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Earlier antibiotic initiation for sepsis did not lead to overuse
There has been a marked increase in the time to antibiotic administration for ICU patients with sepsis across Veterans Affairs (VA) hospitals, but there is no evidence that they are being given inappropriately, according to new findings.
Accelerating time-to-antibiotics in sepsis means that patients will be treated earlier, but it could also result in more patients receiving antibiotics, including those without infection. This in turn may contribute to antimicrobial resistance.
“The time to antibiotics for sepsis accelerated across VA hospitals, and declined from 5.8 to 4.8 hours between 2013 and 2018,” said lead study author Sarah Seelye, PhD, data scientist at the U.S. Department of Veterans Affairs, Ann Arbor, Mich. “Despite this, there was no evidence between hospital level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis.”
The results were presented at the Critical Care Congress sponsored by the Society of Critical Care Medicine, which was held virtually this year.
“Many hospitals have initiated programs like this to accelerate the use of antibiotics in patients with severe sepsis, but at the same time, there is growing concern that earlier antibiotic initiation may result in increased antibiotic treatment overall, including those without infection,” said Dr. Seelye. “However, to date, there is little evidence to support this claim.”
The goal of their study was to investigate whether hospital-level acceleration in antibiotic timing for sepsis was associated with increasing antibiotic use among patients hospitalized with potential infection.
They identified 1,101,239 hospitalizations for potential infection in 132 VA hospitals during the period from 2013 to 2018. Of these patients, 608,128 (55.2%) received antibiotics within 48 hours of presentation to the emergency department. A total of 117,435 (10.7%) met the criteria for sepsis.
Hospitals were classified into tertiles of antibiotic acceleration for sepsis: rapid, slow, and flat.
In the VA system, patients with severe sepsis began receiving faster antibiotic treatment in 2017, compared with earlier years. In 2017-2018 more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
In 2017-2018, more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
Hospitals categorized as rapid accelerators decreased their time to antibiotic initiation from 6.4 hours to 4.5 hours, while slow accelerators went from 5.6 to 4.6 hours from 2013 to 2018, and flat accelerators remained stable during the time period (5.3 hours down to 5.2 hours).
However, statistical analysis showed no real difference between the three groups in antibiotic prescribing.
“Despite this, there was no evidence between hospital-level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis,” said Dr. Seelye.
Weighing in on the study results, Craig M. Coopersmith, MD, professor of surgery at Emory University, Atlanta, noted that these results are very convincing, considering the size of the study and that it encompassed 132 different facilities.
“It’s difficult to say how generalizable these results are but they are definitely generalizable to all hospitals in the VA system,” he said. “In general, there are similarities between large health care systems, and it would be surprising if we found the opposite to be true in non-VA health systems.”
However, he emphasized that there is some possibility that the results would not be identical because different health care systems have different methods of providing care.
“This paper does show that you can get antibiotics into patients faster, which can be life saving, without inappropriately using them on everybody,” Dr. Coopersmith said.
He explained that there is more attention being paid now to antibiotic stewardship, compared with 10 or 15 years ago. “Given the choice of giving someone a single dose of antibiotics who may not need it, as opposed to withholding them from someone who is septic which is life threatening, the risk benefit ratio weighs heavily towards starting them early,” he said. “And then escalate rapidly.”
There has been a marked increase in the time to antibiotic administration for ICU patients with sepsis across Veterans Affairs (VA) hospitals, but there is no evidence that they are being given inappropriately, according to new findings.
Accelerating time-to-antibiotics in sepsis means that patients will be treated earlier, but it could also result in more patients receiving antibiotics, including those without infection. This in turn may contribute to antimicrobial resistance.
“The time to antibiotics for sepsis accelerated across VA hospitals, and declined from 5.8 to 4.8 hours between 2013 and 2018,” said lead study author Sarah Seelye, PhD, data scientist at the U.S. Department of Veterans Affairs, Ann Arbor, Mich. “Despite this, there was no evidence between hospital level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis.”
The results were presented at the Critical Care Congress sponsored by the Society of Critical Care Medicine, which was held virtually this year.
“Many hospitals have initiated programs like this to accelerate the use of antibiotics in patients with severe sepsis, but at the same time, there is growing concern that earlier antibiotic initiation may result in increased antibiotic treatment overall, including those without infection,” said Dr. Seelye. “However, to date, there is little evidence to support this claim.”
The goal of their study was to investigate whether hospital-level acceleration in antibiotic timing for sepsis was associated with increasing antibiotic use among patients hospitalized with potential infection.
They identified 1,101,239 hospitalizations for potential infection in 132 VA hospitals during the period from 2013 to 2018. Of these patients, 608,128 (55.2%) received antibiotics within 48 hours of presentation to the emergency department. A total of 117,435 (10.7%) met the criteria for sepsis.
Hospitals were classified into tertiles of antibiotic acceleration for sepsis: rapid, slow, and flat.
In the VA system, patients with severe sepsis began receiving faster antibiotic treatment in 2017, compared with earlier years. In 2017-2018 more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
In 2017-2018, more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
Hospitals categorized as rapid accelerators decreased their time to antibiotic initiation from 6.4 hours to 4.5 hours, while slow accelerators went from 5.6 to 4.6 hours from 2013 to 2018, and flat accelerators remained stable during the time period (5.3 hours down to 5.2 hours).
However, statistical analysis showed no real difference between the three groups in antibiotic prescribing.
“Despite this, there was no evidence between hospital-level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis,” said Dr. Seelye.
Weighing in on the study results, Craig M. Coopersmith, MD, professor of surgery at Emory University, Atlanta, noted that these results are very convincing, considering the size of the study and that it encompassed 132 different facilities.
“It’s difficult to say how generalizable these results are but they are definitely generalizable to all hospitals in the VA system,” he said. “In general, there are similarities between large health care systems, and it would be surprising if we found the opposite to be true in non-VA health systems.”
However, he emphasized that there is some possibility that the results would not be identical because different health care systems have different methods of providing care.
“This paper does show that you can get antibiotics into patients faster, which can be life saving, without inappropriately using them on everybody,” Dr. Coopersmith said.
He explained that there is more attention being paid now to antibiotic stewardship, compared with 10 or 15 years ago. “Given the choice of giving someone a single dose of antibiotics who may not need it, as opposed to withholding them from someone who is septic which is life threatening, the risk benefit ratio weighs heavily towards starting them early,” he said. “And then escalate rapidly.”
There has been a marked increase in the time to antibiotic administration for ICU patients with sepsis across Veterans Affairs (VA) hospitals, but there is no evidence that they are being given inappropriately, according to new findings.
Accelerating time-to-antibiotics in sepsis means that patients will be treated earlier, but it could also result in more patients receiving antibiotics, including those without infection. This in turn may contribute to antimicrobial resistance.
“The time to antibiotics for sepsis accelerated across VA hospitals, and declined from 5.8 to 4.8 hours between 2013 and 2018,” said lead study author Sarah Seelye, PhD, data scientist at the U.S. Department of Veterans Affairs, Ann Arbor, Mich. “Despite this, there was no evidence between hospital level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis.”
The results were presented at the Critical Care Congress sponsored by the Society of Critical Care Medicine, which was held virtually this year.
“Many hospitals have initiated programs like this to accelerate the use of antibiotics in patients with severe sepsis, but at the same time, there is growing concern that earlier antibiotic initiation may result in increased antibiotic treatment overall, including those without infection,” said Dr. Seelye. “However, to date, there is little evidence to support this claim.”
The goal of their study was to investigate whether hospital-level acceleration in antibiotic timing for sepsis was associated with increasing antibiotic use among patients hospitalized with potential infection.
They identified 1,101,239 hospitalizations for potential infection in 132 VA hospitals during the period from 2013 to 2018. Of these patients, 608,128 (55.2%) received antibiotics within 48 hours of presentation to the emergency department. A total of 117,435 (10.7%) met the criteria for sepsis.
Hospitals were classified into tertiles of antibiotic acceleration for sepsis: rapid, slow, and flat.
In the VA system, patients with severe sepsis began receiving faster antibiotic treatment in 2017, compared with earlier years. In 2017-2018 more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
In 2017-2018, more than 20% of sepsis patients had received their first treatment within 2 hours, compared with 14% in 2013-1014.
Hospitals categorized as rapid accelerators decreased their time to antibiotic initiation from 6.4 hours to 4.5 hours, while slow accelerators went from 5.6 to 4.6 hours from 2013 to 2018, and flat accelerators remained stable during the time period (5.3 hours down to 5.2 hours).
However, statistical analysis showed no real difference between the three groups in antibiotic prescribing.
“Despite this, there was no evidence between hospital-level antibiotic acceleration in sepsis and antibiotic use among all patients with potential sepsis,” said Dr. Seelye.
Weighing in on the study results, Craig M. Coopersmith, MD, professor of surgery at Emory University, Atlanta, noted that these results are very convincing, considering the size of the study and that it encompassed 132 different facilities.
“It’s difficult to say how generalizable these results are but they are definitely generalizable to all hospitals in the VA system,” he said. “In general, there are similarities between large health care systems, and it would be surprising if we found the opposite to be true in non-VA health systems.”
However, he emphasized that there is some possibility that the results would not be identical because different health care systems have different methods of providing care.
“This paper does show that you can get antibiotics into patients faster, which can be life saving, without inappropriately using them on everybody,” Dr. Coopersmith said.
He explained that there is more attention being paid now to antibiotic stewardship, compared with 10 or 15 years ago. “Given the choice of giving someone a single dose of antibiotics who may not need it, as opposed to withholding them from someone who is septic which is life threatening, the risk benefit ratio weighs heavily towards starting them early,” he said. “And then escalate rapidly.”
FROM CCC50
New ASH guidelines: VTE prevention and treatment in cancer patients
New guidelines from the American Society of Hematology “strongly recommend” using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.
The evidence-based guidelines for the prevention and treatment of VTE in patient with cancer, published online in Blood Advances, also include a “conditional recommendation” for using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk.
The purpose of the guidelines, which also address VTE prophylaxis in hospitalized patients with cancer and the use of anticoagulation for VTE treatment in patients with cancer, is to provide clinical decision support for shared decision-making by patients and clinicians, Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, Seattle and Marc Carrier, MD, of the University of Ottawa, and their colleagues from the multidisciplinary guidelines panel explained.
“The recommendations take into consideration the strength of the evidence, risks of mortality, VTE, and bleeding, as well as quality of life, acceptability, and cost considerations,” they wrote, noting that VTE is a common complication in patients with cancer, who are at markedly increased risk for morbidity and mortality from VTE.
Levels of evidence
The panel members relied on updated and original systematic evidence reviews. Conditional recommendations, as opposed to strong recommendations, are defined by the panel as “suggestions,” and all 33 recommendations that make up the guidelines include a statement on the strength of the relevant evidence.
For example, the thromboprophylaxis recommendations for low, intermediate, and high VTE risk are made based on “moderate certainty in the evidence of effects,” and the recommendation for no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists is a strong recommendation based on “very low certainty in the evidence of benefits, but high certainty about the harms.”
The guidelines panel also strongly recommends, based on moderate certainty in the evidence of effects, using low-molecular-weight heparin over unfractionated heparin for the initial treatment of VTE in patients with cancer, and suggests, based on “very low certainty in the evidence of effects,” using LMWH over fondaparinux in this setting.
In addition to primary prophylaxis in ambulatory and hospitalized patients and initial VTE treatment, they also address primary prophylaxis for patients with cancer who have a central venous catheter, VTE treatment in surgical patients with cancer, short-term VTE treatment, and long-term VTE treatment.
For example, the guidelines panel conditionally recommends:
- Not using parenteral or oral thromboprophylaxis in patients with cancer and a central venous catheter
- Using LMWH or fondaparinux for surgical patients with cancer
- Using DOACS for the short-term treatment of VTE, and LMWH or DOACs for the long-term treatment of VTE in patients with cancer.
The perils of VTE
VTE in patients with cancer can interfere with treatment, increase mortality risk, and increase costs, the authors noted, adding that VTE can also adversely affect cancer patients’ quality of life.
“Some have even reported the experience of VTE to be more upsetting than that of the cancer,” they wrote. “More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. Patients, who are still coming to terms with a recent cancer diagnosis, often view the occurrence of VTE as a further threat to life, confirmation of the severity of their condition, and a poor prognostic sign.”
Therefore, the new guidelines aim to reduce VTE frequency, risk of bleeding complications, morbidity, and costs, thereby improving quality of life and the patient experience, the authors said, noting that three other recent guidelines on VTEs in patients with cancer have been published: the 2019 American Society of Clinical Oncology guidelines, the 2019 International Initiative on Thrombosis and Cancer guidelines, and the 2020 National Comprehensive Cancer Network guidelines.
The ASH guidelines are similar in many ways to the other guidelines, but differ in some ways, as well. An example is the timing of initiation of pharmacological thromboprophylaxis in patients undergoing cancer-related major abdominal surgery. The ASCO and ITAC guidelines advise starting thromboprophylaxis preoperatively, whereas the ASH guidelines recommend initiating thromboprophylaxis postoperatively, citing “the limited advantages to initiating thromboprophylaxis preoperatively, in addition to the potential bleeding and logistical considerations associated with neuraxial anesthesia.”
These differences highlight a lack of data in that setting and the need for additional studies, the authors said.
ASH vs. ASCO
James Douketis, MD, a practicing clinician and professor of medicine at McMaster University, Hamilton, Ont., highlighted another difference between the ASH and ASCO guidelines.
“For the treatment of [cancer-associated thrombosis], ASCO gives a strong recommendation to use LMWH or DOACs (with some caveats), which is easy to follow. ASH, on the other hand, suggests LMWH or a DOAC for the first 7-10 days, DOACs for the first 3-6 months, and back to LMWH or DOACs after 6 months,” he said in an interview.
The recommendation is “very evidence based but ambiguous and not helpful for the practicing clinician,” added Dr. Douketis, who helped develop the ITAC guidelines, but was not part of the ASH or ASCO guideline panels.
ASCO also provides a clear recommendation for giving VTE prophylaxis for 4 weeks after cancer surgery in patients with high VTE risk, whereas ASH gives “a somewhat vague recommendation” for thromboprophylaxis after hospital discharge.
The guidelines are “pretty well aligned” with respect to recommendations on VTE prophylaxis in medical cancer patients receiving chemotherapy, and although the “extremely academic” ASH guidelines were developed by “a superb team using the same evidence and excellent methodology,” they are interpreted in slightly different ways and fall short when it comes to being clinician friendly, Dr. Douketis said.
“At the end of day, for practicing clinicians, the ASH guidelines don’t provide a message that’s easy to digest,” he added.
ASH has, however, provided a resource page that includes tools and information for implementing the guidelines in clinical practice, and will maintain the guidelines “through surveillance for new evidence, ongoing review by experts, and regular revisions,” the authors said.
New guidelines from the American Society of Hematology “strongly recommend” using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.
The evidence-based guidelines for the prevention and treatment of VTE in patient with cancer, published online in Blood Advances, also include a “conditional recommendation” for using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk.
The purpose of the guidelines, which also address VTE prophylaxis in hospitalized patients with cancer and the use of anticoagulation for VTE treatment in patients with cancer, is to provide clinical decision support for shared decision-making by patients and clinicians, Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, Seattle and Marc Carrier, MD, of the University of Ottawa, and their colleagues from the multidisciplinary guidelines panel explained.
“The recommendations take into consideration the strength of the evidence, risks of mortality, VTE, and bleeding, as well as quality of life, acceptability, and cost considerations,” they wrote, noting that VTE is a common complication in patients with cancer, who are at markedly increased risk for morbidity and mortality from VTE.
Levels of evidence
The panel members relied on updated and original systematic evidence reviews. Conditional recommendations, as opposed to strong recommendations, are defined by the panel as “suggestions,” and all 33 recommendations that make up the guidelines include a statement on the strength of the relevant evidence.
For example, the thromboprophylaxis recommendations for low, intermediate, and high VTE risk are made based on “moderate certainty in the evidence of effects,” and the recommendation for no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists is a strong recommendation based on “very low certainty in the evidence of benefits, but high certainty about the harms.”
The guidelines panel also strongly recommends, based on moderate certainty in the evidence of effects, using low-molecular-weight heparin over unfractionated heparin for the initial treatment of VTE in patients with cancer, and suggests, based on “very low certainty in the evidence of effects,” using LMWH over fondaparinux in this setting.
In addition to primary prophylaxis in ambulatory and hospitalized patients and initial VTE treatment, they also address primary prophylaxis for patients with cancer who have a central venous catheter, VTE treatment in surgical patients with cancer, short-term VTE treatment, and long-term VTE treatment.
For example, the guidelines panel conditionally recommends:
- Not using parenteral or oral thromboprophylaxis in patients with cancer and a central venous catheter
- Using LMWH or fondaparinux for surgical patients with cancer
- Using DOACS for the short-term treatment of VTE, and LMWH or DOACs for the long-term treatment of VTE in patients with cancer.
The perils of VTE
VTE in patients with cancer can interfere with treatment, increase mortality risk, and increase costs, the authors noted, adding that VTE can also adversely affect cancer patients’ quality of life.
“Some have even reported the experience of VTE to be more upsetting than that of the cancer,” they wrote. “More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. Patients, who are still coming to terms with a recent cancer diagnosis, often view the occurrence of VTE as a further threat to life, confirmation of the severity of their condition, and a poor prognostic sign.”
Therefore, the new guidelines aim to reduce VTE frequency, risk of bleeding complications, morbidity, and costs, thereby improving quality of life and the patient experience, the authors said, noting that three other recent guidelines on VTEs in patients with cancer have been published: the 2019 American Society of Clinical Oncology guidelines, the 2019 International Initiative on Thrombosis and Cancer guidelines, and the 2020 National Comprehensive Cancer Network guidelines.
The ASH guidelines are similar in many ways to the other guidelines, but differ in some ways, as well. An example is the timing of initiation of pharmacological thromboprophylaxis in patients undergoing cancer-related major abdominal surgery. The ASCO and ITAC guidelines advise starting thromboprophylaxis preoperatively, whereas the ASH guidelines recommend initiating thromboprophylaxis postoperatively, citing “the limited advantages to initiating thromboprophylaxis preoperatively, in addition to the potential bleeding and logistical considerations associated with neuraxial anesthesia.”
These differences highlight a lack of data in that setting and the need for additional studies, the authors said.
ASH vs. ASCO
James Douketis, MD, a practicing clinician and professor of medicine at McMaster University, Hamilton, Ont., highlighted another difference between the ASH and ASCO guidelines.
“For the treatment of [cancer-associated thrombosis], ASCO gives a strong recommendation to use LMWH or DOACs (with some caveats), which is easy to follow. ASH, on the other hand, suggests LMWH or a DOAC for the first 7-10 days, DOACs for the first 3-6 months, and back to LMWH or DOACs after 6 months,” he said in an interview.
The recommendation is “very evidence based but ambiguous and not helpful for the practicing clinician,” added Dr. Douketis, who helped develop the ITAC guidelines, but was not part of the ASH or ASCO guideline panels.
ASCO also provides a clear recommendation for giving VTE prophylaxis for 4 weeks after cancer surgery in patients with high VTE risk, whereas ASH gives “a somewhat vague recommendation” for thromboprophylaxis after hospital discharge.
The guidelines are “pretty well aligned” with respect to recommendations on VTE prophylaxis in medical cancer patients receiving chemotherapy, and although the “extremely academic” ASH guidelines were developed by “a superb team using the same evidence and excellent methodology,” they are interpreted in slightly different ways and fall short when it comes to being clinician friendly, Dr. Douketis said.
“At the end of day, for practicing clinicians, the ASH guidelines don’t provide a message that’s easy to digest,” he added.
ASH has, however, provided a resource page that includes tools and information for implementing the guidelines in clinical practice, and will maintain the guidelines “through surveillance for new evidence, ongoing review by experts, and regular revisions,” the authors said.
New guidelines from the American Society of Hematology “strongly recommend” using no thromboprophylaxis over using parenteral thromboprophylaxis in ambulatory patients receiving cancer chemotherapy who have low venous thromboembolism (VTE) risk, and using no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists in those at any VTE risk level.
The evidence-based guidelines for the prevention and treatment of VTE in patient with cancer, published online in Blood Advances, also include a “conditional recommendation” for using either thromboprophylaxis with the direct oral anticoagulants (DOACs) apixaban or rivaroxaban or using no thromboprophylaxis in ambulatory patients with intermediate risk and using the DOACs over no thromboprophylaxis in those with high VTE risk.
The purpose of the guidelines, which also address VTE prophylaxis in hospitalized patients with cancer and the use of anticoagulation for VTE treatment in patients with cancer, is to provide clinical decision support for shared decision-making by patients and clinicians, Gary H. Lyman, MD, of Fred Hutchinson Cancer Research Center, Seattle and Marc Carrier, MD, of the University of Ottawa, and their colleagues from the multidisciplinary guidelines panel explained.
“The recommendations take into consideration the strength of the evidence, risks of mortality, VTE, and bleeding, as well as quality of life, acceptability, and cost considerations,” they wrote, noting that VTE is a common complication in patients with cancer, who are at markedly increased risk for morbidity and mortality from VTE.
Levels of evidence
The panel members relied on updated and original systematic evidence reviews. Conditional recommendations, as opposed to strong recommendations, are defined by the panel as “suggestions,” and all 33 recommendations that make up the guidelines include a statement on the strength of the relevant evidence.
For example, the thromboprophylaxis recommendations for low, intermediate, and high VTE risk are made based on “moderate certainty in the evidence of effects,” and the recommendation for no thromboprophylaxis over oral thromboprophylaxis with vitamin K antagonists is a strong recommendation based on “very low certainty in the evidence of benefits, but high certainty about the harms.”
The guidelines panel also strongly recommends, based on moderate certainty in the evidence of effects, using low-molecular-weight heparin over unfractionated heparin for the initial treatment of VTE in patients with cancer, and suggests, based on “very low certainty in the evidence of effects,” using LMWH over fondaparinux in this setting.
In addition to primary prophylaxis in ambulatory and hospitalized patients and initial VTE treatment, they also address primary prophylaxis for patients with cancer who have a central venous catheter, VTE treatment in surgical patients with cancer, short-term VTE treatment, and long-term VTE treatment.
For example, the guidelines panel conditionally recommends:
- Not using parenteral or oral thromboprophylaxis in patients with cancer and a central venous catheter
- Using LMWH or fondaparinux for surgical patients with cancer
- Using DOACS for the short-term treatment of VTE, and LMWH or DOACs for the long-term treatment of VTE in patients with cancer.
The perils of VTE
VTE in patients with cancer can interfere with treatment, increase mortality risk, and increase costs, the authors noted, adding that VTE can also adversely affect cancer patients’ quality of life.
“Some have even reported the experience of VTE to be more upsetting than that of the cancer,” they wrote. “More than 50% of thrombotic events occur within 3 months of the cancer diagnosis, a time when most cancer treatments will be underway. Patients, who are still coming to terms with a recent cancer diagnosis, often view the occurrence of VTE as a further threat to life, confirmation of the severity of their condition, and a poor prognostic sign.”
Therefore, the new guidelines aim to reduce VTE frequency, risk of bleeding complications, morbidity, and costs, thereby improving quality of life and the patient experience, the authors said, noting that three other recent guidelines on VTEs in patients with cancer have been published: the 2019 American Society of Clinical Oncology guidelines, the 2019 International Initiative on Thrombosis and Cancer guidelines, and the 2020 National Comprehensive Cancer Network guidelines.
The ASH guidelines are similar in many ways to the other guidelines, but differ in some ways, as well. An example is the timing of initiation of pharmacological thromboprophylaxis in patients undergoing cancer-related major abdominal surgery. The ASCO and ITAC guidelines advise starting thromboprophylaxis preoperatively, whereas the ASH guidelines recommend initiating thromboprophylaxis postoperatively, citing “the limited advantages to initiating thromboprophylaxis preoperatively, in addition to the potential bleeding and logistical considerations associated with neuraxial anesthesia.”
These differences highlight a lack of data in that setting and the need for additional studies, the authors said.
ASH vs. ASCO
James Douketis, MD, a practicing clinician and professor of medicine at McMaster University, Hamilton, Ont., highlighted another difference between the ASH and ASCO guidelines.
“For the treatment of [cancer-associated thrombosis], ASCO gives a strong recommendation to use LMWH or DOACs (with some caveats), which is easy to follow. ASH, on the other hand, suggests LMWH or a DOAC for the first 7-10 days, DOACs for the first 3-6 months, and back to LMWH or DOACs after 6 months,” he said in an interview.
The recommendation is “very evidence based but ambiguous and not helpful for the practicing clinician,” added Dr. Douketis, who helped develop the ITAC guidelines, but was not part of the ASH or ASCO guideline panels.
ASCO also provides a clear recommendation for giving VTE prophylaxis for 4 weeks after cancer surgery in patients with high VTE risk, whereas ASH gives “a somewhat vague recommendation” for thromboprophylaxis after hospital discharge.
The guidelines are “pretty well aligned” with respect to recommendations on VTE prophylaxis in medical cancer patients receiving chemotherapy, and although the “extremely academic” ASH guidelines were developed by “a superb team using the same evidence and excellent methodology,” they are interpreted in slightly different ways and fall short when it comes to being clinician friendly, Dr. Douketis said.
“At the end of day, for practicing clinicians, the ASH guidelines don’t provide a message that’s easy to digest,” he added.
ASH has, however, provided a resource page that includes tools and information for implementing the guidelines in clinical practice, and will maintain the guidelines “through surveillance for new evidence, ongoing review by experts, and regular revisions,” the authors said.
FROM BLOOD ADVANCES
Mepolizumab reduced exacerbations in patients with asthma and atopy, depression comorbidities
, according to research from the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
“Mepolizumab has clearly been shown to improve severe asthma control in many clinical trials, but atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate,” Thomas B. Casale, MD, former AAAAI president and professor of medicine and pediatrics at the University of South Florida in Tampa, said in a presentation at the meeting. “Yet, few studies have examined whether asthma therapy with these comorbidities works.”
Dr. Casale and colleagues performed a retrospective analysis of patients in the United States from the MarketScan Commercial and Medicare Supplemental Database between November 2014 and December 2018 who had atopy, obesity, or depression/anxiety in addition to asthma and were receiving mepolizumab. Atopy in the study was defined as allergic rhinitis, anaphylaxis, atopic dermatitis, conjunctivitis, eosinophilic esophagitis, and food allergies. Patients were at least age 12 years, had at least one diagnosis for asthma, at least one diagnosis code for atopic disease, obesity, or depression/anxiety at baseline, and at least two administrations of mepolizumab within 180 days.
The researchers examined the number of exacerbations, oral corticosteroid (OCS) claims, and OCS bursts per year at 12-month follow-up, compared with baseline. They identified exacerbations by examining patients who had an emergency department or outpatient claim related to their asthma, and a claim for systemic corticosteroids made in the 4 days prior to or 5 days after a visit, or if their inpatient hospital admission contained a primary asthma diagnosis. Dr. Casale and colleagues measured OCS bursts as a pharmacy claim of at least 20 mg of prednisone per day for between 3 and 28 days plus a claim for an emergency department visit related to asthma in the 7 days prior or 6 days after the claim.
At baseline, patients across all groups were mean age 50.5-52.4 years with a Charleson Comorbidity Index score between 1.1 and 1.4, a majority were women (59.0%-72.0%) and nearly all were commercially insured (88.0%-90.0%). Patients who used biologics at baseline and/or used a biologic that wasn’t mepolizumab during the follow-up period were excluded.
Medication claims in the groups included inhaled corticosteroids (ICS) (36.8%-48.6%), ICS/long-acting beta-agonist (LABA) (60.2%-63.0%), LABA/ long-acting muscarinic antagonist (LAMA) (1.2%-3.5%), ICS/LABA/LAMA (21.2%-25.1%), short-acting beta-agonist (SABA) (83.2%-87.7%), LAMA alone (33.5%-42.1%), or leukotriene receptor antagonist (LTRA).
In the non–mutually exclusive group of patients with atopy (468 patients), 28.0% had comorbid obesity and 26.0% had comorbid depression/anxiety. For patients with obesity categorized in a non–mutually exclusive subgroup (171 patients), 79.0% had comorbid atopy and 32.0% had comorbid depression/anxiety. Among patients with non–mutually exclusive depression/anxiety (173 patients), 70.0% had comorbid atopy, while 32.0% had comorbid obesity.
The results showed the mean number of overall exacerbations decreased by 48% at 12 months in the atopic group (2.3 vs. 1.2; P < .001), 52% in the group with obesity (2.5 vs. 1.2; P < .001), and 38% in the depression/anxiety group (2.4 vs. 1.5; P < .001). The mean number of exacerbations leading to hospitalizations decreased by 64% in the atopic group (0.11 vs. 0.04; P < .001), 65% in the group with obesity (0.20 vs. 0.07; P < .001), and 68% in the group with depression/anxiety (0.22 vs. 0.07; P < .001).
The researchers also found the mean number of OCS claims and OCS bursts also significantly decreased over the 12-month follow-up period. Mean OCS claims decreased by 33% for patients in the atopic group (5.5 vs. 3.7; P < .001), by 38% in the group with obesity (6.1 vs. 3.8; P < .001), and by 31% in the group with depression/anxiety (6.2 vs. 4.3; P < .001).
The mean number of OCS bursts also significantly decreased by 40% in the atopic group (2.0 vs. 2.1; P < .001), 48% in the group with obesity (2.3 vs. 1.2; P < .001), and by 37% in the group with depression/anxiety (1.9 vs. 1.2; P < .001). In total, 69% of patients with comorbid atopy, 70.8% of patients with comorbid obesity, and 68.2% of patients with comorbid depression/anxiety experienced a mean decrease in their OCS dose over 12 months.
“These data demonstrate that patients with asthma and atopy, obesity, or depression and anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting with treatment of mepolizumab,” Dr. Casale said. “Thus, holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit despite the complexities of medical comorbidities.”
This study was funded by GlaxoSmithKline, and the company also funded graphic design support of the poster. Dr. Casale reports he has received research funds from GlaxoSmithKline. Four authors report being current or former GlaxoSmithKline employees; three authors report holding stock and/or shares of GlaxoSmithKline. Three authors are IBM Watson Health employees, a company GlaxoSmithKline has provided research funding.
, according to research from the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
“Mepolizumab has clearly been shown to improve severe asthma control in many clinical trials, but atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate,” Thomas B. Casale, MD, former AAAAI president and professor of medicine and pediatrics at the University of South Florida in Tampa, said in a presentation at the meeting. “Yet, few studies have examined whether asthma therapy with these comorbidities works.”
Dr. Casale and colleagues performed a retrospective analysis of patients in the United States from the MarketScan Commercial and Medicare Supplemental Database between November 2014 and December 2018 who had atopy, obesity, or depression/anxiety in addition to asthma and were receiving mepolizumab. Atopy in the study was defined as allergic rhinitis, anaphylaxis, atopic dermatitis, conjunctivitis, eosinophilic esophagitis, and food allergies. Patients were at least age 12 years, had at least one diagnosis for asthma, at least one diagnosis code for atopic disease, obesity, or depression/anxiety at baseline, and at least two administrations of mepolizumab within 180 days.
The researchers examined the number of exacerbations, oral corticosteroid (OCS) claims, and OCS bursts per year at 12-month follow-up, compared with baseline. They identified exacerbations by examining patients who had an emergency department or outpatient claim related to their asthma, and a claim for systemic corticosteroids made in the 4 days prior to or 5 days after a visit, or if their inpatient hospital admission contained a primary asthma diagnosis. Dr. Casale and colleagues measured OCS bursts as a pharmacy claim of at least 20 mg of prednisone per day for between 3 and 28 days plus a claim for an emergency department visit related to asthma in the 7 days prior or 6 days after the claim.
At baseline, patients across all groups were mean age 50.5-52.4 years with a Charleson Comorbidity Index score between 1.1 and 1.4, a majority were women (59.0%-72.0%) and nearly all were commercially insured (88.0%-90.0%). Patients who used biologics at baseline and/or used a biologic that wasn’t mepolizumab during the follow-up period were excluded.
Medication claims in the groups included inhaled corticosteroids (ICS) (36.8%-48.6%), ICS/long-acting beta-agonist (LABA) (60.2%-63.0%), LABA/ long-acting muscarinic antagonist (LAMA) (1.2%-3.5%), ICS/LABA/LAMA (21.2%-25.1%), short-acting beta-agonist (SABA) (83.2%-87.7%), LAMA alone (33.5%-42.1%), or leukotriene receptor antagonist (LTRA).
In the non–mutually exclusive group of patients with atopy (468 patients), 28.0% had comorbid obesity and 26.0% had comorbid depression/anxiety. For patients with obesity categorized in a non–mutually exclusive subgroup (171 patients), 79.0% had comorbid atopy and 32.0% had comorbid depression/anxiety. Among patients with non–mutually exclusive depression/anxiety (173 patients), 70.0% had comorbid atopy, while 32.0% had comorbid obesity.
The results showed the mean number of overall exacerbations decreased by 48% at 12 months in the atopic group (2.3 vs. 1.2; P < .001), 52% in the group with obesity (2.5 vs. 1.2; P < .001), and 38% in the depression/anxiety group (2.4 vs. 1.5; P < .001). The mean number of exacerbations leading to hospitalizations decreased by 64% in the atopic group (0.11 vs. 0.04; P < .001), 65% in the group with obesity (0.20 vs. 0.07; P < .001), and 68% in the group with depression/anxiety (0.22 vs. 0.07; P < .001).
The researchers also found the mean number of OCS claims and OCS bursts also significantly decreased over the 12-month follow-up period. Mean OCS claims decreased by 33% for patients in the atopic group (5.5 vs. 3.7; P < .001), by 38% in the group with obesity (6.1 vs. 3.8; P < .001), and by 31% in the group with depression/anxiety (6.2 vs. 4.3; P < .001).
The mean number of OCS bursts also significantly decreased by 40% in the atopic group (2.0 vs. 2.1; P < .001), 48% in the group with obesity (2.3 vs. 1.2; P < .001), and by 37% in the group with depression/anxiety (1.9 vs. 1.2; P < .001). In total, 69% of patients with comorbid atopy, 70.8% of patients with comorbid obesity, and 68.2% of patients with comorbid depression/anxiety experienced a mean decrease in their OCS dose over 12 months.
“These data demonstrate that patients with asthma and atopy, obesity, or depression and anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting with treatment of mepolizumab,” Dr. Casale said. “Thus, holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit despite the complexities of medical comorbidities.”
This study was funded by GlaxoSmithKline, and the company also funded graphic design support of the poster. Dr. Casale reports he has received research funds from GlaxoSmithKline. Four authors report being current or former GlaxoSmithKline employees; three authors report holding stock and/or shares of GlaxoSmithKline. Three authors are IBM Watson Health employees, a company GlaxoSmithKline has provided research funding.
, according to research from the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
“Mepolizumab has clearly been shown to improve severe asthma control in many clinical trials, but atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate,” Thomas B. Casale, MD, former AAAAI president and professor of medicine and pediatrics at the University of South Florida in Tampa, said in a presentation at the meeting. “Yet, few studies have examined whether asthma therapy with these comorbidities works.”
Dr. Casale and colleagues performed a retrospective analysis of patients in the United States from the MarketScan Commercial and Medicare Supplemental Database between November 2014 and December 2018 who had atopy, obesity, or depression/anxiety in addition to asthma and were receiving mepolizumab. Atopy in the study was defined as allergic rhinitis, anaphylaxis, atopic dermatitis, conjunctivitis, eosinophilic esophagitis, and food allergies. Patients were at least age 12 years, had at least one diagnosis for asthma, at least one diagnosis code for atopic disease, obesity, or depression/anxiety at baseline, and at least two administrations of mepolizumab within 180 days.
The researchers examined the number of exacerbations, oral corticosteroid (OCS) claims, and OCS bursts per year at 12-month follow-up, compared with baseline. They identified exacerbations by examining patients who had an emergency department or outpatient claim related to their asthma, and a claim for systemic corticosteroids made in the 4 days prior to or 5 days after a visit, or if their inpatient hospital admission contained a primary asthma diagnosis. Dr. Casale and colleagues measured OCS bursts as a pharmacy claim of at least 20 mg of prednisone per day for between 3 and 28 days plus a claim for an emergency department visit related to asthma in the 7 days prior or 6 days after the claim.
At baseline, patients across all groups were mean age 50.5-52.4 years with a Charleson Comorbidity Index score between 1.1 and 1.4, a majority were women (59.0%-72.0%) and nearly all were commercially insured (88.0%-90.0%). Patients who used biologics at baseline and/or used a biologic that wasn’t mepolizumab during the follow-up period were excluded.
Medication claims in the groups included inhaled corticosteroids (ICS) (36.8%-48.6%), ICS/long-acting beta-agonist (LABA) (60.2%-63.0%), LABA/ long-acting muscarinic antagonist (LAMA) (1.2%-3.5%), ICS/LABA/LAMA (21.2%-25.1%), short-acting beta-agonist (SABA) (83.2%-87.7%), LAMA alone (33.5%-42.1%), or leukotriene receptor antagonist (LTRA).
In the non–mutually exclusive group of patients with atopy (468 patients), 28.0% had comorbid obesity and 26.0% had comorbid depression/anxiety. For patients with obesity categorized in a non–mutually exclusive subgroup (171 patients), 79.0% had comorbid atopy and 32.0% had comorbid depression/anxiety. Among patients with non–mutually exclusive depression/anxiety (173 patients), 70.0% had comorbid atopy, while 32.0% had comorbid obesity.
The results showed the mean number of overall exacerbations decreased by 48% at 12 months in the atopic group (2.3 vs. 1.2; P < .001), 52% in the group with obesity (2.5 vs. 1.2; P < .001), and 38% in the depression/anxiety group (2.4 vs. 1.5; P < .001). The mean number of exacerbations leading to hospitalizations decreased by 64% in the atopic group (0.11 vs. 0.04; P < .001), 65% in the group with obesity (0.20 vs. 0.07; P < .001), and 68% in the group with depression/anxiety (0.22 vs. 0.07; P < .001).
The researchers also found the mean number of OCS claims and OCS bursts also significantly decreased over the 12-month follow-up period. Mean OCS claims decreased by 33% for patients in the atopic group (5.5 vs. 3.7; P < .001), by 38% in the group with obesity (6.1 vs. 3.8; P < .001), and by 31% in the group with depression/anxiety (6.2 vs. 4.3; P < .001).
The mean number of OCS bursts also significantly decreased by 40% in the atopic group (2.0 vs. 2.1; P < .001), 48% in the group with obesity (2.3 vs. 1.2; P < .001), and by 37% in the group with depression/anxiety (1.9 vs. 1.2; P < .001). In total, 69% of patients with comorbid atopy, 70.8% of patients with comorbid obesity, and 68.2% of patients with comorbid depression/anxiety experienced a mean decrease in their OCS dose over 12 months.
“These data demonstrate that patients with asthma and atopy, obesity, or depression and anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting with treatment of mepolizumab,” Dr. Casale said. “Thus, holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit despite the complexities of medical comorbidities.”
This study was funded by GlaxoSmithKline, and the company also funded graphic design support of the poster. Dr. Casale reports he has received research funds from GlaxoSmithKline. Four authors report being current or former GlaxoSmithKline employees; three authors report holding stock and/or shares of GlaxoSmithKline. Three authors are IBM Watson Health employees, a company GlaxoSmithKline has provided research funding.
FROM AAAAI 2021
Bladder cancer indication withdrawn for durvalumab
The change does not affect this indication outside the United States, nor does it affect other approved durvalumab indications within the United States.
For example, durvalumab remains approved by the Food and Drug Administration in the curative-intent setting of unresectable, stage III non–small cell lung cancer after chemoradiotherapy and for the treatment of extensive-stage small cell lung cancer.
AstraZeneca is continuing with clinical trials of durvalumab in various combinations for the treatment of bladder cancer.
Granted accelerated approval
Durvalumab was granted accelerated approval in May 2017 by the FDA specifically for the treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing chemotherapy or who experience disease progression within 12 months of neoadjuvant or adjuvant treatment with that chemotherapy.
That accelerated approval was based on the surrogate markers of tumor response rate and duration of response from Study 1108, a phase 1/2 trial. In this trial, the overall response rate was 17.8% in a cohort of 191 patients with locally advanced or metastatic urothelial cancer that had progressed during or after a platinum-based regimen.
However, in the confirmatory phase 3 DANUBE trial in patients with unresectable metastatic bladder cancer, neither durvalumab nor durvalumab plus tremelimumab met the primary endpoint of improving overall survival in comparison with standard-of-care chemotherapy.
“While the withdrawal in previously treated metastatic bladder cancer is disappointing, we respect the principles FDA set out when the accelerated approval pathway was founded,” Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, said in a company press statement.
A version of this article first appeared on Medscape.com.
The change does not affect this indication outside the United States, nor does it affect other approved durvalumab indications within the United States.
For example, durvalumab remains approved by the Food and Drug Administration in the curative-intent setting of unresectable, stage III non–small cell lung cancer after chemoradiotherapy and for the treatment of extensive-stage small cell lung cancer.
AstraZeneca is continuing with clinical trials of durvalumab in various combinations for the treatment of bladder cancer.
Granted accelerated approval
Durvalumab was granted accelerated approval in May 2017 by the FDA specifically for the treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing chemotherapy or who experience disease progression within 12 months of neoadjuvant or adjuvant treatment with that chemotherapy.
That accelerated approval was based on the surrogate markers of tumor response rate and duration of response from Study 1108, a phase 1/2 trial. In this trial, the overall response rate was 17.8% in a cohort of 191 patients with locally advanced or metastatic urothelial cancer that had progressed during or after a platinum-based regimen.
However, in the confirmatory phase 3 DANUBE trial in patients with unresectable metastatic bladder cancer, neither durvalumab nor durvalumab plus tremelimumab met the primary endpoint of improving overall survival in comparison with standard-of-care chemotherapy.
“While the withdrawal in previously treated metastatic bladder cancer is disappointing, we respect the principles FDA set out when the accelerated approval pathway was founded,” Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, said in a company press statement.
A version of this article first appeared on Medscape.com.
The change does not affect this indication outside the United States, nor does it affect other approved durvalumab indications within the United States.
For example, durvalumab remains approved by the Food and Drug Administration in the curative-intent setting of unresectable, stage III non–small cell lung cancer after chemoradiotherapy and for the treatment of extensive-stage small cell lung cancer.
AstraZeneca is continuing with clinical trials of durvalumab in various combinations for the treatment of bladder cancer.
Granted accelerated approval
Durvalumab was granted accelerated approval in May 2017 by the FDA specifically for the treatment of patients with locally advanced or metastatic urothelial carcinoma who experience disease progression during or following platinum-containing chemotherapy or who experience disease progression within 12 months of neoadjuvant or adjuvant treatment with that chemotherapy.
That accelerated approval was based on the surrogate markers of tumor response rate and duration of response from Study 1108, a phase 1/2 trial. In this trial, the overall response rate was 17.8% in a cohort of 191 patients with locally advanced or metastatic urothelial cancer that had progressed during or after a platinum-based regimen.
However, in the confirmatory phase 3 DANUBE trial in patients with unresectable metastatic bladder cancer, neither durvalumab nor durvalumab plus tremelimumab met the primary endpoint of improving overall survival in comparison with standard-of-care chemotherapy.
“While the withdrawal in previously treated metastatic bladder cancer is disappointing, we respect the principles FDA set out when the accelerated approval pathway was founded,” Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, said in a company press statement.
A version of this article first appeared on Medscape.com.
FDA approves cemiplimab-rwlc for NSCLC with PD-L1 expression
Specifically, the indication is for first-line treatment as monotherapy for patients with locally advanced or metastatic disease who are not candidates for surgical resection or definitive chemoradiotherapy and whose tumors have a high expression of programmed death–ligand 1 (PD-L1) (Tumor Proportion Score >50%), as determined by an FDA-approved test, with no EGFR, ALK, or ROS1 aberrations.
This is the third indication for cemiplimab-rlwc, a monoclonal antibody and PD-1 inhibitor.
In February, it was approved as the first immunotherapy to treat patients with locally advanced or metastatic basal cell carcinoma that was previously treated with a hedgehog pathway inhibitor or for whom a hedgehog inhibitor is inappropriate.
Cemiplimab-rlwc previously received FDA approval in 2018 for locally advanced or metastatic cutaneous squamous cell carcinoma for patients who were not eligible for curative surgery or radiotherapy. At the time, Karl Lewis, MD, a professor at the University of Colorado at Denver, Aurora, and a trial investigator, predicted that the drug “will change the treatment paradigm for patients with advanced basal cell carcinoma.”
Outperforms chemotherapy
The approval for use in NSCLC is based on results from the phase 3, open-label EMPOWER-Lung 1 trial, which randomly assigned 710 patients in a 1:1 ratio to receive either cemiplimab-rwlc or platinum-doublet chemotherapy. Patients had either locally advanced NSCLC and were not candidates for surgical resection or definitive chemoradiotherapy, or they had metastatic NSCLC.
Patients in the experimental arm received cemiplimab-rwlc 350 mg intravenously every 3 weeks. The primary efficacy outcome measures were overall survival (OS) and progression-free survival (PFS), determined on the basis of blinded independent central review.
Results showed statistically significant improvements in both outcomes. Median OS was 22.1 months with cemiplimab-rwlc versus 14.3 months with chemotherapy (hazard ratio, 0.68; P = .0022). Median PFS was 6.2 months versus 5.6 months (HR, 0.59; P < .0001).
The confirmed overall response rate was 37% for the cemiplimab arm versus 21% for the chemotherapy arm.
The most common adverse reactions (>10%) with cemiplimab-rlwc were musculoskeletal pain, rash, anemia, fatigue, decreased appetite, pneumonia, and cough.
This approval “means physicians and patients have a potent new treatment option against this deadly disease,” said Naiyer Rizvi, MD, Price Family Professor of Medicine, director of thoracic oncology, and codirector of cancer immunotherapy at Columbia University Irving Medical Center, New York, in a statement. He was a steering committee member on the EMPOWER-Lung-1 Trial.
“Notably, Libtayo was approved based on a pivotal trial where most chemotherapy patients crossed over to Libtayo following disease progression, and that allowed for frequently underrepresented patients who had pretreated and clinically stable brain metastases or who had locally advanced disease and were not candidates for definitive chemoradiation,” said Dr. Rizvi. “This gives doctors important new data when considering Libtayo for the varied patients and situations they treat in daily clinical practice.”
A version of this article first appeared on Medscape.com.
Specifically, the indication is for first-line treatment as monotherapy for patients with locally advanced or metastatic disease who are not candidates for surgical resection or definitive chemoradiotherapy and whose tumors have a high expression of programmed death–ligand 1 (PD-L1) (Tumor Proportion Score >50%), as determined by an FDA-approved test, with no EGFR, ALK, or ROS1 aberrations.
This is the third indication for cemiplimab-rlwc, a monoclonal antibody and PD-1 inhibitor.
In February, it was approved as the first immunotherapy to treat patients with locally advanced or metastatic basal cell carcinoma that was previously treated with a hedgehog pathway inhibitor or for whom a hedgehog inhibitor is inappropriate.
Cemiplimab-rlwc previously received FDA approval in 2018 for locally advanced or metastatic cutaneous squamous cell carcinoma for patients who were not eligible for curative surgery or radiotherapy. At the time, Karl Lewis, MD, a professor at the University of Colorado at Denver, Aurora, and a trial investigator, predicted that the drug “will change the treatment paradigm for patients with advanced basal cell carcinoma.”
Outperforms chemotherapy
The approval for use in NSCLC is based on results from the phase 3, open-label EMPOWER-Lung 1 trial, which randomly assigned 710 patients in a 1:1 ratio to receive either cemiplimab-rwlc or platinum-doublet chemotherapy. Patients had either locally advanced NSCLC and were not candidates for surgical resection or definitive chemoradiotherapy, or they had metastatic NSCLC.
Patients in the experimental arm received cemiplimab-rwlc 350 mg intravenously every 3 weeks. The primary efficacy outcome measures were overall survival (OS) and progression-free survival (PFS), determined on the basis of blinded independent central review.
Results showed statistically significant improvements in both outcomes. Median OS was 22.1 months with cemiplimab-rwlc versus 14.3 months with chemotherapy (hazard ratio, 0.68; P = .0022). Median PFS was 6.2 months versus 5.6 months (HR, 0.59; P < .0001).
The confirmed overall response rate was 37% for the cemiplimab arm versus 21% for the chemotherapy arm.
The most common adverse reactions (>10%) with cemiplimab-rlwc were musculoskeletal pain, rash, anemia, fatigue, decreased appetite, pneumonia, and cough.
This approval “means physicians and patients have a potent new treatment option against this deadly disease,” said Naiyer Rizvi, MD, Price Family Professor of Medicine, director of thoracic oncology, and codirector of cancer immunotherapy at Columbia University Irving Medical Center, New York, in a statement. He was a steering committee member on the EMPOWER-Lung-1 Trial.
“Notably, Libtayo was approved based on a pivotal trial where most chemotherapy patients crossed over to Libtayo following disease progression, and that allowed for frequently underrepresented patients who had pretreated and clinically stable brain metastases or who had locally advanced disease and were not candidates for definitive chemoradiation,” said Dr. Rizvi. “This gives doctors important new data when considering Libtayo for the varied patients and situations they treat in daily clinical practice.”
A version of this article first appeared on Medscape.com.
Specifically, the indication is for first-line treatment as monotherapy for patients with locally advanced or metastatic disease who are not candidates for surgical resection or definitive chemoradiotherapy and whose tumors have a high expression of programmed death–ligand 1 (PD-L1) (Tumor Proportion Score >50%), as determined by an FDA-approved test, with no EGFR, ALK, or ROS1 aberrations.
This is the third indication for cemiplimab-rlwc, a monoclonal antibody and PD-1 inhibitor.
In February, it was approved as the first immunotherapy to treat patients with locally advanced or metastatic basal cell carcinoma that was previously treated with a hedgehog pathway inhibitor or for whom a hedgehog inhibitor is inappropriate.
Cemiplimab-rlwc previously received FDA approval in 2018 for locally advanced or metastatic cutaneous squamous cell carcinoma for patients who were not eligible for curative surgery or radiotherapy. At the time, Karl Lewis, MD, a professor at the University of Colorado at Denver, Aurora, and a trial investigator, predicted that the drug “will change the treatment paradigm for patients with advanced basal cell carcinoma.”
Outperforms chemotherapy
The approval for use in NSCLC is based on results from the phase 3, open-label EMPOWER-Lung 1 trial, which randomly assigned 710 patients in a 1:1 ratio to receive either cemiplimab-rwlc or platinum-doublet chemotherapy. Patients had either locally advanced NSCLC and were not candidates for surgical resection or definitive chemoradiotherapy, or they had metastatic NSCLC.
Patients in the experimental arm received cemiplimab-rwlc 350 mg intravenously every 3 weeks. The primary efficacy outcome measures were overall survival (OS) and progression-free survival (PFS), determined on the basis of blinded independent central review.
Results showed statistically significant improvements in both outcomes. Median OS was 22.1 months with cemiplimab-rwlc versus 14.3 months with chemotherapy (hazard ratio, 0.68; P = .0022). Median PFS was 6.2 months versus 5.6 months (HR, 0.59; P < .0001).
The confirmed overall response rate was 37% for the cemiplimab arm versus 21% for the chemotherapy arm.
The most common adverse reactions (>10%) with cemiplimab-rlwc were musculoskeletal pain, rash, anemia, fatigue, decreased appetite, pneumonia, and cough.
This approval “means physicians and patients have a potent new treatment option against this deadly disease,” said Naiyer Rizvi, MD, Price Family Professor of Medicine, director of thoracic oncology, and codirector of cancer immunotherapy at Columbia University Irving Medical Center, New York, in a statement. He was a steering committee member on the EMPOWER-Lung-1 Trial.
“Notably, Libtayo was approved based on a pivotal trial where most chemotherapy patients crossed over to Libtayo following disease progression, and that allowed for frequently underrepresented patients who had pretreated and clinically stable brain metastases or who had locally advanced disease and were not candidates for definitive chemoradiation,” said Dr. Rizvi. “This gives doctors important new data when considering Libtayo for the varied patients and situations they treat in daily clinical practice.”
A version of this article first appeared on Medscape.com.
Tips offered for treating co-occurring ADHD and SUDs
When Frances R. Levin, MD, began her clinical psychiatry career in the mid-1990s, she spent a lot of time educating colleagues about the validity of an ADHD diagnosis in adults.
“That’s no longer an issue,” Dr. Levin, the Kennedy-Leavy Professor of Psychiatry at Columbia University, New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “But at the time, we often thought, ‘ADHD is something that’s specific to people who are stimulant users.’ In fact, what we found over the years was that these rates are elevated in a range of substance use populations.”
According to National Comorbidity Survey, a nontreatment sample of more than 3,000 adults, individuals who have SUD have two to three times the risk of having ADHD, while individuals who have ADHD have about three times the rate of having an SUD, compared with those who don’t (Am J Psychiatry. 2006;163[4]:716-23). “When you move to treatment samples, the rates also remain quite high,” said Dr. Levin, who is also chief of the division of substance use disorders at the medical center.
“In the general population, the rates of ADHD are 2%-4%. When we look at people who are coming in specifically for treatment of their SUD, the rates are substantially higher, ranging from 10% to 24%.”
According to a 2014 review of medical literature, potential reasons for the association between ADHD and SUD vary and include underlying biologic deficits, such as parental SUDs and genetics; conduct disorder symptoms, such as defiance, rule breaking, and delinquency; poor performance in school, such as low grades, grade retention, or drop-out; and social difficulties, such as rejection from conventional groups or few quality friendships (Annu Rev Clin Psychol. 2014;10:607-39). Other potential pathways include neurocognitive deficits, stress-negative affect models, impulsive anger, and other underlying traits.
One key reason to treat ADHD in patients with SUDs is that they tend to develop the SUD earlier when the ADHD is present, Dr. Levin said. They’re also less likely to be retained in treatment and have a reduced likelihood of going into remission if dependence develops. “Even when they do achieve remission, it seems to take longer for people to reach remission,” she said. “They have more treatment exposure yet do less well in treatment. This can make it more challenging to treat this population.”
One common assumption from clinicians regarding patients with ADHD and a concomitant SUD is that standard treatments for ADHD do not work in active substance users. Another is that, even if treatments work for ADHD, they do not affect the substance use disorder. “Understandably, there is also concern that active substance abusers will misuse and divert their medications,” she said. “Finally, there are often additional psychiatric comorbidities that may make it harder to effectively treat individuals with ADHD and SUD.”
Since 2002, 15 double-blind outpatient studies using stimulants/atomoxetine to treat substance abusers with ADHD have appeared in the medical literature, Dr. Levin said. Only three have included adolescents. “That’s surprising, because up to 40% of kids who come in for treatment, often for cannabis use disorder, will have ADHD, yet there is very little guidance from empirical studies as to how to best treat them,” she said. “There have been several studies looking at atomoxetine to treat substance abusers with ADHD, but results have been mixed. In the cannabis use populations, atomoxetine has not been shown to be effective in treating the substance use disorder, and results are mixed regarding superiority in reducing ADHD symptoms. There is one study showing that ADHD is more likely to be improved in adults with alcohol use disorders with mixed results regarding the alcohol use.”
Overall, most of the outpatient and inpatient studies conducted in this population have demonstrated some signal in terms of reducing ADHD, she said, while a minority of the outpatient studies suggest some benefit in terms of substance use. “What’s interesting is that when you see a response in terms of the ADHD, you often see an improvement in the substance use as well,” Dr. Levin said. “This potentially suggests that patients may be self-medicating their ADHD symptoms or that if the ADHD responds to treatment, then the patient may benefit from the psychosocial interventions that targets the SUD.”
A separate meta-analysis involving more than 1,000 patients found mixed results from pharmacologic interventions and concluded that, while they modestly improved ADHD symptoms, no beneficial effect was seen on drug abstinence or on treatment discontinuation (J Psychopharmacol. 2015 Jan;29[1]:15-23). “I would argue that you don’t need to be as nihilistic about this as the meta-analysis might suggest, because the devil’s in the details,” said Dr. Levin, whose own research was included in the work.
“First of all, many of the studies had high drop-out rates. The outcome measures were variable, and some of the studies used formulations with poor bioavailability. Also, trials that evaluated atomoxetine or stimulants were combined, which may be problematic given the different mechanisms of action. Further, the meta-analysis did not include two recent placebo-controlled trials in adults with stimulant-use disorders that both found that higher dosing of a long-acting stimulant resulted in greater improvements in ADHD symptoms and stimulant use” (Addict. 2014;109[3]:440-9 and JAMA Psychiatry. 2015;72[6]:593-602).
Dr. Levin went on to note that there are few empirical data to guide treatment for those who have multiple psychiatric disorders, let alone treatment for ADHD and SUDs without additional psychiatric disorders. The challenge is what to treat first and/or how to treat the concomitant conditions safely.
“Generally, if possible, treat what is most clinically impairing first,” she said. “Overall, both stimulants and atomoxetine may work for ADHD even in the presence of additional depression, anxiety disorders, and substance use disorders.”
She cautioned against treating a patient with ADHD medication if there is a preexisting psychosis or bipolar illness. “If you start a stimulant or atomoxetine and psychosis or mania occurs, you clearly want to stop the medication and reassess,” she said. Researchers found that the risk of precipitating mania with a stimulant is uncommon if you alleviate symptoms first with a mood stabilizer. “This is a situation where you probably want to treat the bipolar illness first, but it does not preclude the treatment of ADHD once the mood stabilization has occurred,” she said.
In patients with ADHD and anxiety, she often treats the ADHD first, “because oftentimes the anxiety is driven by the procrastination and the inability to get things done,” she explained. “It’s important to determine whether the anxiety is an independent disorder rather than symptoms of ADHD. Inner restlessness can be described as anxiety.”
When there are concerns that preclude the use of a controlled medication, there are medications, in addition to atomoxetine, that might be considered. While bupropion is not Food and Drug Administration approved for ADHD, it might be useful in comorbid mood disorders for nicotine dependence. Other off-label medications that may help include guanfacine, modafinil, and tricyclic antidepressants.
“To date, robust dosing of long-acting amphetamine or methylphenidate formulations have been shown to be effective for patients with stimulant-use disorder, but as mentioned earlier, the data only come from two studies,” she said.
In order to determine whether stimulant treatment is yielding a benefit in a patient with co-occurring ADHD and SUD, she recommends carrying out a structured assessment of ADHD symptoms. Monitoring for functional improvement is also key.
“If there is no improvement in social, occupational, or academic settings and the patient is still actively using drugs, then there is no reason to keep prescribing,” she said. Close monitoring for cardiovascular or other psychiatric symptoms are key as well. Further, for those individuals with both ADHD and a substance-use disorder, it is critical that both are targeted for treatment.
Dr. Levin reported that she has received research, training, or salary support from the National Institute on Drug Abuse, New York state, and the Substance Abuse and Mental Health Services Administration. She has also received or currently receives industry support from Indivior and U.S. World Meds and for medication and from Major League Baseball. In addition, Dr. Levin has been an unpaid scientific advisory board member for Alkermes, Indivior, and Novartis.
When Frances R. Levin, MD, began her clinical psychiatry career in the mid-1990s, she spent a lot of time educating colleagues about the validity of an ADHD diagnosis in adults.
“That’s no longer an issue,” Dr. Levin, the Kennedy-Leavy Professor of Psychiatry at Columbia University, New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “But at the time, we often thought, ‘ADHD is something that’s specific to people who are stimulant users.’ In fact, what we found over the years was that these rates are elevated in a range of substance use populations.”
According to National Comorbidity Survey, a nontreatment sample of more than 3,000 adults, individuals who have SUD have two to three times the risk of having ADHD, while individuals who have ADHD have about three times the rate of having an SUD, compared with those who don’t (Am J Psychiatry. 2006;163[4]:716-23). “When you move to treatment samples, the rates also remain quite high,” said Dr. Levin, who is also chief of the division of substance use disorders at the medical center.
“In the general population, the rates of ADHD are 2%-4%. When we look at people who are coming in specifically for treatment of their SUD, the rates are substantially higher, ranging from 10% to 24%.”
According to a 2014 review of medical literature, potential reasons for the association between ADHD and SUD vary and include underlying biologic deficits, such as parental SUDs and genetics; conduct disorder symptoms, such as defiance, rule breaking, and delinquency; poor performance in school, such as low grades, grade retention, or drop-out; and social difficulties, such as rejection from conventional groups or few quality friendships (Annu Rev Clin Psychol. 2014;10:607-39). Other potential pathways include neurocognitive deficits, stress-negative affect models, impulsive anger, and other underlying traits.
One key reason to treat ADHD in patients with SUDs is that they tend to develop the SUD earlier when the ADHD is present, Dr. Levin said. They’re also less likely to be retained in treatment and have a reduced likelihood of going into remission if dependence develops. “Even when they do achieve remission, it seems to take longer for people to reach remission,” she said. “They have more treatment exposure yet do less well in treatment. This can make it more challenging to treat this population.”
One common assumption from clinicians regarding patients with ADHD and a concomitant SUD is that standard treatments for ADHD do not work in active substance users. Another is that, even if treatments work for ADHD, they do not affect the substance use disorder. “Understandably, there is also concern that active substance abusers will misuse and divert their medications,” she said. “Finally, there are often additional psychiatric comorbidities that may make it harder to effectively treat individuals with ADHD and SUD.”
Since 2002, 15 double-blind outpatient studies using stimulants/atomoxetine to treat substance abusers with ADHD have appeared in the medical literature, Dr. Levin said. Only three have included adolescents. “That’s surprising, because up to 40% of kids who come in for treatment, often for cannabis use disorder, will have ADHD, yet there is very little guidance from empirical studies as to how to best treat them,” she said. “There have been several studies looking at atomoxetine to treat substance abusers with ADHD, but results have been mixed. In the cannabis use populations, atomoxetine has not been shown to be effective in treating the substance use disorder, and results are mixed regarding superiority in reducing ADHD symptoms. There is one study showing that ADHD is more likely to be improved in adults with alcohol use disorders with mixed results regarding the alcohol use.”
Overall, most of the outpatient and inpatient studies conducted in this population have demonstrated some signal in terms of reducing ADHD, she said, while a minority of the outpatient studies suggest some benefit in terms of substance use. “What’s interesting is that when you see a response in terms of the ADHD, you often see an improvement in the substance use as well,” Dr. Levin said. “This potentially suggests that patients may be self-medicating their ADHD symptoms or that if the ADHD responds to treatment, then the patient may benefit from the psychosocial interventions that targets the SUD.”
A separate meta-analysis involving more than 1,000 patients found mixed results from pharmacologic interventions and concluded that, while they modestly improved ADHD symptoms, no beneficial effect was seen on drug abstinence or on treatment discontinuation (J Psychopharmacol. 2015 Jan;29[1]:15-23). “I would argue that you don’t need to be as nihilistic about this as the meta-analysis might suggest, because the devil’s in the details,” said Dr. Levin, whose own research was included in the work.
“First of all, many of the studies had high drop-out rates. The outcome measures were variable, and some of the studies used formulations with poor bioavailability. Also, trials that evaluated atomoxetine or stimulants were combined, which may be problematic given the different mechanisms of action. Further, the meta-analysis did not include two recent placebo-controlled trials in adults with stimulant-use disorders that both found that higher dosing of a long-acting stimulant resulted in greater improvements in ADHD symptoms and stimulant use” (Addict. 2014;109[3]:440-9 and JAMA Psychiatry. 2015;72[6]:593-602).
Dr. Levin went on to note that there are few empirical data to guide treatment for those who have multiple psychiatric disorders, let alone treatment for ADHD and SUDs without additional psychiatric disorders. The challenge is what to treat first and/or how to treat the concomitant conditions safely.
“Generally, if possible, treat what is most clinically impairing first,” she said. “Overall, both stimulants and atomoxetine may work for ADHD even in the presence of additional depression, anxiety disorders, and substance use disorders.”
She cautioned against treating a patient with ADHD medication if there is a preexisting psychosis or bipolar illness. “If you start a stimulant or atomoxetine and psychosis or mania occurs, you clearly want to stop the medication and reassess,” she said. Researchers found that the risk of precipitating mania with a stimulant is uncommon if you alleviate symptoms first with a mood stabilizer. “This is a situation where you probably want to treat the bipolar illness first, but it does not preclude the treatment of ADHD once the mood stabilization has occurred,” she said.
In patients with ADHD and anxiety, she often treats the ADHD first, “because oftentimes the anxiety is driven by the procrastination and the inability to get things done,” she explained. “It’s important to determine whether the anxiety is an independent disorder rather than symptoms of ADHD. Inner restlessness can be described as anxiety.”
When there are concerns that preclude the use of a controlled medication, there are medications, in addition to atomoxetine, that might be considered. While bupropion is not Food and Drug Administration approved for ADHD, it might be useful in comorbid mood disorders for nicotine dependence. Other off-label medications that may help include guanfacine, modafinil, and tricyclic antidepressants.
“To date, robust dosing of long-acting amphetamine or methylphenidate formulations have been shown to be effective for patients with stimulant-use disorder, but as mentioned earlier, the data only come from two studies,” she said.
In order to determine whether stimulant treatment is yielding a benefit in a patient with co-occurring ADHD and SUD, she recommends carrying out a structured assessment of ADHD symptoms. Monitoring for functional improvement is also key.
“If there is no improvement in social, occupational, or academic settings and the patient is still actively using drugs, then there is no reason to keep prescribing,” she said. Close monitoring for cardiovascular or other psychiatric symptoms are key as well. Further, for those individuals with both ADHD and a substance-use disorder, it is critical that both are targeted for treatment.
Dr. Levin reported that she has received research, training, or salary support from the National Institute on Drug Abuse, New York state, and the Substance Abuse and Mental Health Services Administration. She has also received or currently receives industry support from Indivior and U.S. World Meds and for medication and from Major League Baseball. In addition, Dr. Levin has been an unpaid scientific advisory board member for Alkermes, Indivior, and Novartis.
When Frances R. Levin, MD, began her clinical psychiatry career in the mid-1990s, she spent a lot of time educating colleagues about the validity of an ADHD diagnosis in adults.
“That’s no longer an issue,” Dr. Levin, the Kennedy-Leavy Professor of Psychiatry at Columbia University, New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “But at the time, we often thought, ‘ADHD is something that’s specific to people who are stimulant users.’ In fact, what we found over the years was that these rates are elevated in a range of substance use populations.”
According to National Comorbidity Survey, a nontreatment sample of more than 3,000 adults, individuals who have SUD have two to three times the risk of having ADHD, while individuals who have ADHD have about three times the rate of having an SUD, compared with those who don’t (Am J Psychiatry. 2006;163[4]:716-23). “When you move to treatment samples, the rates also remain quite high,” said Dr. Levin, who is also chief of the division of substance use disorders at the medical center.
“In the general population, the rates of ADHD are 2%-4%. When we look at people who are coming in specifically for treatment of their SUD, the rates are substantially higher, ranging from 10% to 24%.”
According to a 2014 review of medical literature, potential reasons for the association between ADHD and SUD vary and include underlying biologic deficits, such as parental SUDs and genetics; conduct disorder symptoms, such as defiance, rule breaking, and delinquency; poor performance in school, such as low grades, grade retention, or drop-out; and social difficulties, such as rejection from conventional groups or few quality friendships (Annu Rev Clin Psychol. 2014;10:607-39). Other potential pathways include neurocognitive deficits, stress-negative affect models, impulsive anger, and other underlying traits.
One key reason to treat ADHD in patients with SUDs is that they tend to develop the SUD earlier when the ADHD is present, Dr. Levin said. They’re also less likely to be retained in treatment and have a reduced likelihood of going into remission if dependence develops. “Even when they do achieve remission, it seems to take longer for people to reach remission,” she said. “They have more treatment exposure yet do less well in treatment. This can make it more challenging to treat this population.”
One common assumption from clinicians regarding patients with ADHD and a concomitant SUD is that standard treatments for ADHD do not work in active substance users. Another is that, even if treatments work for ADHD, they do not affect the substance use disorder. “Understandably, there is also concern that active substance abusers will misuse and divert their medications,” she said. “Finally, there are often additional psychiatric comorbidities that may make it harder to effectively treat individuals with ADHD and SUD.”
Since 2002, 15 double-blind outpatient studies using stimulants/atomoxetine to treat substance abusers with ADHD have appeared in the medical literature, Dr. Levin said. Only three have included adolescents. “That’s surprising, because up to 40% of kids who come in for treatment, often for cannabis use disorder, will have ADHD, yet there is very little guidance from empirical studies as to how to best treat them,” she said. “There have been several studies looking at atomoxetine to treat substance abusers with ADHD, but results have been mixed. In the cannabis use populations, atomoxetine has not been shown to be effective in treating the substance use disorder, and results are mixed regarding superiority in reducing ADHD symptoms. There is one study showing that ADHD is more likely to be improved in adults with alcohol use disorders with mixed results regarding the alcohol use.”
Overall, most of the outpatient and inpatient studies conducted in this population have demonstrated some signal in terms of reducing ADHD, she said, while a minority of the outpatient studies suggest some benefit in terms of substance use. “What’s interesting is that when you see a response in terms of the ADHD, you often see an improvement in the substance use as well,” Dr. Levin said. “This potentially suggests that patients may be self-medicating their ADHD symptoms or that if the ADHD responds to treatment, then the patient may benefit from the psychosocial interventions that targets the SUD.”
A separate meta-analysis involving more than 1,000 patients found mixed results from pharmacologic interventions and concluded that, while they modestly improved ADHD symptoms, no beneficial effect was seen on drug abstinence or on treatment discontinuation (J Psychopharmacol. 2015 Jan;29[1]:15-23). “I would argue that you don’t need to be as nihilistic about this as the meta-analysis might suggest, because the devil’s in the details,” said Dr. Levin, whose own research was included in the work.
“First of all, many of the studies had high drop-out rates. The outcome measures were variable, and some of the studies used formulations with poor bioavailability. Also, trials that evaluated atomoxetine or stimulants were combined, which may be problematic given the different mechanisms of action. Further, the meta-analysis did not include two recent placebo-controlled trials in adults with stimulant-use disorders that both found that higher dosing of a long-acting stimulant resulted in greater improvements in ADHD symptoms and stimulant use” (Addict. 2014;109[3]:440-9 and JAMA Psychiatry. 2015;72[6]:593-602).
Dr. Levin went on to note that there are few empirical data to guide treatment for those who have multiple psychiatric disorders, let alone treatment for ADHD and SUDs without additional psychiatric disorders. The challenge is what to treat first and/or how to treat the concomitant conditions safely.
“Generally, if possible, treat what is most clinically impairing first,” she said. “Overall, both stimulants and atomoxetine may work for ADHD even in the presence of additional depression, anxiety disorders, and substance use disorders.”
She cautioned against treating a patient with ADHD medication if there is a preexisting psychosis or bipolar illness. “If you start a stimulant or atomoxetine and psychosis or mania occurs, you clearly want to stop the medication and reassess,” she said. Researchers found that the risk of precipitating mania with a stimulant is uncommon if you alleviate symptoms first with a mood stabilizer. “This is a situation where you probably want to treat the bipolar illness first, but it does not preclude the treatment of ADHD once the mood stabilization has occurred,” she said.
In patients with ADHD and anxiety, she often treats the ADHD first, “because oftentimes the anxiety is driven by the procrastination and the inability to get things done,” she explained. “It’s important to determine whether the anxiety is an independent disorder rather than symptoms of ADHD. Inner restlessness can be described as anxiety.”
When there are concerns that preclude the use of a controlled medication, there are medications, in addition to atomoxetine, that might be considered. While bupropion is not Food and Drug Administration approved for ADHD, it might be useful in comorbid mood disorders for nicotine dependence. Other off-label medications that may help include guanfacine, modafinil, and tricyclic antidepressants.
“To date, robust dosing of long-acting amphetamine or methylphenidate formulations have been shown to be effective for patients with stimulant-use disorder, but as mentioned earlier, the data only come from two studies,” she said.
In order to determine whether stimulant treatment is yielding a benefit in a patient with co-occurring ADHD and SUD, she recommends carrying out a structured assessment of ADHD symptoms. Monitoring for functional improvement is also key.
“If there is no improvement in social, occupational, or academic settings and the patient is still actively using drugs, then there is no reason to keep prescribing,” she said. Close monitoring for cardiovascular or other psychiatric symptoms are key as well. Further, for those individuals with both ADHD and a substance-use disorder, it is critical that both are targeted for treatment.
Dr. Levin reported that she has received research, training, or salary support from the National Institute on Drug Abuse, New York state, and the Substance Abuse and Mental Health Services Administration. She has also received or currently receives industry support from Indivior and U.S. World Meds and for medication and from Major League Baseball. In addition, Dr. Levin has been an unpaid scientific advisory board member for Alkermes, Indivior, and Novartis.
FROM NPA 2021
Large study finds trans men on testosterone at risk for blood clots
Over 10% of transgender men (females transitioning to male) who take testosterone develop high hematocrit levels that could put them at greater risk for a thrombotic event, and the largest increase in levels occurs in the first year after starting therapy, a new Dutch study indicates.
Erythrocytosis, defined as a hematocrit greater than 0.50 L/L, is a potentially serious side effect of testosterone therapy, say Milou Cecilia Madsen, MD, and colleagues in their article published online Feb. 18, 2021, in the Journal of Clinical Endocrinology & Metabolism.
When hematocrit was measured twice, 11.1% of the cohort of 1073 trans men had levels in excess of 0.50 L/L over a 20-year follow-up.
“Erythrocytosis is common in transgender men treated with testosterone, especially in those who smoke, have [a] high BMI [body mass index], and [who] use testosterone injections,” Dr. Madsen, of the VU University Medical Center Amsterdam, said in a statement from the Endocrine Society.
“A reasonable first step in the care of transgender men with high red blood cells while on testosterone is to advise them to quit smoking, switch injectable testosterone to gel, and, if BMI is high, to lose weight,” she added.
First large study of testosterone in trans men with 20-year follow-up
Transgender men often undergo testosterone therapy as part of gender-affirming treatment.
Secondary erythrocytosis, a condition where the body makes too many red blood cells, is a common side effect of testosterone therapy that can increase the risk of thrombolic events, heart attack, and stroke, Dr. Madsen and colleagues explained.
This is the first study of a large cohort of trans men taking testosterone therapy followed for up to 20 years. Because of the large sample size, statistical analysis with many determinants could be performed. And because of the long follow-up, a clear time relation between initiation of testosterone therapy and hematocrit could be studied, they noted.
Participants were part of the Amsterdam Cohort of Gender Dysphoria study, a large cohort of individuals seen at the Center of Expertise on Gender Dysphoria at Amsterdam University Medical Center between 1972 and 2015.
Laboratory measurements taken between 2004 and 2018 were available for analysis. Trans men visited the center every 3-6 months during their first year of testosterone therapy and were then monitored every year or every other year.
Long-acting undecanoate injection was associated with the highest risk of a hematocrit level greater than 0.50 L/L, and the risk of erythrocytosis in those who took long-acting intramuscular injections was about threefold higher, compared with testosterone gel (adjusted odds ratio, 3.1).
In contrast, short-acting ester injections and oral administration of testosterone had a similar risk for erythrocytosis, as did testosterone gel.
Other determinants of elevated hematocrit included smoking, medical history of a number of comorbid conditions, and older age on initiation of testosterone.
In contrast, “higher testosterone levels per se were not associated with an increased odds of hematocrit greater than 0.50 L/L”, the authors noted.
Current advice for trans men based on old guidance for hypogonadism
The authors said that current advice for trans men is based on recommendations for testosterone-treated hypogonadal cis men (those assigned male at birth) from 2008, which advises a hematocrit greater than 0.50 L/L has a moderate to high risk of adverse outcome. For levels greater than 0.54 L/L, cessation of testosterone therapy, a dose reduction, or therapeutic phlebotomy to reduce the risk of adverse events is advised. For levels 0.50-0.54 L/L, no clear advice is given.
But questions remain as to whether these guidelines are applicable to trans men because the duration of testosterone therapy is much longer in trans men and hormone treatment often cannot be discontinued without causing distress.
Meanwhile, hematology guidelines indicate an upper limit for hematocrit for cis females of 0.48 L/L.
“It could be argued that the upper limit for cis females should be applied, as trans men are born with female genetics,” the authors said. “This is a subject for further research.”
Duration of testosterone therapy impacts risk of erythrocytosis
In the study, the researchers found that longer duration of testosterone therapy increased the risk of developing hematocrit levels greater than 0.50 L/L. For example, after 1 year, the cumulative incidence of erythrocytosis was 8%; after 10 years, it was 38%; and after 14 years, it was 50%.
Until more specific guidance is developed for trans men, if hematocrit levels rise to 0.50-0.54 L/L, the researchers suggested taking “reasonable” steps to prevent a further increase:
- Consider switching patients who use injectable testosterone to transdermal products.
- Advise patients with a BMI greater than 25 kg/m2 to lose weight to attain a BMI of 18.5-25.
- Advise patients to stop smoking.
- Pursue treatment optimization for chronic lung disease or sleep apnea.
The study had no external funding. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Over 10% of transgender men (females transitioning to male) who take testosterone develop high hematocrit levels that could put them at greater risk for a thrombotic event, and the largest increase in levels occurs in the first year after starting therapy, a new Dutch study indicates.
Erythrocytosis, defined as a hematocrit greater than 0.50 L/L, is a potentially serious side effect of testosterone therapy, say Milou Cecilia Madsen, MD, and colleagues in their article published online Feb. 18, 2021, in the Journal of Clinical Endocrinology & Metabolism.
When hematocrit was measured twice, 11.1% of the cohort of 1073 trans men had levels in excess of 0.50 L/L over a 20-year follow-up.
“Erythrocytosis is common in transgender men treated with testosterone, especially in those who smoke, have [a] high BMI [body mass index], and [who] use testosterone injections,” Dr. Madsen, of the VU University Medical Center Amsterdam, said in a statement from the Endocrine Society.
“A reasonable first step in the care of transgender men with high red blood cells while on testosterone is to advise them to quit smoking, switch injectable testosterone to gel, and, if BMI is high, to lose weight,” she added.
First large study of testosterone in trans men with 20-year follow-up
Transgender men often undergo testosterone therapy as part of gender-affirming treatment.
Secondary erythrocytosis, a condition where the body makes too many red blood cells, is a common side effect of testosterone therapy that can increase the risk of thrombolic events, heart attack, and stroke, Dr. Madsen and colleagues explained.
This is the first study of a large cohort of trans men taking testosterone therapy followed for up to 20 years. Because of the large sample size, statistical analysis with many determinants could be performed. And because of the long follow-up, a clear time relation between initiation of testosterone therapy and hematocrit could be studied, they noted.
Participants were part of the Amsterdam Cohort of Gender Dysphoria study, a large cohort of individuals seen at the Center of Expertise on Gender Dysphoria at Amsterdam University Medical Center between 1972 and 2015.
Laboratory measurements taken between 2004 and 2018 were available for analysis. Trans men visited the center every 3-6 months during their first year of testosterone therapy and were then monitored every year or every other year.
Long-acting undecanoate injection was associated with the highest risk of a hematocrit level greater than 0.50 L/L, and the risk of erythrocytosis in those who took long-acting intramuscular injections was about threefold higher, compared with testosterone gel (adjusted odds ratio, 3.1).
In contrast, short-acting ester injections and oral administration of testosterone had a similar risk for erythrocytosis, as did testosterone gel.
Other determinants of elevated hematocrit included smoking, medical history of a number of comorbid conditions, and older age on initiation of testosterone.
In contrast, “higher testosterone levels per se were not associated with an increased odds of hematocrit greater than 0.50 L/L”, the authors noted.
Current advice for trans men based on old guidance for hypogonadism
The authors said that current advice for trans men is based on recommendations for testosterone-treated hypogonadal cis men (those assigned male at birth) from 2008, which advises a hematocrit greater than 0.50 L/L has a moderate to high risk of adverse outcome. For levels greater than 0.54 L/L, cessation of testosterone therapy, a dose reduction, or therapeutic phlebotomy to reduce the risk of adverse events is advised. For levels 0.50-0.54 L/L, no clear advice is given.
But questions remain as to whether these guidelines are applicable to trans men because the duration of testosterone therapy is much longer in trans men and hormone treatment often cannot be discontinued without causing distress.
Meanwhile, hematology guidelines indicate an upper limit for hematocrit for cis females of 0.48 L/L.
“It could be argued that the upper limit for cis females should be applied, as trans men are born with female genetics,” the authors said. “This is a subject for further research.”
Duration of testosterone therapy impacts risk of erythrocytosis
In the study, the researchers found that longer duration of testosterone therapy increased the risk of developing hematocrit levels greater than 0.50 L/L. For example, after 1 year, the cumulative incidence of erythrocytosis was 8%; after 10 years, it was 38%; and after 14 years, it was 50%.
Until more specific guidance is developed for trans men, if hematocrit levels rise to 0.50-0.54 L/L, the researchers suggested taking “reasonable” steps to prevent a further increase:
- Consider switching patients who use injectable testosterone to transdermal products.
- Advise patients with a BMI greater than 25 kg/m2 to lose weight to attain a BMI of 18.5-25.
- Advise patients to stop smoking.
- Pursue treatment optimization for chronic lung disease or sleep apnea.
The study had no external funding. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Over 10% of transgender men (females transitioning to male) who take testosterone develop high hematocrit levels that could put them at greater risk for a thrombotic event, and the largest increase in levels occurs in the first year after starting therapy, a new Dutch study indicates.
Erythrocytosis, defined as a hematocrit greater than 0.50 L/L, is a potentially serious side effect of testosterone therapy, say Milou Cecilia Madsen, MD, and colleagues in their article published online Feb. 18, 2021, in the Journal of Clinical Endocrinology & Metabolism.
When hematocrit was measured twice, 11.1% of the cohort of 1073 trans men had levels in excess of 0.50 L/L over a 20-year follow-up.
“Erythrocytosis is common in transgender men treated with testosterone, especially in those who smoke, have [a] high BMI [body mass index], and [who] use testosterone injections,” Dr. Madsen, of the VU University Medical Center Amsterdam, said in a statement from the Endocrine Society.
“A reasonable first step in the care of transgender men with high red blood cells while on testosterone is to advise them to quit smoking, switch injectable testosterone to gel, and, if BMI is high, to lose weight,” she added.
First large study of testosterone in trans men with 20-year follow-up
Transgender men often undergo testosterone therapy as part of gender-affirming treatment.
Secondary erythrocytosis, a condition where the body makes too many red blood cells, is a common side effect of testosterone therapy that can increase the risk of thrombolic events, heart attack, and stroke, Dr. Madsen and colleagues explained.
This is the first study of a large cohort of trans men taking testosterone therapy followed for up to 20 years. Because of the large sample size, statistical analysis with many determinants could be performed. And because of the long follow-up, a clear time relation between initiation of testosterone therapy and hematocrit could be studied, they noted.
Participants were part of the Amsterdam Cohort of Gender Dysphoria study, a large cohort of individuals seen at the Center of Expertise on Gender Dysphoria at Amsterdam University Medical Center between 1972 and 2015.
Laboratory measurements taken between 2004 and 2018 were available for analysis. Trans men visited the center every 3-6 months during their first year of testosterone therapy and were then monitored every year or every other year.
Long-acting undecanoate injection was associated with the highest risk of a hematocrit level greater than 0.50 L/L, and the risk of erythrocytosis in those who took long-acting intramuscular injections was about threefold higher, compared with testosterone gel (adjusted odds ratio, 3.1).
In contrast, short-acting ester injections and oral administration of testosterone had a similar risk for erythrocytosis, as did testosterone gel.
Other determinants of elevated hematocrit included smoking, medical history of a number of comorbid conditions, and older age on initiation of testosterone.
In contrast, “higher testosterone levels per se were not associated with an increased odds of hematocrit greater than 0.50 L/L”, the authors noted.
Current advice for trans men based on old guidance for hypogonadism
The authors said that current advice for trans men is based on recommendations for testosterone-treated hypogonadal cis men (those assigned male at birth) from 2008, which advises a hematocrit greater than 0.50 L/L has a moderate to high risk of adverse outcome. For levels greater than 0.54 L/L, cessation of testosterone therapy, a dose reduction, or therapeutic phlebotomy to reduce the risk of adverse events is advised. For levels 0.50-0.54 L/L, no clear advice is given.
But questions remain as to whether these guidelines are applicable to trans men because the duration of testosterone therapy is much longer in trans men and hormone treatment often cannot be discontinued without causing distress.
Meanwhile, hematology guidelines indicate an upper limit for hematocrit for cis females of 0.48 L/L.
“It could be argued that the upper limit for cis females should be applied, as trans men are born with female genetics,” the authors said. “This is a subject for further research.”
Duration of testosterone therapy impacts risk of erythrocytosis
In the study, the researchers found that longer duration of testosterone therapy increased the risk of developing hematocrit levels greater than 0.50 L/L. For example, after 1 year, the cumulative incidence of erythrocytosis was 8%; after 10 years, it was 38%; and after 14 years, it was 50%.
Until more specific guidance is developed for trans men, if hematocrit levels rise to 0.50-0.54 L/L, the researchers suggested taking “reasonable” steps to prevent a further increase:
- Consider switching patients who use injectable testosterone to transdermal products.
- Advise patients with a BMI greater than 25 kg/m2 to lose weight to attain a BMI of 18.5-25.
- Advise patients to stop smoking.
- Pursue treatment optimization for chronic lung disease or sleep apnea.
The study had no external funding. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CAR T-cell products shine in real-world setting, reveal new insights
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
Real-world experience with chimeric antigen receptor (CAR) T-cell therapies for large B-cell lymphomas compares favorably with experience in commercial and trial settings and provides new insights for predicting outcomes, according to Paolo Corradini, MD.
The 12-month duration of response (DOR) and progression-free survival (PFS) rates in 152 real-world patients treated with tisagenlecleucel (tisa-cel; Kymriah) for an approved indication were 48.4% and 26.4%, respectively, data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and published in November 2020 in Blood Advances showed.
who relapsed or were refractory to at least two prior lines of therapy, Dr. Corradini said at the third European CAR T-cell Meeting, jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
A clinical update of the JULIET trial, as presented by Dr. Corradini and colleagues in a poster at the 2020 annual conference of the American Society of Hematology, showed a relapse-free probability of 60.4% at 24 and 30 months among 61 patients with an initial response.
The 12- and 36-month PFS rates as of February 2020, with median follow-up of 40.3 months, were 33% and 31%, respectively, and no new safety signals were identified, said Dr. Corradini, chair of hematology at the University of Milan.
Similarly, real-world data from the U.S. Lymphoma CAR T Consortium showing median PFS of 8.3 months at median follow-up of 12.9 months in 275 patients treated with axicabtagene ciloleucel (axi-cel; YESCARTA) were comparable with outcomes in the ZUMA-1 registrational trial, he noted.
An ongoing response was seen at 2 years in 39% of patients in ZUMA-1, and 3-year survival was 47%, according to an update reported at ASH 2019.
Of note, 43% of patients in the real-world study, which was published in the Journal of Clinical Oncology in September 2020, would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis.
Predicting outcomes
The real-world data also demonstrated that performance status and lactate dehydrogenase (LDH) levels can predict outcomes: Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 versus less than 2, and elevated LDH had shorter PFS and overall survival (OS) on both univariate and multivariate analysis, Dr. Corradini noted.
A subsequent multicenter study showed similar response rates of 70% and 68% in ZUMA-1-eligible and noneligible patients, but significantly improved DOR, PFS, and OS outcomes among the ZUMA-1-eligible patients.
The authors also looked for “clinical predictive factors or some easy clinical biomarkers to predict the outcomes in our patients receiving CAR T-cells,” and found that C-reactive protein levels of more than 30 mg at infusion were associated with poorer DOR, PFS, and OS, he said.
In 60 patients in another U.S. study of both tisa-cel- and axi-cel-treated patients at Memorial Sloan Kettering Cancer Center, 1-year event-free survival and OS were 40% and 69%, and Dr. Corradini’s experience with 55 patients at the University of Milan similarly showed 1-year PFS and OS of 40% and 70%, respectively.
“So all these studies support the notion that the results of CAR T-cells in real-world practice are durable for our patients, and are very similar to results obtained in the studies,” he said.
Other factors that have been shown to be associated with poor outcomes after CAR T-cell therapy include systemic bridging therapy, high metabolic tumor volume, and extranodal involvement; patients with these characteristics, along with those who have poor ECOG performance status or elevated LDH or CRP levels, do not comprise “a group to exclude from CAR T-cell therapy, but rather ... a group for whom there is an unmet need with our currently available treatments,” he said, adding: “So, it’s a group for which we have to do clinical trials and studies to improve the outcomes of our patient with large B-cell lymphomas.”
“These are all real-world data with commercially available products, he noted.
Product selection
Tisa-cel received Food and Drug Administration approval in 2017 and is used to treat relapsed or refractory acute lymphoblastic leukemia in those aged up to 25 years, and non-Hodgkin lymphoma that has relapsed or is refractory after at least two prior lines of therapy.
Axi-cel was also approved in 2017 for relapsed/refractory non-Hodgkin lymphoma, and in February 2021, after Dr. Corradini’s meeting presentation, the FDA granted a third approval to lisocabtagene maraleucel (liso-cel; Breyanzi) for this indication.
The information to date from both the trial and real-world settings are limited with respect to showing any differences in outcomes between the CAR T-cell products, but provide “an initial suggestion” that outcomes with tisa-cel and axi-cel are comparable, he said, adding that decisions should be strictly based on product registration data given the absence of reliable data for choosing one product over another.
Dr. Corradini reported honoraria and/or payment for travel and accommodations from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, and a number of other pharmaceutical companies.
FROM CART21
FDA expands sacubitril/valsartan indication to embrace some HFpEF
The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.
The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.
The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”
The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”
But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.
The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.
PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).
But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.
The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.
The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.
The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”
The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”
But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.
The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.
PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).
But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.
The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.
The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.
The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”
The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”
But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.
The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.
PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).
But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.
The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.
A version of this article first appeared on Medscape.com.
Romosozumab may not increase cardiovascular risk after all
The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.
The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?
However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.
“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.
He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
Potency of romosozumab
Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.
“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.
In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.
Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.
Updated Endocrine Society guidelines
Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.
Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.
The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”
“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.
Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.
The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.
The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?
However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.
“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.
He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
Potency of romosozumab
Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.
“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.
In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.
Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.
Updated Endocrine Society guidelines
Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.
Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.
The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”
“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.
Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.
The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.
The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?
However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.
“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.
He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
Potency of romosozumab
Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.
“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.
In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.
Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.
Updated Endocrine Society guidelines
Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.
Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.
The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”
“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.
Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.
FROM RWCS 2021