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FDA investigates NDMA contamination in metformin
This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.
“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.
The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.
NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.
Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.
The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.
The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.
“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”
This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.
“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.
The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.
NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.
Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.
The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.
The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.
“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”
This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.
“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.
The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.
NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.
Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.
The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.
The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.
“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”
Fast-tracking psilocybin for refractory depression makes sense
A significant proportion of patients with major depressive disorder (MDD) either do not respond or have partial responses to the currently available Food and Drug Administration–approved antidepressants.
In controlled clinical trials, there is about a 40%-60% symptom remission rate with a 20%-40% remission rate in community-based treatment settings. Not only do those medications lack efficacy in treating MDD, but there are currently no cures for this debilitating illness. As a result, many patients with MDD continue to suffer.
In response to those poor outcomes, researchers and clinicians have developed algorithms aimed at diagnosing the condition of treatment-resistant depression (TRD),1 which enable opportunities for various treatment methods.2 Several studies underway across the United States are testing what some might consider medically invasive procedures, such as electroconvulsive therapy (ECT), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). ECT often is considered the gold standard of treatment response, but it requires anesthesia, induces a convulsion, and needs a willing patient and clinician. DBS has been used more widely in neurological treatment of movement disorders. Pioneering neurosurgical treatment for TRD reported recently in the American Journal of Psychiatry found that DBS of an area in the brain called the subcallosal cingulate produces clear and apparently sustained antidepressant effects.3 VNS4 remains an experimental treatment for MDD. TMS is safe, noninvasive, and approved by the FDA for depression, but responses appear similar to those with usual antidepressants.
It is not surprising, given those outcomes, that ketamine was fast-tracked in 2016. The enthusiasm related to ketamine’s effect on MDD and TRD has grown over time as more research findings reach the public. While it is unknown how ketamine affects the biological neural network, a single intravenous dose of ketamine (0.5 mg/kg) in patients diagnosed with TRD can lead to improved depression symptoms outcomes within a few hours – and those effects were sustained in 65%-70% of patients at 24 hours. Antidepressants take many weeks to show effects. Ketamine’s exciting findings also offered hope to clinicians and patients trying to manage suicidal thoughts and plans. Ketamine was quickly approved by the FDA as a nasal spray medication.
Now, in another encouraging development, the FDA has granted the Usona Institute Breakthrough Therapy designation for psilocybin for the treatment of MDD. The medical benefits of psilocybin, or “magic mushrooms,” has a long empirical history in our literature. Most recently, psilocybin was featured on “60 Minutes,”5 and in his book, “How to Change Your Mind,”6Michael Pollan details how psychedelic drugs where used to investigate and treat psychiatric disorders until the 1960s, when street use and unsupervised administration led to restrictions on their research and clinical use.
With protocol-driven specific trials, they might become critical medications for a wide range of psychiatric disorders, such as depression, PTSD, anxiety, and addictions. Exciting findings are coming from Roland R. Griffiths, PhD, and his team at Johns Hopkins University’s Center for Psychedelic and Consciousness Research. In a recent study8 with cancer patients suffering from depression and anxiety, carefully administered, specific and supervised high doses of psilocybin produced decreases in depression and anxiety, and increases in quality of life and life meaning attitudes. Those improved attitudes, behavior, and responses were sustained by 80% of the sample 6 months post treatment.
Dr. Griffiths’ center is collaborating with Usona, and this collaboration should result in specific guidelines for dose, safety, and protection against abuse and diversion,9 as the study and FDA trials for ketamine have as well.10 It is very encouraging that psychedelic drugs are receiving fast-track designations, and this development reflects a shift in the risk-benefit considerations taking place in our society. Changing attitudes about depression and other psychiatric diseases are encouraging new approaches and new treatments. Psychiatric suffering and pain are being prioritized in research and appreciated by the general public as devastating. Serious, random assignment placebo-controlled and double- blind research studies will define just how valuable these medications might be, what is the safe dose and duration, and for whom they might prove more effective than existing treatments.
The process will take some time. And it is worth remembering that, although research has been promising,11 the number of patients studied, research design, and outcomes are not yet proven for psilosybin.12 The FDA fast-track makes sense, and the agency should continue supporting these efforts for psychedelics. In fact, we think the FDA also should support the promising trials of nitrous oxide13 (laughing gas), and other safe and novel approaches to successfully treat refractory depression. While we wait for personalized psychiatric medicines to be developed and validated through the long process of FDA approval, we will at least have a larger suite of treatment options to match patients with, along with some new algorithms that treat MDD,* TRD, and other disorders just are around the corner.
Dr. Patterson Silver Wolf is an associate professor at Washington University in St. Louis’s Brown School of Social Work. He is a training faculty member for two National Institutes of Health–funded (T32) training programs and serves as the director of the Community Academic Partnership on Addiction (CAPA). He’s chief research officer at the new CAPA Clinic, a teaching addiction treatment facility that is incorporating and testing various performance-based practice technology tools to respond to the opioid crisis and improve addiction treatment outcomes. Dr. Gold is professor of psychiatry (adjunct) at Washington University, St. Louis. He is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville. For more than 40 years, Dr. Gold has worked on developing models for understanding the effects of opioid, tobacco, cocaine, and other drugs, as well as food, on the brain and behavior. He has written several books and published more than 1,000 peer-reviewed scientific articles, texts, and practice guidelines.
References
1. Sackeim HA et al. J Psychiatr Res. 2019 Jun;113:125-36.
2. Conway CR et al. J Clin Psychiatry. 25 Nov;76(11):1569-70.
3. Crowell AL et al. Am J Psychiatry. 2019 Oct 4. doi: 10.1176.appi.ajp.2019.18121427.
4. Kumar A et al. Neuropsychiatr Dis Treat. 2019 Feb 13;15:457-68.
5. Psilocybin sessions: Psychedelics could help people with addiction and anxiety. “60 Minutes” CBS News. 2019 Oct 13.
6. Pollan M. How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence (Penguin Random House, 2018).
7. Nutt D. Dialogues Clin Neurosci. 2019;21(2):139-47.
8. Griffiths RR et al. J Psychopharmacol 2016 Dec;30(12):1181-97.
9. Johnson MW et al. Neuropsychopharmacology. 2018 Nov;142:143-66.
10. Schwenk ES et al. Reg Anesth Pain Med. 2018 Jul;43(5):456-66.
11. Johnson MW et al. Neurotherapeutics. 2017 Jul;14(3):734-40.
12. Mutonni S et al. J Affect Disord. 2019 Nov.1;258:11-24.
13. Nagele P et al. J Clin Psychopharmacol. 2018 Apr;38(2):144-8.
*Correction, 1/9/2020: An earlier version of this story misidentified the intended disease state.
A significant proportion of patients with major depressive disorder (MDD) either do not respond or have partial responses to the currently available Food and Drug Administration–approved antidepressants.
In controlled clinical trials, there is about a 40%-60% symptom remission rate with a 20%-40% remission rate in community-based treatment settings. Not only do those medications lack efficacy in treating MDD, but there are currently no cures for this debilitating illness. As a result, many patients with MDD continue to suffer.
In response to those poor outcomes, researchers and clinicians have developed algorithms aimed at diagnosing the condition of treatment-resistant depression (TRD),1 which enable opportunities for various treatment methods.2 Several studies underway across the United States are testing what some might consider medically invasive procedures, such as electroconvulsive therapy (ECT), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). ECT often is considered the gold standard of treatment response, but it requires anesthesia, induces a convulsion, and needs a willing patient and clinician. DBS has been used more widely in neurological treatment of movement disorders. Pioneering neurosurgical treatment for TRD reported recently in the American Journal of Psychiatry found that DBS of an area in the brain called the subcallosal cingulate produces clear and apparently sustained antidepressant effects.3 VNS4 remains an experimental treatment for MDD. TMS is safe, noninvasive, and approved by the FDA for depression, but responses appear similar to those with usual antidepressants.
It is not surprising, given those outcomes, that ketamine was fast-tracked in 2016. The enthusiasm related to ketamine’s effect on MDD and TRD has grown over time as more research findings reach the public. While it is unknown how ketamine affects the biological neural network, a single intravenous dose of ketamine (0.5 mg/kg) in patients diagnosed with TRD can lead to improved depression symptoms outcomes within a few hours – and those effects were sustained in 65%-70% of patients at 24 hours. Antidepressants take many weeks to show effects. Ketamine’s exciting findings also offered hope to clinicians and patients trying to manage suicidal thoughts and plans. Ketamine was quickly approved by the FDA as a nasal spray medication.
Now, in another encouraging development, the FDA has granted the Usona Institute Breakthrough Therapy designation for psilocybin for the treatment of MDD. The medical benefits of psilocybin, or “magic mushrooms,” has a long empirical history in our literature. Most recently, psilocybin was featured on “60 Minutes,”5 and in his book, “How to Change Your Mind,”6Michael Pollan details how psychedelic drugs where used to investigate and treat psychiatric disorders until the 1960s, when street use and unsupervised administration led to restrictions on their research and clinical use.
With protocol-driven specific trials, they might become critical medications for a wide range of psychiatric disorders, such as depression, PTSD, anxiety, and addictions. Exciting findings are coming from Roland R. Griffiths, PhD, and his team at Johns Hopkins University’s Center for Psychedelic and Consciousness Research. In a recent study8 with cancer patients suffering from depression and anxiety, carefully administered, specific and supervised high doses of psilocybin produced decreases in depression and anxiety, and increases in quality of life and life meaning attitudes. Those improved attitudes, behavior, and responses were sustained by 80% of the sample 6 months post treatment.
Dr. Griffiths’ center is collaborating with Usona, and this collaboration should result in specific guidelines for dose, safety, and protection against abuse and diversion,9 as the study and FDA trials for ketamine have as well.10 It is very encouraging that psychedelic drugs are receiving fast-track designations, and this development reflects a shift in the risk-benefit considerations taking place in our society. Changing attitudes about depression and other psychiatric diseases are encouraging new approaches and new treatments. Psychiatric suffering and pain are being prioritized in research and appreciated by the general public as devastating. Serious, random assignment placebo-controlled and double- blind research studies will define just how valuable these medications might be, what is the safe dose and duration, and for whom they might prove more effective than existing treatments.
The process will take some time. And it is worth remembering that, although research has been promising,11 the number of patients studied, research design, and outcomes are not yet proven for psilosybin.12 The FDA fast-track makes sense, and the agency should continue supporting these efforts for psychedelics. In fact, we think the FDA also should support the promising trials of nitrous oxide13 (laughing gas), and other safe and novel approaches to successfully treat refractory depression. While we wait for personalized psychiatric medicines to be developed and validated through the long process of FDA approval, we will at least have a larger suite of treatment options to match patients with, along with some new algorithms that treat MDD,* TRD, and other disorders just are around the corner.
Dr. Patterson Silver Wolf is an associate professor at Washington University in St. Louis’s Brown School of Social Work. He is a training faculty member for two National Institutes of Health–funded (T32) training programs and serves as the director of the Community Academic Partnership on Addiction (CAPA). He’s chief research officer at the new CAPA Clinic, a teaching addiction treatment facility that is incorporating and testing various performance-based practice technology tools to respond to the opioid crisis and improve addiction treatment outcomes. Dr. Gold is professor of psychiatry (adjunct) at Washington University, St. Louis. He is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville. For more than 40 years, Dr. Gold has worked on developing models for understanding the effects of opioid, tobacco, cocaine, and other drugs, as well as food, on the brain and behavior. He has written several books and published more than 1,000 peer-reviewed scientific articles, texts, and practice guidelines.
References
1. Sackeim HA et al. J Psychiatr Res. 2019 Jun;113:125-36.
2. Conway CR et al. J Clin Psychiatry. 25 Nov;76(11):1569-70.
3. Crowell AL et al. Am J Psychiatry. 2019 Oct 4. doi: 10.1176.appi.ajp.2019.18121427.
4. Kumar A et al. Neuropsychiatr Dis Treat. 2019 Feb 13;15:457-68.
5. Psilocybin sessions: Psychedelics could help people with addiction and anxiety. “60 Minutes” CBS News. 2019 Oct 13.
6. Pollan M. How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence (Penguin Random House, 2018).
7. Nutt D. Dialogues Clin Neurosci. 2019;21(2):139-47.
8. Griffiths RR et al. J Psychopharmacol 2016 Dec;30(12):1181-97.
9. Johnson MW et al. Neuropsychopharmacology. 2018 Nov;142:143-66.
10. Schwenk ES et al. Reg Anesth Pain Med. 2018 Jul;43(5):456-66.
11. Johnson MW et al. Neurotherapeutics. 2017 Jul;14(3):734-40.
12. Mutonni S et al. J Affect Disord. 2019 Nov.1;258:11-24.
13. Nagele P et al. J Clin Psychopharmacol. 2018 Apr;38(2):144-8.
*Correction, 1/9/2020: An earlier version of this story misidentified the intended disease state.
A significant proportion of patients with major depressive disorder (MDD) either do not respond or have partial responses to the currently available Food and Drug Administration–approved antidepressants.
In controlled clinical trials, there is about a 40%-60% symptom remission rate with a 20%-40% remission rate in community-based treatment settings. Not only do those medications lack efficacy in treating MDD, but there are currently no cures for this debilitating illness. As a result, many patients with MDD continue to suffer.
In response to those poor outcomes, researchers and clinicians have developed algorithms aimed at diagnosing the condition of treatment-resistant depression (TRD),1 which enable opportunities for various treatment methods.2 Several studies underway across the United States are testing what some might consider medically invasive procedures, such as electroconvulsive therapy (ECT), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). ECT often is considered the gold standard of treatment response, but it requires anesthesia, induces a convulsion, and needs a willing patient and clinician. DBS has been used more widely in neurological treatment of movement disorders. Pioneering neurosurgical treatment for TRD reported recently in the American Journal of Psychiatry found that DBS of an area in the brain called the subcallosal cingulate produces clear and apparently sustained antidepressant effects.3 VNS4 remains an experimental treatment for MDD. TMS is safe, noninvasive, and approved by the FDA for depression, but responses appear similar to those with usual antidepressants.
It is not surprising, given those outcomes, that ketamine was fast-tracked in 2016. The enthusiasm related to ketamine’s effect on MDD and TRD has grown over time as more research findings reach the public. While it is unknown how ketamine affects the biological neural network, a single intravenous dose of ketamine (0.5 mg/kg) in patients diagnosed with TRD can lead to improved depression symptoms outcomes within a few hours – and those effects were sustained in 65%-70% of patients at 24 hours. Antidepressants take many weeks to show effects. Ketamine’s exciting findings also offered hope to clinicians and patients trying to manage suicidal thoughts and plans. Ketamine was quickly approved by the FDA as a nasal spray medication.
Now, in another encouraging development, the FDA has granted the Usona Institute Breakthrough Therapy designation for psilocybin for the treatment of MDD. The medical benefits of psilocybin, or “magic mushrooms,” has a long empirical history in our literature. Most recently, psilocybin was featured on “60 Minutes,”5 and in his book, “How to Change Your Mind,”6Michael Pollan details how psychedelic drugs where used to investigate and treat psychiatric disorders until the 1960s, when street use and unsupervised administration led to restrictions on their research and clinical use.
With protocol-driven specific trials, they might become critical medications for a wide range of psychiatric disorders, such as depression, PTSD, anxiety, and addictions. Exciting findings are coming from Roland R. Griffiths, PhD, and his team at Johns Hopkins University’s Center for Psychedelic and Consciousness Research. In a recent study8 with cancer patients suffering from depression and anxiety, carefully administered, specific and supervised high doses of psilocybin produced decreases in depression and anxiety, and increases in quality of life and life meaning attitudes. Those improved attitudes, behavior, and responses were sustained by 80% of the sample 6 months post treatment.
Dr. Griffiths’ center is collaborating with Usona, and this collaboration should result in specific guidelines for dose, safety, and protection against abuse and diversion,9 as the study and FDA trials for ketamine have as well.10 It is very encouraging that psychedelic drugs are receiving fast-track designations, and this development reflects a shift in the risk-benefit considerations taking place in our society. Changing attitudes about depression and other psychiatric diseases are encouraging new approaches and new treatments. Psychiatric suffering and pain are being prioritized in research and appreciated by the general public as devastating. Serious, random assignment placebo-controlled and double- blind research studies will define just how valuable these medications might be, what is the safe dose and duration, and for whom they might prove more effective than existing treatments.
The process will take some time. And it is worth remembering that, although research has been promising,11 the number of patients studied, research design, and outcomes are not yet proven for psilosybin.12 The FDA fast-track makes sense, and the agency should continue supporting these efforts for psychedelics. In fact, we think the FDA also should support the promising trials of nitrous oxide13 (laughing gas), and other safe and novel approaches to successfully treat refractory depression. While we wait for personalized psychiatric medicines to be developed and validated through the long process of FDA approval, we will at least have a larger suite of treatment options to match patients with, along with some new algorithms that treat MDD,* TRD, and other disorders just are around the corner.
Dr. Patterson Silver Wolf is an associate professor at Washington University in St. Louis’s Brown School of Social Work. He is a training faculty member for two National Institutes of Health–funded (T32) training programs and serves as the director of the Community Academic Partnership on Addiction (CAPA). He’s chief research officer at the new CAPA Clinic, a teaching addiction treatment facility that is incorporating and testing various performance-based practice technology tools to respond to the opioid crisis and improve addiction treatment outcomes. Dr. Gold is professor of psychiatry (adjunct) at Washington University, St. Louis. He is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville. For more than 40 years, Dr. Gold has worked on developing models for understanding the effects of opioid, tobacco, cocaine, and other drugs, as well as food, on the brain and behavior. He has written several books and published more than 1,000 peer-reviewed scientific articles, texts, and practice guidelines.
References
1. Sackeim HA et al. J Psychiatr Res. 2019 Jun;113:125-36.
2. Conway CR et al. J Clin Psychiatry. 25 Nov;76(11):1569-70.
3. Crowell AL et al. Am J Psychiatry. 2019 Oct 4. doi: 10.1176.appi.ajp.2019.18121427.
4. Kumar A et al. Neuropsychiatr Dis Treat. 2019 Feb 13;15:457-68.
5. Psilocybin sessions: Psychedelics could help people with addiction and anxiety. “60 Minutes” CBS News. 2019 Oct 13.
6. Pollan M. How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence (Penguin Random House, 2018).
7. Nutt D. Dialogues Clin Neurosci. 2019;21(2):139-47.
8. Griffiths RR et al. J Psychopharmacol 2016 Dec;30(12):1181-97.
9. Johnson MW et al. Neuropsychopharmacology. 2018 Nov;142:143-66.
10. Schwenk ES et al. Reg Anesth Pain Med. 2018 Jul;43(5):456-66.
11. Johnson MW et al. Neurotherapeutics. 2017 Jul;14(3):734-40.
12. Mutonni S et al. J Affect Disord. 2019 Nov.1;258:11-24.
13. Nagele P et al. J Clin Psychopharmacol. 2018 Apr;38(2):144-8.
*Correction, 1/9/2020: An earlier version of this story misidentified the intended disease state.
Efficacy of postvenetoclax therapy may depend on prior agent exposure in CLL
ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.
If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.
“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”
The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.
All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.
“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.
While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.
“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.
Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.
“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.
They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.
In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.
PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.
However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.
Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”
Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract 502.
ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.
If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.
“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”
The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.
All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.
“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.
While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.
“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.
Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.
“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.
They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.
In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.
PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.
However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.
Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”
Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract 502.
ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.
If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.
“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”
The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.
All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.
“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.
While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.
“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.
Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.
“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.
They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.
In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.
PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.
However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.
Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”
Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract 502.
REPORTING FROM ASH 2019
A triple-antibiotic cure for Crohn’s disease?
SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.
In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.
RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.
“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”
For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.
“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.
The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.
The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.
The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.
“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.
The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.
In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.
Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.
The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.
Several audience members rose to urge caution in interpreting the MAP US data.
“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.
“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.
Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.
“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.
Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.
SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.
In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.
RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.
“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”
For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.
“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.
The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.
The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.
The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.
“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.
The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.
In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.
Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.
The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.
Several audience members rose to urge caution in interpreting the MAP US data.
“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.
“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.
Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.
“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.
Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.
SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.
In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.
RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.
“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”
For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.
“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.
The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.
The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.
The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.
“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.
The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.
In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.
Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.
The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.
Several audience members rose to urge caution in interpreting the MAP US data.
“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.
“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.
Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.
“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.
Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.
REPORTING FROM ACG 2019
Study halted; ‘hyperprogression’ seen with nivolumab for R/R PTCL
ORLANDO – There is an urgent need for new therapies to treat relapsed or refractory peripheral T-cell lymphoma, but results of a phase 2 study suggest that monotherapy with the immune checkpoint inhibitor nivolumab (Opdivo) is not the hoped-for salvage treatment.
An interim analysis of data on 12 patients with peripheral T-cell lymphoma (PTCL) treated with nivolumab monotherapy showed an overall response rate of 33%, consisting of 2 complete responses and 2 partial responses. But the responses were short lived, and one patient had hyperprogressive disease – dramatic progression within one cycle of treatment – while two more had progression within two cycles, leading to a trial halt, reported N. Nora Bennani, MD, from the Mayo Clinic in Rochester, Minn.
“These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases,” she said at the annual meeting of the American Society of Hematology.
The rationale for using an immune checkpoint inhibitor directed against the programmed death–1 protein and its ligands (PD and PD-L1/2) is that malignant cells in PTCL induce a profoundly immunosuppressive tumor microenvironment. Checkpoint inhibitors have shown strong activity against relapsed Hodgkin lymphoma, and the Mayo Clinic researchers speculated that an anti-PD-1 agent could have a similar effect in PTCL.
They had originally planned to enroll 29 patients into a phase 2 trial with nivolumab delivered 240 mg every 2 weeks for eight cycles, followed by a dose of 480 mg given every 4 weeks until disease progression or intolerable toxicities.
Patients were eligible if they had biopsy-confirmed relapsed or refractory PTCL, measurable disease on cross-sectional imaging of at least 1.5 cm, and prior systemic chemoimmunotherapy and/or autologous stem cell transplantation.
The interim analysis included 12 patients who received at least one dose of nivolumab. Of the 12 patients, 6 had angioimmunoblastic T-cell lymphoma (AITL), 3 had PTCL not otherwise specified, and 1 each had ALK-negative anaplastic large cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), or hepatosplenic gamma/delta T-cell lymphoma.
All patients had Ann Arbor stage III/IV disease, and 11 had extranodal involvement.
As noted, there were 4 responses among the 12 patients, consisting of 1 complete response in the patient with ALK-ALCL and 1 in a patient with AITL, and 2 partial responses – 1 in a patient with PTCL-NOS, and 1 in the patient with EATL.
The median progression-free survival for all 12 patients was short at 2.7 months, and the median overall survival was estimated at 6.7 months.
“It was staggering to see this: The duration of response was significantly short, less than 2 months,” Dr. Bennani said.
Nonhematologic toxicities were seen in 5 of the 12 patients (42%), and hematologic adverse events occurred in 3 (25%). All patients are now off treatment, 10 because of disease progression, 1 because of acute pancreatitis, and the aforementioned patient with hyperprogressive disease.
The patient with hyperprogressive disease had significant progression in tonsillar and cervical lymphadenopathy within 7-10 days of nivolumab infusion, with biopsy-proven AITL in the involved nodes.
“I believe that, in this patient population, combination therapies will be key. I think checkpoint blockers alone are not going to be sufficient to see meaningful outcomes in these patients,” Dr. Bennani said in an interview.
“An overall response rate of 33% is significant, because most other agents that were FDA approved in this patient population have response rates around 30%,” she said, adding that it’s possible that the patients with rapid progression had disease too advanced to be effectively treated with a checkpoint inhibitor.
“Ideally however, if we want to move forward, it will need to be with combinations of checkpoint inhibitors with HDAC [histone deacetylase] inhibitors, hypomethylating agents, or even PI3 kinase inhibitors,” she said.
The study was supported by Bristol-Myers Squibb. Dr. Bennani reported research funding and advisory board activities for Bristol-Myers Squibb and others.
SOURCE: Bennani NN et al. ASH 2019, Abstract 467.
ORLANDO – There is an urgent need for new therapies to treat relapsed or refractory peripheral T-cell lymphoma, but results of a phase 2 study suggest that monotherapy with the immune checkpoint inhibitor nivolumab (Opdivo) is not the hoped-for salvage treatment.
An interim analysis of data on 12 patients with peripheral T-cell lymphoma (PTCL) treated with nivolumab monotherapy showed an overall response rate of 33%, consisting of 2 complete responses and 2 partial responses. But the responses were short lived, and one patient had hyperprogressive disease – dramatic progression within one cycle of treatment – while two more had progression within two cycles, leading to a trial halt, reported N. Nora Bennani, MD, from the Mayo Clinic in Rochester, Minn.
“These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases,” she said at the annual meeting of the American Society of Hematology.
The rationale for using an immune checkpoint inhibitor directed against the programmed death–1 protein and its ligands (PD and PD-L1/2) is that malignant cells in PTCL induce a profoundly immunosuppressive tumor microenvironment. Checkpoint inhibitors have shown strong activity against relapsed Hodgkin lymphoma, and the Mayo Clinic researchers speculated that an anti-PD-1 agent could have a similar effect in PTCL.
They had originally planned to enroll 29 patients into a phase 2 trial with nivolumab delivered 240 mg every 2 weeks for eight cycles, followed by a dose of 480 mg given every 4 weeks until disease progression or intolerable toxicities.
Patients were eligible if they had biopsy-confirmed relapsed or refractory PTCL, measurable disease on cross-sectional imaging of at least 1.5 cm, and prior systemic chemoimmunotherapy and/or autologous stem cell transplantation.
The interim analysis included 12 patients who received at least one dose of nivolumab. Of the 12 patients, 6 had angioimmunoblastic T-cell lymphoma (AITL), 3 had PTCL not otherwise specified, and 1 each had ALK-negative anaplastic large cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), or hepatosplenic gamma/delta T-cell lymphoma.
All patients had Ann Arbor stage III/IV disease, and 11 had extranodal involvement.
As noted, there were 4 responses among the 12 patients, consisting of 1 complete response in the patient with ALK-ALCL and 1 in a patient with AITL, and 2 partial responses – 1 in a patient with PTCL-NOS, and 1 in the patient with EATL.
The median progression-free survival for all 12 patients was short at 2.7 months, and the median overall survival was estimated at 6.7 months.
“It was staggering to see this: The duration of response was significantly short, less than 2 months,” Dr. Bennani said.
Nonhematologic toxicities were seen in 5 of the 12 patients (42%), and hematologic adverse events occurred in 3 (25%). All patients are now off treatment, 10 because of disease progression, 1 because of acute pancreatitis, and the aforementioned patient with hyperprogressive disease.
The patient with hyperprogressive disease had significant progression in tonsillar and cervical lymphadenopathy within 7-10 days of nivolumab infusion, with biopsy-proven AITL in the involved nodes.
“I believe that, in this patient population, combination therapies will be key. I think checkpoint blockers alone are not going to be sufficient to see meaningful outcomes in these patients,” Dr. Bennani said in an interview.
“An overall response rate of 33% is significant, because most other agents that were FDA approved in this patient population have response rates around 30%,” she said, adding that it’s possible that the patients with rapid progression had disease too advanced to be effectively treated with a checkpoint inhibitor.
“Ideally however, if we want to move forward, it will need to be with combinations of checkpoint inhibitors with HDAC [histone deacetylase] inhibitors, hypomethylating agents, or even PI3 kinase inhibitors,” she said.
The study was supported by Bristol-Myers Squibb. Dr. Bennani reported research funding and advisory board activities for Bristol-Myers Squibb and others.
SOURCE: Bennani NN et al. ASH 2019, Abstract 467.
ORLANDO – There is an urgent need for new therapies to treat relapsed or refractory peripheral T-cell lymphoma, but results of a phase 2 study suggest that monotherapy with the immune checkpoint inhibitor nivolumab (Opdivo) is not the hoped-for salvage treatment.
An interim analysis of data on 12 patients with peripheral T-cell lymphoma (PTCL) treated with nivolumab monotherapy showed an overall response rate of 33%, consisting of 2 complete responses and 2 partial responses. But the responses were short lived, and one patient had hyperprogressive disease – dramatic progression within one cycle of treatment – while two more had progression within two cycles, leading to a trial halt, reported N. Nora Bennani, MD, from the Mayo Clinic in Rochester, Minn.
“These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases,” she said at the annual meeting of the American Society of Hematology.
The rationale for using an immune checkpoint inhibitor directed against the programmed death–1 protein and its ligands (PD and PD-L1/2) is that malignant cells in PTCL induce a profoundly immunosuppressive tumor microenvironment. Checkpoint inhibitors have shown strong activity against relapsed Hodgkin lymphoma, and the Mayo Clinic researchers speculated that an anti-PD-1 agent could have a similar effect in PTCL.
They had originally planned to enroll 29 patients into a phase 2 trial with nivolumab delivered 240 mg every 2 weeks for eight cycles, followed by a dose of 480 mg given every 4 weeks until disease progression or intolerable toxicities.
Patients were eligible if they had biopsy-confirmed relapsed or refractory PTCL, measurable disease on cross-sectional imaging of at least 1.5 cm, and prior systemic chemoimmunotherapy and/or autologous stem cell transplantation.
The interim analysis included 12 patients who received at least one dose of nivolumab. Of the 12 patients, 6 had angioimmunoblastic T-cell lymphoma (AITL), 3 had PTCL not otherwise specified, and 1 each had ALK-negative anaplastic large cell lymphoma (ALK-ALCL), enteropathy-associated T-cell lymphoma (EATL), or hepatosplenic gamma/delta T-cell lymphoma.
All patients had Ann Arbor stage III/IV disease, and 11 had extranodal involvement.
As noted, there were 4 responses among the 12 patients, consisting of 1 complete response in the patient with ALK-ALCL and 1 in a patient with AITL, and 2 partial responses – 1 in a patient with PTCL-NOS, and 1 in the patient with EATL.
The median progression-free survival for all 12 patients was short at 2.7 months, and the median overall survival was estimated at 6.7 months.
“It was staggering to see this: The duration of response was significantly short, less than 2 months,” Dr. Bennani said.
Nonhematologic toxicities were seen in 5 of the 12 patients (42%), and hematologic adverse events occurred in 3 (25%). All patients are now off treatment, 10 because of disease progression, 1 because of acute pancreatitis, and the aforementioned patient with hyperprogressive disease.
The patient with hyperprogressive disease had significant progression in tonsillar and cervical lymphadenopathy within 7-10 days of nivolumab infusion, with biopsy-proven AITL in the involved nodes.
“I believe that, in this patient population, combination therapies will be key. I think checkpoint blockers alone are not going to be sufficient to see meaningful outcomes in these patients,” Dr. Bennani said in an interview.
“An overall response rate of 33% is significant, because most other agents that were FDA approved in this patient population have response rates around 30%,” she said, adding that it’s possible that the patients with rapid progression had disease too advanced to be effectively treated with a checkpoint inhibitor.
“Ideally however, if we want to move forward, it will need to be with combinations of checkpoint inhibitors with HDAC [histone deacetylase] inhibitors, hypomethylating agents, or even PI3 kinase inhibitors,” she said.
The study was supported by Bristol-Myers Squibb. Dr. Bennani reported research funding and advisory board activities for Bristol-Myers Squibb and others.
SOURCE: Bennani NN et al. ASH 2019, Abstract 467.
REPORTING FROM ASH 2019
Aspirin plus a DOAC may do more harm than good in some
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
ORLANDO – in a large registry-based cohort.
The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.
Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.
“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).
No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.
The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.
“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.
Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.
“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.
Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.
“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.
In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.
“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”
Dr. Schaefer reported having no disclosures.
SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.
REPORTING FROM ASH 2019
Bispecific CAR T-cells yield high response rate in relapsed/refractory myeloma
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
REPORTING FROM ASH 2019
High complete response rate seen with novel CAR-T for myeloma
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
REPORTING FROM ASH 2019
Patient-reported outcomes support first-line pembrolizumab for NSCLC
Patient-reported outcomes support pembrolizumab plus chemotherapy for first-line treatment of metastatic non–small cell lung cancer (NSCLC), based on results from the KEYNOTE-407 trial.
At week 18, patients given pembrolizumab more often reported clinically meaningful health-related quality of life improvements than those in the placebo group, according to lead author Julien Mazieres, MD, PhD, of Paul Sabatier University in Toulouse, France, and colleagues.
Writing in the Journal of Clinical Oncology, the investigators explained that these findings build upon previously published results from KEYNOTE-407, which showed that adding pembrolizumab to chemotherapy in the first line could extend both progression-free and overall survival among patients with NSCLC. The benefits to quality of life associated with pembrolizumab align with similar findings from the KEYNOTE-024 and KEYNOTE-189 trials, they added.
The present analysis involved 559 patients with treatment-naive metastatic NSCLC. Patients were randomized to receive 4 cycles of placebo or pembrolizumab once every 3 weeks with carboplatin-based chemotherapy, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life was assessed by two measures: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Lung Cancer Module 13 (QLQ-LC13).
Of the 559 patients enrolled, 554 completed at least one QLQ-C30 assessment and 553 completed at least one QLQ-LC13 assessment. These quality of life scores were compared temporally within treatment groups, from baseline to week 9 and week 18, and between groups. The investigators also analyzed median time to deterioration in chest pain, cough, and dyspnea.
Results showed that patients in the pembrolizumab group had statistically significant improvements in patient-reported outcomes over time and more frequently reported improvements than patients in the placebo group. Specifically, in the pembrolizumab group, least-squares mean score improved from baseline to week 9 (1.8) and week 18 (4.3); in comparison, least-squares mean score deteriorated in the placebo group from baseline to week 9 (–1.8) and week 18 (–0.57). Compared with placebo, treatment with pembrolizumab was associated with a least-squares mean change of 3.6 at week 9 (nominal P = .0337) and 4.9 at week 18 (nominal P = .0060). Stated differently, at week 18, compared with placebo, more patients in the pembrolizumab group reported clinically meaningful improvements in health-related quality of life (36.2% vs. 27.7%), and relatively fewer reported deterioration (22.8% vs. 31.3%). Median time to deterioration in symptoms was not reached in either treatment arm.
“These health-related quality of life findings, along with the improved efficacy (including overall survival benefit) of pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel, support its use as a first-line treatment of metastatic squamous NSCLC, regardless of programmed death–ligand 1 expression,” the investigators concluded.
The study was funded by Merck. The investigators reported additional relationships with Novartis, Genentech, Pfizer, and others.
SOURCE: Mazieres J et al. J Clin Oncol. 2019 Nov 21. doi: 10.1200/JCO.19.01348.
Patient-reported outcomes support pembrolizumab plus chemotherapy for first-line treatment of metastatic non–small cell lung cancer (NSCLC), based on results from the KEYNOTE-407 trial.
At week 18, patients given pembrolizumab more often reported clinically meaningful health-related quality of life improvements than those in the placebo group, according to lead author Julien Mazieres, MD, PhD, of Paul Sabatier University in Toulouse, France, and colleagues.
Writing in the Journal of Clinical Oncology, the investigators explained that these findings build upon previously published results from KEYNOTE-407, which showed that adding pembrolizumab to chemotherapy in the first line could extend both progression-free and overall survival among patients with NSCLC. The benefits to quality of life associated with pembrolizumab align with similar findings from the KEYNOTE-024 and KEYNOTE-189 trials, they added.
The present analysis involved 559 patients with treatment-naive metastatic NSCLC. Patients were randomized to receive 4 cycles of placebo or pembrolizumab once every 3 weeks with carboplatin-based chemotherapy, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life was assessed by two measures: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Lung Cancer Module 13 (QLQ-LC13).
Of the 559 patients enrolled, 554 completed at least one QLQ-C30 assessment and 553 completed at least one QLQ-LC13 assessment. These quality of life scores were compared temporally within treatment groups, from baseline to week 9 and week 18, and between groups. The investigators also analyzed median time to deterioration in chest pain, cough, and dyspnea.
Results showed that patients in the pembrolizumab group had statistically significant improvements in patient-reported outcomes over time and more frequently reported improvements than patients in the placebo group. Specifically, in the pembrolizumab group, least-squares mean score improved from baseline to week 9 (1.8) and week 18 (4.3); in comparison, least-squares mean score deteriorated in the placebo group from baseline to week 9 (–1.8) and week 18 (–0.57). Compared with placebo, treatment with pembrolizumab was associated with a least-squares mean change of 3.6 at week 9 (nominal P = .0337) and 4.9 at week 18 (nominal P = .0060). Stated differently, at week 18, compared with placebo, more patients in the pembrolizumab group reported clinically meaningful improvements in health-related quality of life (36.2% vs. 27.7%), and relatively fewer reported deterioration (22.8% vs. 31.3%). Median time to deterioration in symptoms was not reached in either treatment arm.
“These health-related quality of life findings, along with the improved efficacy (including overall survival benefit) of pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel, support its use as a first-line treatment of metastatic squamous NSCLC, regardless of programmed death–ligand 1 expression,” the investigators concluded.
The study was funded by Merck. The investigators reported additional relationships with Novartis, Genentech, Pfizer, and others.
SOURCE: Mazieres J et al. J Clin Oncol. 2019 Nov 21. doi: 10.1200/JCO.19.01348.
Patient-reported outcomes support pembrolizumab plus chemotherapy for first-line treatment of metastatic non–small cell lung cancer (NSCLC), based on results from the KEYNOTE-407 trial.
At week 18, patients given pembrolizumab more often reported clinically meaningful health-related quality of life improvements than those in the placebo group, according to lead author Julien Mazieres, MD, PhD, of Paul Sabatier University in Toulouse, France, and colleagues.
Writing in the Journal of Clinical Oncology, the investigators explained that these findings build upon previously published results from KEYNOTE-407, which showed that adding pembrolizumab to chemotherapy in the first line could extend both progression-free and overall survival among patients with NSCLC. The benefits to quality of life associated with pembrolizumab align with similar findings from the KEYNOTE-024 and KEYNOTE-189 trials, they added.
The present analysis involved 559 patients with treatment-naive metastatic NSCLC. Patients were randomized to receive 4 cycles of placebo or pembrolizumab once every 3 weeks with carboplatin-based chemotherapy, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life was assessed by two measures: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Lung Cancer Module 13 (QLQ-LC13).
Of the 559 patients enrolled, 554 completed at least one QLQ-C30 assessment and 553 completed at least one QLQ-LC13 assessment. These quality of life scores were compared temporally within treatment groups, from baseline to week 9 and week 18, and between groups. The investigators also analyzed median time to deterioration in chest pain, cough, and dyspnea.
Results showed that patients in the pembrolizumab group had statistically significant improvements in patient-reported outcomes over time and more frequently reported improvements than patients in the placebo group. Specifically, in the pembrolizumab group, least-squares mean score improved from baseline to week 9 (1.8) and week 18 (4.3); in comparison, least-squares mean score deteriorated in the placebo group from baseline to week 9 (–1.8) and week 18 (–0.57). Compared with placebo, treatment with pembrolizumab was associated with a least-squares mean change of 3.6 at week 9 (nominal P = .0337) and 4.9 at week 18 (nominal P = .0060). Stated differently, at week 18, compared with placebo, more patients in the pembrolizumab group reported clinically meaningful improvements in health-related quality of life (36.2% vs. 27.7%), and relatively fewer reported deterioration (22.8% vs. 31.3%). Median time to deterioration in symptoms was not reached in either treatment arm.
“These health-related quality of life findings, along with the improved efficacy (including overall survival benefit) of pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel, support its use as a first-line treatment of metastatic squamous NSCLC, regardless of programmed death–ligand 1 expression,” the investigators concluded.
The study was funded by Merck. The investigators reported additional relationships with Novartis, Genentech, Pfizer, and others.
SOURCE: Mazieres J et al. J Clin Oncol. 2019 Nov 21. doi: 10.1200/JCO.19.01348.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Intensive BP control reduced dementia but increased brain atrophy and hurt cognition
SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.
Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.
“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”
The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.
SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.
At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.
Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.
After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.
Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.
Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.
The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.
There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.
“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”
The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.
Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.
The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm3 vs. 0.92 cm3). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm3, compared with a loss of 26.9 cm3 in the standard-treatment group.
“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.
Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.
However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.
SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.
SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.
Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.
“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”
The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.
SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.
At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.
Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.
After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.
Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.
Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.
The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.
There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.
“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”
The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.
Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.
The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm3 vs. 0.92 cm3). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm3, compared with a loss of 26.9 cm3 in the standard-treatment group.
“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.
Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.
However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.
SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.
SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.
Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.
“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”
The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.
SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.
At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.
Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.
After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.
Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.
Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.
The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.
There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.
“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”
The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.
Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.
The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm3 vs. 0.92 cm3). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm3, compared with a loss of 26.9 cm3 in the standard-treatment group.
“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.
Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.
However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.
SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.
REPORTING FROM CTAD 2019