researching about cannabis and depression,” Dr. Richison said.

“I’ve always been interested in this population because they are very vulnerable to legal implications and can be accused of perinatal substance use. I think it is very important to screen for depression as well as cannabis use in this population,” she added.

To shed some light on the impact of cannabis use by pregnant patients with OUD, the investigators conducted a retrospective chart review of 121 pregnant women with OUD who attended outpatient OAT. All were prescribed buprenorphine.

At each visit, Beck Depression Inventory (BDI) scores were obtained and urine drug screens were administered. The primary outcome was BDI score. Other measures included retention, urinary drug screen results, and antidepressant use.

The women were divided into two groups. The first comprised cannabis users, defined as having more than one urine drug screen that was positive for cannabis (n = 35). The other group comprised nonusers, defined as having urine drug screens that were negative for cannabis (n = 86).

Cannabis users were a little younger (mean age, 27 years) than non–cannabis users (mean age, 29.5 years; P = .006). Most of the participants were White (80.2%). Roughly half were on Medicaid, and most of the other participants had private insurance; a small number of women had no insurance.

Results showed that cannabis users had significantly higher BDI scores than non–cannabis users (mean scores, 16 vs. 9.3; P < .001).

Cannabis use continued to be associated with elevated scores for depression when controlling for opioid misuse and antidepressant use. There were no significant differences in retention or lapse to opioid misuse between the two groups.
 

More evidence of risk

Commenting on the findings in an interview, Carla Marienfeld, MD, professor of psychiatry at the University of California, San Diego, said there is a growing body of evidence about risks from cannabis use during pregnancy, “a time where we already know the endocannabinoid system is very active in the developing fetus.”

She noted that the current study’s design makes it hard to know whether marijuana use causes worse depression.

However, “it clearly is not associated with helping to improve mood the way people who are using it believe or hope for,” said Dr. Marienfeld, who was not part of the research.

“The risk for harm in terms of worse mood for the pregnant woman or risks for harm to the developing fetus are being better understood with many new studies,” she added.

Yet as more and more states legalize medical marijuana, cannabis use during pregnancy is only going to rise, experts fear.

Cornel Stanciu, MD, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., who was asked for comment, noted that public endorsement for potential benefits of the marijuana plant is at an all-time high.

“To date, 33 states and the District of Columbia have responded by legalizing medical marijuana, with 10 states also having legalized recreational use of marijuana. The current practice is said to be ahead of science, as robust research has been hindered by strict regulations – and most epidemiological studies point toward harmful associations,” Dr. Stanciu said in an interview.

“Given the decreased perception of harm by the general public, women are certainly compelled to seek what they perceive as more natural self-management remedies,” he said.
 

A harmful habit

Dr. Stanciu cited a recent study conducted in Colorado in which researchers contacted cannabis dispensaries, identified themselves as being pregnant, and asked for guidance in managing pregnancy-related symptoms.

Almost 70% of dispensaries recommended products to treat symptoms, particularly in the vulnerable first trimester; 36% of them also provided reassurance of the safety profile. Very few encouraged a discussion with the physician.

“Consumption of cannabis during pregnancy results in cannabinoid placental crossing and accumulation in the fetal brain, as well as other organs, where it interferes with neurodevelopment and the endocannabinoid system,” he said.

In addition, retrospective studies have shown an association between prenatal cannabis ingestion and anemia in the mothers, low birth weight, greater risk for preterm and stillbirths, and increased need for neonatal ICU admissions.

“Children born to mothers who used cannabis during pregnancy have higher rates of impulsivity, delinquency, learning and memory impairment, as well as executive function deficits. There is also an increased association with proneness to psychosis during middle childhood,” Dr. Stanciu said.

When used during pregnancy, cannabis has been associated with increased anxiety in mothers, as well as increased risk for depressive disorders, incidence of suicidal ideations and behavior, and symptoms of mania and psychosis among those with bipolar and schizophrenia spectrum conditions. Cannabis has also been linked to coingestion of other substances and with alcohol use.

“So cannabis can pose harm, especially when used by those with affective disorders,” Dr. Stanciu said.

The study was funded by the National Institute on Drug Abuse. Dr. Richison, Dr. Marienfeld, and Dr. Stanciu have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com

Cannabis is ineffective at alleviating depression in pregnant women undergoing opioid agonist therapy (OAT), new research shows.

RyanKing999/iStock/Getty Images

A study of more than 120 pregnant women undergoing treatment of opioid use disorder (OUD) showed that those who used cannabis to alleviate their depressive symptoms while undergoing OAT continued to have high depression scores at the end of opioid treatment.

In addition, depression scores improved for those who abstained from cannabis use after their first positive screen. Interestingly, cannabis use did not affect patient retention in treatment for OUD, the investigators note.

“To our knowledge, this is the first time looking at the impact of cannabis on the specific population of pregnant women with opioid use disorder, who are very vulnerable to depression,” lead author Abigail Richison, MD, University of Arkansas for Medical Sciences, Little Rock, said in an interview.

The findings were presented at the American Academy of Addiction Psychiatry (AAAP) 31st Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

A safer alternative?

Data from the National Survey on Drug Use and Health show that perinatal cannabis use increased by 62% between 2002 and 2014. Many women try to ameliorate their depression symptoms by using cannabis in the mistaken belief that it will help their depression, the investigators noted.

In addition, many women consider cannabis safer during pregnancy than prescribed medications for improving mood, said Dr. Richison. She said that cannabis does not alleviate depression and may even worsen it.

Dr. Richison noted that at her center, which has a women’s health program that treats pregnant women with OUDs, she was seeing a lot of patients who reported using cannabis to improve their mood.

“However, it didn’t seem like it was really helping, so I started researching about cannabis and depression,” Dr. Richison said.

“I’ve always been interested in this population because they are very vulnerable to legal implications and can be accused of perinatal substance use. I think it is very important to screen for depression as well as cannabis use in this population,” she added.

To shed some light on the impact of cannabis use by pregnant patients with OUD, the investigators conducted a retrospective chart review of 121 pregnant women with OUD who attended outpatient OAT. All were prescribed buprenorphine.

At each visit, Beck Depression Inventory (BDI) scores were obtained and urine drug screens were administered. The primary outcome was BDI score. Other measures included retention, urinary drug screen results, and antidepressant use.

The women were divided into two groups. The first comprised cannabis users, defined as having more than one urine drug screen that was positive for cannabis (n = 35). The other group comprised nonusers, defined as having urine drug screens that were negative for cannabis (n = 86).

Cannabis users were a little younger (mean age, 27 years) than non–cannabis users (mean age, 29.5 years; P = .006). Most of the participants were White (80.2%). Roughly half were on Medicaid, and most of the other participants had private insurance; a small number of women had no insurance.

Results showed that cannabis users had significantly higher BDI scores than non–cannabis users (mean scores, 16 vs. 9.3; P < .001).

Cannabis use continued to be associated with elevated scores for depression when controlling for opioid misuse and antidepressant use. There were no significant differences in retention or lapse to opioid misuse between the two groups.
 

More evidence of risk

Commenting on the findings in an interview, Carla Marienfeld, MD, professor of psychiatry at the University of California, San Diego, said there is a growing body of evidence about risks from cannabis use during pregnancy, “a time where we already know the endocannabinoid system is very active in the developing fetus.”

She noted that the current study’s design makes it hard to know whether marijuana use causes worse depression.

However, “it clearly is not associated with helping to improve mood the way people who are using it believe or hope for,” said Dr. Marienfeld, who was not part of the research.

“The risk for harm in terms of worse mood for the pregnant woman or risks for harm to the developing fetus are being better understood with many new studies,” she added.

Yet as more and more states legalize medical marijuana, cannabis use during pregnancy is only going to rise, experts fear.

Cornel Stanciu, MD, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., who was asked for comment, noted that public endorsement for potential benefits of the marijuana plant is at an all-time high.

“To date, 33 states and the District of Columbia have responded by legalizing medical marijuana, with 10 states also having legalized recreational use of marijuana. The current practice is said to be ahead of science, as robust research has been hindered by strict regulations – and most epidemiological studies point toward harmful associations,” Dr. Stanciu said in an interview.

“Given the decreased perception of harm by the general public, women are certainly compelled to seek what they perceive as more natural self-management remedies,” he said.
 

A harmful habit

Dr. Stanciu cited a recent study conducted in Colorado in which researchers contacted cannabis dispensaries, identified themselves as being pregnant, and asked for guidance in managing pregnancy-related symptoms.

Almost 70% of dispensaries recommended products to treat symptoms, particularly in the vulnerable first trimester; 36% of them also provided reassurance of the safety profile. Very few encouraged a discussion with the physician.

“Consumption of cannabis during pregnancy results in cannabinoid placental crossing and accumulation in the fetal brain, as well as other organs, where it interferes with neurodevelopment and the endocannabinoid system,” he said.

In addition, retrospective studies have shown an association between prenatal cannabis ingestion and anemia in the mothers, low birth weight, greater risk for preterm and stillbirths, and increased need for neonatal ICU admissions.

“Children born to mothers who used cannabis during pregnancy have higher rates of impulsivity, delinquency, learning and memory impairment, as well as executive function deficits. There is also an increased association with proneness to psychosis during middle childhood,” Dr. Stanciu said.

When used during pregnancy, cannabis has been associated with increased anxiety in mothers, as well as increased risk for depressive disorders, incidence of suicidal ideations and behavior, and symptoms of mania and psychosis among those with bipolar and schizophrenia spectrum conditions. Cannabis has also been linked to coingestion of other substances and with alcohol use.

“So cannabis can pose harm, especially when used by those with affective disorders,” Dr. Stanciu said.

The study was funded by the National Institute on Drug Abuse. Dr. Richison, Dr. Marienfeld, and Dr. Stanciu have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com

Cannabis is ineffective at alleviating depression in pregnant women undergoing opioid agonist therapy (OAT), new research shows.

RyanKing999/iStock/Getty Images

A study of more than 120 pregnant women undergoing treatment of opioid use disorder (OUD) showed that those who used cannabis to alleviate their depressive symptoms while undergoing OAT continued to have high depression scores at the end of opioid treatment.

In addition, depression scores improved for those who abstained from cannabis use after their first positive screen. Interestingly, cannabis use did not affect patient retention in treatment for OUD, the investigators note.

“To our knowledge, this is the first time looking at the impact of cannabis on the specific population of pregnant women with opioid use disorder, who are very vulnerable to depression,” lead author Abigail Richison, MD, University of Arkansas for Medical Sciences, Little Rock, said in an interview.

The findings were presented at the American Academy of Addiction Psychiatry (AAAP) 31st Annual Meeting, which was held online this year because of the COVID-19 pandemic.
 

A safer alternative?

Data from the National Survey on Drug Use and Health show that perinatal cannabis use increased by 62% between 2002 and 2014. Many women try to ameliorate their depression symptoms by using cannabis in the mistaken belief that it will help their depression, the investigators noted.

In addition, many women consider cannabis safer during pregnancy than prescribed medications for improving mood, said Dr. Richison. She said that cannabis does not alleviate depression and may even worsen it.

Dr. Richison noted that at her center, which has a women’s health program that treats pregnant women with OUDs, she was seeing a lot of patients who reported using cannabis to improve their mood.

“However, it didn’t seem like it was really helping, so I started researching about cannabis and depression,” Dr. Richison said.

“I’ve always been interested in this population because they are very vulnerable to legal implications and can be accused of perinatal substance use. I think it is very important to screen for depression as well as cannabis use in this population,” she added.

To shed some light on the impact of cannabis use by pregnant patients with OUD, the investigators conducted a retrospective chart review of 121 pregnant women with OUD who attended outpatient OAT. All were prescribed buprenorphine.

At each visit, Beck Depression Inventory (BDI) scores were obtained and urine drug screens were administered. The primary outcome was BDI score. Other measures included retention, urinary drug screen results, and antidepressant use.

The women were divided into two groups. The first comprised cannabis users, defined as having more than one urine drug screen that was positive for cannabis (n = 35). The other group comprised nonusers, defined as having urine drug screens that were negative for cannabis (n = 86).

Cannabis users were a little younger (mean age, 27 years) than non–cannabis users (mean age, 29.5 years; P = .006). Most of the participants were White (80.2%). Roughly half were on Medicaid, and most of the other participants had private insurance; a small number of women had no insurance.

Results showed that cannabis users had significantly higher BDI scores than non–cannabis users (mean scores, 16 vs. 9.3; P < .001).

Cannabis use continued to be associated with elevated scores for depression when controlling for opioid misuse and antidepressant use. There were no significant differences in retention or lapse to opioid misuse between the two groups.
 

More evidence of risk

Commenting on the findings in an interview, Carla Marienfeld, MD, professor of psychiatry at the University of California, San Diego, said there is a growing body of evidence about risks from cannabis use during pregnancy, “a time where we already know the endocannabinoid system is very active in the developing fetus.”

She noted that the current study’s design makes it hard to know whether marijuana use causes worse depression.

However, “it clearly is not associated with helping to improve mood the way people who are using it believe or hope for,” said Dr. Marienfeld, who was not part of the research.

“The risk for harm in terms of worse mood for the pregnant woman or risks for harm to the developing fetus are being better understood with many new studies,” she added.

Yet as more and more states legalize medical marijuana, cannabis use during pregnancy is only going to rise, experts fear.

Cornel Stanciu, MD, of Dartmouth-Hitchcock Medical Center, Lebanon, N.H., who was asked for comment, noted that public endorsement for potential benefits of the marijuana plant is at an all-time high.

“To date, 33 states and the District of Columbia have responded by legalizing medical marijuana, with 10 states also having legalized recreational use of marijuana. The current practice is said to be ahead of science, as robust research has been hindered by strict regulations – and most epidemiological studies point toward harmful associations,” Dr. Stanciu said in an interview.

“Given the decreased perception of harm by the general public, women are certainly compelled to seek what they perceive as more natural self-management remedies,” he said.
 

A harmful habit

Dr. Stanciu cited a recent study conducted in Colorado in which researchers contacted cannabis dispensaries, identified themselves as being pregnant, and asked for guidance in managing pregnancy-related symptoms.

Almost 70% of dispensaries recommended products to treat symptoms, particularly in the vulnerable first trimester; 36% of them also provided reassurance of the safety profile. Very few encouraged a discussion with the physician.

“Consumption of cannabis during pregnancy results in cannabinoid placental crossing and accumulation in the fetal brain, as well as other organs, where it interferes with neurodevelopment and the endocannabinoid system,” he said.

In addition, retrospective studies have shown an association between prenatal cannabis ingestion and anemia in the mothers, low birth weight, greater risk for preterm and stillbirths, and increased need for neonatal ICU admissions.

“Children born to mothers who used cannabis during pregnancy have higher rates of impulsivity, delinquency, learning and memory impairment, as well as executive function deficits. There is also an increased association with proneness to psychosis during middle childhood,” Dr. Stanciu said.

When used during pregnancy, cannabis has been associated with increased anxiety in mothers, as well as increased risk for depressive disorders, incidence of suicidal ideations and behavior, and symptoms of mania and psychosis among those with bipolar and schizophrenia spectrum conditions. Cannabis has also been linked to coingestion of other substances and with alcohol use.

“So cannabis can pose harm, especially when used by those with affective disorders,” Dr. Stanciu said.

The study was funded by the National Institute on Drug Abuse. Dr. Richison, Dr. Marienfeld, and Dr. Stanciu have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The pretreatment gut microbiome can determine response to methotrexate therapy in patients with newly diagnosed rheumatoid arthritis, according to recent research published in Arthritis & Rheumatology.

About half of patients do not respond to methotrexate (MTX), despite it being a first-line therapy for RA, according to Alejandro Artacho of the Centro Superior de Investigación en Salud Pública in Valencia, Spain, and colleagues. In addition, there is currently no way to predict which patients will respond to MTX.

Dr. Veena Taneja, a researcher and associate professor in the Department of Immunology and Division of Rheumatology at the Mayo Clinic in Rochester, Minn.

The role of the microbiome in drug response for patients with RA “has been known since it was discovered in 1972 that sulfasalazine requires gut bacteria for its activity,” Veena Taneja, PhD, a researcher and associate professor of immunology at the Mayo Clinic in Rochester, Minn., said in an interview. The microbiome and how it functions “needs to be explored as biomarkers as well as for treatment options for RA and other diseases,” added Dr. Taneja, who was not involved with the study.

Using 16S rRNA gene and shotgun metagenomic sequencing, the researchers evaluated whether the gut microbiome of a patient newly diagnosed with RA (NORA) influenced their response to MTX. The researchers extracted DNA from fecal samples in 26 patients from New York University Langone Medical Center, Lutheran Hospital, Staten Island, and Mount Sinai School of Medicine rheumatology clinics 48 hours prior to treatment with MTX and determined the bacterial taxa, operational taxonomic units (OTUs), and ribosomal sequence variants in each sample. These patients then received oral MTX with an average dose of 20 mg per week (range, 15-25 mg). The patients were grouped based on whether they responded (39%) or did not respond (61%) to MTX based on improvement of at least 1.8 in their Disease Activity Score in 28 joints (DAS28) after 4 months and no need to add a biologic.

Patients with a statistically significantly lower level of microbial diversity (P < .05) as measured by OTU level tended to respond better to MTX therapy. In patients who did not respond to MTX, there was a significantly higher abundance of Firmicutes, a significantly lower abundance of Bacteroidetes (P < .05), and a higher ratio of Firmicutes to Bacteroidetes.

There was also a consistent difference between abundance of gut microbial genes in patients who did not respond to MTX. “Taken together, these results indicate that the gut microbiome of NORA patients that respond favorably to MTX is distinct from that of MTX-NR, prompting us to hypothesize that the pretreatment microbiome could be used to predict clinical nonresponse,” the researchers said.

Using machine learning, Mr. Artacho and colleagues developed a predictive model based on the initial training cohort of 26 patients to assess MTX response. When the researchers tested the model in a validation cohort of 21 patients, they found it correctly predicted 78% of MTX responders and 83.3% of patients who did not respond to MTX, with the percentage of correct predictions increasing “when considering only those patients with the highest probability score of belonging to either group.”

In a separate set of 20 patients with RA who were prescribed either different conventional synthetic disease-modifying antirheumatic drugs or biologics or had not started any medications, the researchers’ model could not predict clinical response, “suggesting that the potential clinical utility of the model is restricted to RA patients that are both drug naive and exposed directly to MTX, but not to other drugs.”

“Our results open the possibility to rationally design microbiome-modulating strategies to improve oral absorption of MTX and its downstream immune effects, inform clinical decision-making or both,” they said.

Clinical application

Dr. Taneja said the findings of the study are novel and intriguing. “The observations suggest a strong influence of [the] host’s microbiome in response to MTX and in future may inform best treatment options for patients. The study speculates that certain microbial clades or microbes can be used to derive a favorable response in patients. This could explain why “one drug fits all” does not apply in treatment for RA,” she said.

The study is also a “step forward” in using the microbiome in regular clinical practice, she noted. “Since MTX is used as a first line of treatment and is one of the most affordable treatments for RA, the observations are definitely exciting.”

In an interview, Martin Kriegel, MD, PhD, of the department of immunobiology at Yale University, New Haven, Conn., and chair of rheumatology and clinical immunology at the University of Münster (Germany), explained that the prediction model has the potential to one day be a tool for clinicians to predict MTX response in patients with RA. However, he noted the researchers did not test a functional link between MTX and gut microbes in vivo.

“It would be useful to test mechanistic effects of MTX on gut microbial communities in vitro and in vivo,” he said. “In addition, it would be informative to apply the prediction model in other cohorts of RA with a different geographic background, possibly also a different duration of disease. If confirmed in a more heterogeneous group of patients, the tool could potentially be used in the clinic to tell some patients that they might not respond to MTX and therefore start therapy with another agent.”

This study was funded by the National Institutes of Health, the Rheumatology Research Foundation, the Searle Scholars Program, various funds from the Spanish government, the UCSF Breakthrough Program for Rheumatoid Arthritis-related Research, and the Arthritis Foundation Center for Excellence. Four authors report consultancies and memberships on scientific advisory boards with pharmaceutical and biotechnology companies that do not overlap with the current study.

Dr. Taneja reported that her institution holds a patent for developing Prevotella histicola as an anti-inflammatory treatment, of which she is a coinventor. Evelo Biosciences is a licensee for the patent, and Dr. Taneja reported receiving research support from the company. Dr. Kriegel reported receiving salary, consulting fees, honoraria, or research funds from AbbVie, Bristol-Myers Squibb, Cell Applications, Eligo Bioscience, and Roche. He also holds a patent on the use of antibiotics and commensal vaccination to treat autoimmunity.

SOURCE: Artacho A et al. Arthritis Rheumatol. 2020 Dec 13. doi: 10.1002/art.41622.

The pretreatment gut microbiome can determine response to methotrexate therapy in patients with newly diagnosed rheumatoid arthritis, according to recent research published in Arthritis & Rheumatology.

About half of patients do not respond to methotrexate (MTX), despite it being a first-line therapy for RA, according to Alejandro Artacho of the Centro Superior de Investigación en Salud Pública in Valencia, Spain, and colleagues. In addition, there is currently no way to predict which patients will respond to MTX.

Dr. Veena Taneja, a researcher and associate professor in the Department of Immunology and Division of Rheumatology at the Mayo Clinic in Rochester, Minn.

The role of the microbiome in drug response for patients with RA “has been known since it was discovered in 1972 that sulfasalazine requires gut bacteria for its activity,” Veena Taneja, PhD, a researcher and associate professor of immunology at the Mayo Clinic in Rochester, Minn., said in an interview. The microbiome and how it functions “needs to be explored as biomarkers as well as for treatment options for RA and other diseases,” added Dr. Taneja, who was not involved with the study.

Using 16S rRNA gene and shotgun metagenomic sequencing, the researchers evaluated whether the gut microbiome of a patient newly diagnosed with RA (NORA) influenced their response to MTX. The researchers extracted DNA from fecal samples in 26 patients from New York University Langone Medical Center, Lutheran Hospital, Staten Island, and Mount Sinai School of Medicine rheumatology clinics 48 hours prior to treatment with MTX and determined the bacterial taxa, operational taxonomic units (OTUs), and ribosomal sequence variants in each sample. These patients then received oral MTX with an average dose of 20 mg per week (range, 15-25 mg). The patients were grouped based on whether they responded (39%) or did not respond (61%) to MTX based on improvement of at least 1.8 in their Disease Activity Score in 28 joints (DAS28) after 4 months and no need to add a biologic.

Patients with a statistically significantly lower level of microbial diversity (P < .05) as measured by OTU level tended to respond better to MTX therapy. In patients who did not respond to MTX, there was a significantly higher abundance of Firmicutes, a significantly lower abundance of Bacteroidetes (P < .05), and a higher ratio of Firmicutes to Bacteroidetes.

There was also a consistent difference between abundance of gut microbial genes in patients who did not respond to MTX. “Taken together, these results indicate that the gut microbiome of NORA patients that respond favorably to MTX is distinct from that of MTX-NR, prompting us to hypothesize that the pretreatment microbiome could be used to predict clinical nonresponse,” the researchers said.

Using machine learning, Mr. Artacho and colleagues developed a predictive model based on the initial training cohort of 26 patients to assess MTX response. When the researchers tested the model in a validation cohort of 21 patients, they found it correctly predicted 78% of MTX responders and 83.3% of patients who did not respond to MTX, with the percentage of correct predictions increasing “when considering only those patients with the highest probability score of belonging to either group.”

In a separate set of 20 patients with RA who were prescribed either different conventional synthetic disease-modifying antirheumatic drugs or biologics or had not started any medications, the researchers’ model could not predict clinical response, “suggesting that the potential clinical utility of the model is restricted to RA patients that are both drug naive and exposed directly to MTX, but not to other drugs.”

“Our results open the possibility to rationally design microbiome-modulating strategies to improve oral absorption of MTX and its downstream immune effects, inform clinical decision-making or both,” they said.

Clinical application

Dr. Taneja said the findings of the study are novel and intriguing. “The observations suggest a strong influence of [the] host’s microbiome in response to MTX and in future may inform best treatment options for patients. The study speculates that certain microbial clades or microbes can be used to derive a favorable response in patients. This could explain why “one drug fits all” does not apply in treatment for RA,” she said.

The study is also a “step forward” in using the microbiome in regular clinical practice, she noted. “Since MTX is used as a first line of treatment and is one of the most affordable treatments for RA, the observations are definitely exciting.”

In an interview, Martin Kriegel, MD, PhD, of the department of immunobiology at Yale University, New Haven, Conn., and chair of rheumatology and clinical immunology at the University of Münster (Germany), explained that the prediction model has the potential to one day be a tool for clinicians to predict MTX response in patients with RA. However, he noted the researchers did not test a functional link between MTX and gut microbes in vivo.

“It would be useful to test mechanistic effects of MTX on gut microbial communities in vitro and in vivo,” he said. “In addition, it would be informative to apply the prediction model in other cohorts of RA with a different geographic background, possibly also a different duration of disease. If confirmed in a more heterogeneous group of patients, the tool could potentially be used in the clinic to tell some patients that they might not respond to MTX and therefore start therapy with another agent.”

This study was funded by the National Institutes of Health, the Rheumatology Research Foundation, the Searle Scholars Program, various funds from the Spanish government, the UCSF Breakthrough Program for Rheumatoid Arthritis-related Research, and the Arthritis Foundation Center for Excellence. Four authors report consultancies and memberships on scientific advisory boards with pharmaceutical and biotechnology companies that do not overlap with the current study.

Dr. Taneja reported that her institution holds a patent for developing Prevotella histicola as an anti-inflammatory treatment, of which she is a coinventor. Evelo Biosciences is a licensee for the patent, and Dr. Taneja reported receiving research support from the company. Dr. Kriegel reported receiving salary, consulting fees, honoraria, or research funds from AbbVie, Bristol-Myers Squibb, Cell Applications, Eligo Bioscience, and Roche. He also holds a patent on the use of antibiotics and commensal vaccination to treat autoimmunity.

SOURCE: Artacho A et al. Arthritis Rheumatol. 2020 Dec 13. doi: 10.1002/art.41622.

The pretreatment gut microbiome can determine response to methotrexate therapy in patients with newly diagnosed rheumatoid arthritis, according to recent research published in Arthritis & Rheumatology.

About half of patients do not respond to methotrexate (MTX), despite it being a first-line therapy for RA, according to Alejandro Artacho of the Centro Superior de Investigación en Salud Pública in Valencia, Spain, and colleagues. In addition, there is currently no way to predict which patients will respond to MTX.

Dr. Veena Taneja, a researcher and associate professor in the Department of Immunology and Division of Rheumatology at the Mayo Clinic in Rochester, Minn.

The role of the microbiome in drug response for patients with RA “has been known since it was discovered in 1972 that sulfasalazine requires gut bacteria for its activity,” Veena Taneja, PhD, a researcher and associate professor of immunology at the Mayo Clinic in Rochester, Minn., said in an interview. The microbiome and how it functions “needs to be explored as biomarkers as well as for treatment options for RA and other diseases,” added Dr. Taneja, who was not involved with the study.

Using 16S rRNA gene and shotgun metagenomic sequencing, the researchers evaluated whether the gut microbiome of a patient newly diagnosed with RA (NORA) influenced their response to MTX. The researchers extracted DNA from fecal samples in 26 patients from New York University Langone Medical Center, Lutheran Hospital, Staten Island, and Mount Sinai School of Medicine rheumatology clinics 48 hours prior to treatment with MTX and determined the bacterial taxa, operational taxonomic units (OTUs), and ribosomal sequence variants in each sample. These patients then received oral MTX with an average dose of 20 mg per week (range, 15-25 mg). The patients were grouped based on whether they responded (39%) or did not respond (61%) to MTX based on improvement of at least 1.8 in their Disease Activity Score in 28 joints (DAS28) after 4 months and no need to add a biologic.

Patients with a statistically significantly lower level of microbial diversity (P < .05) as measured by OTU level tended to respond better to MTX therapy. In patients who did not respond to MTX, there was a significantly higher abundance of Firmicutes, a significantly lower abundance of Bacteroidetes (P < .05), and a higher ratio of Firmicutes to Bacteroidetes.

There was also a consistent difference between abundance of gut microbial genes in patients who did not respond to MTX. “Taken together, these results indicate that the gut microbiome of NORA patients that respond favorably to MTX is distinct from that of MTX-NR, prompting us to hypothesize that the pretreatment microbiome could be used to predict clinical nonresponse,” the researchers said.

Using machine learning, Mr. Artacho and colleagues developed a predictive model based on the initial training cohort of 26 patients to assess MTX response. When the researchers tested the model in a validation cohort of 21 patients, they found it correctly predicted 78% of MTX responders and 83.3% of patients who did not respond to MTX, with the percentage of correct predictions increasing “when considering only those patients with the highest probability score of belonging to either group.”

In a separate set of 20 patients with RA who were prescribed either different conventional synthetic disease-modifying antirheumatic drugs or biologics or had not started any medications, the researchers’ model could not predict clinical response, “suggesting that the potential clinical utility of the model is restricted to RA patients that are both drug naive and exposed directly to MTX, but not to other drugs.”

“Our results open the possibility to rationally design microbiome-modulating strategies to improve oral absorption of MTX and its downstream immune effects, inform clinical decision-making or both,” they said.

Clinical application

Dr. Taneja said the findings of the study are novel and intriguing. “The observations suggest a strong influence of [the] host’s microbiome in response to MTX and in future may inform best treatment options for patients. The study speculates that certain microbial clades or microbes can be used to derive a favorable response in patients. This could explain why “one drug fits all” does not apply in treatment for RA,” she said.

The study is also a “step forward” in using the microbiome in regular clinical practice, she noted. “Since MTX is used as a first line of treatment and is one of the most affordable treatments for RA, the observations are definitely exciting.”

In an interview, Martin Kriegel, MD, PhD, of the department of immunobiology at Yale University, New Haven, Conn., and chair of rheumatology and clinical immunology at the University of Münster (Germany), explained that the prediction model has the potential to one day be a tool for clinicians to predict MTX response in patients with RA. However, he noted the researchers did not test a functional link between MTX and gut microbes in vivo.

“It would be useful to test mechanistic effects of MTX on gut microbial communities in vitro and in vivo,” he said. “In addition, it would be informative to apply the prediction model in other cohorts of RA with a different geographic background, possibly also a different duration of disease. If confirmed in a more heterogeneous group of patients, the tool could potentially be used in the clinic to tell some patients that they might not respond to MTX and therefore start therapy with another agent.”

This study was funded by the National Institutes of Health, the Rheumatology Research Foundation, the Searle Scholars Program, various funds from the Spanish government, the UCSF Breakthrough Program for Rheumatoid Arthritis-related Research, and the Arthritis Foundation Center for Excellence. Four authors report consultancies and memberships on scientific advisory boards with pharmaceutical and biotechnology companies that do not overlap with the current study.

Dr. Taneja reported that her institution holds a patent for developing Prevotella histicola as an anti-inflammatory treatment, of which she is a coinventor. Evelo Biosciences is a licensee for the patent, and Dr. Taneja reported receiving research support from the company. Dr. Kriegel reported receiving salary, consulting fees, honoraria, or research funds from AbbVie, Bristol-Myers Squibb, Cell Applications, Eligo Bioscience, and Roche. He also holds a patent on the use of antibiotics and commensal vaccination to treat autoimmunity.

SOURCE: Artacho A et al. Arthritis Rheumatol. 2020 Dec 13. doi: 10.1002/art.41622.

Sleep medications for older patients who report sleep problems may not be the best treatment given growing evidence of the link between these medications and the risk of incident dementia.

Adults aged 65 years and older who used sleep medications 5-7 days a week demonstrated a 30% increased risk of dementia, compared with those who did not use sleep medications, findings from a prospective study of 6,373 individuals show.

Adults aged 65 and older report a higher burden of sleep problems than other age groups, but major medical associations discourage the use of sleep medications by older adults because of growing evidence of a link between sleep medication use and cognitive decline, wrote Rebecca Robbins, MD, of Brigham and Women’s Hospital, Boston, and colleagues. However, data on this association among adults in the United States are limited, they said.

In a study published in Sleep Medicine, the researchers surveyed 6,373 adults aged 65 years and older who were enrolled in the nationally representative National Health and Aging Trends Study (NHATS). The majority of the participants were non-Hispanic White (71%), 59% were women, and 21% ranged in age from 70 to 74 years.

Participants responded to questions about routine sleep medication use. Routine was defined as “most nights” or “every night.” The data were collected for an 8-year period from 2011 to 2018. The study began in 2011, with a core interview administered annually.

Approximately 15% of the study population reported routine use of sleep medications. Overall, routine use of sleep medication was significantly associated with risk of incident dementia (hazard ratio, 1.30; P < .01) after controlling for multiple variables including age, sex, education level, and chronic conditions.

Dementia screening was conducted by participants rating their memory and then performing a memory-related activity (immediate and delayed 10-word recall) and other exercises to assess executive function and orientation. A separate eight-item informant screener was performed for patient proxies. The researcher noted, “Sensitivity of the NHATS probable dementia screening measure has been determined in previous research to be 66%, and specificity is 87%, with respect to a clinical dementia diagnosis.”

The study findings were limited by several factors including the use of self-reports, the lack of data on type or dose of sleep medication, and lack of data on the indication for the prescription, the researchers noted.

“Also, sleep medication use leads to worse performance on cognitive testing, such as the questionnaires used to screen for dementia in this study, and therefore could have resulted in a false diagnosis of dementia,” they added.

However, the results were strengthened by the large, nationally representative study population and support the need for quality geriatric care, the researchers said.

“Our findings provide further support and evidence that sleep medications are all too commonly administered, yet associated with greater risk for incident dementia, and that the U.S. health care system is in need of creative solutions for addressing poor sleep among older individuals,” they concluded.
 

Implications and alternatives

The study is important as the number of aging Americans increases, said Carolyn M. D’Ambrosio, MD, FCCP, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in an interview. “In the elderly, inability to fall asleep or stay asleep are common issues that are brought to a health care provider,” she said. Dr. D’Ambrosio said she was not surprised by the study findings “as elderly patients often have sleep issues and sometimes a well-meaning health care provider gives them sleep medication to help. We have known that some of these sleep medications such as benzodiazepines affect cognitive performance,” she said.

Dr. D’Ambrosio said she avoids prescribing sleep medications for older adults if possible. “A deep dive into sleep habits, environment, and other things that disrupt sleep often gets to the problem rather than just masking it with a sleep medication,” she noted. Alternatives to improve sleep in older adults include exercise, exposure to bright light during the day, and good healthy sleep habits, all of which contribute to improved sleep in the elderly, said Dr. D’Ambrosio. She also recommends screening older adults for other issues that affect sleep, such as chronic pain.

The current study highlighted the association between sleep medication use and dementia, but it does not show causation, Dr. D’Ambrosio said. “So much more needs to be done to determine whether the sleep medications are causing worsening cognitive function long term, or if the dementia is starting but not yet diagnosed and the sleep medication is given but not the cause of the dementia, she noted.
 

Research gaps and treatment strategies

Older adults experiencing sleep difficulties may try various medications including pharmacologics (e.g., benzodiazepines), over-the-counter agents, such as diphenhydramine or doxylamine preparations, and/or herbal and nutritional supplements such as valerian or melatonin, said Mary Jo S. Farmer, MD, FCCP, of the University of Massachusetts Medical School–Baystate, Springfield, in an interview. “However, sleep medications, particularly benzodiazepines, are strongly discouraged by major medical associations including the American Geriatrics Society in part because of the growing evidence that use of sleep medications is associated with cognitive impairment and decline,” she said.

The current study results contribute to previous work demonstrating that both pharmacologic and nonpharmacologic sleep medication, although commonly administered, is associated with subsequent adverse outcomes in older adults, Dr. Farmer said. This association sets the stage for creative and different solutions for addressing poor sleep among older adults, such as behavioral treatments including cognitive-behavioral therapy, she noted.

Dr. Farmer said, “Areas for future research include exploring the causal link between prescription and/or over-the-counter sleep medication use and incident dementia in a randomized controlled trial,” she added.

“Another interesting opportunity for future research is to explore the indications for sleep medications among older adults since it has been shown in the general population that sleep difficulties represent only 12% of the indication for sleep medication prescriptions,” Dr. Farmer noted. “Future research could examine the strength of the underlying motivation to use sleep medication even in light of suggested long-term effects, and the effectiveness of other measures to avoid or minimize sleep difficulties,” she said.

“My experience is that the majority of ambulatory patients recently seen in sleep clinic want to avoid long-term use of sleep medications and will ask what other measures can be tried to consistently achieve a good night’s sleep without medication use,” Dr. Farmer said. “If medications are used, patients would rather try melatonin than a benzodiazepine. Many patients who come to sleep clinic with sleep medications already prescribed and are subsequently found to have sleep apnea and/or restless legs find that they no longer need sleep medication when these other medical conditions are appropriately diagnosed and managed,” she explained. “Finally, many patients tell me they feel less energetic upon awakening, almost feel hung over, and express being less sharp cognitively when taking pharmacologic sleep medication, whether for short or long periods of time, and therefore they want to avoid continuing with sleep medication use,” she said.

Dr. Farmer’s strategy for developing alternatives to sleep medications in older adults includes taking a careful history, including a complete list of medical problems, review of medications, and a thorough sleep history including usual time of sleep onset, awake time, and the frequency of daytime naps. “Tips for improving the quality of nighttime sleep may include adequately treating pain and other medical conditions such as heartburn, sleep apnea, and restless legs, creating a soothing environment to promote sleep by eliminating noise and bright lights, avoiding stimulant medications and substances such as caffeine and nicotine before bedtime, avoiding excessive amounts of alcohol, avoiding diuretics before bedtime, encouraging physical activity during the day, spending time in the sunlight as much as possible to help regulate the sleep cycle, limiting daytime naps, and establishing a regular sleep schedule,” she said.

The study was supported by National Institutes of Health awards K01HL150339, U54MD000538, K07AG052685, R01AG056531, R01AG056031. Lead author Dr. Robbins had no financial conflicts to disclose. Dr. D’Ambrosio disclosed serving as a section editor for sleep medicine for Dynamed and owning a patent on a circadian programming device. Dr. Farmer had no disclosures.

SOURCE: Robbins R et al. Sleep Med. 2020 Nov 11. doi: 10.1016/j.sleep.2020.11.004.

Sleep medications for older patients who report sleep problems may not be the best treatment given growing evidence of the link between these medications and the risk of incident dementia.

Adults aged 65 years and older who used sleep medications 5-7 days a week demonstrated a 30% increased risk of dementia, compared with those who did not use sleep medications, findings from a prospective study of 6,373 individuals show.

Adults aged 65 and older report a higher burden of sleep problems than other age groups, but major medical associations discourage the use of sleep medications by older adults because of growing evidence of a link between sleep medication use and cognitive decline, wrote Rebecca Robbins, MD, of Brigham and Women’s Hospital, Boston, and colleagues. However, data on this association among adults in the United States are limited, they said.

In a study published in Sleep Medicine, the researchers surveyed 6,373 adults aged 65 years and older who were enrolled in the nationally representative National Health and Aging Trends Study (NHATS). The majority of the participants were non-Hispanic White (71%), 59% were women, and 21% ranged in age from 70 to 74 years.

Participants responded to questions about routine sleep medication use. Routine was defined as “most nights” or “every night.” The data were collected for an 8-year period from 2011 to 2018. The study began in 2011, with a core interview administered annually.

Approximately 15% of the study population reported routine use of sleep medications. Overall, routine use of sleep medication was significantly associated with risk of incident dementia (hazard ratio, 1.30; P < .01) after controlling for multiple variables including age, sex, education level, and chronic conditions.

Dementia screening was conducted by participants rating their memory and then performing a memory-related activity (immediate and delayed 10-word recall) and other exercises to assess executive function and orientation. A separate eight-item informant screener was performed for patient proxies. The researcher noted, “Sensitivity of the NHATS probable dementia screening measure has been determined in previous research to be 66%, and specificity is 87%, with respect to a clinical dementia diagnosis.”

The study findings were limited by several factors including the use of self-reports, the lack of data on type or dose of sleep medication, and lack of data on the indication for the prescription, the researchers noted.

“Also, sleep medication use leads to worse performance on cognitive testing, such as the questionnaires used to screen for dementia in this study, and therefore could have resulted in a false diagnosis of dementia,” they added.

However, the results were strengthened by the large, nationally representative study population and support the need for quality geriatric care, the researchers said.

“Our findings provide further support and evidence that sleep medications are all too commonly administered, yet associated with greater risk for incident dementia, and that the U.S. health care system is in need of creative solutions for addressing poor sleep among older individuals,” they concluded.
 

Implications and alternatives

The study is important as the number of aging Americans increases, said Carolyn M. D’Ambrosio, MD, FCCP, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in an interview. “In the elderly, inability to fall asleep or stay asleep are common issues that are brought to a health care provider,” she said. Dr. D’Ambrosio said she was not surprised by the study findings “as elderly patients often have sleep issues and sometimes a well-meaning health care provider gives them sleep medication to help. We have known that some of these sleep medications such as benzodiazepines affect cognitive performance,” she said.

Dr. D’Ambrosio said she avoids prescribing sleep medications for older adults if possible. “A deep dive into sleep habits, environment, and other things that disrupt sleep often gets to the problem rather than just masking it with a sleep medication,” she noted. Alternatives to improve sleep in older adults include exercise, exposure to bright light during the day, and good healthy sleep habits, all of which contribute to improved sleep in the elderly, said Dr. D’Ambrosio. She also recommends screening older adults for other issues that affect sleep, such as chronic pain.

The current study highlighted the association between sleep medication use and dementia, but it does not show causation, Dr. D’Ambrosio said. “So much more needs to be done to determine whether the sleep medications are causing worsening cognitive function long term, or if the dementia is starting but not yet diagnosed and the sleep medication is given but not the cause of the dementia, she noted.
 

Research gaps and treatment strategies

Older adults experiencing sleep difficulties may try various medications including pharmacologics (e.g., benzodiazepines), over-the-counter agents, such as diphenhydramine or doxylamine preparations, and/or herbal and nutritional supplements such as valerian or melatonin, said Mary Jo S. Farmer, MD, FCCP, of the University of Massachusetts Medical School–Baystate, Springfield, in an interview. “However, sleep medications, particularly benzodiazepines, are strongly discouraged by major medical associations including the American Geriatrics Society in part because of the growing evidence that use of sleep medications is associated with cognitive impairment and decline,” she said.

The current study results contribute to previous work demonstrating that both pharmacologic and nonpharmacologic sleep medication, although commonly administered, is associated with subsequent adverse outcomes in older adults, Dr. Farmer said. This association sets the stage for creative and different solutions for addressing poor sleep among older adults, such as behavioral treatments including cognitive-behavioral therapy, she noted.

Dr. Farmer said, “Areas for future research include exploring the causal link between prescription and/or over-the-counter sleep medication use and incident dementia in a randomized controlled trial,” she added.

“Another interesting opportunity for future research is to explore the indications for sleep medications among older adults since it has been shown in the general population that sleep difficulties represent only 12% of the indication for sleep medication prescriptions,” Dr. Farmer noted. “Future research could examine the strength of the underlying motivation to use sleep medication even in light of suggested long-term effects, and the effectiveness of other measures to avoid or minimize sleep difficulties,” she said.

“My experience is that the majority of ambulatory patients recently seen in sleep clinic want to avoid long-term use of sleep medications and will ask what other measures can be tried to consistently achieve a good night’s sleep without medication use,” Dr. Farmer said. “If medications are used, patients would rather try melatonin than a benzodiazepine. Many patients who come to sleep clinic with sleep medications already prescribed and are subsequently found to have sleep apnea and/or restless legs find that they no longer need sleep medication when these other medical conditions are appropriately diagnosed and managed,” she explained. “Finally, many patients tell me they feel less energetic upon awakening, almost feel hung over, and express being less sharp cognitively when taking pharmacologic sleep medication, whether for short or long periods of time, and therefore they want to avoid continuing with sleep medication use,” she said.

Dr. Farmer’s strategy for developing alternatives to sleep medications in older adults includes taking a careful history, including a complete list of medical problems, review of medications, and a thorough sleep history including usual time of sleep onset, awake time, and the frequency of daytime naps. “Tips for improving the quality of nighttime sleep may include adequately treating pain and other medical conditions such as heartburn, sleep apnea, and restless legs, creating a soothing environment to promote sleep by eliminating noise and bright lights, avoiding stimulant medications and substances such as caffeine and nicotine before bedtime, avoiding excessive amounts of alcohol, avoiding diuretics before bedtime, encouraging physical activity during the day, spending time in the sunlight as much as possible to help regulate the sleep cycle, limiting daytime naps, and establishing a regular sleep schedule,” she said.

The study was supported by National Institutes of Health awards K01HL150339, U54MD000538, K07AG052685, R01AG056531, R01AG056031. Lead author Dr. Robbins had no financial conflicts to disclose. Dr. D’Ambrosio disclosed serving as a section editor for sleep medicine for Dynamed and owning a patent on a circadian programming device. Dr. Farmer had no disclosures.

SOURCE: Robbins R et al. Sleep Med. 2020 Nov 11. doi: 10.1016/j.sleep.2020.11.004.

Sleep medications for older patients who report sleep problems may not be the best treatment given growing evidence of the link between these medications and the risk of incident dementia.

Adults aged 65 years and older who used sleep medications 5-7 days a week demonstrated a 30% increased risk of dementia, compared with those who did not use sleep medications, findings from a prospective study of 6,373 individuals show.

Adults aged 65 and older report a higher burden of sleep problems than other age groups, but major medical associations discourage the use of sleep medications by older adults because of growing evidence of a link between sleep medication use and cognitive decline, wrote Rebecca Robbins, MD, of Brigham and Women’s Hospital, Boston, and colleagues. However, data on this association among adults in the United States are limited, they said.

In a study published in Sleep Medicine, the researchers surveyed 6,373 adults aged 65 years and older who were enrolled in the nationally representative National Health and Aging Trends Study (NHATS). The majority of the participants were non-Hispanic White (71%), 59% were women, and 21% ranged in age from 70 to 74 years.

Participants responded to questions about routine sleep medication use. Routine was defined as “most nights” or “every night.” The data were collected for an 8-year period from 2011 to 2018. The study began in 2011, with a core interview administered annually.

Approximately 15% of the study population reported routine use of sleep medications. Overall, routine use of sleep medication was significantly associated with risk of incident dementia (hazard ratio, 1.30; P < .01) after controlling for multiple variables including age, sex, education level, and chronic conditions.

Dementia screening was conducted by participants rating their memory and then performing a memory-related activity (immediate and delayed 10-word recall) and other exercises to assess executive function and orientation. A separate eight-item informant screener was performed for patient proxies. The researcher noted, “Sensitivity of the NHATS probable dementia screening measure has been determined in previous research to be 66%, and specificity is 87%, with respect to a clinical dementia diagnosis.”

The study findings were limited by several factors including the use of self-reports, the lack of data on type or dose of sleep medication, and lack of data on the indication for the prescription, the researchers noted.

“Also, sleep medication use leads to worse performance on cognitive testing, such as the questionnaires used to screen for dementia in this study, and therefore could have resulted in a false diagnosis of dementia,” they added.

However, the results were strengthened by the large, nationally representative study population and support the need for quality geriatric care, the researchers said.

“Our findings provide further support and evidence that sleep medications are all too commonly administered, yet associated with greater risk for incident dementia, and that the U.S. health care system is in need of creative solutions for addressing poor sleep among older individuals,” they concluded.
 

Implications and alternatives

The study is important as the number of aging Americans increases, said Carolyn M. D’Ambrosio, MD, FCCP, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in an interview. “In the elderly, inability to fall asleep or stay asleep are common issues that are brought to a health care provider,” she said. Dr. D’Ambrosio said she was not surprised by the study findings “as elderly patients often have sleep issues and sometimes a well-meaning health care provider gives them sleep medication to help. We have known that some of these sleep medications such as benzodiazepines affect cognitive performance,” she said.

Dr. D’Ambrosio said she avoids prescribing sleep medications for older adults if possible. “A deep dive into sleep habits, environment, and other things that disrupt sleep often gets to the problem rather than just masking it with a sleep medication,” she noted. Alternatives to improve sleep in older adults include exercise, exposure to bright light during the day, and good healthy sleep habits, all of which contribute to improved sleep in the elderly, said Dr. D’Ambrosio. She also recommends screening older adults for other issues that affect sleep, such as chronic pain.

The current study highlighted the association between sleep medication use and dementia, but it does not show causation, Dr. D’Ambrosio said. “So much more needs to be done to determine whether the sleep medications are causing worsening cognitive function long term, or if the dementia is starting but not yet diagnosed and the sleep medication is given but not the cause of the dementia, she noted.
 

Research gaps and treatment strategies

Older adults experiencing sleep difficulties may try various medications including pharmacologics (e.g., benzodiazepines), over-the-counter agents, such as diphenhydramine or doxylamine preparations, and/or herbal and nutritional supplements such as valerian or melatonin, said Mary Jo S. Farmer, MD, FCCP, of the University of Massachusetts Medical School–Baystate, Springfield, in an interview. “However, sleep medications, particularly benzodiazepines, are strongly discouraged by major medical associations including the American Geriatrics Society in part because of the growing evidence that use of sleep medications is associated with cognitive impairment and decline,” she said.

The current study results contribute to previous work demonstrating that both pharmacologic and nonpharmacologic sleep medication, although commonly administered, is associated with subsequent adverse outcomes in older adults, Dr. Farmer said. This association sets the stage for creative and different solutions for addressing poor sleep among older adults, such as behavioral treatments including cognitive-behavioral therapy, she noted.

Dr. Farmer said, “Areas for future research include exploring the causal link between prescription and/or over-the-counter sleep medication use and incident dementia in a randomized controlled trial,” she added.

“Another interesting opportunity for future research is to explore the indications for sleep medications among older adults since it has been shown in the general population that sleep difficulties represent only 12% of the indication for sleep medication prescriptions,” Dr. Farmer noted. “Future research could examine the strength of the underlying motivation to use sleep medication even in light of suggested long-term effects, and the effectiveness of other measures to avoid or minimize sleep difficulties,” she said.

“My experience is that the majority of ambulatory patients recently seen in sleep clinic want to avoid long-term use of sleep medications and will ask what other measures can be tried to consistently achieve a good night’s sleep without medication use,” Dr. Farmer said. “If medications are used, patients would rather try melatonin than a benzodiazepine. Many patients who come to sleep clinic with sleep medications already prescribed and are subsequently found to have sleep apnea and/or restless legs find that they no longer need sleep medication when these other medical conditions are appropriately diagnosed and managed,” she explained. “Finally, many patients tell me they feel less energetic upon awakening, almost feel hung over, and express being less sharp cognitively when taking pharmacologic sleep medication, whether for short or long periods of time, and therefore they want to avoid continuing with sleep medication use,” she said.

Dr. Farmer’s strategy for developing alternatives to sleep medications in older adults includes taking a careful history, including a complete list of medical problems, review of medications, and a thorough sleep history including usual time of sleep onset, awake time, and the frequency of daytime naps. “Tips for improving the quality of nighttime sleep may include adequately treating pain and other medical conditions such as heartburn, sleep apnea, and restless legs, creating a soothing environment to promote sleep by eliminating noise and bright lights, avoiding stimulant medications and substances such as caffeine and nicotine before bedtime, avoiding excessive amounts of alcohol, avoiding diuretics before bedtime, encouraging physical activity during the day, spending time in the sunlight as much as possible to help regulate the sleep cycle, limiting daytime naps, and establishing a regular sleep schedule,” she said.

The study was supported by National Institutes of Health awards K01HL150339, U54MD000538, K07AG052685, R01AG056531, R01AG056031. Lead author Dr. Robbins had no financial conflicts to disclose. Dr. D’Ambrosio disclosed serving as a section editor for sleep medicine for Dynamed and owning a patent on a circadian programming device. Dr. Farmer had no disclosures.

SOURCE: Robbins R et al. Sleep Med. 2020 Nov 11. doi: 10.1016/j.sleep.2020.11.004.

Rheumatoid arthritis patients who are on both oral glucocorticoids (CGs) and proton pump inhibitors (PPIs) have an increased risk of osteoporotic fractures, according to a retrospective study of RA patients in the United Kingdom.

“Considering the increasing life expectancies and high consumption of PPIs among elderly patients, fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs,” wrote Shahab Abtahi, MD, of Maastricht (Netherlands) University Medical Centre and colleagues. The study was published in Annals of the Rheumatic Diseases.

To determine if concomitant use of the two medications – both already associated with osteoporotic fractures – would lead to a notable increase in fracture risk, the researchers conducted a population-based cohort study of RA patients aged 50 years or older who were diagnosed during 1997-2017. Patient data was gathered via the Clinical Practice Research Datalink, a primary care database of millions of U.K. medical records.

Patients with a recent history of GC/PPI use or those with a previous osteoporotic fracture were excluded from the study. Osteoporotic fractures were defined as fractures of the hip, vertebrae, humerus, forearm, pelvis, or rib. The study population included 12,351 patients, roughly two-thirds of whom were women, with a mean age of 68 years. Of the population, 4,254 patients were concomitant users of oral GCs and PPIs, compared with 3,138 patients who were not on either medication.

Among all patients, 1,411 osteoporotic fractures occurred, 264 of which occurred in the concomitant users group. After adjustments for age and sex, patients on both medications had a higher risk of fracture (adjusted hazard ratio, 1.93; 95% confidence interval, 1.65-2.27), compared to patients on oral GCs alone (aHR, 1.34; 95% CI, 1.12-1.59) or PPIs alone (aHR, 1.32; 95% CI, 1.14-1.54). After full adjustment, concomitant users again had a higher risk of fracture (aHR, 1.60; 95% CI, 1.35-1.89).

Regarding specific types of breaks, the concomitant users had a notably higher risk of hip (aHR, 1.45; 95% CI, 1.11-1.91), vertebrae (aHR, 2.84; 95% CI, 1.87-4.32), pelvis (aHR, 2.47; 95% CI, 1.41-4.34), and rib fractures (aHR, 4.03; 95% CI, 2.13-7.63). No increased risk was found for either humerus or forearm fractures. The risk of fracture did not rise for concomitant users who had either increasing daily doses of PPI or a longer duration of use.

The authors noted their study’s potential limitations, including having access to data on prescriptions only, not the actual use of medication, and a lack of information in the medical records regarding biologic therapies or certain indicators of RA disease activity. In addition, there was a likelihood that some patients who were improving might have stopped taking the drugs and lessened their risk of fracture, though the researchers attempted to account for this by “adjusting our analyses for six indicators of RA severity, including analgesics and csDMARDs.”

Two of the authors reported receiving research grants and speakers’ fees from various pharmaceutical companies. The others reported no conflicts of interest.

SOURCE: Abtahi S et al. Ann Rheum Dis. 2020 Dec 11. doi: 10.1136/annrheumdis-2020-218758.

Rheumatoid arthritis patients who are on both oral glucocorticoids (CGs) and proton pump inhibitors (PPIs) have an increased risk of osteoporotic fractures, according to a retrospective study of RA patients in the United Kingdom.

“Considering the increasing life expectancies and high consumption of PPIs among elderly patients, fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs,” wrote Shahab Abtahi, MD, of Maastricht (Netherlands) University Medical Centre and colleagues. The study was published in Annals of the Rheumatic Diseases.

To determine if concomitant use of the two medications – both already associated with osteoporotic fractures – would lead to a notable increase in fracture risk, the researchers conducted a population-based cohort study of RA patients aged 50 years or older who were diagnosed during 1997-2017. Patient data was gathered via the Clinical Practice Research Datalink, a primary care database of millions of U.K. medical records.

Patients with a recent history of GC/PPI use or those with a previous osteoporotic fracture were excluded from the study. Osteoporotic fractures were defined as fractures of the hip, vertebrae, humerus, forearm, pelvis, or rib. The study population included 12,351 patients, roughly two-thirds of whom were women, with a mean age of 68 years. Of the population, 4,254 patients were concomitant users of oral GCs and PPIs, compared with 3,138 patients who were not on either medication.

Among all patients, 1,411 osteoporotic fractures occurred, 264 of which occurred in the concomitant users group. After adjustments for age and sex, patients on both medications had a higher risk of fracture (adjusted hazard ratio, 1.93; 95% confidence interval, 1.65-2.27), compared to patients on oral GCs alone (aHR, 1.34; 95% CI, 1.12-1.59) or PPIs alone (aHR, 1.32; 95% CI, 1.14-1.54). After full adjustment, concomitant users again had a higher risk of fracture (aHR, 1.60; 95% CI, 1.35-1.89).

Regarding specific types of breaks, the concomitant users had a notably higher risk of hip (aHR, 1.45; 95% CI, 1.11-1.91), vertebrae (aHR, 2.84; 95% CI, 1.87-4.32), pelvis (aHR, 2.47; 95% CI, 1.41-4.34), and rib fractures (aHR, 4.03; 95% CI, 2.13-7.63). No increased risk was found for either humerus or forearm fractures. The risk of fracture did not rise for concomitant users who had either increasing daily doses of PPI or a longer duration of use.

The authors noted their study’s potential limitations, including having access to data on prescriptions only, not the actual use of medication, and a lack of information in the medical records regarding biologic therapies or certain indicators of RA disease activity. In addition, there was a likelihood that some patients who were improving might have stopped taking the drugs and lessened their risk of fracture, though the researchers attempted to account for this by “adjusting our analyses for six indicators of RA severity, including analgesics and csDMARDs.”

Two of the authors reported receiving research grants and speakers’ fees from various pharmaceutical companies. The others reported no conflicts of interest.

SOURCE: Abtahi S et al. Ann Rheum Dis. 2020 Dec 11. doi: 10.1136/annrheumdis-2020-218758.

Rheumatoid arthritis patients who are on both oral glucocorticoids (CGs) and proton pump inhibitors (PPIs) have an increased risk of osteoporotic fractures, according to a retrospective study of RA patients in the United Kingdom.

“Considering the increasing life expectancies and high consumption of PPIs among elderly patients, fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs,” wrote Shahab Abtahi, MD, of Maastricht (Netherlands) University Medical Centre and colleagues. The study was published in Annals of the Rheumatic Diseases.

To determine if concomitant use of the two medications – both already associated with osteoporotic fractures – would lead to a notable increase in fracture risk, the researchers conducted a population-based cohort study of RA patients aged 50 years or older who were diagnosed during 1997-2017. Patient data was gathered via the Clinical Practice Research Datalink, a primary care database of millions of U.K. medical records.

Patients with a recent history of GC/PPI use or those with a previous osteoporotic fracture were excluded from the study. Osteoporotic fractures were defined as fractures of the hip, vertebrae, humerus, forearm, pelvis, or rib. The study population included 12,351 patients, roughly two-thirds of whom were women, with a mean age of 68 years. Of the population, 4,254 patients were concomitant users of oral GCs and PPIs, compared with 3,138 patients who were not on either medication.

Among all patients, 1,411 osteoporotic fractures occurred, 264 of which occurred in the concomitant users group. After adjustments for age and sex, patients on both medications had a higher risk of fracture (adjusted hazard ratio, 1.93; 95% confidence interval, 1.65-2.27), compared to patients on oral GCs alone (aHR, 1.34; 95% CI, 1.12-1.59) or PPIs alone (aHR, 1.32; 95% CI, 1.14-1.54). After full adjustment, concomitant users again had a higher risk of fracture (aHR, 1.60; 95% CI, 1.35-1.89).

Regarding specific types of breaks, the concomitant users had a notably higher risk of hip (aHR, 1.45; 95% CI, 1.11-1.91), vertebrae (aHR, 2.84; 95% CI, 1.87-4.32), pelvis (aHR, 2.47; 95% CI, 1.41-4.34), and rib fractures (aHR, 4.03; 95% CI, 2.13-7.63). No increased risk was found for either humerus or forearm fractures. The risk of fracture did not rise for concomitant users who had either increasing daily doses of PPI or a longer duration of use.

The authors noted their study’s potential limitations, including having access to data on prescriptions only, not the actual use of medication, and a lack of information in the medical records regarding biologic therapies or certain indicators of RA disease activity. In addition, there was a likelihood that some patients who were improving might have stopped taking the drugs and lessened their risk of fracture, though the researchers attempted to account for this by “adjusting our analyses for six indicators of RA severity, including analgesics and csDMARDs.”

Two of the authors reported receiving research grants and speakers’ fees from various pharmaceutical companies. The others reported no conflicts of interest.

SOURCE: Abtahi S et al. Ann Rheum Dis. 2020 Dec 11. doi: 10.1136/annrheumdis-2020-218758.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.

Among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in the minimal residual disease (MRD) cohort of the phase 2 CAPTIVATE trial, a 1-year disease-free survival (DFS) rate of 95% in those randomized to placebo after 12 cycles of combined ibrutinib plus venetoclax supports a fixed-duration treatment approach, according to William G. Wierda, MD, PhD, University of Texas, MD Anderson Cancer Center, Houston.

Ibrutinib, a once-daily Bruton kinase inhibitor, is the only targeted therapy for first-line treatment of CLL that has demonstrated significant overall survival benefit in randomized phase 3 studies, Dr. Wierda said at the American Society of Hematology annual meeting, held virtually.

Ibrutinib and venetoclax have synergistic and complementary antitumor activity, he noted, through mobilizing and clearing CLL cells from protective niches and disease compartments beyond blood and bone marrow.

Fixed-duration study

CAPTIVATE (PCYC-1142), an international phase 2 study, evaluated first-line treatment with 12 cycles of the ibrutinib/venetoclax combination in MRD and fixed-duration cohorts. The current primary analysis of 1-year DFS from the MRD cohort tested whether the regimen allows for treatment-free remission in the setting of confirmed undetectable MRD (uMRD).

Patients (n = 164, median age 58 years) in the CAPTIVATE study MRD cohort had previously untreated active CLL/SLL requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

They received 3 cycles of lead-in ibrutinib (420 mg once daily) followed by 12 cycles of ibrutinib (420 mg once daily plus venetoclax ramp-up to 400 mg once daily). Thereafter, in an MRD-guided 1:1 randomization stratified by immunoglobulin heavy chain (IGHV) mutational status, those with confirmed uMRD received either placebo or ibrutinib, and those with uMRD not confirmed received either ibrutinib or ibrutinib plus venetoclax (both open-label).

Among high-risk features in CAPTIVATE subjects, 60% of patients had unmutated IGHV, with del(17p)/TP53 mutation in 20%, del(11Q) in 17%, complex karyotype in 19%, cytopenias in 36%, bulky lymph nodes in 32%, and absolute neutrophil count ≥25x109/L in 76%.
 

Response findings

The ibrutinib lead-in, Dr. Wierda said, reduced tumor lysis syndrome (TLS) risk, shifting 90% of patients with high baseline TLS risk to medium or low-risk categories (from 77 to 51 patients), precluding need for hospitalization with venetoclax initiation.

The rate for best response of uMRD (defined as uMRD over at least 3 cycles in both peripheral blood and bone marrow) in evaluable patients was 75% in peripheral blood (n = 163) and 72% in bone marrow (n = 155).

Confirmed uMRD was achieved in 86/149 (58%), with uMRD not confirmed in 63/149 (uMRD 32% in bone marrow and 48% in peripheral blood). One-year DFS after the further randomization to placebo or ibrutinib in the confirmed uMRD group was 95.3% in the placebo group and 100% in the ibrutinib group (P = .1475). In the uMRD not confirmed group, 30-month progression-free survival (PFS) was 95.2% and 96.7% in the ibrutinib and ibrutinib plus venetoclax groups, respectively. Thirty-month PFS rates in the confirmed uMRD placebo and ibrutinib arms were 95.3% and 100%. “Thirty-month PFS rates were greater than 95% across all randomized arms,” Dr. Wierda stated.

In patients without confirmed uMRD after 12 cycles of combined ibrutinib plus venetoclax, additional randomized treatment led to greater increases in uMRD in the ibrutinib plus venetoclax group than in the ibrutinib alone group (bone marrow additional 10% ibrutinib alone, 34% ibrutinib plus venetoclax; peripheral blood 0% ibrutinib, 19% ibrutinib plus venetoclax).

Adverse events generally decreased after the first 6 months of ibrutinib plus venetoclax treatment, with no new safety signals emerging over time. “There were no safety concerns with this highly active combination of first-line ibrutinib plus venetoclax. It’s an oral, once-daily fixed duration regimen that achieves undetectable MRD in blood or bone marrow in three-fourths of patients after 12 cycles of combined treatment.”

When asked, in a question-and-answer session after his presentation, if the findings were “practice changing,” Dr. Wierda responded: “We need additional data from ongoing studies looking at various combinations of targeted therapy. But this study does clearly show efficacy in terms of depth of remission, and it supports the concept of fixed duration treatment, particularly for those patients who achieved undetectable MRD status.”
 

SOURCE: William G. Wierda, MD, PhD. ASH 2020, Abstract 123.