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FDA approves first oral somatostatin analog for acromegaly
who previously responded to and tolerated octreotide or lanreotide injections.
“People living with acromegaly experience many challenges associated with injectable therapies and are in need of new treatment options,” Jill Sisco, president of Acromegaly Community, a patient support group, said in a Chiasma press release.
“The entire acromegaly community has long awaited oral therapeutic options and it is gratifying to see that the FDA has now approved the first oral somatostatin analog (SSA) therapy with the potential to make a significant impact in the lives of people with acromegaly and their caregivers,” she added.
Acromegaly, a rare, chronic disease usually caused by a benign pituitary tumor that leads to excess production of growth hormone and insulin-like growth factor-1 (IGF-1) hormone, can be cured through the successful surgical removal of the pituitary tumor. However, management of the disease remains a lifelong challenge for many who must rely on chronic injections.
The new oral formulation of octreotide is the first and only oral somatostatin analog approved by the FDA.
The approval was based on the results of the 9-month, phase 3 pivotal CHIASMA OPTIMAL clinical trial, involving 56 adults with acromegaly controlled by injectable SSAs.
The patients, who were randomized 1:1 to octreotide capsules or placebo, were dose-titrated from 40 mg/day up to a maximum of 80 mg/day, equaling two capsules in the morning and two in the evening.
The study met its primary endpoint. Overall, 58% of patients taking octreotide maintained IGF-1 response compared with 19% of those on placebo at the end of 9 months (P = .008), according to the average of the last two IGF-1 levels that were 1 times or less the upper limit of normal, assessed at weeks 34 and 36.
The trial also met its secondary endpoints, which included the proportion of patients who maintain growth hormone response at week 36 compared with screening; time to loss of response; and proportion of patients requiring reversion to prior treatment.
Safety data were favorable. Adverse reactions to the drug, detailed in the prescribing information, include cholelithiasis and associated complications; hyperglycemia and hypoglycemia; thyroid function abnormalities; cardiac function abnormalities; decreased vitamin B12 levels, and abnormal Schilling’s test results.
Results from the clinical trial “are encouraging for patients with acromegaly,” the study’s principal investigator, Susan Samson, MD, PhD, of Baylor College of Medicine, Houston, said in the Chiasma statement.
“Based on data from the CHIASMA OPTIMAL trial showing patients on therapy being able to maintain mean IGF-1 levels within the normal range at the end of treatment, I believe oral octreotide capsules hold meaningful promise for patients with this disease and will address a long-standing unmet treatment need,” she added.
Chiasma reports that it expects Mycapssa to be available in the fourth quarter of 2020, pending FDA approval of a planned manufacturing supplement to the approved new drug application.
The company further plans to provide patient support services including assistance with insurance providers and specialty pharmacies and support in incorporating treatment into patients’ daily routines.
Despite effective biochemical control of growth hormone, many patients with acromegaly continue to suffer symptoms, mainly because of comorbidities, so it is important that these are also adequately treated, a consensus group concluded earlier this year.
The CHIASMA OPTIMAL trial was funded by Chiasma.
A version of this article originally appeared on Medscape.com.
who previously responded to and tolerated octreotide or lanreotide injections.
“People living with acromegaly experience many challenges associated with injectable therapies and are in need of new treatment options,” Jill Sisco, president of Acromegaly Community, a patient support group, said in a Chiasma press release.
“The entire acromegaly community has long awaited oral therapeutic options and it is gratifying to see that the FDA has now approved the first oral somatostatin analog (SSA) therapy with the potential to make a significant impact in the lives of people with acromegaly and their caregivers,” she added.
Acromegaly, a rare, chronic disease usually caused by a benign pituitary tumor that leads to excess production of growth hormone and insulin-like growth factor-1 (IGF-1) hormone, can be cured through the successful surgical removal of the pituitary tumor. However, management of the disease remains a lifelong challenge for many who must rely on chronic injections.
The new oral formulation of octreotide is the first and only oral somatostatin analog approved by the FDA.
The approval was based on the results of the 9-month, phase 3 pivotal CHIASMA OPTIMAL clinical trial, involving 56 adults with acromegaly controlled by injectable SSAs.
The patients, who were randomized 1:1 to octreotide capsules or placebo, were dose-titrated from 40 mg/day up to a maximum of 80 mg/day, equaling two capsules in the morning and two in the evening.
The study met its primary endpoint. Overall, 58% of patients taking octreotide maintained IGF-1 response compared with 19% of those on placebo at the end of 9 months (P = .008), according to the average of the last two IGF-1 levels that were 1 times or less the upper limit of normal, assessed at weeks 34 and 36.
The trial also met its secondary endpoints, which included the proportion of patients who maintain growth hormone response at week 36 compared with screening; time to loss of response; and proportion of patients requiring reversion to prior treatment.
Safety data were favorable. Adverse reactions to the drug, detailed in the prescribing information, include cholelithiasis and associated complications; hyperglycemia and hypoglycemia; thyroid function abnormalities; cardiac function abnormalities; decreased vitamin B12 levels, and abnormal Schilling’s test results.
Results from the clinical trial “are encouraging for patients with acromegaly,” the study’s principal investigator, Susan Samson, MD, PhD, of Baylor College of Medicine, Houston, said in the Chiasma statement.
“Based on data from the CHIASMA OPTIMAL trial showing patients on therapy being able to maintain mean IGF-1 levels within the normal range at the end of treatment, I believe oral octreotide capsules hold meaningful promise for patients with this disease and will address a long-standing unmet treatment need,” she added.
Chiasma reports that it expects Mycapssa to be available in the fourth quarter of 2020, pending FDA approval of a planned manufacturing supplement to the approved new drug application.
The company further plans to provide patient support services including assistance with insurance providers and specialty pharmacies and support in incorporating treatment into patients’ daily routines.
Despite effective biochemical control of growth hormone, many patients with acromegaly continue to suffer symptoms, mainly because of comorbidities, so it is important that these are also adequately treated, a consensus group concluded earlier this year.
The CHIASMA OPTIMAL trial was funded by Chiasma.
A version of this article originally appeared on Medscape.com.
who previously responded to and tolerated octreotide or lanreotide injections.
“People living with acromegaly experience many challenges associated with injectable therapies and are in need of new treatment options,” Jill Sisco, president of Acromegaly Community, a patient support group, said in a Chiasma press release.
“The entire acromegaly community has long awaited oral therapeutic options and it is gratifying to see that the FDA has now approved the first oral somatostatin analog (SSA) therapy with the potential to make a significant impact in the lives of people with acromegaly and their caregivers,” she added.
Acromegaly, a rare, chronic disease usually caused by a benign pituitary tumor that leads to excess production of growth hormone and insulin-like growth factor-1 (IGF-1) hormone, can be cured through the successful surgical removal of the pituitary tumor. However, management of the disease remains a lifelong challenge for many who must rely on chronic injections.
The new oral formulation of octreotide is the first and only oral somatostatin analog approved by the FDA.
The approval was based on the results of the 9-month, phase 3 pivotal CHIASMA OPTIMAL clinical trial, involving 56 adults with acromegaly controlled by injectable SSAs.
The patients, who were randomized 1:1 to octreotide capsules or placebo, were dose-titrated from 40 mg/day up to a maximum of 80 mg/day, equaling two capsules in the morning and two in the evening.
The study met its primary endpoint. Overall, 58% of patients taking octreotide maintained IGF-1 response compared with 19% of those on placebo at the end of 9 months (P = .008), according to the average of the last two IGF-1 levels that were 1 times or less the upper limit of normal, assessed at weeks 34 and 36.
The trial also met its secondary endpoints, which included the proportion of patients who maintain growth hormone response at week 36 compared with screening; time to loss of response; and proportion of patients requiring reversion to prior treatment.
Safety data were favorable. Adverse reactions to the drug, detailed in the prescribing information, include cholelithiasis and associated complications; hyperglycemia and hypoglycemia; thyroid function abnormalities; cardiac function abnormalities; decreased vitamin B12 levels, and abnormal Schilling’s test results.
Results from the clinical trial “are encouraging for patients with acromegaly,” the study’s principal investigator, Susan Samson, MD, PhD, of Baylor College of Medicine, Houston, said in the Chiasma statement.
“Based on data from the CHIASMA OPTIMAL trial showing patients on therapy being able to maintain mean IGF-1 levels within the normal range at the end of treatment, I believe oral octreotide capsules hold meaningful promise for patients with this disease and will address a long-standing unmet treatment need,” she added.
Chiasma reports that it expects Mycapssa to be available in the fourth quarter of 2020, pending FDA approval of a planned manufacturing supplement to the approved new drug application.
The company further plans to provide patient support services including assistance with insurance providers and specialty pharmacies and support in incorporating treatment into patients’ daily routines.
Despite effective biochemical control of growth hormone, many patients with acromegaly continue to suffer symptoms, mainly because of comorbidities, so it is important that these are also adequately treated, a consensus group concluded earlier this year.
The CHIASMA OPTIMAL trial was funded by Chiasma.
A version of this article originally appeared on Medscape.com.
CMSC MRI guidelines evolve into international consensus protocol
, with the hope that internationally accepted consensus guidelines will improve lagging conformity with the recommendations.
“We’ve always envisioned the guidelines as being international, but now we have harmony with the groups, so this is truly a global protocol,” Anthony Traboulsee, MD, a professor of neurology and director of the MS clinic and neuromyelitis optica clinic at the University of British Columbia in Vancouver, said in presenting the proposed updates during the virtual meeting of the CMSC.
The updates reflect the input of an international expert panel convened by the CMSC in October 2019, made up of neurologists, radiologists, magnetic resonance technologists, and imaging scientists with expertise in MS. Attendees represented groups including the European-based Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, National MS Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis.
Standardizing scans
While the mission was to review and update the current guidelines, an important overriding objective was to boost universal acceptance and improve the utilization of the protocol, which research shows is surprisingly low. According to one poster presented at the meeting, a real-world MRI dataset of 1,233 sessions showed only 8% satisfied criteria for the T1 sequence outlined in the 2018 guidelines, and only 7% satisfied criteria for the T2 sequence. “In a real-world MRI dataset of patients with MS, the conformance to the CMSC brain MRI guidelines was extremely low,” concluded the authors, who were with Icometrix, in Chicago and Belgium.
David Li, MD, also of the University of British Columbia and cochair of the MRI guideline committee, said the nonconformity has important implications. “Nonstandardized scans, with inconsistent slice thickness and gaps, nonstandardized slice acquisition (not in the subcallosal plane), and incomplete brain coverage, all contribute to scans that are difficult to compare,” he said. Those factors, “allow for assessment of new lesions and lesion activity that are invaluable for diagnosis as well as determining the effectiveness of therapy or the need for initiating/changing therapy.”
Dr. Traboulsee said the lack of adherence to guidelines may simply have to do with a mistaken perception of complexity. “Part of the challenge is MRI centers don’t realize how easy it is to implement these guidelines,” he said in presenting the proposed updates.
Dr. Traboulsee noted that the CMSC has been working with manufacturers to try to incorporate the protocol into the scanners “so that it’s just a button to press” for the MRI. “I think that will get us over a major hurdle of adaptation,” Dr. Traboulsee said. “Most radiologists said once they started using it they were really happy with it. They found they were using it beyond MS for other basic neurologic imaging, so just raising awareness and making things more of a one-step process for individuals to use will be helpful,” he said.
Repositioning consistency is key
Among key suggestions that the expert panel proposed for guideline updates include the use of the subcallosal plane for consistent repositioning, which should allow for more accuracy and consistency in the identification of lesions in MS, Dr. Traboulsee said. “A major change reflecting improvements in MRI technology is the ability to acquire high-resolution 3-D images and that’s particularly helpful with fluid attenuation inversion recovery (FLAIR) sequences, which is what we do to identify lesions,” he explained. “The repositioning along the subcallosal line is important because it allows us to easily compare studies over time. It takes very little time but allows us to prepare studies over time much more easily,” he said.
Central vein sign
Another update is the establishment of a new category of optimum plus sequences allowing for the monitoring of brain atrophy and identifying lesions with a central vein sign, which has gained high interest as a marker on 3T MRI of demyelinating plaques in MS. As described in recent research, the central vein sign shows high accuracy in differentiating between MS and non-MS lesions.
“Many people have a few white spots on neuroimaging, but with MRI so much more available around the world, many of them are being misdiagnosed with MS,” Dr. Traboulsee said. “But the central vein sign, using a very simple MRI technique, can identify lesions with a vein in the center that (distinguishes them as) MS lesions.”
Though the process is still several years from routine clinical use, the proposed update would better implement susceptibility weighted imaging, which has traditionally been used for functional MRI.
PML Surveillance
The updates also include recommendations to help in the detection of the rare but potentially serious complication of some disease-modifying therapies of progressive multifocal leukoencephalopathy (PML). “We need a very quick and comprehensive way to monitor patients for PML before symptoms develop,” Dr. Traboulsee said. “The sequences we recommended were based on expert opinion of people who have worked quite a bit with PML in MS, and if one wants to survey for PML it’s only about a 10-minute scan.”
International protocol
Corey Ford, MD, a professor of neurology and director of the MS Specialty Clinic at the University of New Mexico Health Sciences Center in Albuquerque, commented that, with imaging playing such an important role in MS, the lack of adherence to the protocol can be a significant hindrance. “MRI is the most important imaging tool we have in the diagnosing and management of MS, but ... it’s quite amazing how different the sequences that are used can be when imaging centers are asked to image someone with a diagnosis of MS, so it’s a problem,” he said.
Dr. Ford speculated that part of the problem is simply inertia at some imaging centers. “Practices will have been programmed into their protocol for a long time, so when a patient comes in for imaging regarding MS, they may [turn to] their typical sequence,” he said. “There is an inertial barrier to upgrading that sequence, which can involve testing it out on the machine, training the techs to do it that way, and interpreting it for the physician clients who requested the imaging.”
In addition, there is a lack of exposure of MS imaging guidelines in the radiology literature, Dr. Ford added. “Maybe it’s a matter of giving more presentations at meetings that include radiologists, or getting the information out through the manufacturers. I think at the end of the day it could be a combination of all of those things,” he said.
However, the CMSC collaboration could make a big difference, Dr. Ford noted. “This is where the international protocol could be important in terms of making all of this happen,” he said. “What we’re seeing is the confluence of representatives of the U.S. and European centers hash out a consensus, and if it’s international, I think that adds a lot of weight to an eventual implementation on a wider basis.”
“I think the group has done a stellar job, and we should not try to be too focused on adding everyone’s little tweak,” he noted. “If we can get a good baseline foundational imaging sequence that can be implemented worldwide, we would be much better off.”
The CMSC updated imaging guidelines are expected to be published in coming months. The most recent previous updates are available online.
Dr. Traboulsee disclosed relationships with Biogen, Chugai, Roche, Sanofi, and Teva. Dr. Ford and Dr. Li have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
, with the hope that internationally accepted consensus guidelines will improve lagging conformity with the recommendations.
“We’ve always envisioned the guidelines as being international, but now we have harmony with the groups, so this is truly a global protocol,” Anthony Traboulsee, MD, a professor of neurology and director of the MS clinic and neuromyelitis optica clinic at the University of British Columbia in Vancouver, said in presenting the proposed updates during the virtual meeting of the CMSC.
The updates reflect the input of an international expert panel convened by the CMSC in October 2019, made up of neurologists, radiologists, magnetic resonance technologists, and imaging scientists with expertise in MS. Attendees represented groups including the European-based Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, National MS Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis.
Standardizing scans
While the mission was to review and update the current guidelines, an important overriding objective was to boost universal acceptance and improve the utilization of the protocol, which research shows is surprisingly low. According to one poster presented at the meeting, a real-world MRI dataset of 1,233 sessions showed only 8% satisfied criteria for the T1 sequence outlined in the 2018 guidelines, and only 7% satisfied criteria for the T2 sequence. “In a real-world MRI dataset of patients with MS, the conformance to the CMSC brain MRI guidelines was extremely low,” concluded the authors, who were with Icometrix, in Chicago and Belgium.
David Li, MD, also of the University of British Columbia and cochair of the MRI guideline committee, said the nonconformity has important implications. “Nonstandardized scans, with inconsistent slice thickness and gaps, nonstandardized slice acquisition (not in the subcallosal plane), and incomplete brain coverage, all contribute to scans that are difficult to compare,” he said. Those factors, “allow for assessment of new lesions and lesion activity that are invaluable for diagnosis as well as determining the effectiveness of therapy or the need for initiating/changing therapy.”
Dr. Traboulsee said the lack of adherence to guidelines may simply have to do with a mistaken perception of complexity. “Part of the challenge is MRI centers don’t realize how easy it is to implement these guidelines,” he said in presenting the proposed updates.
Dr. Traboulsee noted that the CMSC has been working with manufacturers to try to incorporate the protocol into the scanners “so that it’s just a button to press” for the MRI. “I think that will get us over a major hurdle of adaptation,” Dr. Traboulsee said. “Most radiologists said once they started using it they were really happy with it. They found they were using it beyond MS for other basic neurologic imaging, so just raising awareness and making things more of a one-step process for individuals to use will be helpful,” he said.
Repositioning consistency is key
Among key suggestions that the expert panel proposed for guideline updates include the use of the subcallosal plane for consistent repositioning, which should allow for more accuracy and consistency in the identification of lesions in MS, Dr. Traboulsee said. “A major change reflecting improvements in MRI technology is the ability to acquire high-resolution 3-D images and that’s particularly helpful with fluid attenuation inversion recovery (FLAIR) sequences, which is what we do to identify lesions,” he explained. “The repositioning along the subcallosal line is important because it allows us to easily compare studies over time. It takes very little time but allows us to prepare studies over time much more easily,” he said.
Central vein sign
Another update is the establishment of a new category of optimum plus sequences allowing for the monitoring of brain atrophy and identifying lesions with a central vein sign, which has gained high interest as a marker on 3T MRI of demyelinating plaques in MS. As described in recent research, the central vein sign shows high accuracy in differentiating between MS and non-MS lesions.
“Many people have a few white spots on neuroimaging, but with MRI so much more available around the world, many of them are being misdiagnosed with MS,” Dr. Traboulsee said. “But the central vein sign, using a very simple MRI technique, can identify lesions with a vein in the center that (distinguishes them as) MS lesions.”
Though the process is still several years from routine clinical use, the proposed update would better implement susceptibility weighted imaging, which has traditionally been used for functional MRI.
PML Surveillance
The updates also include recommendations to help in the detection of the rare but potentially serious complication of some disease-modifying therapies of progressive multifocal leukoencephalopathy (PML). “We need a very quick and comprehensive way to monitor patients for PML before symptoms develop,” Dr. Traboulsee said. “The sequences we recommended were based on expert opinion of people who have worked quite a bit with PML in MS, and if one wants to survey for PML it’s only about a 10-minute scan.”
International protocol
Corey Ford, MD, a professor of neurology and director of the MS Specialty Clinic at the University of New Mexico Health Sciences Center in Albuquerque, commented that, with imaging playing such an important role in MS, the lack of adherence to the protocol can be a significant hindrance. “MRI is the most important imaging tool we have in the diagnosing and management of MS, but ... it’s quite amazing how different the sequences that are used can be when imaging centers are asked to image someone with a diagnosis of MS, so it’s a problem,” he said.
Dr. Ford speculated that part of the problem is simply inertia at some imaging centers. “Practices will have been programmed into their protocol for a long time, so when a patient comes in for imaging regarding MS, they may [turn to] their typical sequence,” he said. “There is an inertial barrier to upgrading that sequence, which can involve testing it out on the machine, training the techs to do it that way, and interpreting it for the physician clients who requested the imaging.”
In addition, there is a lack of exposure of MS imaging guidelines in the radiology literature, Dr. Ford added. “Maybe it’s a matter of giving more presentations at meetings that include radiologists, or getting the information out through the manufacturers. I think at the end of the day it could be a combination of all of those things,” he said.
However, the CMSC collaboration could make a big difference, Dr. Ford noted. “This is where the international protocol could be important in terms of making all of this happen,” he said. “What we’re seeing is the confluence of representatives of the U.S. and European centers hash out a consensus, and if it’s international, I think that adds a lot of weight to an eventual implementation on a wider basis.”
“I think the group has done a stellar job, and we should not try to be too focused on adding everyone’s little tweak,” he noted. “If we can get a good baseline foundational imaging sequence that can be implemented worldwide, we would be much better off.”
The CMSC updated imaging guidelines are expected to be published in coming months. The most recent previous updates are available online.
Dr. Traboulsee disclosed relationships with Biogen, Chugai, Roche, Sanofi, and Teva. Dr. Ford and Dr. Li have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
, with the hope that internationally accepted consensus guidelines will improve lagging conformity with the recommendations.
“We’ve always envisioned the guidelines as being international, but now we have harmony with the groups, so this is truly a global protocol,” Anthony Traboulsee, MD, a professor of neurology and director of the MS clinic and neuromyelitis optica clinic at the University of British Columbia in Vancouver, said in presenting the proposed updates during the virtual meeting of the CMSC.
The updates reflect the input of an international expert panel convened by the CMSC in October 2019, made up of neurologists, radiologists, magnetic resonance technologists, and imaging scientists with expertise in MS. Attendees represented groups including the European-based Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, National MS Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis.
Standardizing scans
While the mission was to review and update the current guidelines, an important overriding objective was to boost universal acceptance and improve the utilization of the protocol, which research shows is surprisingly low. According to one poster presented at the meeting, a real-world MRI dataset of 1,233 sessions showed only 8% satisfied criteria for the T1 sequence outlined in the 2018 guidelines, and only 7% satisfied criteria for the T2 sequence. “In a real-world MRI dataset of patients with MS, the conformance to the CMSC brain MRI guidelines was extremely low,” concluded the authors, who were with Icometrix, in Chicago and Belgium.
David Li, MD, also of the University of British Columbia and cochair of the MRI guideline committee, said the nonconformity has important implications. “Nonstandardized scans, with inconsistent slice thickness and gaps, nonstandardized slice acquisition (not in the subcallosal plane), and incomplete brain coverage, all contribute to scans that are difficult to compare,” he said. Those factors, “allow for assessment of new lesions and lesion activity that are invaluable for diagnosis as well as determining the effectiveness of therapy or the need for initiating/changing therapy.”
Dr. Traboulsee said the lack of adherence to guidelines may simply have to do with a mistaken perception of complexity. “Part of the challenge is MRI centers don’t realize how easy it is to implement these guidelines,” he said in presenting the proposed updates.
Dr. Traboulsee noted that the CMSC has been working with manufacturers to try to incorporate the protocol into the scanners “so that it’s just a button to press” for the MRI. “I think that will get us over a major hurdle of adaptation,” Dr. Traboulsee said. “Most radiologists said once they started using it they were really happy with it. They found they were using it beyond MS for other basic neurologic imaging, so just raising awareness and making things more of a one-step process for individuals to use will be helpful,” he said.
Repositioning consistency is key
Among key suggestions that the expert panel proposed for guideline updates include the use of the subcallosal plane for consistent repositioning, which should allow for more accuracy and consistency in the identification of lesions in MS, Dr. Traboulsee said. “A major change reflecting improvements in MRI technology is the ability to acquire high-resolution 3-D images and that’s particularly helpful with fluid attenuation inversion recovery (FLAIR) sequences, which is what we do to identify lesions,” he explained. “The repositioning along the subcallosal line is important because it allows us to easily compare studies over time. It takes very little time but allows us to prepare studies over time much more easily,” he said.
Central vein sign
Another update is the establishment of a new category of optimum plus sequences allowing for the monitoring of brain atrophy and identifying lesions with a central vein sign, which has gained high interest as a marker on 3T MRI of demyelinating plaques in MS. As described in recent research, the central vein sign shows high accuracy in differentiating between MS and non-MS lesions.
“Many people have a few white spots on neuroimaging, but with MRI so much more available around the world, many of them are being misdiagnosed with MS,” Dr. Traboulsee said. “But the central vein sign, using a very simple MRI technique, can identify lesions with a vein in the center that (distinguishes them as) MS lesions.”
Though the process is still several years from routine clinical use, the proposed update would better implement susceptibility weighted imaging, which has traditionally been used for functional MRI.
PML Surveillance
The updates also include recommendations to help in the detection of the rare but potentially serious complication of some disease-modifying therapies of progressive multifocal leukoencephalopathy (PML). “We need a very quick and comprehensive way to monitor patients for PML before symptoms develop,” Dr. Traboulsee said. “The sequences we recommended were based on expert opinion of people who have worked quite a bit with PML in MS, and if one wants to survey for PML it’s only about a 10-minute scan.”
International protocol
Corey Ford, MD, a professor of neurology and director of the MS Specialty Clinic at the University of New Mexico Health Sciences Center in Albuquerque, commented that, with imaging playing such an important role in MS, the lack of adherence to the protocol can be a significant hindrance. “MRI is the most important imaging tool we have in the diagnosing and management of MS, but ... it’s quite amazing how different the sequences that are used can be when imaging centers are asked to image someone with a diagnosis of MS, so it’s a problem,” he said.
Dr. Ford speculated that part of the problem is simply inertia at some imaging centers. “Practices will have been programmed into their protocol for a long time, so when a patient comes in for imaging regarding MS, they may [turn to] their typical sequence,” he said. “There is an inertial barrier to upgrading that sequence, which can involve testing it out on the machine, training the techs to do it that way, and interpreting it for the physician clients who requested the imaging.”
In addition, there is a lack of exposure of MS imaging guidelines in the radiology literature, Dr. Ford added. “Maybe it’s a matter of giving more presentations at meetings that include radiologists, or getting the information out through the manufacturers. I think at the end of the day it could be a combination of all of those things,” he said.
However, the CMSC collaboration could make a big difference, Dr. Ford noted. “This is where the international protocol could be important in terms of making all of this happen,” he said. “What we’re seeing is the confluence of representatives of the U.S. and European centers hash out a consensus, and if it’s international, I think that adds a lot of weight to an eventual implementation on a wider basis.”
“I think the group has done a stellar job, and we should not try to be too focused on adding everyone’s little tweak,” he noted. “If we can get a good baseline foundational imaging sequence that can be implemented worldwide, we would be much better off.”
The CMSC updated imaging guidelines are expected to be published in coming months. The most recent previous updates are available online.
Dr. Traboulsee disclosed relationships with Biogen, Chugai, Roche, Sanofi, and Teva. Dr. Ford and Dr. Li have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
From CMSC 2020
Safe to skip radiotherapy with negative PET in Hodgkin lymphoma
and can skip the additional radiotherapy that is normally included in the combined modality treatment, say experts reporting the final results from an international phase 3 randomized trial dubbed HD17.
“Most patients with this disease will not need radiotherapy any longer,” concluded first author Peter Borchmann, MD, assistant medical director in the department of hematology/oncology at the University Hospital Cologne (Germany).
Dr. Borchmann was speaking online as part of the virtual edition of the European Hematology Association 25th Annual Congress 2020.
“Importantly, the mortality of patients with early-stage unfavorable Hodgkin lymphoma in the HD17 study did not differ from the normal healthy German population, and this is the first time we have had this finding in one of our studies,” he emphasized.
Dr. Borchmann added that positron emission tomography imaging is key in deciding which patients can skip radiation.
“We conclude from the HD17 trial that the combined modality concept can and should be replaced by a PET-guided omission of radiotherapy for patients with newly diagnosed early-stage unfavorable Hodgkin lymphoma,” he said.
“The vast majority of early-stage unfavorable Hodgkin lymphoma patients can be treated with the brief and highly effective 2+2 chemotherapy alone,” he added.
Therefore, he continued, “PET-guided 2+2 chemotherapy is the new standard of care for the German Hodgkin study group,” which conducted the trial.
The use of both chemotherapy and radiation has long been a standard approach to treatment, and this combined modality treatment is highly effective, Dr. Borchmann explained. But it can cause long-term damage, and the known longer-term negative effects of radiotherapy, such as cardiovascular disease and second malignancies, are a particular concern because patients with early-stage Hodgkin lymphoma are relatively young, with a median age of around 30 years at disease onset.
An expert approached for comment said that the momentum to skip radiotherapy when possible is an ongoing issue, and importantly, this study adds to those efforts.
“The treatment of Hodgkin lymphoma has moved for many years now to less radiation therapy, and this trend will continue with the results of this study,” commented John G. Gribben, MD, director of the Stem Cell Transplantation Program and medical director of the North East London Cancer Research Network Centre at Barts Cancer Center of Excellence and the London School of Medicine.
“We have moved to lower doses and involved fields with the intent of decreasing toxicity, and particularly long-term toxicity from radiotherapy,” he said in an interview.
HD17 study details
For the multicenter, phase 3 HD17 trial, Dr. Borchmann and colleagues turned to PET to identify patients who had and had not responded well to chemotherapy (PET negative and PET positive) and to determine if those who had responded well could safely avoid radiotherapy without compromising efficacy.
“We wanted to determine if we could reduce the treatment intensity by omission of radiotherapy in patients who respond very well to the systemic treatment, so who have a complete metabolic remission after the chemotherapy,” Dr. Borchmann said.
The 2+2 treatment approach includes two cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and two subsequent cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).
The trial enrolled 1,100 patients with newly diagnosed Hodgkin lymphoma between January 2012 and March 2017. Of these, 979 patients had confirmed PET results, with 651 (66.5%) found to be PET negative, defined as having a Deauville score (DS) of less than 3 (DS3); 238 (24.3%) were DS3, and 90 (9.2%) were DS4.
The study met its primary endpoint of noninferiority in progression-free survival (PFS) at 5 years, with a PFS of 95.1% in the PET-guided group (n = 447), compared with 97.3% in the standard combined-modality treatment group (n = 428), over a median observation time of 45 months, for a difference of 2.2% (P = .12).
“We found that the survival levels were very high, and we can safely conclude the noninferiority of the PET-guided approach in PET-negative patients,” Dr. Borchmann said.
A further analysis showed that the 597 PET-negative patients who did not receive radiotherapy because of their PET status had 5-year PFS that was noninferior to the combined modality group (95.9% vs. 97.7%, respectively; P = .20).
And among 646 patients who received the 2+2 regimen plus radiotherapy, of those confirmed as PET positive (n = 328), the estimated 5-year PFS was significantly lower (94.2%), compared with those determined to be PET negative (n = 318; 97.6%; hazard ratio, 3.03).
A cut-off of DS4 for positivity was associated with a stronger effect, with a lower estimated 5-year PFS of 81.6% vs. 98.8% for DS3 patients and 97.6% for DS less than 3 (P < .0001).
“Only DS4 has a prognostic impact, but not DS3,” Dr. Borchmann said. “DS4 positivity indicates a relevant risk for treatment failure, however, there are few patients in this risk group (9.2% in this trial).”
The 5-year overall survival rates in an intent-to-treat analysis were 98.8% in the standard combined modality group and 98.4% in the PET-guided group.
With a median observation time of 47 months, there have been 10 fatal events in the trial out of 1,100 patients, including two Hodgkin lymphoma-related events and one treatment-related death.
“Overall, Hodgkin lymphoma or treatment-related mortality rates were extremely low,” Dr. Borchmann said.
The study was funded by Deutsche Krebshilfe. Dr. Borchmann and Dr. Gribben have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
and can skip the additional radiotherapy that is normally included in the combined modality treatment, say experts reporting the final results from an international phase 3 randomized trial dubbed HD17.
“Most patients with this disease will not need radiotherapy any longer,” concluded first author Peter Borchmann, MD, assistant medical director in the department of hematology/oncology at the University Hospital Cologne (Germany).
Dr. Borchmann was speaking online as part of the virtual edition of the European Hematology Association 25th Annual Congress 2020.
“Importantly, the mortality of patients with early-stage unfavorable Hodgkin lymphoma in the HD17 study did not differ from the normal healthy German population, and this is the first time we have had this finding in one of our studies,” he emphasized.
Dr. Borchmann added that positron emission tomography imaging is key in deciding which patients can skip radiation.
“We conclude from the HD17 trial that the combined modality concept can and should be replaced by a PET-guided omission of radiotherapy for patients with newly diagnosed early-stage unfavorable Hodgkin lymphoma,” he said.
“The vast majority of early-stage unfavorable Hodgkin lymphoma patients can be treated with the brief and highly effective 2+2 chemotherapy alone,” he added.
Therefore, he continued, “PET-guided 2+2 chemotherapy is the new standard of care for the German Hodgkin study group,” which conducted the trial.
The use of both chemotherapy and radiation has long been a standard approach to treatment, and this combined modality treatment is highly effective, Dr. Borchmann explained. But it can cause long-term damage, and the known longer-term negative effects of radiotherapy, such as cardiovascular disease and second malignancies, are a particular concern because patients with early-stage Hodgkin lymphoma are relatively young, with a median age of around 30 years at disease onset.
An expert approached for comment said that the momentum to skip radiotherapy when possible is an ongoing issue, and importantly, this study adds to those efforts.
“The treatment of Hodgkin lymphoma has moved for many years now to less radiation therapy, and this trend will continue with the results of this study,” commented John G. Gribben, MD, director of the Stem Cell Transplantation Program and medical director of the North East London Cancer Research Network Centre at Barts Cancer Center of Excellence and the London School of Medicine.
“We have moved to lower doses and involved fields with the intent of decreasing toxicity, and particularly long-term toxicity from radiotherapy,” he said in an interview.
HD17 study details
For the multicenter, phase 3 HD17 trial, Dr. Borchmann and colleagues turned to PET to identify patients who had and had not responded well to chemotherapy (PET negative and PET positive) and to determine if those who had responded well could safely avoid radiotherapy without compromising efficacy.
“We wanted to determine if we could reduce the treatment intensity by omission of radiotherapy in patients who respond very well to the systemic treatment, so who have a complete metabolic remission after the chemotherapy,” Dr. Borchmann said.
The 2+2 treatment approach includes two cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and two subsequent cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).
The trial enrolled 1,100 patients with newly diagnosed Hodgkin lymphoma between January 2012 and March 2017. Of these, 979 patients had confirmed PET results, with 651 (66.5%) found to be PET negative, defined as having a Deauville score (DS) of less than 3 (DS3); 238 (24.3%) were DS3, and 90 (9.2%) were DS4.
The study met its primary endpoint of noninferiority in progression-free survival (PFS) at 5 years, with a PFS of 95.1% in the PET-guided group (n = 447), compared with 97.3% in the standard combined-modality treatment group (n = 428), over a median observation time of 45 months, for a difference of 2.2% (P = .12).
“We found that the survival levels were very high, and we can safely conclude the noninferiority of the PET-guided approach in PET-negative patients,” Dr. Borchmann said.
A further analysis showed that the 597 PET-negative patients who did not receive radiotherapy because of their PET status had 5-year PFS that was noninferior to the combined modality group (95.9% vs. 97.7%, respectively; P = .20).
And among 646 patients who received the 2+2 regimen plus radiotherapy, of those confirmed as PET positive (n = 328), the estimated 5-year PFS was significantly lower (94.2%), compared with those determined to be PET negative (n = 318; 97.6%; hazard ratio, 3.03).
A cut-off of DS4 for positivity was associated with a stronger effect, with a lower estimated 5-year PFS of 81.6% vs. 98.8% for DS3 patients and 97.6% for DS less than 3 (P < .0001).
“Only DS4 has a prognostic impact, but not DS3,” Dr. Borchmann said. “DS4 positivity indicates a relevant risk for treatment failure, however, there are few patients in this risk group (9.2% in this trial).”
The 5-year overall survival rates in an intent-to-treat analysis were 98.8% in the standard combined modality group and 98.4% in the PET-guided group.
With a median observation time of 47 months, there have been 10 fatal events in the trial out of 1,100 patients, including two Hodgkin lymphoma-related events and one treatment-related death.
“Overall, Hodgkin lymphoma or treatment-related mortality rates were extremely low,” Dr. Borchmann said.
The study was funded by Deutsche Krebshilfe. Dr. Borchmann and Dr. Gribben have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
and can skip the additional radiotherapy that is normally included in the combined modality treatment, say experts reporting the final results from an international phase 3 randomized trial dubbed HD17.
“Most patients with this disease will not need radiotherapy any longer,” concluded first author Peter Borchmann, MD, assistant medical director in the department of hematology/oncology at the University Hospital Cologne (Germany).
Dr. Borchmann was speaking online as part of the virtual edition of the European Hematology Association 25th Annual Congress 2020.
“Importantly, the mortality of patients with early-stage unfavorable Hodgkin lymphoma in the HD17 study did not differ from the normal healthy German population, and this is the first time we have had this finding in one of our studies,” he emphasized.
Dr. Borchmann added that positron emission tomography imaging is key in deciding which patients can skip radiation.
“We conclude from the HD17 trial that the combined modality concept can and should be replaced by a PET-guided omission of radiotherapy for patients with newly diagnosed early-stage unfavorable Hodgkin lymphoma,” he said.
“The vast majority of early-stage unfavorable Hodgkin lymphoma patients can be treated with the brief and highly effective 2+2 chemotherapy alone,” he added.
Therefore, he continued, “PET-guided 2+2 chemotherapy is the new standard of care for the German Hodgkin study group,” which conducted the trial.
The use of both chemotherapy and radiation has long been a standard approach to treatment, and this combined modality treatment is highly effective, Dr. Borchmann explained. But it can cause long-term damage, and the known longer-term negative effects of radiotherapy, such as cardiovascular disease and second malignancies, are a particular concern because patients with early-stage Hodgkin lymphoma are relatively young, with a median age of around 30 years at disease onset.
An expert approached for comment said that the momentum to skip radiotherapy when possible is an ongoing issue, and importantly, this study adds to those efforts.
“The treatment of Hodgkin lymphoma has moved for many years now to less radiation therapy, and this trend will continue with the results of this study,” commented John G. Gribben, MD, director of the Stem Cell Transplantation Program and medical director of the North East London Cancer Research Network Centre at Barts Cancer Center of Excellence and the London School of Medicine.
“We have moved to lower doses and involved fields with the intent of decreasing toxicity, and particularly long-term toxicity from radiotherapy,” he said in an interview.
HD17 study details
For the multicenter, phase 3 HD17 trial, Dr. Borchmann and colleagues turned to PET to identify patients who had and had not responded well to chemotherapy (PET negative and PET positive) and to determine if those who had responded well could safely avoid radiotherapy without compromising efficacy.
“We wanted to determine if we could reduce the treatment intensity by omission of radiotherapy in patients who respond very well to the systemic treatment, so who have a complete metabolic remission after the chemotherapy,” Dr. Borchmann said.
The 2+2 treatment approach includes two cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and two subsequent cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine).
The trial enrolled 1,100 patients with newly diagnosed Hodgkin lymphoma between January 2012 and March 2017. Of these, 979 patients had confirmed PET results, with 651 (66.5%) found to be PET negative, defined as having a Deauville score (DS) of less than 3 (DS3); 238 (24.3%) were DS3, and 90 (9.2%) were DS4.
The study met its primary endpoint of noninferiority in progression-free survival (PFS) at 5 years, with a PFS of 95.1% in the PET-guided group (n = 447), compared with 97.3% in the standard combined-modality treatment group (n = 428), over a median observation time of 45 months, for a difference of 2.2% (P = .12).
“We found that the survival levels were very high, and we can safely conclude the noninferiority of the PET-guided approach in PET-negative patients,” Dr. Borchmann said.
A further analysis showed that the 597 PET-negative patients who did not receive radiotherapy because of their PET status had 5-year PFS that was noninferior to the combined modality group (95.9% vs. 97.7%, respectively; P = .20).
And among 646 patients who received the 2+2 regimen plus radiotherapy, of those confirmed as PET positive (n = 328), the estimated 5-year PFS was significantly lower (94.2%), compared with those determined to be PET negative (n = 318; 97.6%; hazard ratio, 3.03).
A cut-off of DS4 for positivity was associated with a stronger effect, with a lower estimated 5-year PFS of 81.6% vs. 98.8% for DS3 patients and 97.6% for DS less than 3 (P < .0001).
“Only DS4 has a prognostic impact, but not DS3,” Dr. Borchmann said. “DS4 positivity indicates a relevant risk for treatment failure, however, there are few patients in this risk group (9.2% in this trial).”
The 5-year overall survival rates in an intent-to-treat analysis were 98.8% in the standard combined modality group and 98.4% in the PET-guided group.
With a median observation time of 47 months, there have been 10 fatal events in the trial out of 1,100 patients, including two Hodgkin lymphoma-related events and one treatment-related death.
“Overall, Hodgkin lymphoma or treatment-related mortality rates were extremely low,” Dr. Borchmann said.
The study was funded by Deutsche Krebshilfe. Dr. Borchmann and Dr. Gribben have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Omitting whole body irradiation before HSCT: Trial stopped early
Hematopoietic stem cell transplantation (HSCT) may offer the chance of a cure for patients with leukemia and other blood cancers, but the process of preparing the body to receive such a transplant can be brutal, involving whole body irradiation as well as chemotherapy conditioning. New results show that both steps are needed: a trial that omitted whole body irradiation in young patients with acute lymphoblastic leukemia (ALL) was stopped early because of significantly poorer outcomes.
The multicenter, global FORUM (For Omitting Radiation Under Majority Age) trial involved 75 centers in 17 countries between 2013 and 2018.
“Our study shows significantly better outcomes for total body irradiation compared to myeloablative chemo-conditioning arms, with no differences between the [two] chemo-conditioning groups,” concluded Christina Peters, MD, professor of pediatrics in the department of stem cell transplantation at St Anna Children’s Hospital in Vienna.
, she added.
Dr. Peters presented the findings as part of the virtual annual congress of the European Hematology Association.
Describing the results as “sobering,” session comoderator Shai Izraeli, MD, director of the department of hematology-oncology at Schneider Children’s Medical Center, in Petah Tikva, Israel, said an online comment from the virtual meeting audience reflected the reaction to these unwelcome results: “So we are still stuck with total body irradiation?”
Dr. Peters said the good news is that the number of patients needing to undergo stem cell transplants is low, and with research advances, may hopefully drop even further.
“Only 10% of patients under the age of 18 nowadays undergo allogeneic HSCT, and perhaps in the future that will become even less if we are able to rescue some of the groups with other immunological measures such as CAR-T cells and antibodies,” she said.
“I think it is very important to better identify those who really need total body irradiation in the future,” she added.
In an interview, Dr. Izraeli agreed.
“The prognosis of children after bone marrow transplantation is excellent – the majority are cured from their leukemia,” he said. “And we have to remember that those who undergo bone marrow transplant have the worst leukemias.”
He pointed out that, in fact, contemporary chemotherapy alone is effective in the treatment of more than 90% of patients with ALL younger than aged 18.
For the 10% of patients who do not respond to chemotherapy alone and undergo allogeneic HSCT, about 50%-80% of pediatric patients who have resistant leukemia are cured. However, the total body irradiation used to prepare the body to receive the transplant is linked to potentially serious consequences later in life, including sterility, lung problems, growth retardation, and secondary cancer.
To determine if the irradiation component could be safely replaced with a chemotherapy-based conditioning approach, Dr. Peters and colleagues conducted the FORUM trial.
In total 413 patients undergoing HSCT were enrolled and randomized to pretransplant conditioning with total body irradiation and etoposide (n = 202) or a chemotherapy-only approach with fludarabine/thiotepa/busulfan (flu/thio/bu; n = 99) or fludarabine/thiotepa/treosulfan (treo; n = 93).
Most patients (72%) had B-cell precursor ALL and 23% had T-cell ALL. Just over half (54%) were transplanted in first complete remission (CR1), 40% in CR2, and 4% in CR3.
The source of stem cells was bone marrow for most patients (82%); peripheral blood stem cell for 12%, and cord blood for 4%.
Study stopped early
The aim of the study was to demonstrate noninferiority with the chemotherapy approach.
However, the significantly inferior outcome observed in the chemotherapy-only group led to randomization being halted in March 2019.
The 2-year overall survival in the intent-to-treat (ITT) analysis, with a mean observation time of 2.1 years, was 0.75 ± 0.04 for chemo-conditioning versus 0.91 ± 0.02 for total body irradiation/etoposide (ITT P < .001).
The ITT analysis showed relapses were significantly higher in the chemo-conditioning group (2-year cumulative incidence of relapse [CIR], 0.33) compared with the total body irradiation group (CIR, 0.12; P < .001).
The 2-year event-free survival (EFS) rate was also significantly higher in the total body irradiation group (0.86 vs 0.58; P < .001), and transplant-related mortality over 2 years was lower with total body irradiation (0.02 vs 0.09; P = .02).
A per-protocol analysis showed the 2-year overall survival to be the same in the two chemotherapy groups (both 0.77 ± 0.05) compared with 0.91 ± 0.02 in the total body irradiation group (P = .003).
“In this cohort [the 91% overall survival rate] may even be lower than contemporary intensive frontline therapy results that are achieved nowadays,” Dr. Peters said.
In looking at subgroups, there were no significant differences according to age group or cancer phenotype, while MLL rearrangement was associated with higher relapse incidence.
Remission status was found to notably influence EFS, dropping from 0.91 in CR1 patients with total body irradiation to 0.76 in CR2 patients. However, total body irradiation remained significantly higher compared with the chemo-conditioning groups in CR1 (P = .004) and CR2 (P < .001).
Transplant-related mortality was not significantly different between the total body irradiation and chemo-conditioning groups in the CR1 or CR2 groups (P = .09 and P = .18, respectively), despite the significant difference when remission status was not included.
Overall, “we tried to identify subgroups in which total body irradiation might be eliminated, however in all analyses, total body irradiation was better than chemo-conditioning in all arms,” Dr. Peters said.
Meanwhile, the findings underscore that even when patients cannot receive total body irradiation, the alternative chemo-conditioning therapy in fact shows favorable efficacy on its own, Dr. Izraeli said.
“The prognosis of the chemotherapy group is also quite remarkably good, although less than the total body irradiation arm. This means that if for some reason total body irradiation cannot be given, the chemotherapy is a very reasonable alternative.”
Dr. Peters has reported relationships with Amgen, Novartis, Pfizer, Medac, Jazz, and Neovii. Dr. Izraeli has reported no relevant financial relationships.
SOURCE: EHA Congress. Abstract S102.
A version of this article originally appeared on Medscape.com.
Hematopoietic stem cell transplantation (HSCT) may offer the chance of a cure for patients with leukemia and other blood cancers, but the process of preparing the body to receive such a transplant can be brutal, involving whole body irradiation as well as chemotherapy conditioning. New results show that both steps are needed: a trial that omitted whole body irradiation in young patients with acute lymphoblastic leukemia (ALL) was stopped early because of significantly poorer outcomes.
The multicenter, global FORUM (For Omitting Radiation Under Majority Age) trial involved 75 centers in 17 countries between 2013 and 2018.
“Our study shows significantly better outcomes for total body irradiation compared to myeloablative chemo-conditioning arms, with no differences between the [two] chemo-conditioning groups,” concluded Christina Peters, MD, professor of pediatrics in the department of stem cell transplantation at St Anna Children’s Hospital in Vienna.
, she added.
Dr. Peters presented the findings as part of the virtual annual congress of the European Hematology Association.
Describing the results as “sobering,” session comoderator Shai Izraeli, MD, director of the department of hematology-oncology at Schneider Children’s Medical Center, in Petah Tikva, Israel, said an online comment from the virtual meeting audience reflected the reaction to these unwelcome results: “So we are still stuck with total body irradiation?”
Dr. Peters said the good news is that the number of patients needing to undergo stem cell transplants is low, and with research advances, may hopefully drop even further.
“Only 10% of patients under the age of 18 nowadays undergo allogeneic HSCT, and perhaps in the future that will become even less if we are able to rescue some of the groups with other immunological measures such as CAR-T cells and antibodies,” she said.
“I think it is very important to better identify those who really need total body irradiation in the future,” she added.
In an interview, Dr. Izraeli agreed.
“The prognosis of children after bone marrow transplantation is excellent – the majority are cured from their leukemia,” he said. “And we have to remember that those who undergo bone marrow transplant have the worst leukemias.”
He pointed out that, in fact, contemporary chemotherapy alone is effective in the treatment of more than 90% of patients with ALL younger than aged 18.
For the 10% of patients who do not respond to chemotherapy alone and undergo allogeneic HSCT, about 50%-80% of pediatric patients who have resistant leukemia are cured. However, the total body irradiation used to prepare the body to receive the transplant is linked to potentially serious consequences later in life, including sterility, lung problems, growth retardation, and secondary cancer.
To determine if the irradiation component could be safely replaced with a chemotherapy-based conditioning approach, Dr. Peters and colleagues conducted the FORUM trial.
In total 413 patients undergoing HSCT were enrolled and randomized to pretransplant conditioning with total body irradiation and etoposide (n = 202) or a chemotherapy-only approach with fludarabine/thiotepa/busulfan (flu/thio/bu; n = 99) or fludarabine/thiotepa/treosulfan (treo; n = 93).
Most patients (72%) had B-cell precursor ALL and 23% had T-cell ALL. Just over half (54%) were transplanted in first complete remission (CR1), 40% in CR2, and 4% in CR3.
The source of stem cells was bone marrow for most patients (82%); peripheral blood stem cell for 12%, and cord blood for 4%.
Study stopped early
The aim of the study was to demonstrate noninferiority with the chemotherapy approach.
However, the significantly inferior outcome observed in the chemotherapy-only group led to randomization being halted in March 2019.
The 2-year overall survival in the intent-to-treat (ITT) analysis, with a mean observation time of 2.1 years, was 0.75 ± 0.04 for chemo-conditioning versus 0.91 ± 0.02 for total body irradiation/etoposide (ITT P < .001).
The ITT analysis showed relapses were significantly higher in the chemo-conditioning group (2-year cumulative incidence of relapse [CIR], 0.33) compared with the total body irradiation group (CIR, 0.12; P < .001).
The 2-year event-free survival (EFS) rate was also significantly higher in the total body irradiation group (0.86 vs 0.58; P < .001), and transplant-related mortality over 2 years was lower with total body irradiation (0.02 vs 0.09; P = .02).
A per-protocol analysis showed the 2-year overall survival to be the same in the two chemotherapy groups (both 0.77 ± 0.05) compared with 0.91 ± 0.02 in the total body irradiation group (P = .003).
“In this cohort [the 91% overall survival rate] may even be lower than contemporary intensive frontline therapy results that are achieved nowadays,” Dr. Peters said.
In looking at subgroups, there were no significant differences according to age group or cancer phenotype, while MLL rearrangement was associated with higher relapse incidence.
Remission status was found to notably influence EFS, dropping from 0.91 in CR1 patients with total body irradiation to 0.76 in CR2 patients. However, total body irradiation remained significantly higher compared with the chemo-conditioning groups in CR1 (P = .004) and CR2 (P < .001).
Transplant-related mortality was not significantly different between the total body irradiation and chemo-conditioning groups in the CR1 or CR2 groups (P = .09 and P = .18, respectively), despite the significant difference when remission status was not included.
Overall, “we tried to identify subgroups in which total body irradiation might be eliminated, however in all analyses, total body irradiation was better than chemo-conditioning in all arms,” Dr. Peters said.
Meanwhile, the findings underscore that even when patients cannot receive total body irradiation, the alternative chemo-conditioning therapy in fact shows favorable efficacy on its own, Dr. Izraeli said.
“The prognosis of the chemotherapy group is also quite remarkably good, although less than the total body irradiation arm. This means that if for some reason total body irradiation cannot be given, the chemotherapy is a very reasonable alternative.”
Dr. Peters has reported relationships with Amgen, Novartis, Pfizer, Medac, Jazz, and Neovii. Dr. Izraeli has reported no relevant financial relationships.
SOURCE: EHA Congress. Abstract S102.
A version of this article originally appeared on Medscape.com.
Hematopoietic stem cell transplantation (HSCT) may offer the chance of a cure for patients with leukemia and other blood cancers, but the process of preparing the body to receive such a transplant can be brutal, involving whole body irradiation as well as chemotherapy conditioning. New results show that both steps are needed: a trial that omitted whole body irradiation in young patients with acute lymphoblastic leukemia (ALL) was stopped early because of significantly poorer outcomes.
The multicenter, global FORUM (For Omitting Radiation Under Majority Age) trial involved 75 centers in 17 countries between 2013 and 2018.
“Our study shows significantly better outcomes for total body irradiation compared to myeloablative chemo-conditioning arms, with no differences between the [two] chemo-conditioning groups,” concluded Christina Peters, MD, professor of pediatrics in the department of stem cell transplantation at St Anna Children’s Hospital in Vienna.
, she added.
Dr. Peters presented the findings as part of the virtual annual congress of the European Hematology Association.
Describing the results as “sobering,” session comoderator Shai Izraeli, MD, director of the department of hematology-oncology at Schneider Children’s Medical Center, in Petah Tikva, Israel, said an online comment from the virtual meeting audience reflected the reaction to these unwelcome results: “So we are still stuck with total body irradiation?”
Dr. Peters said the good news is that the number of patients needing to undergo stem cell transplants is low, and with research advances, may hopefully drop even further.
“Only 10% of patients under the age of 18 nowadays undergo allogeneic HSCT, and perhaps in the future that will become even less if we are able to rescue some of the groups with other immunological measures such as CAR-T cells and antibodies,” she said.
“I think it is very important to better identify those who really need total body irradiation in the future,” she added.
In an interview, Dr. Izraeli agreed.
“The prognosis of children after bone marrow transplantation is excellent – the majority are cured from their leukemia,” he said. “And we have to remember that those who undergo bone marrow transplant have the worst leukemias.”
He pointed out that, in fact, contemporary chemotherapy alone is effective in the treatment of more than 90% of patients with ALL younger than aged 18.
For the 10% of patients who do not respond to chemotherapy alone and undergo allogeneic HSCT, about 50%-80% of pediatric patients who have resistant leukemia are cured. However, the total body irradiation used to prepare the body to receive the transplant is linked to potentially serious consequences later in life, including sterility, lung problems, growth retardation, and secondary cancer.
To determine if the irradiation component could be safely replaced with a chemotherapy-based conditioning approach, Dr. Peters and colleagues conducted the FORUM trial.
In total 413 patients undergoing HSCT were enrolled and randomized to pretransplant conditioning with total body irradiation and etoposide (n = 202) or a chemotherapy-only approach with fludarabine/thiotepa/busulfan (flu/thio/bu; n = 99) or fludarabine/thiotepa/treosulfan (treo; n = 93).
Most patients (72%) had B-cell precursor ALL and 23% had T-cell ALL. Just over half (54%) were transplanted in first complete remission (CR1), 40% in CR2, and 4% in CR3.
The source of stem cells was bone marrow for most patients (82%); peripheral blood stem cell for 12%, and cord blood for 4%.
Study stopped early
The aim of the study was to demonstrate noninferiority with the chemotherapy approach.
However, the significantly inferior outcome observed in the chemotherapy-only group led to randomization being halted in March 2019.
The 2-year overall survival in the intent-to-treat (ITT) analysis, with a mean observation time of 2.1 years, was 0.75 ± 0.04 for chemo-conditioning versus 0.91 ± 0.02 for total body irradiation/etoposide (ITT P < .001).
The ITT analysis showed relapses were significantly higher in the chemo-conditioning group (2-year cumulative incidence of relapse [CIR], 0.33) compared with the total body irradiation group (CIR, 0.12; P < .001).
The 2-year event-free survival (EFS) rate was also significantly higher in the total body irradiation group (0.86 vs 0.58; P < .001), and transplant-related mortality over 2 years was lower with total body irradiation (0.02 vs 0.09; P = .02).
A per-protocol analysis showed the 2-year overall survival to be the same in the two chemotherapy groups (both 0.77 ± 0.05) compared with 0.91 ± 0.02 in the total body irradiation group (P = .003).
“In this cohort [the 91% overall survival rate] may even be lower than contemporary intensive frontline therapy results that are achieved nowadays,” Dr. Peters said.
In looking at subgroups, there were no significant differences according to age group or cancer phenotype, while MLL rearrangement was associated with higher relapse incidence.
Remission status was found to notably influence EFS, dropping from 0.91 in CR1 patients with total body irradiation to 0.76 in CR2 patients. However, total body irradiation remained significantly higher compared with the chemo-conditioning groups in CR1 (P = .004) and CR2 (P < .001).
Transplant-related mortality was not significantly different between the total body irradiation and chemo-conditioning groups in the CR1 or CR2 groups (P = .09 and P = .18, respectively), despite the significant difference when remission status was not included.
Overall, “we tried to identify subgroups in which total body irradiation might be eliminated, however in all analyses, total body irradiation was better than chemo-conditioning in all arms,” Dr. Peters said.
Meanwhile, the findings underscore that even when patients cannot receive total body irradiation, the alternative chemo-conditioning therapy in fact shows favorable efficacy on its own, Dr. Izraeli said.
“The prognosis of the chemotherapy group is also quite remarkably good, although less than the total body irradiation arm. This means that if for some reason total body irradiation cannot be given, the chemotherapy is a very reasonable alternative.”
Dr. Peters has reported relationships with Amgen, Novartis, Pfizer, Medac, Jazz, and Neovii. Dr. Izraeli has reported no relevant financial relationships.
SOURCE: EHA Congress. Abstract S102.
A version of this article originally appeared on Medscape.com.
FROM EHA CONGRESS
Thyroid cancer overdiagnosis reaches beyond affluent regions
The rapid increase in thyroid cancer incidence that has occurred since the 1990s – considered an “epidemic of overdiagnosis,” has extended beyond high-income countries to less affluent settings, where unnecessary – and sometimes opportunistic – screening could continue to thrive.
“The impact of overdiagnosis on the increasing incidence of thyroid cancer highlighted in our report is a warning sign for countries with growing economies, where diagnostic technologies are increasingly and routinely offered, usually in exchange for payment, despite evidence that the harms far outweigh benefits,” the authors say.
“Overdiagnosis could turn healthy people into patients, and expose them to unnecessary harms and lifelong treatments,” say Mengmeng Li, PhD, of the International Agency for Research on Cancer, Lyon, France, and colleagues in their article published in Lancet Diabetes & Endocrinology.
With their previous research showing high rates of overdiagnosis in high-income countries, for this new analysis, they sought to evaluate whether similar patterns were occurring in less affluent settings.
They examined data from population-based cancer registries in 26 countries on four continents, looking at all cases of thyroid cancer reported between 1998 and 2012 in men and women aged 15 to 84 years.
A global public health problem
The results showed that while the incidence of thyroid cancer steadily increased from 1998 to 2002 and from 2008 to 2012 in all high-income countries, similar trends were also seen in less affluent nations, particularly in Belarus, China, Colombia, and Lithuania.
The increases were consistently greater among middle-aged women aged 35-64 years in all countries.
To determine what proportion of the higher incidence was overdiagnosis, the authors turned to historic age-specific thyroid cancer incidence data prior to the introduction of ultrasound and then looked at the progressive departure from that pattern, likely the result of the increased detection by ultrasound of thyroid nodules in middle-aged adults.
The results showed the proportion of thyroid cancer cases in women estimated to be attributable to overdiagnosis between 2008 and 2012 was as much as 93% in South Korea, 91% in Belarus, 87% in China, 84% in Italy and Croatia, and 83% in Slovakia and France.
Proportions attributable to overdiagnosis were lower in Denmark (66%), Norway (65%), Ireland (63%), United Kingdom (58%), Japan (55%), and Thailand (44%).
Women were much more likely to be overdiagnosed than men, with an approximate ratio of 3:1 in all countries; however, mortality and prevalence of thyroid cancer in autopsies were similar between genders.
Although researchers only looked at data up until 2012, Dr. Li said that, even in that year, “the amplitude of the phenomenon” was “already large and is increasing rapidly over time.”
Figures for periods subsequent to those assessed in the study “are likely to be higher.”
And the overdiagnosis is particularly remarkable in the context of the true risk of thyroid cancer, senior author Salvatore Vaccarella, PhD, told this news organization.
“What is surprising is the magnitude of this. Without overdiagnosis, thyroid cancer would probably still be a relatively rare cancer,” he said.
“Currently, it is the fifth most commonly diagnosed cancer in women of all ages and is third in women under 50 years of age. And the rates are still rising fast.”
“Overdiagnosis of thyroid cancer is still rapidly expanding in many high-income countries, and for the first time, we document and quantify the phenomenon also for several middle-income socioeconomically transitioning countries,” he observed. “In short, it is a global public health problem.”
Guidelines, physicians: No symptoms should mean no screening
With the implications of overdiagnosis ranging from physical, psychological in terms of the patient, and significant personal as well as societal costs, most international guidelines explicitly recommend against screening asymptomatic individuals and call for active surveillance of microcarcinomas that are detected.
The messaging appears to be making a difference.
As reported in research by American authors discussing the thyroid cancer epidemic from a 2017 perspective, the overdiagnosis situation in South Korea prompted a group of physicians there to make a high-profile public appeal in print and on television recommending against thyroid screening with ultrasound.
The result was a 35% reduction in the number of thyroidectomies performed in the subsequent year.
“This seems to be a striking example that the issue of overdiagnosis and overtreatment resonates with patients, and that public awareness can lead to changes in behavior,” say the U.S. authors of that article.
Senior author Louise Davies, MD, of the VA Outcomes Group, in White River Junction, Vt., said in an interview that the new study sheds more light on this issue.
“Even though the data only go through 2012, I think they give a nice snapshot of what’s happening across the globe with thyroid cancer incidence in countries of different levels of development,” she said.
The findings underscore that “it’s important that people are educated about the limits of medical testing and that sometimes when we see abnormalities we are truly catching a cancer early, but sometimes we’re seeing things that have been there a long time and may not change or become a problem in the future,” Dr. Davies remarked.
Important to know what size of cancers are being detected
One particular concern about overdiagnosis in middle-income countries is that the common approach of active monitoring may be more difficult in these settings, Dr. Davies added.
“In order to manage overdiagnosis, the health care systems in those countries have to think about whether they have the infrastructure for active monitoring and whether the patients will show up for the monitoring – so that’s a challenge.”
Also, she noted that the new study does not detail the size of cancers detected.
“We don’t know much about the size of the cancers being detected and whether these are truly the small asymptomatic cancers that we are worried about being overdiagnosed.”
“Probably, at least some of what we’re seeing is appropriate detection of cancers that, before there was economic development, were in fact being missed and people were dying of,” she said.
“So while overdiagnosis can be occurring, some of this represents better detection of disease overall, and that’s a good thing actually.”
The authors and Dr. Davies have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The rapid increase in thyroid cancer incidence that has occurred since the 1990s – considered an “epidemic of overdiagnosis,” has extended beyond high-income countries to less affluent settings, where unnecessary – and sometimes opportunistic – screening could continue to thrive.
“The impact of overdiagnosis on the increasing incidence of thyroid cancer highlighted in our report is a warning sign for countries with growing economies, where diagnostic technologies are increasingly and routinely offered, usually in exchange for payment, despite evidence that the harms far outweigh benefits,” the authors say.
“Overdiagnosis could turn healthy people into patients, and expose them to unnecessary harms and lifelong treatments,” say Mengmeng Li, PhD, of the International Agency for Research on Cancer, Lyon, France, and colleagues in their article published in Lancet Diabetes & Endocrinology.
With their previous research showing high rates of overdiagnosis in high-income countries, for this new analysis, they sought to evaluate whether similar patterns were occurring in less affluent settings.
They examined data from population-based cancer registries in 26 countries on four continents, looking at all cases of thyroid cancer reported between 1998 and 2012 in men and women aged 15 to 84 years.
A global public health problem
The results showed that while the incidence of thyroid cancer steadily increased from 1998 to 2002 and from 2008 to 2012 in all high-income countries, similar trends were also seen in less affluent nations, particularly in Belarus, China, Colombia, and Lithuania.
The increases were consistently greater among middle-aged women aged 35-64 years in all countries.
To determine what proportion of the higher incidence was overdiagnosis, the authors turned to historic age-specific thyroid cancer incidence data prior to the introduction of ultrasound and then looked at the progressive departure from that pattern, likely the result of the increased detection by ultrasound of thyroid nodules in middle-aged adults.
The results showed the proportion of thyroid cancer cases in women estimated to be attributable to overdiagnosis between 2008 and 2012 was as much as 93% in South Korea, 91% in Belarus, 87% in China, 84% in Italy and Croatia, and 83% in Slovakia and France.
Proportions attributable to overdiagnosis were lower in Denmark (66%), Norway (65%), Ireland (63%), United Kingdom (58%), Japan (55%), and Thailand (44%).
Women were much more likely to be overdiagnosed than men, with an approximate ratio of 3:1 in all countries; however, mortality and prevalence of thyroid cancer in autopsies were similar between genders.
Although researchers only looked at data up until 2012, Dr. Li said that, even in that year, “the amplitude of the phenomenon” was “already large and is increasing rapidly over time.”
Figures for periods subsequent to those assessed in the study “are likely to be higher.”
And the overdiagnosis is particularly remarkable in the context of the true risk of thyroid cancer, senior author Salvatore Vaccarella, PhD, told this news organization.
“What is surprising is the magnitude of this. Without overdiagnosis, thyroid cancer would probably still be a relatively rare cancer,” he said.
“Currently, it is the fifth most commonly diagnosed cancer in women of all ages and is third in women under 50 years of age. And the rates are still rising fast.”
“Overdiagnosis of thyroid cancer is still rapidly expanding in many high-income countries, and for the first time, we document and quantify the phenomenon also for several middle-income socioeconomically transitioning countries,” he observed. “In short, it is a global public health problem.”
Guidelines, physicians: No symptoms should mean no screening
With the implications of overdiagnosis ranging from physical, psychological in terms of the patient, and significant personal as well as societal costs, most international guidelines explicitly recommend against screening asymptomatic individuals and call for active surveillance of microcarcinomas that are detected.
The messaging appears to be making a difference.
As reported in research by American authors discussing the thyroid cancer epidemic from a 2017 perspective, the overdiagnosis situation in South Korea prompted a group of physicians there to make a high-profile public appeal in print and on television recommending against thyroid screening with ultrasound.
The result was a 35% reduction in the number of thyroidectomies performed in the subsequent year.
“This seems to be a striking example that the issue of overdiagnosis and overtreatment resonates with patients, and that public awareness can lead to changes in behavior,” say the U.S. authors of that article.
Senior author Louise Davies, MD, of the VA Outcomes Group, in White River Junction, Vt., said in an interview that the new study sheds more light on this issue.
“Even though the data only go through 2012, I think they give a nice snapshot of what’s happening across the globe with thyroid cancer incidence in countries of different levels of development,” she said.
The findings underscore that “it’s important that people are educated about the limits of medical testing and that sometimes when we see abnormalities we are truly catching a cancer early, but sometimes we’re seeing things that have been there a long time and may not change or become a problem in the future,” Dr. Davies remarked.
Important to know what size of cancers are being detected
One particular concern about overdiagnosis in middle-income countries is that the common approach of active monitoring may be more difficult in these settings, Dr. Davies added.
“In order to manage overdiagnosis, the health care systems in those countries have to think about whether they have the infrastructure for active monitoring and whether the patients will show up for the monitoring – so that’s a challenge.”
Also, she noted that the new study does not detail the size of cancers detected.
“We don’t know much about the size of the cancers being detected and whether these are truly the small asymptomatic cancers that we are worried about being overdiagnosed.”
“Probably, at least some of what we’re seeing is appropriate detection of cancers that, before there was economic development, were in fact being missed and people were dying of,” she said.
“So while overdiagnosis can be occurring, some of this represents better detection of disease overall, and that’s a good thing actually.”
The authors and Dr. Davies have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The rapid increase in thyroid cancer incidence that has occurred since the 1990s – considered an “epidemic of overdiagnosis,” has extended beyond high-income countries to less affluent settings, where unnecessary – and sometimes opportunistic – screening could continue to thrive.
“The impact of overdiagnosis on the increasing incidence of thyroid cancer highlighted in our report is a warning sign for countries with growing economies, where diagnostic technologies are increasingly and routinely offered, usually in exchange for payment, despite evidence that the harms far outweigh benefits,” the authors say.
“Overdiagnosis could turn healthy people into patients, and expose them to unnecessary harms and lifelong treatments,” say Mengmeng Li, PhD, of the International Agency for Research on Cancer, Lyon, France, and colleagues in their article published in Lancet Diabetes & Endocrinology.
With their previous research showing high rates of overdiagnosis in high-income countries, for this new analysis, they sought to evaluate whether similar patterns were occurring in less affluent settings.
They examined data from population-based cancer registries in 26 countries on four continents, looking at all cases of thyroid cancer reported between 1998 and 2012 in men and women aged 15 to 84 years.
A global public health problem
The results showed that while the incidence of thyroid cancer steadily increased from 1998 to 2002 and from 2008 to 2012 in all high-income countries, similar trends were also seen in less affluent nations, particularly in Belarus, China, Colombia, and Lithuania.
The increases were consistently greater among middle-aged women aged 35-64 years in all countries.
To determine what proportion of the higher incidence was overdiagnosis, the authors turned to historic age-specific thyroid cancer incidence data prior to the introduction of ultrasound and then looked at the progressive departure from that pattern, likely the result of the increased detection by ultrasound of thyroid nodules in middle-aged adults.
The results showed the proportion of thyroid cancer cases in women estimated to be attributable to overdiagnosis between 2008 and 2012 was as much as 93% in South Korea, 91% in Belarus, 87% in China, 84% in Italy and Croatia, and 83% in Slovakia and France.
Proportions attributable to overdiagnosis were lower in Denmark (66%), Norway (65%), Ireland (63%), United Kingdom (58%), Japan (55%), and Thailand (44%).
Women were much more likely to be overdiagnosed than men, with an approximate ratio of 3:1 in all countries; however, mortality and prevalence of thyroid cancer in autopsies were similar between genders.
Although researchers only looked at data up until 2012, Dr. Li said that, even in that year, “the amplitude of the phenomenon” was “already large and is increasing rapidly over time.”
Figures for periods subsequent to those assessed in the study “are likely to be higher.”
And the overdiagnosis is particularly remarkable in the context of the true risk of thyroid cancer, senior author Salvatore Vaccarella, PhD, told this news organization.
“What is surprising is the magnitude of this. Without overdiagnosis, thyroid cancer would probably still be a relatively rare cancer,” he said.
“Currently, it is the fifth most commonly diagnosed cancer in women of all ages and is third in women under 50 years of age. And the rates are still rising fast.”
“Overdiagnosis of thyroid cancer is still rapidly expanding in many high-income countries, and for the first time, we document and quantify the phenomenon also for several middle-income socioeconomically transitioning countries,” he observed. “In short, it is a global public health problem.”
Guidelines, physicians: No symptoms should mean no screening
With the implications of overdiagnosis ranging from physical, psychological in terms of the patient, and significant personal as well as societal costs, most international guidelines explicitly recommend against screening asymptomatic individuals and call for active surveillance of microcarcinomas that are detected.
The messaging appears to be making a difference.
As reported in research by American authors discussing the thyroid cancer epidemic from a 2017 perspective, the overdiagnosis situation in South Korea prompted a group of physicians there to make a high-profile public appeal in print and on television recommending against thyroid screening with ultrasound.
The result was a 35% reduction in the number of thyroidectomies performed in the subsequent year.
“This seems to be a striking example that the issue of overdiagnosis and overtreatment resonates with patients, and that public awareness can lead to changes in behavior,” say the U.S. authors of that article.
Senior author Louise Davies, MD, of the VA Outcomes Group, in White River Junction, Vt., said in an interview that the new study sheds more light on this issue.
“Even though the data only go through 2012, I think they give a nice snapshot of what’s happening across the globe with thyroid cancer incidence in countries of different levels of development,” she said.
The findings underscore that “it’s important that people are educated about the limits of medical testing and that sometimes when we see abnormalities we are truly catching a cancer early, but sometimes we’re seeing things that have been there a long time and may not change or become a problem in the future,” Dr. Davies remarked.
Important to know what size of cancers are being detected
One particular concern about overdiagnosis in middle-income countries is that the common approach of active monitoring may be more difficult in these settings, Dr. Davies added.
“In order to manage overdiagnosis, the health care systems in those countries have to think about whether they have the infrastructure for active monitoring and whether the patients will show up for the monitoring – so that’s a challenge.”
Also, she noted that the new study does not detail the size of cancers detected.
“We don’t know much about the size of the cancers being detected and whether these are truly the small asymptomatic cancers that we are worried about being overdiagnosed.”
“Probably, at least some of what we’re seeing is appropriate detection of cancers that, before there was economic development, were in fact being missed and people were dying of,” she said.
“So while overdiagnosis can be occurring, some of this represents better detection of disease overall, and that’s a good thing actually.”
The authors and Dr. Davies have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Herpes zoster infection with MS treatment higher in women?
a new study of adverse event reports on a variety of DMTs suggests.
DMTs are known to be associated with a potentially increased risk of opportunistic infections, including HZV. However, data are lacking on issues such as the relative frequency of HZV and the distribution of cases among age and gender groups, said senior author Ahmed Zayed Obeidat, MD, PhD, assistant professor at the Medical College of Wisconsin, Milwaukee.
“In my practice, we noticed patients being treated with DMTs were developing shingles at much younger ages than would be typical, so we were interested in looking at the distribution of cases among people treated with DMTs,” he said.
For the study, which was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Obeidat, first author Nicola Carlisle, MD, also of the Medical College of Wisconsin, and their colleagues turned to data from the Food and Drug Administration’s Adverse Event Reporting System.
They analyzed reports on adverse events involving HZV and varicella among patients with MS received between January 1999 and June 2019. The reports involved a range of MS DMTs, including interferon-beta, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, or ocrelizumab. Recently approved DMTs including cladribine and siponimod were excluded because of an insufficient number of reports.
Among 3,335 reports that were identified, they found highest mean annual report rates of HZV were for natalizumab, at 115.4, and lowest for glatiramer acetate, with just 5.3 reports. The mean annual report rates for HZV among the other DMTs were ocrelizumab, 88.3; dimethyl fumarate, 73.4; fingolimod, 72.9; interferon beta, 32.9; alemtuzumab, 21.7; and teriflunomide, 13.9.
Overall, the reports of HZV were 4.5 times more common among females, ranging from 2.1 times greater with alemtuzumab to 11.4 times greater for females with interferon-beta. The highest percentages of reports involved people in their 50s, with the exceptions of fingolimod, which had the highest rate of reports among patients in their 40s, and alemtuzumab, in which the highest percentage of reports involved patients in their 30s.
Meanwhile, as many as 25.7% of cases occurred in people under the age of 40 years, while 77.6% of total reports of HZV were in age groups between 31 years and 60 years.
“These rates are different than what is expected in the shingles population, which usually involves people over 60,” Dr. Obeidat said. He noted that, while MS is known to affect more women than men, the fivefold increase in HZV well exceeds the female-male ratio in MS, which is about 2.5:1.
Dr. Obeidat speculated that one factor explaining the higher reports of younger patients could be that fewer older patients are taking DMTs. “Many of our patients with MS may not be treated with DMTs when they are older or they may be on older DMTs that don’t have as much of a risk of opportunistic infections or activation, or some older patients may not be on medications anymore, so this may be why we are seeing this,” he said.
In commenting on the study, Joshua Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care, Wellesley, Mass., speculated that numerous factors could explain the higher rates of women developing HZV.
“One wonders, for instance, did pregnancy play a role, were some of the women on prior medications?”
The statistical difference is interesting, he said, “but it’s hard to see what the explanation could be.”
While DMTs typically can be effective in suppressing an MS flare even if a patient develops shingles, the risks of the shingles, itself, is a concern, Dr. Katz added. “Just about any infection that stimulates an inflammatory response has some risk of worsening symptoms with MS; however, the bigger risk is probably the shingles itself and getting postherpetic neuralgia,” he explained.
“Sometimes there can be independent neurological problems just from MS, and that’s probably a bigger risk than worsening the MS,” he said. Clinicians should therefore keep shingles on their radar before starting patients on DMTs, Dr. Katz added.
“For many of the medications that are immunosuppressive, you want to check patients’ baseline levels of antibodies for zoster and if they don’t have antibodies, then you do want to vaccinate them.”
He noted that the new HZV vaccine is not a live vaccine and has a high efficacy rate, “so we think we can safely administer it in most cases.
“A concern is whether some DMTs may render the vaccine less effective, and we are looking at studying that with ocrelizumab and maybe some other B-cell depleting treatments.”
Dr. Obeidat disclosed relationships with Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Sanofi and Novartis. Dr. Katz has been a speaker for Biogen, Genetech, Sanofi, and EMD Serono.
This article first appeared on Medscape.com.
a new study of adverse event reports on a variety of DMTs suggests.
DMTs are known to be associated with a potentially increased risk of opportunistic infections, including HZV. However, data are lacking on issues such as the relative frequency of HZV and the distribution of cases among age and gender groups, said senior author Ahmed Zayed Obeidat, MD, PhD, assistant professor at the Medical College of Wisconsin, Milwaukee.
“In my practice, we noticed patients being treated with DMTs were developing shingles at much younger ages than would be typical, so we were interested in looking at the distribution of cases among people treated with DMTs,” he said.
For the study, which was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Obeidat, first author Nicola Carlisle, MD, also of the Medical College of Wisconsin, and their colleagues turned to data from the Food and Drug Administration’s Adverse Event Reporting System.
They analyzed reports on adverse events involving HZV and varicella among patients with MS received between January 1999 and June 2019. The reports involved a range of MS DMTs, including interferon-beta, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, or ocrelizumab. Recently approved DMTs including cladribine and siponimod were excluded because of an insufficient number of reports.
Among 3,335 reports that were identified, they found highest mean annual report rates of HZV were for natalizumab, at 115.4, and lowest for glatiramer acetate, with just 5.3 reports. The mean annual report rates for HZV among the other DMTs were ocrelizumab, 88.3; dimethyl fumarate, 73.4; fingolimod, 72.9; interferon beta, 32.9; alemtuzumab, 21.7; and teriflunomide, 13.9.
Overall, the reports of HZV were 4.5 times more common among females, ranging from 2.1 times greater with alemtuzumab to 11.4 times greater for females with interferon-beta. The highest percentages of reports involved people in their 50s, with the exceptions of fingolimod, which had the highest rate of reports among patients in their 40s, and alemtuzumab, in which the highest percentage of reports involved patients in their 30s.
Meanwhile, as many as 25.7% of cases occurred in people under the age of 40 years, while 77.6% of total reports of HZV were in age groups between 31 years and 60 years.
“These rates are different than what is expected in the shingles population, which usually involves people over 60,” Dr. Obeidat said. He noted that, while MS is known to affect more women than men, the fivefold increase in HZV well exceeds the female-male ratio in MS, which is about 2.5:1.
Dr. Obeidat speculated that one factor explaining the higher reports of younger patients could be that fewer older patients are taking DMTs. “Many of our patients with MS may not be treated with DMTs when they are older or they may be on older DMTs that don’t have as much of a risk of opportunistic infections or activation, or some older patients may not be on medications anymore, so this may be why we are seeing this,” he said.
In commenting on the study, Joshua Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care, Wellesley, Mass., speculated that numerous factors could explain the higher rates of women developing HZV.
“One wonders, for instance, did pregnancy play a role, were some of the women on prior medications?”
The statistical difference is interesting, he said, “but it’s hard to see what the explanation could be.”
While DMTs typically can be effective in suppressing an MS flare even if a patient develops shingles, the risks of the shingles, itself, is a concern, Dr. Katz added. “Just about any infection that stimulates an inflammatory response has some risk of worsening symptoms with MS; however, the bigger risk is probably the shingles itself and getting postherpetic neuralgia,” he explained.
“Sometimes there can be independent neurological problems just from MS, and that’s probably a bigger risk than worsening the MS,” he said. Clinicians should therefore keep shingles on their radar before starting patients on DMTs, Dr. Katz added.
“For many of the medications that are immunosuppressive, you want to check patients’ baseline levels of antibodies for zoster and if they don’t have antibodies, then you do want to vaccinate them.”
He noted that the new HZV vaccine is not a live vaccine and has a high efficacy rate, “so we think we can safely administer it in most cases.
“A concern is whether some DMTs may render the vaccine less effective, and we are looking at studying that with ocrelizumab and maybe some other B-cell depleting treatments.”
Dr. Obeidat disclosed relationships with Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Sanofi and Novartis. Dr. Katz has been a speaker for Biogen, Genetech, Sanofi, and EMD Serono.
This article first appeared on Medscape.com.
a new study of adverse event reports on a variety of DMTs suggests.
DMTs are known to be associated with a potentially increased risk of opportunistic infections, including HZV. However, data are lacking on issues such as the relative frequency of HZV and the distribution of cases among age and gender groups, said senior author Ahmed Zayed Obeidat, MD, PhD, assistant professor at the Medical College of Wisconsin, Milwaukee.
“In my practice, we noticed patients being treated with DMTs were developing shingles at much younger ages than would be typical, so we were interested in looking at the distribution of cases among people treated with DMTs,” he said.
For the study, which was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Obeidat, first author Nicola Carlisle, MD, also of the Medical College of Wisconsin, and their colleagues turned to data from the Food and Drug Administration’s Adverse Event Reporting System.
They analyzed reports on adverse events involving HZV and varicella among patients with MS received between January 1999 and June 2019. The reports involved a range of MS DMTs, including interferon-beta, glatiramer acetate, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, or ocrelizumab. Recently approved DMTs including cladribine and siponimod were excluded because of an insufficient number of reports.
Among 3,335 reports that were identified, they found highest mean annual report rates of HZV were for natalizumab, at 115.4, and lowest for glatiramer acetate, with just 5.3 reports. The mean annual report rates for HZV among the other DMTs were ocrelizumab, 88.3; dimethyl fumarate, 73.4; fingolimod, 72.9; interferon beta, 32.9; alemtuzumab, 21.7; and teriflunomide, 13.9.
Overall, the reports of HZV were 4.5 times more common among females, ranging from 2.1 times greater with alemtuzumab to 11.4 times greater for females with interferon-beta. The highest percentages of reports involved people in their 50s, with the exceptions of fingolimod, which had the highest rate of reports among patients in their 40s, and alemtuzumab, in which the highest percentage of reports involved patients in their 30s.
Meanwhile, as many as 25.7% of cases occurred in people under the age of 40 years, while 77.6% of total reports of HZV were in age groups between 31 years and 60 years.
“These rates are different than what is expected in the shingles population, which usually involves people over 60,” Dr. Obeidat said. He noted that, while MS is known to affect more women than men, the fivefold increase in HZV well exceeds the female-male ratio in MS, which is about 2.5:1.
Dr. Obeidat speculated that one factor explaining the higher reports of younger patients could be that fewer older patients are taking DMTs. “Many of our patients with MS may not be treated with DMTs when they are older or they may be on older DMTs that don’t have as much of a risk of opportunistic infections or activation, or some older patients may not be on medications anymore, so this may be why we are seeing this,” he said.
In commenting on the study, Joshua Katz, MD, codirector of the Elliot Lewis Center for Multiple Sclerosis Care, Wellesley, Mass., speculated that numerous factors could explain the higher rates of women developing HZV.
“One wonders, for instance, did pregnancy play a role, were some of the women on prior medications?”
The statistical difference is interesting, he said, “but it’s hard to see what the explanation could be.”
While DMTs typically can be effective in suppressing an MS flare even if a patient develops shingles, the risks of the shingles, itself, is a concern, Dr. Katz added. “Just about any infection that stimulates an inflammatory response has some risk of worsening symptoms with MS; however, the bigger risk is probably the shingles itself and getting postherpetic neuralgia,” he explained.
“Sometimes there can be independent neurological problems just from MS, and that’s probably a bigger risk than worsening the MS,” he said. Clinicians should therefore keep shingles on their radar before starting patients on DMTs, Dr. Katz added.
“For many of the medications that are immunosuppressive, you want to check patients’ baseline levels of antibodies for zoster and if they don’t have antibodies, then you do want to vaccinate them.”
He noted that the new HZV vaccine is not a live vaccine and has a high efficacy rate, “so we think we can safely administer it in most cases.
“A concern is whether some DMTs may render the vaccine less effective, and we are looking at studying that with ocrelizumab and maybe some other B-cell depleting treatments.”
Dr. Obeidat disclosed relationships with Alexion, Biogen, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Sanofi and Novartis. Dr. Katz has been a speaker for Biogen, Genetech, Sanofi, and EMD Serono.
This article first appeared on Medscape.com.
Constraint-induced movement therapy may boost neuroplasticity in MS
, compared with alternative interventions with medicines. “The findings suggest for the first time that physical behavioral change therapy can significantly stimulate cortical neuroplasticity in a degenerative central nervous system disorder,” said the authors of research presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
CIMT, an intervention involving 3.5 hours/day of therapist-supervised treatment over 10 consecutive weekdays, has been shown to significantly improve paretic limb use for patients with progressive MS, and the effects are long lasting.
For patients with asymmetric upper limb nonuse, the treatment “is highly successful for promoting increased use by the more-affected arm for everyday activities,” said lead author Victor W. Mark, MD, an associate professor and medical director of the Constraint-Induced Movement Therapy Research Programs at the University of Alabama at Birmingham. “The improvements after CIMT can be found to remain as much as 1 year after the completion of the treatment, and even later. That by itself is novel for MS,” he said.
The team’s previous research in Neurorehabilitation and Neural Repair showed that the CIMT intervention is associated with statistically significant changes in white matter integrity in the brain. In this new study, Dr. Mark and colleagues sought to determine whether the effects would also translate to improvements in cortical gray matter.
Promoting neuroplasticity, improving motor function
For their study, they enrolled 20 adults with chronic MS who were matched with respect to unilateral arm disability. The participants were randomly assigned to receive 35 hours of either CIMT or a holistic complementary alternative medicine program, which included yoga, aquatic therapy, massage, and/or relaxation techniques, over the course of 2 weeks.
Both groups expressed the same degree of expectancy of benefits from the intervention. Those who received CIMT showed a significantly larger effect size on the Motor Activity Log, a measure that has been validated against real-world upper-limb accelerometry, compared with the control group (d = 3.2, vs. d = 0.7).
Imaging with tensor-based morphometry showed an increase in the thickness of the primary motor cortex in patients who underwent CIMT but not those who received the alternative medicine treatment. Furthermore, a change in the primary motor cortex was observed in the CIMT group on voxel-based morphometry, suggesting an increase in cortical density or volume, or both. Similar changes were not seen in the alternative medicine group.
“We evaluated the density of the brain cortical gray area before and after treatment, and we found increased gray matter in the area of the brain that is concentrated with voluntary limb movement (the motor cortex),” Dr. Mark said. “As in (previous) studies, we did not find such changes, or any changes, after the other form of treatment,” he said.
The results are important, Dr. Mark noted, “because CIMT seems to specifically promote neuroplasticity changes that appear to be healthy, for what is otherwise a chronically progressive degenerative neurological disorder.”
In addition to the improvements in MS, CIMT has led to improvement in motor function for patients who have experienced other central nervous system injuries, including stroke, traumatic brain injury, cerebral palsy, and, in musicians, focal hand dystonia.
The new findings offer intriguing insights into the effects in progressive MS, commented rehabilitation specialist Patricia Bobryk, MHS, a physical therapist with the UCHealth Yampa Valley Medical Center, in Colorado Springs.
“There is more evidence for CIMT in the area of stroke, which is more acute onset and with more potential recovery, especially early on, so this is exciting initial work in terms of MS,” she said.
“If we’re trying to find new avenues in the brain for better pathways, rather than using something that’s damaged in MS, it makes perfect sense that CIMT really forces and drives those connections, because you’re doing a repetitive, high-intensity patterning throughout the day, so you set up that environment for things to progress, especially in motor functioning,” she said.
Repetition, ‘prevention of compensation’
CIMT was developed at the University of Alabama, Birmingham, 30 years ago and involves four components. The first, described as “massed practice,” involves intensive, repetitive arm movements of the affected arm. The second component involves “shaping,” in which the patient is encouraged to perform his or her best attempts at the movements.
For the third component, described as “prevention of compensation,” the patient’s more-functional arm is inhibited from being used in everyday activities by wearing a padded mitt.
“This permits the patient to brace him- or herself whenever needed, but the better hand nonetheless lacks the dexterity to take over the activities that should be performed by the worse arm,” Dr. Mark explained.
“The patient wears the padded mitt after hours, too, except when using water or when sleeping,” he said.
The fourth component is a set of behavioral enforcement techniques involving goal-setting; daily interviews and discussion of progress and challenges; nightly homework; diary keeping; and telephone follow-up.
Dr. Mark noted that the intervention could have benefits that are secondary to motor and movement function. “We consider that the improvement of limb activity in a motor-challenged person with MS could afford a way to offset the deleterious effects of inactivity that can occur, such as weight gain, diabetes, osteoporosis, cardiac disease, and other conditions associated with prolonged inactivity,” he said.
Although it was developed at the University of Alabama, CIMT is currently more widely practiced in Europe than the United States, likely because of differences in care support, which in Europe is provided through socialized medicine, Dr. Mark pointed out.
Although the detailed methods for conducting CIMT are published in peer-reviewed journals, Dr. Mark recommends hands-on and interactive teaching. Such training is offered to clinicians and affiliated physical therapists and occupational therapists through Mark’s program at the University of Alabama in a semiannual, week-long training course, which includes hands-on treatment practice with actual patients.
Proof of principle
In further commenting on the study, Kathy M. Zackowski, PhD, of the National MS Society, said the findings provide an intriguing proof of concept that should be tested in a larger cohort. “The question of how much a behavioral (therapy) can impact true brain structural change or change in the pathologic mechanism is intriguing and of high importance,” she said.
“It is important to take this information as ‘proof of principle’ of the importance of CIMT for improving upper limb activity,” according to Dr. Zackowski, senior director, patient management, care and rehabilitation research at the society.
“Importantly, this team needs to move forward testing their hypothesis in a larger randomized, clinical trial with a full control group in order to show causal evidence that one intervention caused the structural brain changes seen,” she said in an interview.
Dr. Zackowski added that a caveat of CIMT is that the approach assumes one limb is more impaired than the other, which is always the case in stroke but is true only in some cases of MS. “Therefore, this method may not be effective for everyone with MS, but offers another option for tailoring an intervention to a person’s abilities and interests,” she said.
“Another important detail is that CIMT is also being explored for lower extremity use,” she added. “This is exciting, as lower extremity dysfunction is a very common problem in MS, and may be useful in treating walking disability.”
The authors, Ms. Bobryk, and Dr. Zackowski have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
, compared with alternative interventions with medicines. “The findings suggest for the first time that physical behavioral change therapy can significantly stimulate cortical neuroplasticity in a degenerative central nervous system disorder,” said the authors of research presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
CIMT, an intervention involving 3.5 hours/day of therapist-supervised treatment over 10 consecutive weekdays, has been shown to significantly improve paretic limb use for patients with progressive MS, and the effects are long lasting.
For patients with asymmetric upper limb nonuse, the treatment “is highly successful for promoting increased use by the more-affected arm for everyday activities,” said lead author Victor W. Mark, MD, an associate professor and medical director of the Constraint-Induced Movement Therapy Research Programs at the University of Alabama at Birmingham. “The improvements after CIMT can be found to remain as much as 1 year after the completion of the treatment, and even later. That by itself is novel for MS,” he said.
The team’s previous research in Neurorehabilitation and Neural Repair showed that the CIMT intervention is associated with statistically significant changes in white matter integrity in the brain. In this new study, Dr. Mark and colleagues sought to determine whether the effects would also translate to improvements in cortical gray matter.
Promoting neuroplasticity, improving motor function
For their study, they enrolled 20 adults with chronic MS who were matched with respect to unilateral arm disability. The participants were randomly assigned to receive 35 hours of either CIMT or a holistic complementary alternative medicine program, which included yoga, aquatic therapy, massage, and/or relaxation techniques, over the course of 2 weeks.
Both groups expressed the same degree of expectancy of benefits from the intervention. Those who received CIMT showed a significantly larger effect size on the Motor Activity Log, a measure that has been validated against real-world upper-limb accelerometry, compared with the control group (d = 3.2, vs. d = 0.7).
Imaging with tensor-based morphometry showed an increase in the thickness of the primary motor cortex in patients who underwent CIMT but not those who received the alternative medicine treatment. Furthermore, a change in the primary motor cortex was observed in the CIMT group on voxel-based morphometry, suggesting an increase in cortical density or volume, or both. Similar changes were not seen in the alternative medicine group.
“We evaluated the density of the brain cortical gray area before and after treatment, and we found increased gray matter in the area of the brain that is concentrated with voluntary limb movement (the motor cortex),” Dr. Mark said. “As in (previous) studies, we did not find such changes, or any changes, after the other form of treatment,” he said.
The results are important, Dr. Mark noted, “because CIMT seems to specifically promote neuroplasticity changes that appear to be healthy, for what is otherwise a chronically progressive degenerative neurological disorder.”
In addition to the improvements in MS, CIMT has led to improvement in motor function for patients who have experienced other central nervous system injuries, including stroke, traumatic brain injury, cerebral palsy, and, in musicians, focal hand dystonia.
The new findings offer intriguing insights into the effects in progressive MS, commented rehabilitation specialist Patricia Bobryk, MHS, a physical therapist with the UCHealth Yampa Valley Medical Center, in Colorado Springs.
“There is more evidence for CIMT in the area of stroke, which is more acute onset and with more potential recovery, especially early on, so this is exciting initial work in terms of MS,” she said.
“If we’re trying to find new avenues in the brain for better pathways, rather than using something that’s damaged in MS, it makes perfect sense that CIMT really forces and drives those connections, because you’re doing a repetitive, high-intensity patterning throughout the day, so you set up that environment for things to progress, especially in motor functioning,” she said.
Repetition, ‘prevention of compensation’
CIMT was developed at the University of Alabama, Birmingham, 30 years ago and involves four components. The first, described as “massed practice,” involves intensive, repetitive arm movements of the affected arm. The second component involves “shaping,” in which the patient is encouraged to perform his or her best attempts at the movements.
For the third component, described as “prevention of compensation,” the patient’s more-functional arm is inhibited from being used in everyday activities by wearing a padded mitt.
“This permits the patient to brace him- or herself whenever needed, but the better hand nonetheless lacks the dexterity to take over the activities that should be performed by the worse arm,” Dr. Mark explained.
“The patient wears the padded mitt after hours, too, except when using water or when sleeping,” he said.
The fourth component is a set of behavioral enforcement techniques involving goal-setting; daily interviews and discussion of progress and challenges; nightly homework; diary keeping; and telephone follow-up.
Dr. Mark noted that the intervention could have benefits that are secondary to motor and movement function. “We consider that the improvement of limb activity in a motor-challenged person with MS could afford a way to offset the deleterious effects of inactivity that can occur, such as weight gain, diabetes, osteoporosis, cardiac disease, and other conditions associated with prolonged inactivity,” he said.
Although it was developed at the University of Alabama, CIMT is currently more widely practiced in Europe than the United States, likely because of differences in care support, which in Europe is provided through socialized medicine, Dr. Mark pointed out.
Although the detailed methods for conducting CIMT are published in peer-reviewed journals, Dr. Mark recommends hands-on and interactive teaching. Such training is offered to clinicians and affiliated physical therapists and occupational therapists through Mark’s program at the University of Alabama in a semiannual, week-long training course, which includes hands-on treatment practice with actual patients.
Proof of principle
In further commenting on the study, Kathy M. Zackowski, PhD, of the National MS Society, said the findings provide an intriguing proof of concept that should be tested in a larger cohort. “The question of how much a behavioral (therapy) can impact true brain structural change or change in the pathologic mechanism is intriguing and of high importance,” she said.
“It is important to take this information as ‘proof of principle’ of the importance of CIMT for improving upper limb activity,” according to Dr. Zackowski, senior director, patient management, care and rehabilitation research at the society.
“Importantly, this team needs to move forward testing their hypothesis in a larger randomized, clinical trial with a full control group in order to show causal evidence that one intervention caused the structural brain changes seen,” she said in an interview.
Dr. Zackowski added that a caveat of CIMT is that the approach assumes one limb is more impaired than the other, which is always the case in stroke but is true only in some cases of MS. “Therefore, this method may not be effective for everyone with MS, but offers another option for tailoring an intervention to a person’s abilities and interests,” she said.
“Another important detail is that CIMT is also being explored for lower extremity use,” she added. “This is exciting, as lower extremity dysfunction is a very common problem in MS, and may be useful in treating walking disability.”
The authors, Ms. Bobryk, and Dr. Zackowski have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
, compared with alternative interventions with medicines. “The findings suggest for the first time that physical behavioral change therapy can significantly stimulate cortical neuroplasticity in a degenerative central nervous system disorder,” said the authors of research presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
CIMT, an intervention involving 3.5 hours/day of therapist-supervised treatment over 10 consecutive weekdays, has been shown to significantly improve paretic limb use for patients with progressive MS, and the effects are long lasting.
For patients with asymmetric upper limb nonuse, the treatment “is highly successful for promoting increased use by the more-affected arm for everyday activities,” said lead author Victor W. Mark, MD, an associate professor and medical director of the Constraint-Induced Movement Therapy Research Programs at the University of Alabama at Birmingham. “The improvements after CIMT can be found to remain as much as 1 year after the completion of the treatment, and even later. That by itself is novel for MS,” he said.
The team’s previous research in Neurorehabilitation and Neural Repair showed that the CIMT intervention is associated with statistically significant changes in white matter integrity in the brain. In this new study, Dr. Mark and colleagues sought to determine whether the effects would also translate to improvements in cortical gray matter.
Promoting neuroplasticity, improving motor function
For their study, they enrolled 20 adults with chronic MS who were matched with respect to unilateral arm disability. The participants were randomly assigned to receive 35 hours of either CIMT or a holistic complementary alternative medicine program, which included yoga, aquatic therapy, massage, and/or relaxation techniques, over the course of 2 weeks.
Both groups expressed the same degree of expectancy of benefits from the intervention. Those who received CIMT showed a significantly larger effect size on the Motor Activity Log, a measure that has been validated against real-world upper-limb accelerometry, compared with the control group (d = 3.2, vs. d = 0.7).
Imaging with tensor-based morphometry showed an increase in the thickness of the primary motor cortex in patients who underwent CIMT but not those who received the alternative medicine treatment. Furthermore, a change in the primary motor cortex was observed in the CIMT group on voxel-based morphometry, suggesting an increase in cortical density or volume, or both. Similar changes were not seen in the alternative medicine group.
“We evaluated the density of the brain cortical gray area before and after treatment, and we found increased gray matter in the area of the brain that is concentrated with voluntary limb movement (the motor cortex),” Dr. Mark said. “As in (previous) studies, we did not find such changes, or any changes, after the other form of treatment,” he said.
The results are important, Dr. Mark noted, “because CIMT seems to specifically promote neuroplasticity changes that appear to be healthy, for what is otherwise a chronically progressive degenerative neurological disorder.”
In addition to the improvements in MS, CIMT has led to improvement in motor function for patients who have experienced other central nervous system injuries, including stroke, traumatic brain injury, cerebral palsy, and, in musicians, focal hand dystonia.
The new findings offer intriguing insights into the effects in progressive MS, commented rehabilitation specialist Patricia Bobryk, MHS, a physical therapist with the UCHealth Yampa Valley Medical Center, in Colorado Springs.
“There is more evidence for CIMT in the area of stroke, which is more acute onset and with more potential recovery, especially early on, so this is exciting initial work in terms of MS,” she said.
“If we’re trying to find new avenues in the brain for better pathways, rather than using something that’s damaged in MS, it makes perfect sense that CIMT really forces and drives those connections, because you’re doing a repetitive, high-intensity patterning throughout the day, so you set up that environment for things to progress, especially in motor functioning,” she said.
Repetition, ‘prevention of compensation’
CIMT was developed at the University of Alabama, Birmingham, 30 years ago and involves four components. The first, described as “massed practice,” involves intensive, repetitive arm movements of the affected arm. The second component involves “shaping,” in which the patient is encouraged to perform his or her best attempts at the movements.
For the third component, described as “prevention of compensation,” the patient’s more-functional arm is inhibited from being used in everyday activities by wearing a padded mitt.
“This permits the patient to brace him- or herself whenever needed, but the better hand nonetheless lacks the dexterity to take over the activities that should be performed by the worse arm,” Dr. Mark explained.
“The patient wears the padded mitt after hours, too, except when using water or when sleeping,” he said.
The fourth component is a set of behavioral enforcement techniques involving goal-setting; daily interviews and discussion of progress and challenges; nightly homework; diary keeping; and telephone follow-up.
Dr. Mark noted that the intervention could have benefits that are secondary to motor and movement function. “We consider that the improvement of limb activity in a motor-challenged person with MS could afford a way to offset the deleterious effects of inactivity that can occur, such as weight gain, diabetes, osteoporosis, cardiac disease, and other conditions associated with prolonged inactivity,” he said.
Although it was developed at the University of Alabama, CIMT is currently more widely practiced in Europe than the United States, likely because of differences in care support, which in Europe is provided through socialized medicine, Dr. Mark pointed out.
Although the detailed methods for conducting CIMT are published in peer-reviewed journals, Dr. Mark recommends hands-on and interactive teaching. Such training is offered to clinicians and affiliated physical therapists and occupational therapists through Mark’s program at the University of Alabama in a semiannual, week-long training course, which includes hands-on treatment practice with actual patients.
Proof of principle
In further commenting on the study, Kathy M. Zackowski, PhD, of the National MS Society, said the findings provide an intriguing proof of concept that should be tested in a larger cohort. “The question of how much a behavioral (therapy) can impact true brain structural change or change in the pathologic mechanism is intriguing and of high importance,” she said.
“It is important to take this information as ‘proof of principle’ of the importance of CIMT for improving upper limb activity,” according to Dr. Zackowski, senior director, patient management, care and rehabilitation research at the society.
“Importantly, this team needs to move forward testing their hypothesis in a larger randomized, clinical trial with a full control group in order to show causal evidence that one intervention caused the structural brain changes seen,” she said in an interview.
Dr. Zackowski added that a caveat of CIMT is that the approach assumes one limb is more impaired than the other, which is always the case in stroke but is true only in some cases of MS. “Therefore, this method may not be effective for everyone with MS, but offers another option for tailoring an intervention to a person’s abilities and interests,” she said.
“Another important detail is that CIMT is also being explored for lower extremity use,” she added. “This is exciting, as lower extremity dysfunction is a very common problem in MS, and may be useful in treating walking disability.”
The authors, Ms. Bobryk, and Dr. Zackowski have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM CMSC 2020
Ofatumumab shows high elimination of disease activity in MS
, a new study shows.
The drug, which is already approved for the treatment of chronic lymphocytic leukemia, is currently under review for relapsing MS as a once-per-month self-injected therapy that could offer a convenient alternative to DMTs that require in-office infusion.
The new findings are from a pooled analysis from the phase 3 ASCLEPIOS I/II trials of the use of ofatumumab for patients with relapsing MS. There were 927 patients in the ASCLEPIOS I trial and 955 in the ASCLEPIOS II trial. The trials were conducted in 37 countries and involved patients aged 18-55 years.
The late-breaking research was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
The studies compared patients who were treated with subcutaneous ofatumumab 20 mg with patients treated with oral teriflunomide 14 mg once daily for up to 30 months. The average duration of follow-up was 18 months.
NEDA-3, commonly used to determine treatment outcomes for patients with relapsing MS, was defined as a composite of having no worsening of disability over a 6-month period (6mCDW), no confirmed MS relapse, no new/enlarging T2 lesions, and no gadolinium-enhancing T1 lesions.
The pooled results showed that the odds of achieving NEDA-3 during the first 12 months were three times greater with ofatumumab than with teriflunomide (47.0% vs. 24.5%; odds ratio [OR], 3.36; P < .001) and were more than eight times greater from months 12 to 24 (87.8% vs. 48.2%; OR, 8.09; P < .001).
In addition, compared with patients who received teriflunomide, a higher proportion of patients who received ofatumumab were free from 6mCDW over 2 years (91.9% vs. 88.9%), as well as from relapses (82.3% vs 69.2%) and lesion activity (54.1% vs. 27.5%).
There was a significantly greater reduction in annualized relapse rate with ofatumumab compared with teriflunomide at all cumulative time intervals, including months 0 to 3 (P = .011), and at all subsequent time intervals from month 0 to 27 (P < .001).
The pooled findings further showed that ofatumumab reduced the mean number of gadolinium-enhancing T1 lesions per scan by 95.9% compared with teriflunomide (P < .001).
“Ofatumumab increased the probability of achieving NEDA-3 and demonstrated superior efficacy vs teriflunomide in patients with relapsing MS,” said the authors, led by Stephen L. Hauser, MD, of the department of neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco.
Ofatumumab superior in primary, secondary outcomes
As previously reported, subcutaneous ofatumumab also demonstrated superior efficacy over oral teriflunomide in the primary and secondary endpoints in the ASCLEPIOS I/II trials. The annualized relapse rate was reduced by 0.22 in the teriflunomide group, vs 0.11 in the ofatumumab group (50.5% relative reduction; P < .001) in the ASCLEPIOS I trial, and by 0.25 vs. 0.10 (58.5% relative reduction P < .001) in ASCLEPIOS II.
Ofatumumab also reduced the number of gadolinium-enhancing T1 lesions and new or enlarging T2 lesions compared with teriflunomide (all P < .001). It reduced the risk for disability progression by 34.4% over 3 months and by 32.5% over 6 months.
In the studies, the rate of serious infection with ofatumumab was 2.5%, compared with 1.8% with teriflunomide. Rates of malignancies were 0.5% and 0.3%, respectively.
“Ofatumumab demonstrated superior efficacy versus teriflunomide, with an acceptable safety profile, in patients with relapsing MS,” the authors reported.
Adherence rates with self-injection encouraging
An additional analysis from the two trials presented virtually in a separate abstract at the CMSC showed greater adherence to the self-administered regimen.
The analysis shows that in the ASCLEPIOS I study, 86.0% patients who were randomly assigned to receive ofatumumab and 77.7% who received teriflunomide completed the study on the assigned study drug. The proportion of patients who received ofatumumab and who discontinued treatment was 14.0%, versus 21.2% for those in the teriflunomide group. The most common reasons for discontinuation were patient/guardian decision (ofatumumab, 4.9%; teriflunomide, 8.2%), adverse event (ofatumumab, 5.2%; teriflunomide, 5.0%), and physician decision (ofatumumab, 2.2%; teriflunomide, 6.5%).
In the ASCLEPIOS II study, the rates were similar in all measures.
“In ASCLEPIOS trials, compliance with home-administered subcutaneous ofatumumab was high, and fewer patients discontinued ofatumumab as compared to teriflunomide,” the authors concluded.
Comparator drug a weak choice?
In commenting on the research, Stephen Kamin, MD, professor, vice chair, and chief of service, department of neurology, New Jersey Medical School, in Newark, noted that a limitation of the ASCLEPIOS trials is the comparison with teriflunomide.
“The comparator drug, teriflunomide, is one of the least effective DMTs, and one that some clinicians, including myself, don’t use,” he said.
Previously, when asked in an interview about the choice of teriflunomide as the comparator, Dr. Hauser noted that considerable discussion had gone into the decision. “The rationale was that we wanted to have a comparator that would be present not only against focal disease activity but also potentially against progression, and we were also able to blind the study successfully,” he said at the time.
Dr. Kamin said that ofatumumab will nevertheless likely represent a welcome addition to the tool kit of treatment options for MS. “Any new drug is helpful in adding to our choices as a general rule,” he said. “Subcutaneous injection does have increased convenience.”
It is not likely that the drug will be a game changer, he added, although the treatment’s efficacy compared with other drugs remains to be seen. “It all depends upon the relative efficacy of ofatumumab versus ocrelizumab or siponimod,” Dr. Kamin said.
“There has been another subcutaneous monoclonal for MS, daclizumab, although this was withdrawn from the market due to severe adverse effects not related to route of administration,” he added.
Dr. Hauser has relationships with Alector, Annexon, Bionure, Molecular Stethoscope, Symbiotix, and F. Hoffmann-La Roche. Dr. Kamin has received research support from Biogen, Novartis and CMSC.
A version of this article originally appeared on Medscape.com.
, a new study shows.
The drug, which is already approved for the treatment of chronic lymphocytic leukemia, is currently under review for relapsing MS as a once-per-month self-injected therapy that could offer a convenient alternative to DMTs that require in-office infusion.
The new findings are from a pooled analysis from the phase 3 ASCLEPIOS I/II trials of the use of ofatumumab for patients with relapsing MS. There were 927 patients in the ASCLEPIOS I trial and 955 in the ASCLEPIOS II trial. The trials were conducted in 37 countries and involved patients aged 18-55 years.
The late-breaking research was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
The studies compared patients who were treated with subcutaneous ofatumumab 20 mg with patients treated with oral teriflunomide 14 mg once daily for up to 30 months. The average duration of follow-up was 18 months.
NEDA-3, commonly used to determine treatment outcomes for patients with relapsing MS, was defined as a composite of having no worsening of disability over a 6-month period (6mCDW), no confirmed MS relapse, no new/enlarging T2 lesions, and no gadolinium-enhancing T1 lesions.
The pooled results showed that the odds of achieving NEDA-3 during the first 12 months were three times greater with ofatumumab than with teriflunomide (47.0% vs. 24.5%; odds ratio [OR], 3.36; P < .001) and were more than eight times greater from months 12 to 24 (87.8% vs. 48.2%; OR, 8.09; P < .001).
In addition, compared with patients who received teriflunomide, a higher proportion of patients who received ofatumumab were free from 6mCDW over 2 years (91.9% vs. 88.9%), as well as from relapses (82.3% vs 69.2%) and lesion activity (54.1% vs. 27.5%).
There was a significantly greater reduction in annualized relapse rate with ofatumumab compared with teriflunomide at all cumulative time intervals, including months 0 to 3 (P = .011), and at all subsequent time intervals from month 0 to 27 (P < .001).
The pooled findings further showed that ofatumumab reduced the mean number of gadolinium-enhancing T1 lesions per scan by 95.9% compared with teriflunomide (P < .001).
“Ofatumumab increased the probability of achieving NEDA-3 and demonstrated superior efficacy vs teriflunomide in patients with relapsing MS,” said the authors, led by Stephen L. Hauser, MD, of the department of neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco.
Ofatumumab superior in primary, secondary outcomes
As previously reported, subcutaneous ofatumumab also demonstrated superior efficacy over oral teriflunomide in the primary and secondary endpoints in the ASCLEPIOS I/II trials. The annualized relapse rate was reduced by 0.22 in the teriflunomide group, vs 0.11 in the ofatumumab group (50.5% relative reduction; P < .001) in the ASCLEPIOS I trial, and by 0.25 vs. 0.10 (58.5% relative reduction P < .001) in ASCLEPIOS II.
Ofatumumab also reduced the number of gadolinium-enhancing T1 lesions and new or enlarging T2 lesions compared with teriflunomide (all P < .001). It reduced the risk for disability progression by 34.4% over 3 months and by 32.5% over 6 months.
In the studies, the rate of serious infection with ofatumumab was 2.5%, compared with 1.8% with teriflunomide. Rates of malignancies were 0.5% and 0.3%, respectively.
“Ofatumumab demonstrated superior efficacy versus teriflunomide, with an acceptable safety profile, in patients with relapsing MS,” the authors reported.
Adherence rates with self-injection encouraging
An additional analysis from the two trials presented virtually in a separate abstract at the CMSC showed greater adherence to the self-administered regimen.
The analysis shows that in the ASCLEPIOS I study, 86.0% patients who were randomly assigned to receive ofatumumab and 77.7% who received teriflunomide completed the study on the assigned study drug. The proportion of patients who received ofatumumab and who discontinued treatment was 14.0%, versus 21.2% for those in the teriflunomide group. The most common reasons for discontinuation were patient/guardian decision (ofatumumab, 4.9%; teriflunomide, 8.2%), adverse event (ofatumumab, 5.2%; teriflunomide, 5.0%), and physician decision (ofatumumab, 2.2%; teriflunomide, 6.5%).
In the ASCLEPIOS II study, the rates were similar in all measures.
“In ASCLEPIOS trials, compliance with home-administered subcutaneous ofatumumab was high, and fewer patients discontinued ofatumumab as compared to teriflunomide,” the authors concluded.
Comparator drug a weak choice?
In commenting on the research, Stephen Kamin, MD, professor, vice chair, and chief of service, department of neurology, New Jersey Medical School, in Newark, noted that a limitation of the ASCLEPIOS trials is the comparison with teriflunomide.
“The comparator drug, teriflunomide, is one of the least effective DMTs, and one that some clinicians, including myself, don’t use,” he said.
Previously, when asked in an interview about the choice of teriflunomide as the comparator, Dr. Hauser noted that considerable discussion had gone into the decision. “The rationale was that we wanted to have a comparator that would be present not only against focal disease activity but also potentially against progression, and we were also able to blind the study successfully,” he said at the time.
Dr. Kamin said that ofatumumab will nevertheless likely represent a welcome addition to the tool kit of treatment options for MS. “Any new drug is helpful in adding to our choices as a general rule,” he said. “Subcutaneous injection does have increased convenience.”
It is not likely that the drug will be a game changer, he added, although the treatment’s efficacy compared with other drugs remains to be seen. “It all depends upon the relative efficacy of ofatumumab versus ocrelizumab or siponimod,” Dr. Kamin said.
“There has been another subcutaneous monoclonal for MS, daclizumab, although this was withdrawn from the market due to severe adverse effects not related to route of administration,” he added.
Dr. Hauser has relationships with Alector, Annexon, Bionure, Molecular Stethoscope, Symbiotix, and F. Hoffmann-La Roche. Dr. Kamin has received research support from Biogen, Novartis and CMSC.
A version of this article originally appeared on Medscape.com.
, a new study shows.
The drug, which is already approved for the treatment of chronic lymphocytic leukemia, is currently under review for relapsing MS as a once-per-month self-injected therapy that could offer a convenient alternative to DMTs that require in-office infusion.
The new findings are from a pooled analysis from the phase 3 ASCLEPIOS I/II trials of the use of ofatumumab for patients with relapsing MS. There were 927 patients in the ASCLEPIOS I trial and 955 in the ASCLEPIOS II trial. The trials were conducted in 37 countries and involved patients aged 18-55 years.
The late-breaking research was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).
The studies compared patients who were treated with subcutaneous ofatumumab 20 mg with patients treated with oral teriflunomide 14 mg once daily for up to 30 months. The average duration of follow-up was 18 months.
NEDA-3, commonly used to determine treatment outcomes for patients with relapsing MS, was defined as a composite of having no worsening of disability over a 6-month period (6mCDW), no confirmed MS relapse, no new/enlarging T2 lesions, and no gadolinium-enhancing T1 lesions.
The pooled results showed that the odds of achieving NEDA-3 during the first 12 months were three times greater with ofatumumab than with teriflunomide (47.0% vs. 24.5%; odds ratio [OR], 3.36; P < .001) and were more than eight times greater from months 12 to 24 (87.8% vs. 48.2%; OR, 8.09; P < .001).
In addition, compared with patients who received teriflunomide, a higher proportion of patients who received ofatumumab were free from 6mCDW over 2 years (91.9% vs. 88.9%), as well as from relapses (82.3% vs 69.2%) and lesion activity (54.1% vs. 27.5%).
There was a significantly greater reduction in annualized relapse rate with ofatumumab compared with teriflunomide at all cumulative time intervals, including months 0 to 3 (P = .011), and at all subsequent time intervals from month 0 to 27 (P < .001).
The pooled findings further showed that ofatumumab reduced the mean number of gadolinium-enhancing T1 lesions per scan by 95.9% compared with teriflunomide (P < .001).
“Ofatumumab increased the probability of achieving NEDA-3 and demonstrated superior efficacy vs teriflunomide in patients with relapsing MS,” said the authors, led by Stephen L. Hauser, MD, of the department of neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco.
Ofatumumab superior in primary, secondary outcomes
As previously reported, subcutaneous ofatumumab also demonstrated superior efficacy over oral teriflunomide in the primary and secondary endpoints in the ASCLEPIOS I/II trials. The annualized relapse rate was reduced by 0.22 in the teriflunomide group, vs 0.11 in the ofatumumab group (50.5% relative reduction; P < .001) in the ASCLEPIOS I trial, and by 0.25 vs. 0.10 (58.5% relative reduction P < .001) in ASCLEPIOS II.
Ofatumumab also reduced the number of gadolinium-enhancing T1 lesions and new or enlarging T2 lesions compared with teriflunomide (all P < .001). It reduced the risk for disability progression by 34.4% over 3 months and by 32.5% over 6 months.
In the studies, the rate of serious infection with ofatumumab was 2.5%, compared with 1.8% with teriflunomide. Rates of malignancies were 0.5% and 0.3%, respectively.
“Ofatumumab demonstrated superior efficacy versus teriflunomide, with an acceptable safety profile, in patients with relapsing MS,” the authors reported.
Adherence rates with self-injection encouraging
An additional analysis from the two trials presented virtually in a separate abstract at the CMSC showed greater adherence to the self-administered regimen.
The analysis shows that in the ASCLEPIOS I study, 86.0% patients who were randomly assigned to receive ofatumumab and 77.7% who received teriflunomide completed the study on the assigned study drug. The proportion of patients who received ofatumumab and who discontinued treatment was 14.0%, versus 21.2% for those in the teriflunomide group. The most common reasons for discontinuation were patient/guardian decision (ofatumumab, 4.9%; teriflunomide, 8.2%), adverse event (ofatumumab, 5.2%; teriflunomide, 5.0%), and physician decision (ofatumumab, 2.2%; teriflunomide, 6.5%).
In the ASCLEPIOS II study, the rates were similar in all measures.
“In ASCLEPIOS trials, compliance with home-administered subcutaneous ofatumumab was high, and fewer patients discontinued ofatumumab as compared to teriflunomide,” the authors concluded.
Comparator drug a weak choice?
In commenting on the research, Stephen Kamin, MD, professor, vice chair, and chief of service, department of neurology, New Jersey Medical School, in Newark, noted that a limitation of the ASCLEPIOS trials is the comparison with teriflunomide.
“The comparator drug, teriflunomide, is one of the least effective DMTs, and one that some clinicians, including myself, don’t use,” he said.
Previously, when asked in an interview about the choice of teriflunomide as the comparator, Dr. Hauser noted that considerable discussion had gone into the decision. “The rationale was that we wanted to have a comparator that would be present not only against focal disease activity but also potentially against progression, and we were also able to blind the study successfully,” he said at the time.
Dr. Kamin said that ofatumumab will nevertheless likely represent a welcome addition to the tool kit of treatment options for MS. “Any new drug is helpful in adding to our choices as a general rule,” he said. “Subcutaneous injection does have increased convenience.”
It is not likely that the drug will be a game changer, he added, although the treatment’s efficacy compared with other drugs remains to be seen. “It all depends upon the relative efficacy of ofatumumab versus ocrelizumab or siponimod,” Dr. Kamin said.
“There has been another subcutaneous monoclonal for MS, daclizumab, although this was withdrawn from the market due to severe adverse effects not related to route of administration,” he added.
Dr. Hauser has relationships with Alector, Annexon, Bionure, Molecular Stethoscope, Symbiotix, and F. Hoffmann-La Roche. Dr. Kamin has received research support from Biogen, Novartis and CMSC.
A version of this article originally appeared on Medscape.com.
From CMSC 2020
Natalizumab switch to moderate-efficacy DMT increases disability risk
, new research shows.
“Owing to the vast number of available DMTs, not only understanding DMT performance but answering the question of what can come next if a patient needs to discontinue treatment due to safety or breakthrough disease is important,” said lead author Carrie M. Hersh, DO, of the Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas.
The study shows that, “patients transitioning from natalizumab to another high-efficacy therapy have better inflammatory and disability outcomes compared with those who de-escalate their therapy to a moderate-efficacy DMT,” she said.
Natalizumab (Tysabri) offers significant benefits in the treatment of relapsing forms of MS, however, its long-term use is associated with safety concerns, notably an increased risk of progressive multifocal leukoencephalopathy (PML). Although the risk can be reduced with a switch to a different DMT, the transition can have risks of its own, including a rebound of disease activity that could prove to be worse than the pre-natalizumab treatment period, and there is a lack of consensus on the safest avenues for switching to another DMT following discontinuation of natalizumab.
In research presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Hersh and colleagues explored the issue in a real-world population of 556 patients discontinuing natalizumab at two MS centers. Of these, 270 switched to a moderate DMT (dimethyl fumarate, n = 130; or fingolimod, n = 140) and 130 switched to a highly effective DMT (ocrelizumab, n = 106; rituximab, n = 17; or alemtuzumab, n = 7).
Reasons for switching included a PML risk for 54.9%, breakthrough disease for 15.3%, and adverse effects for 17.3%.
At 24-month follow-up after the switch and after adjustment for propensity score matching, no differences were seen between the moderate and highly effective DMT groups in terms of the annualized relapse rate (ARR; P = 0.33) or the time to first relapse (P = 0.09).
However, significantly higher proportions of patients switching to moderate DMTs showed new T2 lesions (odds ratio, 2.15; P = .01), as well as new gadolinium-enhancing lesions (OR, 1.99; P = .02), and a 20% worsening of the timed 25-foot walk test (T25FW; OR, 1.83; P = .04) and 9-hole peg test (9-HPT; OR, 1.81; P = .04)
Those switching to moderate DMTs also had significantly lower rates of absence of disease activity over the 24 months (OR, 0.41, P = .004), and they had a higher risk of earlier time-to-first gadolinium-enhancing lesion (hazard ratio, 6.67, P = .002), compared with those switching to a high-efficacy DMT.
Other factors that have previously been shown to be associated with rebounds that are worse than pre-natalizumab treatment include washout periods that are longer than 3 months.
The authors noted that there were no significant differences between the groups in terms of mean washout duration, which were relatively short (moderate DMT, 1.4 months; highly effective treatment, 1.8 months; P = .34), In addition, there were no significant differences between the groups in terms of the average duration of natalizumab treatment.
Dr. Hersh speculated that the lack of ARR differences may reflect that the measure is not as objective as the more specific determinants of performance. “One could consider the comparable ARR as a little surprising, but relapse evaluation in a retrospective manner is limited,” she explained.
“Historically, radiographic markers of new inflammation via brain magnetic resonance imaging (MRI) and neuroperformance measures (T25FW and 9-HPT) are more objective compared to assessing clinical relapses, especially in a retrospective cohort where relapses cannot be validated by a central agency or the principal investigator. Therefore, one can surmise that patients transitioning from natalizumab to another high-efficacy DMT fare better than de-escalating treatment to a moderate-efficacy DMT.”
Dr. Hersh and team plan a larger, multicenter study to investigate the short- and long-term effects of post-natalizumab DMT sequencing to help validate the current findings.
Commenting on the research, Stephen Kamin, MD, professor, vice chair and chief of service, department of neurology, New Jersey Medical School, Newark, said the results are consistent with natalizumab’s general profile.
“In general, natalizumab has been used in patients with highly active disease, so I would expect fewer patients with no evidence of disease activity when switched to a moderately active drug rather than a highly active one,” he said in an interview.
Caveats of the findings include the trial’s observational nature, meaning potential confounding factors of baseline characteristics among patients who switched regimens are not known, noted Dr. Kamin, who was not involved with the study.
“Also, the patients were switched to a variety of drugs and even within a class there may be differences in outcome,” he explained.
Dr. Hersh reported consulting or research relationships with Biogen, Genentech, EMD Serono, Genzyme, Novartis, and PCORI. Dr. Kamin has received research support from Biogen, Novartis, and the Consortium of Multiple Sclerosis Centers.
This article first appeared on Medscape.com.
, new research shows.
“Owing to the vast number of available DMTs, not only understanding DMT performance but answering the question of what can come next if a patient needs to discontinue treatment due to safety or breakthrough disease is important,” said lead author Carrie M. Hersh, DO, of the Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas.
The study shows that, “patients transitioning from natalizumab to another high-efficacy therapy have better inflammatory and disability outcomes compared with those who de-escalate their therapy to a moderate-efficacy DMT,” she said.
Natalizumab (Tysabri) offers significant benefits in the treatment of relapsing forms of MS, however, its long-term use is associated with safety concerns, notably an increased risk of progressive multifocal leukoencephalopathy (PML). Although the risk can be reduced with a switch to a different DMT, the transition can have risks of its own, including a rebound of disease activity that could prove to be worse than the pre-natalizumab treatment period, and there is a lack of consensus on the safest avenues for switching to another DMT following discontinuation of natalizumab.
In research presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Hersh and colleagues explored the issue in a real-world population of 556 patients discontinuing natalizumab at two MS centers. Of these, 270 switched to a moderate DMT (dimethyl fumarate, n = 130; or fingolimod, n = 140) and 130 switched to a highly effective DMT (ocrelizumab, n = 106; rituximab, n = 17; or alemtuzumab, n = 7).
Reasons for switching included a PML risk for 54.9%, breakthrough disease for 15.3%, and adverse effects for 17.3%.
At 24-month follow-up after the switch and after adjustment for propensity score matching, no differences were seen between the moderate and highly effective DMT groups in terms of the annualized relapse rate (ARR; P = 0.33) or the time to first relapse (P = 0.09).
However, significantly higher proportions of patients switching to moderate DMTs showed new T2 lesions (odds ratio, 2.15; P = .01), as well as new gadolinium-enhancing lesions (OR, 1.99; P = .02), and a 20% worsening of the timed 25-foot walk test (T25FW; OR, 1.83; P = .04) and 9-hole peg test (9-HPT; OR, 1.81; P = .04)
Those switching to moderate DMTs also had significantly lower rates of absence of disease activity over the 24 months (OR, 0.41, P = .004), and they had a higher risk of earlier time-to-first gadolinium-enhancing lesion (hazard ratio, 6.67, P = .002), compared with those switching to a high-efficacy DMT.
Other factors that have previously been shown to be associated with rebounds that are worse than pre-natalizumab treatment include washout periods that are longer than 3 months.
The authors noted that there were no significant differences between the groups in terms of mean washout duration, which were relatively short (moderate DMT, 1.4 months; highly effective treatment, 1.8 months; P = .34), In addition, there were no significant differences between the groups in terms of the average duration of natalizumab treatment.
Dr. Hersh speculated that the lack of ARR differences may reflect that the measure is not as objective as the more specific determinants of performance. “One could consider the comparable ARR as a little surprising, but relapse evaluation in a retrospective manner is limited,” she explained.
“Historically, radiographic markers of new inflammation via brain magnetic resonance imaging (MRI) and neuroperformance measures (T25FW and 9-HPT) are more objective compared to assessing clinical relapses, especially in a retrospective cohort where relapses cannot be validated by a central agency or the principal investigator. Therefore, one can surmise that patients transitioning from natalizumab to another high-efficacy DMT fare better than de-escalating treatment to a moderate-efficacy DMT.”
Dr. Hersh and team plan a larger, multicenter study to investigate the short- and long-term effects of post-natalizumab DMT sequencing to help validate the current findings.
Commenting on the research, Stephen Kamin, MD, professor, vice chair and chief of service, department of neurology, New Jersey Medical School, Newark, said the results are consistent with natalizumab’s general profile.
“In general, natalizumab has been used in patients with highly active disease, so I would expect fewer patients with no evidence of disease activity when switched to a moderately active drug rather than a highly active one,” he said in an interview.
Caveats of the findings include the trial’s observational nature, meaning potential confounding factors of baseline characteristics among patients who switched regimens are not known, noted Dr. Kamin, who was not involved with the study.
“Also, the patients were switched to a variety of drugs and even within a class there may be differences in outcome,” he explained.
Dr. Hersh reported consulting or research relationships with Biogen, Genentech, EMD Serono, Genzyme, Novartis, and PCORI. Dr. Kamin has received research support from Biogen, Novartis, and the Consortium of Multiple Sclerosis Centers.
This article first appeared on Medscape.com.
, new research shows.
“Owing to the vast number of available DMTs, not only understanding DMT performance but answering the question of what can come next if a patient needs to discontinue treatment due to safety or breakthrough disease is important,” said lead author Carrie M. Hersh, DO, of the Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas.
The study shows that, “patients transitioning from natalizumab to another high-efficacy therapy have better inflammatory and disability outcomes compared with those who de-escalate their therapy to a moderate-efficacy DMT,” she said.
Natalizumab (Tysabri) offers significant benefits in the treatment of relapsing forms of MS, however, its long-term use is associated with safety concerns, notably an increased risk of progressive multifocal leukoencephalopathy (PML). Although the risk can be reduced with a switch to a different DMT, the transition can have risks of its own, including a rebound of disease activity that could prove to be worse than the pre-natalizumab treatment period, and there is a lack of consensus on the safest avenues for switching to another DMT following discontinuation of natalizumab.
In research presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers, Dr. Hersh and colleagues explored the issue in a real-world population of 556 patients discontinuing natalizumab at two MS centers. Of these, 270 switched to a moderate DMT (dimethyl fumarate, n = 130; or fingolimod, n = 140) and 130 switched to a highly effective DMT (ocrelizumab, n = 106; rituximab, n = 17; or alemtuzumab, n = 7).
Reasons for switching included a PML risk for 54.9%, breakthrough disease for 15.3%, and adverse effects for 17.3%.
At 24-month follow-up after the switch and after adjustment for propensity score matching, no differences were seen between the moderate and highly effective DMT groups in terms of the annualized relapse rate (ARR; P = 0.33) or the time to first relapse (P = 0.09).
However, significantly higher proportions of patients switching to moderate DMTs showed new T2 lesions (odds ratio, 2.15; P = .01), as well as new gadolinium-enhancing lesions (OR, 1.99; P = .02), and a 20% worsening of the timed 25-foot walk test (T25FW; OR, 1.83; P = .04) and 9-hole peg test (9-HPT; OR, 1.81; P = .04)
Those switching to moderate DMTs also had significantly lower rates of absence of disease activity over the 24 months (OR, 0.41, P = .004), and they had a higher risk of earlier time-to-first gadolinium-enhancing lesion (hazard ratio, 6.67, P = .002), compared with those switching to a high-efficacy DMT.
Other factors that have previously been shown to be associated with rebounds that are worse than pre-natalizumab treatment include washout periods that are longer than 3 months.
The authors noted that there were no significant differences between the groups in terms of mean washout duration, which were relatively short (moderate DMT, 1.4 months; highly effective treatment, 1.8 months; P = .34), In addition, there were no significant differences between the groups in terms of the average duration of natalizumab treatment.
Dr. Hersh speculated that the lack of ARR differences may reflect that the measure is not as objective as the more specific determinants of performance. “One could consider the comparable ARR as a little surprising, but relapse evaluation in a retrospective manner is limited,” she explained.
“Historically, radiographic markers of new inflammation via brain magnetic resonance imaging (MRI) and neuroperformance measures (T25FW and 9-HPT) are more objective compared to assessing clinical relapses, especially in a retrospective cohort where relapses cannot be validated by a central agency or the principal investigator. Therefore, one can surmise that patients transitioning from natalizumab to another high-efficacy DMT fare better than de-escalating treatment to a moderate-efficacy DMT.”
Dr. Hersh and team plan a larger, multicenter study to investigate the short- and long-term effects of post-natalizumab DMT sequencing to help validate the current findings.
Commenting on the research, Stephen Kamin, MD, professor, vice chair and chief of service, department of neurology, New Jersey Medical School, Newark, said the results are consistent with natalizumab’s general profile.
“In general, natalizumab has been used in patients with highly active disease, so I would expect fewer patients with no evidence of disease activity when switched to a moderately active drug rather than a highly active one,” he said in an interview.
Caveats of the findings include the trial’s observational nature, meaning potential confounding factors of baseline characteristics among patients who switched regimens are not known, noted Dr. Kamin, who was not involved with the study.
“Also, the patients were switched to a variety of drugs and even within a class there may be differences in outcome,” he explained.
Dr. Hersh reported consulting or research relationships with Biogen, Genentech, EMD Serono, Genzyme, Novartis, and PCORI. Dr. Kamin has received research support from Biogen, Novartis, and the Consortium of Multiple Sclerosis Centers.
This article first appeared on Medscape.com.
Endocrinologists’ pay remains at lower end of physician scale
U.S. endocrinologists reported an average income that continues to be among the lowest of all specialist groups, according to results from the latest Medscape Annual Compensation Report.
In the survey, which represents the responses of over 17,000 physicians in more than 30 specialties, endocrinologists report an average annual income of $236,000, which is unchanged from that detailed last year.
The report reflects data collected from Oct. 4, 2019 to Feb. 10, 2020, so does not take into account any effects of the COVID-19 pandemic.
It puts the diabetes and endocrinology specialty above family medicine, public health and preventive medicine, and pediatrics but nevertheless among the lowest-earning specialties.
At the opposite end of the earnings scale, orthopedics is at the top, with those doctors earning an average of $511,000 per year, followed by plastic surgery, otolaryngology, cardiology, and radiology.
The reported compensation reflects full-time salaries with patient care, including salary, bonus, and profit-sharing contributions for employed physicians, and earnings after taxes and deductible business expenses for self-employed physicians practicing medicine in the United States.
A gender gap in compensation is still apparent, with male endocrinologists earning about 23% more ($258,000) than their female counterparts ($209,000).
Overall, male specialists earn 31% more than women, which is a slight improvement on the 33% gender pay gap reported in 2019.
Survey respondents were 64% male and 34% female, with 2% declining to respond.
Half happy with pay, most would still choose same path
Around half (49%) of endocrinologists reported feeling fairly compensated for their work, an increase from last year’s rate of 42%.
In all, 82% said – if given another chance – they would choose a career in medicine again, higher than the rate of 77% of physicians overall. And as many as 80% said they would remain in the specialty of endocrinology.
For 35% of endocrinologists, the most rewarding part of their job is gratitude and relationships with patients. The most challenging part is “having so many rules and regulations,” cited by 25% of respondents, followed by working with an EHR system, reported by 20%.
Endocrinologists spent an average of about 34 hours per week seeing patients, lower than the 37.9 hours per week reported among all physicians. And the average of 16.5 hours per week spent on paperwork and administration by endocrinologists is similar to the 15.6 hours reported by physicians overall.
In terms of Medicare and Medicaid patients, 71% of endocrinologists said they had no plans to stop providing services to Medicare and Medicaid patients, which is similar to the overall rate of 73%.
About half of endocrinologists (51%) reported using nurse practitioners and 25% used physician assistants, while 42% used neither.
Among those using nurse practitioners or physician assistants, 50% reported that the assistance increased profitability; 44% said the staffers had no effect on profitability, and 6% reported decreased profitability.
Only about 13% of endocrinologists reported having claims denied or needing to be resubmitted, well below the highest levels of 28% and 22% reported in plastic surgery and emergency medicine, respectively.
COVID-19 suppresses compensation, but boosts telemedicine
Subsequent compensation surveys can be expected to reflect the heavy toll that COVID-19 pandemic has taken on nearly all professions in health care – as well as global economies as a whole.
Specialist practices in general report as much as a 55% decrease in revenue, on average, and a 60% decrease in patient volume since the beginning of the crisis, according to the report.
As many as 43,000 U.S. health care workers were reportedly laid off in March 2020 alone, as hospitals and physician groups announced layoffs, furloughs, and pay cuts in response to the fallout from the pandemic. And a reported 9% of independent medical practices have had to close, at least temporarily.
Meanwhile, the use of remote technologies for patient engagement has increased by 225%.
Specialties that rely heavily on elective procedures that were for the most part delayed during the pandemic have been particularly hard-hit, notably in those practicing orthopedics, plastic surgery, dermatology, cardiology, and ophthalmology.
“The health impact of COVID-19 has been grave, and the financial fallout is widespread,” according to the Medscape report.
A version of this article originally appeared on Medscape.com.
U.S. endocrinologists reported an average income that continues to be among the lowest of all specialist groups, according to results from the latest Medscape Annual Compensation Report.
In the survey, which represents the responses of over 17,000 physicians in more than 30 specialties, endocrinologists report an average annual income of $236,000, which is unchanged from that detailed last year.
The report reflects data collected from Oct. 4, 2019 to Feb. 10, 2020, so does not take into account any effects of the COVID-19 pandemic.
It puts the diabetes and endocrinology specialty above family medicine, public health and preventive medicine, and pediatrics but nevertheless among the lowest-earning specialties.
At the opposite end of the earnings scale, orthopedics is at the top, with those doctors earning an average of $511,000 per year, followed by plastic surgery, otolaryngology, cardiology, and radiology.
The reported compensation reflects full-time salaries with patient care, including salary, bonus, and profit-sharing contributions for employed physicians, and earnings after taxes and deductible business expenses for self-employed physicians practicing medicine in the United States.
A gender gap in compensation is still apparent, with male endocrinologists earning about 23% more ($258,000) than their female counterparts ($209,000).
Overall, male specialists earn 31% more than women, which is a slight improvement on the 33% gender pay gap reported in 2019.
Survey respondents were 64% male and 34% female, with 2% declining to respond.
Half happy with pay, most would still choose same path
Around half (49%) of endocrinologists reported feeling fairly compensated for their work, an increase from last year’s rate of 42%.
In all, 82% said – if given another chance – they would choose a career in medicine again, higher than the rate of 77% of physicians overall. And as many as 80% said they would remain in the specialty of endocrinology.
For 35% of endocrinologists, the most rewarding part of their job is gratitude and relationships with patients. The most challenging part is “having so many rules and regulations,” cited by 25% of respondents, followed by working with an EHR system, reported by 20%.
Endocrinologists spent an average of about 34 hours per week seeing patients, lower than the 37.9 hours per week reported among all physicians. And the average of 16.5 hours per week spent on paperwork and administration by endocrinologists is similar to the 15.6 hours reported by physicians overall.
In terms of Medicare and Medicaid patients, 71% of endocrinologists said they had no plans to stop providing services to Medicare and Medicaid patients, which is similar to the overall rate of 73%.
About half of endocrinologists (51%) reported using nurse practitioners and 25% used physician assistants, while 42% used neither.
Among those using nurse practitioners or physician assistants, 50% reported that the assistance increased profitability; 44% said the staffers had no effect on profitability, and 6% reported decreased profitability.
Only about 13% of endocrinologists reported having claims denied or needing to be resubmitted, well below the highest levels of 28% and 22% reported in plastic surgery and emergency medicine, respectively.
COVID-19 suppresses compensation, but boosts telemedicine
Subsequent compensation surveys can be expected to reflect the heavy toll that COVID-19 pandemic has taken on nearly all professions in health care – as well as global economies as a whole.
Specialist practices in general report as much as a 55% decrease in revenue, on average, and a 60% decrease in patient volume since the beginning of the crisis, according to the report.
As many as 43,000 U.S. health care workers were reportedly laid off in March 2020 alone, as hospitals and physician groups announced layoffs, furloughs, and pay cuts in response to the fallout from the pandemic. And a reported 9% of independent medical practices have had to close, at least temporarily.
Meanwhile, the use of remote technologies for patient engagement has increased by 225%.
Specialties that rely heavily on elective procedures that were for the most part delayed during the pandemic have been particularly hard-hit, notably in those practicing orthopedics, plastic surgery, dermatology, cardiology, and ophthalmology.
“The health impact of COVID-19 has been grave, and the financial fallout is widespread,” according to the Medscape report.
A version of this article originally appeared on Medscape.com.
U.S. endocrinologists reported an average income that continues to be among the lowest of all specialist groups, according to results from the latest Medscape Annual Compensation Report.
In the survey, which represents the responses of over 17,000 physicians in more than 30 specialties, endocrinologists report an average annual income of $236,000, which is unchanged from that detailed last year.
The report reflects data collected from Oct. 4, 2019 to Feb. 10, 2020, so does not take into account any effects of the COVID-19 pandemic.
It puts the diabetes and endocrinology specialty above family medicine, public health and preventive medicine, and pediatrics but nevertheless among the lowest-earning specialties.
At the opposite end of the earnings scale, orthopedics is at the top, with those doctors earning an average of $511,000 per year, followed by plastic surgery, otolaryngology, cardiology, and radiology.
The reported compensation reflects full-time salaries with patient care, including salary, bonus, and profit-sharing contributions for employed physicians, and earnings after taxes and deductible business expenses for self-employed physicians practicing medicine in the United States.
A gender gap in compensation is still apparent, with male endocrinologists earning about 23% more ($258,000) than their female counterparts ($209,000).
Overall, male specialists earn 31% more than women, which is a slight improvement on the 33% gender pay gap reported in 2019.
Survey respondents were 64% male and 34% female, with 2% declining to respond.
Half happy with pay, most would still choose same path
Around half (49%) of endocrinologists reported feeling fairly compensated for their work, an increase from last year’s rate of 42%.
In all, 82% said – if given another chance – they would choose a career in medicine again, higher than the rate of 77% of physicians overall. And as many as 80% said they would remain in the specialty of endocrinology.
For 35% of endocrinologists, the most rewarding part of their job is gratitude and relationships with patients. The most challenging part is “having so many rules and regulations,” cited by 25% of respondents, followed by working with an EHR system, reported by 20%.
Endocrinologists spent an average of about 34 hours per week seeing patients, lower than the 37.9 hours per week reported among all physicians. And the average of 16.5 hours per week spent on paperwork and administration by endocrinologists is similar to the 15.6 hours reported by physicians overall.
In terms of Medicare and Medicaid patients, 71% of endocrinologists said they had no plans to stop providing services to Medicare and Medicaid patients, which is similar to the overall rate of 73%.
About half of endocrinologists (51%) reported using nurse practitioners and 25% used physician assistants, while 42% used neither.
Among those using nurse practitioners or physician assistants, 50% reported that the assistance increased profitability; 44% said the staffers had no effect on profitability, and 6% reported decreased profitability.
Only about 13% of endocrinologists reported having claims denied or needing to be resubmitted, well below the highest levels of 28% and 22% reported in plastic surgery and emergency medicine, respectively.
COVID-19 suppresses compensation, but boosts telemedicine
Subsequent compensation surveys can be expected to reflect the heavy toll that COVID-19 pandemic has taken on nearly all professions in health care – as well as global economies as a whole.
Specialist practices in general report as much as a 55% decrease in revenue, on average, and a 60% decrease in patient volume since the beginning of the crisis, according to the report.
As many as 43,000 U.S. health care workers were reportedly laid off in March 2020 alone, as hospitals and physician groups announced layoffs, furloughs, and pay cuts in response to the fallout from the pandemic. And a reported 9% of independent medical practices have had to close, at least temporarily.
Meanwhile, the use of remote technologies for patient engagement has increased by 225%.
Specialties that rely heavily on elective procedures that were for the most part delayed during the pandemic have been particularly hard-hit, notably in those practicing orthopedics, plastic surgery, dermatology, cardiology, and ophthalmology.
“The health impact of COVID-19 has been grave, and the financial fallout is widespread,” according to the Medscape report.
A version of this article originally appeared on Medscape.com.