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Two case reports identify Guillain-Barré variants after SARS-CoV-2 vaccination
Guillain-Barré syndrome, a rare peripheral nerve disorder that can occur after certain types of viral and bacterial infections, has not to date been definitively linked to infection by SARS-CoV-2 or with vaccination against the virus, despite surveillance searching for such associations.
Spikes in Guillain-Barré syndrome incidence have previously, but rarely, been associated with outbreaks of other viral diseases, including Zika, but not with vaccination, except for a 1976-1977 swine influenza vaccine campaign in the United States that was seen associated with a slight elevation in risk, and was halted when that risk became known. Since then, all sorts of vaccines in the European Union and United States have come with warnings about Guillain-Barré syndrome in their package inserts – a fact that some Guillain-Barré syndrome experts lament as perpetuating the notion that vaccines cause Guillain-Barré syndrome.
Epidemiologic studies in the United Kingdom and Singapore did not detect increases in Guillain-Barré syndrome incidence during the COVID-19 pandemic. And as mass vaccination against COVID-19 got underway early this year, experts cautioned against the temptation to attribute incident Guillain-Barré syndrome cases following vaccination to SARS-CoV-2 without careful statistical and epidemiological analysis. Until now reports of Guillain-Barré syndrome have been scant: clinical trials of a viral vector vaccine developed by Johnson & Johnson saw one in the placebo arm and another in the intervention arm, while another case was reported following administration of a Pfizer mRNA SARS-Cov-2 vaccine.
Recent case reports
None of the patients had evidence of current SARS-CoV-2 infection.
From India, Boby V. Maramattom, MD, of Aster Medcity in Kochi, India, and colleagues reported on seven severe cases of Guillain-Barré syndrome occurring between 10 and 14 days after a first dose of the AstraZeneca vaccine. All but one of the patients were women, all had bilateral facial paresis, all progressed to areflexic quadriplegia, and six required respiratory support. Patients’ ages ranged from 43 to 70. Four developed other cranial neuropathies, including abducens palsy and trigeminal sensory nerve involvement, which are rare in reports of Guillain-Barré syndrome from India, Dr. Maramattom and colleagues noted.
The authors argued that their findings “should prompt all physicians to be vigilant in recognizing Guillain-Barré syndrome in patients who have received the AstraZeneca vaccine. While the risk per patient (5.8 per million) may be relatively low, our observations suggest that this clinically distinct [Guillain-Barré syndrome] variant is more severe than usual and may require mechanical ventilation.”
The U.K. cases, reported by Christopher Martin Allen, MD, and colleagues at Nottingham (England) University Hospitals NHS Trust, describe bifacial weakness and normal facial sensation in four men between 11 and 22 days after their first doses of the Astra-Zeneca vaccine. This type of facial palsy, the authors wrote, was unusual Guillain-Barré syndrome variant that one rapid review found in 3 of 42 European patients diagnosed with Guillain-Barré syndrome following SARS-CoV-2 infection.
Dr. Allen and colleagues acknowledged that causality could not be assumed from the temporal relationship of immunization to onset of bifacial weakness in their report, but argued that their findings argued for “robust postvaccination surveillance” and that “the report of a similar syndrome in the setting of SARS-CoV-2 infection suggests an immunologic response to the spike protein.” If the link is casual, they wrote, “it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system.”
‘The jury is still out’
Asked for comment, neurologist Anthony Amato, MD, of Brigham and Women’s Hospital, Boston, said that he did not see what the two new studies add to what is already known. “Guillain-Barré syndrome has already been reported temporally following COVID-19 along with accompanying editorials that such temporal occurrences do not imply causation and there is a need for surveillance and epidemiological studies.”
Robert Lisak, MD, of Wayne State University, Detroit, and a longtime adviser to the GBS-CIDP Foundation International, commented that “the relationship between vaccines and association with Guillain-Barré syndrome continues to be controversial in part because Guillain-Barré syndrome, a rare disorder, has many reported associated illnesses including infections. Many vaccines have been implicated but with the probable exception of the ‘swine flu’ vaccine in the 1970s, most have not stood up to scrutiny.”
With SARS-Cov-2 infection and vaccines, “the jury is still out,” Dr. Lisak said. “The report from the U.K. is intriguing since they report several cases of an uncommon variant, but the cases from India seem to be more of the usual forms of Guillain-Barré syndrome.”
Dr. Lisak noted that, even if an association turns out to be valid, “we are talking about a very low incidence of Guillain-Barré syndrome associated with COVID-19 vaccines,” one that would not justify avoiding them because of a possible association with Guillain-Barré syndrome.
The GBS-CIDP Foundation, which supports research into Guillain-Barré syndrome and related diseases, has likewise stressed the low risk presented by SARS-CoV-2 vaccines, noting on its website that “the risk of death or long-term complications from COVID in adults still far exceeds the risk of any possible risk of Guillain-Barré syndrome by several orders of magnitude.”
None of the study authors reported financial conflicts of interest related to their research. Dr. Amato is an adviser to the pharmaceutical firms Alexion and Argenx, while Dr. Lisak has received research support or honoraria from Alexion, Novartis, Hoffmann–La Roche, and others.
Guillain-Barré syndrome, a rare peripheral nerve disorder that can occur after certain types of viral and bacterial infections, has not to date been definitively linked to infection by SARS-CoV-2 or with vaccination against the virus, despite surveillance searching for such associations.
Spikes in Guillain-Barré syndrome incidence have previously, but rarely, been associated with outbreaks of other viral diseases, including Zika, but not with vaccination, except for a 1976-1977 swine influenza vaccine campaign in the United States that was seen associated with a slight elevation in risk, and was halted when that risk became known. Since then, all sorts of vaccines in the European Union and United States have come with warnings about Guillain-Barré syndrome in their package inserts – a fact that some Guillain-Barré syndrome experts lament as perpetuating the notion that vaccines cause Guillain-Barré syndrome.
Epidemiologic studies in the United Kingdom and Singapore did not detect increases in Guillain-Barré syndrome incidence during the COVID-19 pandemic. And as mass vaccination against COVID-19 got underway early this year, experts cautioned against the temptation to attribute incident Guillain-Barré syndrome cases following vaccination to SARS-CoV-2 without careful statistical and epidemiological analysis. Until now reports of Guillain-Barré syndrome have been scant: clinical trials of a viral vector vaccine developed by Johnson & Johnson saw one in the placebo arm and another in the intervention arm, while another case was reported following administration of a Pfizer mRNA SARS-Cov-2 vaccine.
Recent case reports
None of the patients had evidence of current SARS-CoV-2 infection.
From India, Boby V. Maramattom, MD, of Aster Medcity in Kochi, India, and colleagues reported on seven severe cases of Guillain-Barré syndrome occurring between 10 and 14 days after a first dose of the AstraZeneca vaccine. All but one of the patients were women, all had bilateral facial paresis, all progressed to areflexic quadriplegia, and six required respiratory support. Patients’ ages ranged from 43 to 70. Four developed other cranial neuropathies, including abducens palsy and trigeminal sensory nerve involvement, which are rare in reports of Guillain-Barré syndrome from India, Dr. Maramattom and colleagues noted.
The authors argued that their findings “should prompt all physicians to be vigilant in recognizing Guillain-Barré syndrome in patients who have received the AstraZeneca vaccine. While the risk per patient (5.8 per million) may be relatively low, our observations suggest that this clinically distinct [Guillain-Barré syndrome] variant is more severe than usual and may require mechanical ventilation.”
The U.K. cases, reported by Christopher Martin Allen, MD, and colleagues at Nottingham (England) University Hospitals NHS Trust, describe bifacial weakness and normal facial sensation in four men between 11 and 22 days after their first doses of the Astra-Zeneca vaccine. This type of facial palsy, the authors wrote, was unusual Guillain-Barré syndrome variant that one rapid review found in 3 of 42 European patients diagnosed with Guillain-Barré syndrome following SARS-CoV-2 infection.
Dr. Allen and colleagues acknowledged that causality could not be assumed from the temporal relationship of immunization to onset of bifacial weakness in their report, but argued that their findings argued for “robust postvaccination surveillance” and that “the report of a similar syndrome in the setting of SARS-CoV-2 infection suggests an immunologic response to the spike protein.” If the link is casual, they wrote, “it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system.”
‘The jury is still out’
Asked for comment, neurologist Anthony Amato, MD, of Brigham and Women’s Hospital, Boston, said that he did not see what the two new studies add to what is already known. “Guillain-Barré syndrome has already been reported temporally following COVID-19 along with accompanying editorials that such temporal occurrences do not imply causation and there is a need for surveillance and epidemiological studies.”
Robert Lisak, MD, of Wayne State University, Detroit, and a longtime adviser to the GBS-CIDP Foundation International, commented that “the relationship between vaccines and association with Guillain-Barré syndrome continues to be controversial in part because Guillain-Barré syndrome, a rare disorder, has many reported associated illnesses including infections. Many vaccines have been implicated but with the probable exception of the ‘swine flu’ vaccine in the 1970s, most have not stood up to scrutiny.”
With SARS-Cov-2 infection and vaccines, “the jury is still out,” Dr. Lisak said. “The report from the U.K. is intriguing since they report several cases of an uncommon variant, but the cases from India seem to be more of the usual forms of Guillain-Barré syndrome.”
Dr. Lisak noted that, even if an association turns out to be valid, “we are talking about a very low incidence of Guillain-Barré syndrome associated with COVID-19 vaccines,” one that would not justify avoiding them because of a possible association with Guillain-Barré syndrome.
The GBS-CIDP Foundation, which supports research into Guillain-Barré syndrome and related diseases, has likewise stressed the low risk presented by SARS-CoV-2 vaccines, noting on its website that “the risk of death or long-term complications from COVID in adults still far exceeds the risk of any possible risk of Guillain-Barré syndrome by several orders of magnitude.”
None of the study authors reported financial conflicts of interest related to their research. Dr. Amato is an adviser to the pharmaceutical firms Alexion and Argenx, while Dr. Lisak has received research support or honoraria from Alexion, Novartis, Hoffmann–La Roche, and others.
Guillain-Barré syndrome, a rare peripheral nerve disorder that can occur after certain types of viral and bacterial infections, has not to date been definitively linked to infection by SARS-CoV-2 or with vaccination against the virus, despite surveillance searching for such associations.
Spikes in Guillain-Barré syndrome incidence have previously, but rarely, been associated with outbreaks of other viral diseases, including Zika, but not with vaccination, except for a 1976-1977 swine influenza vaccine campaign in the United States that was seen associated with a slight elevation in risk, and was halted when that risk became known. Since then, all sorts of vaccines in the European Union and United States have come with warnings about Guillain-Barré syndrome in their package inserts – a fact that some Guillain-Barré syndrome experts lament as perpetuating the notion that vaccines cause Guillain-Barré syndrome.
Epidemiologic studies in the United Kingdom and Singapore did not detect increases in Guillain-Barré syndrome incidence during the COVID-19 pandemic. And as mass vaccination against COVID-19 got underway early this year, experts cautioned against the temptation to attribute incident Guillain-Barré syndrome cases following vaccination to SARS-CoV-2 without careful statistical and epidemiological analysis. Until now reports of Guillain-Barré syndrome have been scant: clinical trials of a viral vector vaccine developed by Johnson & Johnson saw one in the placebo arm and another in the intervention arm, while another case was reported following administration of a Pfizer mRNA SARS-Cov-2 vaccine.
Recent case reports
None of the patients had evidence of current SARS-CoV-2 infection.
From India, Boby V. Maramattom, MD, of Aster Medcity in Kochi, India, and colleagues reported on seven severe cases of Guillain-Barré syndrome occurring between 10 and 14 days after a first dose of the AstraZeneca vaccine. All but one of the patients were women, all had bilateral facial paresis, all progressed to areflexic quadriplegia, and six required respiratory support. Patients’ ages ranged from 43 to 70. Four developed other cranial neuropathies, including abducens palsy and trigeminal sensory nerve involvement, which are rare in reports of Guillain-Barré syndrome from India, Dr. Maramattom and colleagues noted.
The authors argued that their findings “should prompt all physicians to be vigilant in recognizing Guillain-Barré syndrome in patients who have received the AstraZeneca vaccine. While the risk per patient (5.8 per million) may be relatively low, our observations suggest that this clinically distinct [Guillain-Barré syndrome] variant is more severe than usual and may require mechanical ventilation.”
The U.K. cases, reported by Christopher Martin Allen, MD, and colleagues at Nottingham (England) University Hospitals NHS Trust, describe bifacial weakness and normal facial sensation in four men between 11 and 22 days after their first doses of the Astra-Zeneca vaccine. This type of facial palsy, the authors wrote, was unusual Guillain-Barré syndrome variant that one rapid review found in 3 of 42 European patients diagnosed with Guillain-Barré syndrome following SARS-CoV-2 infection.
Dr. Allen and colleagues acknowledged that causality could not be assumed from the temporal relationship of immunization to onset of bifacial weakness in their report, but argued that their findings argued for “robust postvaccination surveillance” and that “the report of a similar syndrome in the setting of SARS-CoV-2 infection suggests an immunologic response to the spike protein.” If the link is casual, they wrote, “it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system.”
‘The jury is still out’
Asked for comment, neurologist Anthony Amato, MD, of Brigham and Women’s Hospital, Boston, said that he did not see what the two new studies add to what is already known. “Guillain-Barré syndrome has already been reported temporally following COVID-19 along with accompanying editorials that such temporal occurrences do not imply causation and there is a need for surveillance and epidemiological studies.”
Robert Lisak, MD, of Wayne State University, Detroit, and a longtime adviser to the GBS-CIDP Foundation International, commented that “the relationship between vaccines and association with Guillain-Barré syndrome continues to be controversial in part because Guillain-Barré syndrome, a rare disorder, has many reported associated illnesses including infections. Many vaccines have been implicated but with the probable exception of the ‘swine flu’ vaccine in the 1970s, most have not stood up to scrutiny.”
With SARS-Cov-2 infection and vaccines, “the jury is still out,” Dr. Lisak said. “The report from the U.K. is intriguing since they report several cases of an uncommon variant, but the cases from India seem to be more of the usual forms of Guillain-Barré syndrome.”
Dr. Lisak noted that, even if an association turns out to be valid, “we are talking about a very low incidence of Guillain-Barré syndrome associated with COVID-19 vaccines,” one that would not justify avoiding them because of a possible association with Guillain-Barré syndrome.
The GBS-CIDP Foundation, which supports research into Guillain-Barré syndrome and related diseases, has likewise stressed the low risk presented by SARS-CoV-2 vaccines, noting on its website that “the risk of death or long-term complications from COVID in adults still far exceeds the risk of any possible risk of Guillain-Barré syndrome by several orders of magnitude.”
None of the study authors reported financial conflicts of interest related to their research. Dr. Amato is an adviser to the pharmaceutical firms Alexion and Argenx, while Dr. Lisak has received research support or honoraria from Alexion, Novartis, Hoffmann–La Roche, and others.
FROM ANNALS OF NEUROLOGY
Real-world CAR T outcomes for DLBCL mimic clinical trials
Data from a large French registry on a multicenter experience with chimeric antigen receptor T-cell (CAR T) therapy for aggressive lymphoma suggests that the favorable outcomes seen in clinical trials can be replicated in the real world.
Among 481 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with either of two commercially available CAR T products – tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) – the duration of responses, progression-free survival (PFS), and overall survival (OS) rates at 6 months mirror those seen in clinical trials, reported Steven LeGouill, MD, PhD, from the University of Nantes (France), on behalf of colleagues in the DESCAR-T (Dispositive d’Evaluation et de Suivi des CAR-T) registry.
“CAR T has now become a standard of care in a lot of French centers, with more than 640 patients treated with CAR T in less than 2 years. The DESCAR-T real-life experience mimics the experience that had been previously by other real-life registries but also in clinical trials. We didn’t see new emerging toxicity signals in real life,” he said in an oral abstract session during the European Hematology Association annual congress (Abstract S216).
“I am convinced that a population registry about CAR T–treated patients is needed,” commented Pieter Sonneveld, MD, from Erasmus Medical Center in Rotterdam, the Netherlands, who was not involved in the study.
“Selection criteria for CAR T trials have been incredibly restrictive, and academic trials have not gained ground yet. It is important to collect and analyze more data, include non-trial patients and analyze long-term follow-up in order to determine the real effects of this innovative treatment in lymphoma and other diseases,” he said.
Dr. Sonneveld, EHA past president, was the moderator a briefing where Dr. LeGouill presented the DESCAR-T study findings.
Natalie Sophia Grover, MD, a leukemia and lymphoma specialist at the University of North Carolina at Chapel Hill, noted in an interview that “there have been several publications recently that have shown that these promising outcomes for these really refractory, high-risk patients with diffuse large B-cell lymphoma seem to be similar with what we’ve seen in trials, which is definitely exciting.”
She noted that the median time from CAR T order to treatment in the study, 50 days, was longer than in her experience.
“Generally, from collection to treatment is less than a month. Looking at that, I would have expected more patients not to make it CAR T, but nearly 90% of patients who had collections got treatment, which is pretty good. Those patients that didn’t make it to treatment had really poor outcomes,” she said.
Dr. Grover was not involved in the study.
More data, s’il vous plait
The DESCAR-T registry was created in response to a request from French health authorities for data beyond that provided in the EBMT patient registry. The health authorities asked for characterization of the CAR T–eligible population in an intention to treat, 15-year follow-up of both CAR T recipients and candidates who were not treated for whatever reasons, and a full accounting of previous lines of therapy.
Dr. LeGouill presented the first analysis of data from the registry involving 19 enrolling site and 647 patients with DLBCL for whom CAR T cells were ordered from January 2018 to March 2021.
Of the 647 candidates, 10 did not have CAR T ordered for reasons that included patient deaths or disease progression, infection, and patient refusal. An additional 30 patients either had leukapheresis performed or pending, and 607 had CAR T ordered.
Of the 607 patients, 53 did not receive CAR T infusions because of disease progression, death before product administration, manufacturing or leukapheresis failures, uncontrolled infections, patient choice, or progression of other malignancies.
That left 550 patients (85%) who received a CAR T product, either tisagenlecleucel (200 patients) or axicabtagene ciloleucel (350 patients).
Among all patients, the median age at CAR T order was 63 for patients who received tisagenlecleucel, and 65 for patients receiving axicabtagene ciloleucel. Patients 65 and older comprised 44% and 51% of the population, respectively.
Patients treated with each CAR T product had a median of three prior lines of therapy.
Manageable toxicities
Toxicities within 10 days of CAR T infusion included 418 cases among 515 patients (81.2%) of cytokine release syndrome, with most being grade 1 or 2 in severity; 44 patients had grade 3 or 4 CRS.
Any-grade neurotoxicity was seen in 184 patients (35.7%), primarily grade 1 or 2 in severity; 50 patients had grade 3 or greater neurotoxicity.
Of 427 patients with at least one CAR T–specific toxicity within 10 days, 139 (32.8%) required ICU admission, 325 (76,1%) were treated for CAR T–specific toxicities, 278 (65.1%) received tocilizumab, 13 (3%) received siltuximab, and 176 (41.2%) received corticosteroids.
Favorable outcomes
Overall response rates, at 1, 3, and 6 months post infusions were 70.6%, 56.3%, and 60%, respectively, with the majority of response at each time point being complete responses (CR).
The 6-month overall survival (OS) rate among all patients who were treated was 83.7%, compared with 5.5% for patients who did not receive CAR T infusions.
Progression-free survival (PFS) at 6 months was 44.5%, and 57.7% of patients had an ongoing response at the same time point.
Among patients who received bridging therapy between leukapheresis and CAR T infusion, the 6-month PFS was 58.4% for patients with either a CR, partial response, or stable disease, compared with 63.3% for patients who did not receive bridging therapy, and 29.8% for those with disease progression.
The respective 6 months OS rates were 87.4%, 82.3%, and 65.5%.
The results showed that patients who do not have at least stable disease at the time of CAR T infusion are at risk for early relapse, but approximately 30% of these patients still had long-term disease control, Dr. LeGouill said.
He acknowledged that longer follow-up will be need to see whether the plateaus in the PFS and OS curves the investigators observed can be maintained over time. Questions that still need to be answered include the impact of bridging therapy or disease status at the start of treatment on outcomes, and how to improve CAR T efficacy based on individual patient characteristics.
The registry will be extended to include data on patients treated with CAR T for mantle cell lymphoma and multiple myeloma, investigators announced.
The study is supported by participating centers and Gilead/Kite and Novartis. Dr. LeGouill disclosed advisory board activity and honoraria from the companies and others. Dr. Grover disclosed advisory board participating for Kite and others. Dr. Sonneveld has disclosed research grants and honoraria from several companies, not including Kite or Novartis.
Data from a large French registry on a multicenter experience with chimeric antigen receptor T-cell (CAR T) therapy for aggressive lymphoma suggests that the favorable outcomes seen in clinical trials can be replicated in the real world.
Among 481 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with either of two commercially available CAR T products – tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) – the duration of responses, progression-free survival (PFS), and overall survival (OS) rates at 6 months mirror those seen in clinical trials, reported Steven LeGouill, MD, PhD, from the University of Nantes (France), on behalf of colleagues in the DESCAR-T (Dispositive d’Evaluation et de Suivi des CAR-T) registry.
“CAR T has now become a standard of care in a lot of French centers, with more than 640 patients treated with CAR T in less than 2 years. The DESCAR-T real-life experience mimics the experience that had been previously by other real-life registries but also in clinical trials. We didn’t see new emerging toxicity signals in real life,” he said in an oral abstract session during the European Hematology Association annual congress (Abstract S216).
“I am convinced that a population registry about CAR T–treated patients is needed,” commented Pieter Sonneveld, MD, from Erasmus Medical Center in Rotterdam, the Netherlands, who was not involved in the study.
“Selection criteria for CAR T trials have been incredibly restrictive, and academic trials have not gained ground yet. It is important to collect and analyze more data, include non-trial patients and analyze long-term follow-up in order to determine the real effects of this innovative treatment in lymphoma and other diseases,” he said.
Dr. Sonneveld, EHA past president, was the moderator a briefing where Dr. LeGouill presented the DESCAR-T study findings.
Natalie Sophia Grover, MD, a leukemia and lymphoma specialist at the University of North Carolina at Chapel Hill, noted in an interview that “there have been several publications recently that have shown that these promising outcomes for these really refractory, high-risk patients with diffuse large B-cell lymphoma seem to be similar with what we’ve seen in trials, which is definitely exciting.”
She noted that the median time from CAR T order to treatment in the study, 50 days, was longer than in her experience.
“Generally, from collection to treatment is less than a month. Looking at that, I would have expected more patients not to make it CAR T, but nearly 90% of patients who had collections got treatment, which is pretty good. Those patients that didn’t make it to treatment had really poor outcomes,” she said.
Dr. Grover was not involved in the study.
More data, s’il vous plait
The DESCAR-T registry was created in response to a request from French health authorities for data beyond that provided in the EBMT patient registry. The health authorities asked for characterization of the CAR T–eligible population in an intention to treat, 15-year follow-up of both CAR T recipients and candidates who were not treated for whatever reasons, and a full accounting of previous lines of therapy.
Dr. LeGouill presented the first analysis of data from the registry involving 19 enrolling site and 647 patients with DLBCL for whom CAR T cells were ordered from January 2018 to March 2021.
Of the 647 candidates, 10 did not have CAR T ordered for reasons that included patient deaths or disease progression, infection, and patient refusal. An additional 30 patients either had leukapheresis performed or pending, and 607 had CAR T ordered.
Of the 607 patients, 53 did not receive CAR T infusions because of disease progression, death before product administration, manufacturing or leukapheresis failures, uncontrolled infections, patient choice, or progression of other malignancies.
That left 550 patients (85%) who received a CAR T product, either tisagenlecleucel (200 patients) or axicabtagene ciloleucel (350 patients).
Among all patients, the median age at CAR T order was 63 for patients who received tisagenlecleucel, and 65 for patients receiving axicabtagene ciloleucel. Patients 65 and older comprised 44% and 51% of the population, respectively.
Patients treated with each CAR T product had a median of three prior lines of therapy.
Manageable toxicities
Toxicities within 10 days of CAR T infusion included 418 cases among 515 patients (81.2%) of cytokine release syndrome, with most being grade 1 or 2 in severity; 44 patients had grade 3 or 4 CRS.
Any-grade neurotoxicity was seen in 184 patients (35.7%), primarily grade 1 or 2 in severity; 50 patients had grade 3 or greater neurotoxicity.
Of 427 patients with at least one CAR T–specific toxicity within 10 days, 139 (32.8%) required ICU admission, 325 (76,1%) were treated for CAR T–specific toxicities, 278 (65.1%) received tocilizumab, 13 (3%) received siltuximab, and 176 (41.2%) received corticosteroids.
Favorable outcomes
Overall response rates, at 1, 3, and 6 months post infusions were 70.6%, 56.3%, and 60%, respectively, with the majority of response at each time point being complete responses (CR).
The 6-month overall survival (OS) rate among all patients who were treated was 83.7%, compared with 5.5% for patients who did not receive CAR T infusions.
Progression-free survival (PFS) at 6 months was 44.5%, and 57.7% of patients had an ongoing response at the same time point.
Among patients who received bridging therapy between leukapheresis and CAR T infusion, the 6-month PFS was 58.4% for patients with either a CR, partial response, or stable disease, compared with 63.3% for patients who did not receive bridging therapy, and 29.8% for those with disease progression.
The respective 6 months OS rates were 87.4%, 82.3%, and 65.5%.
The results showed that patients who do not have at least stable disease at the time of CAR T infusion are at risk for early relapse, but approximately 30% of these patients still had long-term disease control, Dr. LeGouill said.
He acknowledged that longer follow-up will be need to see whether the plateaus in the PFS and OS curves the investigators observed can be maintained over time. Questions that still need to be answered include the impact of bridging therapy or disease status at the start of treatment on outcomes, and how to improve CAR T efficacy based on individual patient characteristics.
The registry will be extended to include data on patients treated with CAR T for mantle cell lymphoma and multiple myeloma, investigators announced.
The study is supported by participating centers and Gilead/Kite and Novartis. Dr. LeGouill disclosed advisory board activity and honoraria from the companies and others. Dr. Grover disclosed advisory board participating for Kite and others. Dr. Sonneveld has disclosed research grants and honoraria from several companies, not including Kite or Novartis.
Data from a large French registry on a multicenter experience with chimeric antigen receptor T-cell (CAR T) therapy for aggressive lymphoma suggests that the favorable outcomes seen in clinical trials can be replicated in the real world.
Among 481 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with either of two commercially available CAR T products – tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) – the duration of responses, progression-free survival (PFS), and overall survival (OS) rates at 6 months mirror those seen in clinical trials, reported Steven LeGouill, MD, PhD, from the University of Nantes (France), on behalf of colleagues in the DESCAR-T (Dispositive d’Evaluation et de Suivi des CAR-T) registry.
“CAR T has now become a standard of care in a lot of French centers, with more than 640 patients treated with CAR T in less than 2 years. The DESCAR-T real-life experience mimics the experience that had been previously by other real-life registries but also in clinical trials. We didn’t see new emerging toxicity signals in real life,” he said in an oral abstract session during the European Hematology Association annual congress (Abstract S216).
“I am convinced that a population registry about CAR T–treated patients is needed,” commented Pieter Sonneveld, MD, from Erasmus Medical Center in Rotterdam, the Netherlands, who was not involved in the study.
“Selection criteria for CAR T trials have been incredibly restrictive, and academic trials have not gained ground yet. It is important to collect and analyze more data, include non-trial patients and analyze long-term follow-up in order to determine the real effects of this innovative treatment in lymphoma and other diseases,” he said.
Dr. Sonneveld, EHA past president, was the moderator a briefing where Dr. LeGouill presented the DESCAR-T study findings.
Natalie Sophia Grover, MD, a leukemia and lymphoma specialist at the University of North Carolina at Chapel Hill, noted in an interview that “there have been several publications recently that have shown that these promising outcomes for these really refractory, high-risk patients with diffuse large B-cell lymphoma seem to be similar with what we’ve seen in trials, which is definitely exciting.”
She noted that the median time from CAR T order to treatment in the study, 50 days, was longer than in her experience.
“Generally, from collection to treatment is less than a month. Looking at that, I would have expected more patients not to make it CAR T, but nearly 90% of patients who had collections got treatment, which is pretty good. Those patients that didn’t make it to treatment had really poor outcomes,” she said.
Dr. Grover was not involved in the study.
More data, s’il vous plait
The DESCAR-T registry was created in response to a request from French health authorities for data beyond that provided in the EBMT patient registry. The health authorities asked for characterization of the CAR T–eligible population in an intention to treat, 15-year follow-up of both CAR T recipients and candidates who were not treated for whatever reasons, and a full accounting of previous lines of therapy.
Dr. LeGouill presented the first analysis of data from the registry involving 19 enrolling site and 647 patients with DLBCL for whom CAR T cells were ordered from January 2018 to March 2021.
Of the 647 candidates, 10 did not have CAR T ordered for reasons that included patient deaths or disease progression, infection, and patient refusal. An additional 30 patients either had leukapheresis performed or pending, and 607 had CAR T ordered.
Of the 607 patients, 53 did not receive CAR T infusions because of disease progression, death before product administration, manufacturing or leukapheresis failures, uncontrolled infections, patient choice, or progression of other malignancies.
That left 550 patients (85%) who received a CAR T product, either tisagenlecleucel (200 patients) or axicabtagene ciloleucel (350 patients).
Among all patients, the median age at CAR T order was 63 for patients who received tisagenlecleucel, and 65 for patients receiving axicabtagene ciloleucel. Patients 65 and older comprised 44% and 51% of the population, respectively.
Patients treated with each CAR T product had a median of three prior lines of therapy.
Manageable toxicities
Toxicities within 10 days of CAR T infusion included 418 cases among 515 patients (81.2%) of cytokine release syndrome, with most being grade 1 or 2 in severity; 44 patients had grade 3 or 4 CRS.
Any-grade neurotoxicity was seen in 184 patients (35.7%), primarily grade 1 or 2 in severity; 50 patients had grade 3 or greater neurotoxicity.
Of 427 patients with at least one CAR T–specific toxicity within 10 days, 139 (32.8%) required ICU admission, 325 (76,1%) were treated for CAR T–specific toxicities, 278 (65.1%) received tocilizumab, 13 (3%) received siltuximab, and 176 (41.2%) received corticosteroids.
Favorable outcomes
Overall response rates, at 1, 3, and 6 months post infusions were 70.6%, 56.3%, and 60%, respectively, with the majority of response at each time point being complete responses (CR).
The 6-month overall survival (OS) rate among all patients who were treated was 83.7%, compared with 5.5% for patients who did not receive CAR T infusions.
Progression-free survival (PFS) at 6 months was 44.5%, and 57.7% of patients had an ongoing response at the same time point.
Among patients who received bridging therapy between leukapheresis and CAR T infusion, the 6-month PFS was 58.4% for patients with either a CR, partial response, or stable disease, compared with 63.3% for patients who did not receive bridging therapy, and 29.8% for those with disease progression.
The respective 6 months OS rates were 87.4%, 82.3%, and 65.5%.
The results showed that patients who do not have at least stable disease at the time of CAR T infusion are at risk for early relapse, but approximately 30% of these patients still had long-term disease control, Dr. LeGouill said.
He acknowledged that longer follow-up will be need to see whether the plateaus in the PFS and OS curves the investigators observed can be maintained over time. Questions that still need to be answered include the impact of bridging therapy or disease status at the start of treatment on outcomes, and how to improve CAR T efficacy based on individual patient characteristics.
The registry will be extended to include data on patients treated with CAR T for mantle cell lymphoma and multiple myeloma, investigators announced.
The study is supported by participating centers and Gilead/Kite and Novartis. Dr. LeGouill disclosed advisory board activity and honoraria from the companies and others. Dr. Grover disclosed advisory board participating for Kite and others. Dr. Sonneveld has disclosed research grants and honoraria from several companies, not including Kite or Novartis.
FROM EHA 2021
Potential first-in-class, targeted therapy for myasthenia gravis
(gMG), new research suggests. Results from the phase 3, randomized, placebo-controlled ADAPT trial showed that reduction in disease burden and improvement in strength and quality of life in patients with gMG were consistent across four MG-specific scales for those receiving the novel treatment. In addition, these benefits were observed early and were reproducible and durable, the researchers noted.
Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work, and the side effect profile is much like placebo,” said principal investigator James Howard, Jr., MD, Distinguished Professor of Neuromuscular Disease, department of neurology, University of North Carolina at Chapel Hill.
The ADAPT results are “important for the MG community, and I am hopeful efgartigimod will provide a first-in-class targeted therapy that can be dosed in an individual way for people living with this chronic autoimmune disease,” Dr. Howard added in a news release.
The findings were published online June 17 in Lancet Neurology.
Targeted molecular therapy
The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have immunoglobulin G (IgG) antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.
Efgartigimod is an investigational antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.
The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.
The ADAPT trial was conducted at 56 neuromuscular academic and community centers in 15 countries in North America, Europe, and Japan. The study included 167 adults with gMG, regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (greater than 50% non-ocular) on a background of a stable dose of at least one MG drug.
For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.
ADAPT was designed to allow an individualized treatment approach with an initial treatment cycle followed by a variable number of subsequent treatment cycles, the investigators noted.
Primary endpoint met
The primary efficacy endpoint was number of acetylcholine receptor antibody-positive (AChR-Ab+) patients who achieved a clinically meaningful response on the MG-ADL score. This was defined as at least a 2-point improvement from baseline for 4 or more consecutive weeks. Forty-four (68%) of 65 AChR-Ab+ patients treated with efgartigimod met this endpoint versus 19 (30%) of 64 patients treated with placebo (odds ratio, 4.95; 95% confidence interval, 2.21-11.53; P < .0001).
Many of the patients treated with efgartigimod showed improvement “beyond the clinically meaningful threshold, achieving up to 9-point reductions in MG-ADL,” the investigators reported. In addition, 40% of the efgartigimod group attained an MG-ADL score of 0 or 1 (minimal symptom expression) in cycle 1 versus 11% of the placebo group (P < .0001).
Nearly two-thirds (63%) of AChR-Ab+ patients responded to the first cycle of efgartigimod, and most of these patients (83%) responded to treatment within the first 2 weeks. Among the AChR-Ab+ participants who responded to efgartigimod in cycle 1, the duration of responder status was 6 to 7 weeks in 32% of patients, 8 to 11 weeks in 23% of patients, and 12 weeks or more in 34% of patients.
Safety profile
“Some patients never required retreatment over the 26-week period that they were under observation,” Dr. Howard said. “Patients want to be individuals. They don’t want to be assigned to a regimented therapy, and I think these results show that this therapy can be tailored to the individual patient, rather than simply giving it to them in a cookbook fashion,” he added.
The safety profile of efgartigimod was comparable to placebo. Most adverse events were mild or moderate in severity. The most commonly reported adverse events were headache, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, and urinary tract infection.
Four (5%) efgartigimod-treated patients had a serious adverse event, which included thrombocytosis, rectal adenocarcinoma, worsening MG, and depression.
The novel agent is currently under review with the U.S. Food and Drug Administration for the treatment of gMG, with a Prescription Drug User Fee Act target action date of Dec. 17. If approved, it would become the first FDA-approved FcRn antagonist.
Expanding therapeutic landscape
In a linked commentary, Shigeaki Suzuki, MD, PhD, department of neurology, Keio University School of Medicine, Tokyo, noted that the therapeutic landscape for patients with MG is “expanding year by year,” with several additional complement inhibitors and FcRn antagonists now in phase 3 testing.
“Biological drugs should be preferentially used as the treatment for patients with refractory myasthenia gravis, although the definition of refractory myasthenia gravis is different depending on the criteria used,” Dr. Suzuki wrote.
He noted that when “cost-effectiveness is not taken into account, targeted molecular therapy might be used widely” in patients with MG.
“Risks of myasthenic exacerbation and crises should be substantially decreased, particularly in patients with refractory myasthenia gravis,” Dr. Suzuki added.
The ADAPT study was supported by argenx. Dr. Howard has reported receiving research support from argenx, Alexion Pharmaceuticals, the Centers for Disease Control and Prevention, the Muscular Dystrophy Association, the National Institutes of Health, Patient-Centered Outcomes Research Institute, and Ra Pharmaceuticals; honoraria from argenx, Alexion, Immunovant, Ra, Regeneron Pharmaceuticals, and Viela Bio; and nonfinancial support from argenx, Alexion, Ra, and Toleranzia. Disclosures for the other investigators are listed in the original article. Dr. Suzuki has reported relationships with Alexion Pharmaceuticals, Japan Blood Products Organization, and Asahi Kasei Medical.
A version of this article first appeared on Medscape.com.
(gMG), new research suggests. Results from the phase 3, randomized, placebo-controlled ADAPT trial showed that reduction in disease burden and improvement in strength and quality of life in patients with gMG were consistent across four MG-specific scales for those receiving the novel treatment. In addition, these benefits were observed early and were reproducible and durable, the researchers noted.
Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work, and the side effect profile is much like placebo,” said principal investigator James Howard, Jr., MD, Distinguished Professor of Neuromuscular Disease, department of neurology, University of North Carolina at Chapel Hill.
The ADAPT results are “important for the MG community, and I am hopeful efgartigimod will provide a first-in-class targeted therapy that can be dosed in an individual way for people living with this chronic autoimmune disease,” Dr. Howard added in a news release.
The findings were published online June 17 in Lancet Neurology.
Targeted molecular therapy
The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have immunoglobulin G (IgG) antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.
Efgartigimod is an investigational antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.
The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.
The ADAPT trial was conducted at 56 neuromuscular academic and community centers in 15 countries in North America, Europe, and Japan. The study included 167 adults with gMG, regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (greater than 50% non-ocular) on a background of a stable dose of at least one MG drug.
For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.
ADAPT was designed to allow an individualized treatment approach with an initial treatment cycle followed by a variable number of subsequent treatment cycles, the investigators noted.
Primary endpoint met
The primary efficacy endpoint was number of acetylcholine receptor antibody-positive (AChR-Ab+) patients who achieved a clinically meaningful response on the MG-ADL score. This was defined as at least a 2-point improvement from baseline for 4 or more consecutive weeks. Forty-four (68%) of 65 AChR-Ab+ patients treated with efgartigimod met this endpoint versus 19 (30%) of 64 patients treated with placebo (odds ratio, 4.95; 95% confidence interval, 2.21-11.53; P < .0001).
Many of the patients treated with efgartigimod showed improvement “beyond the clinically meaningful threshold, achieving up to 9-point reductions in MG-ADL,” the investigators reported. In addition, 40% of the efgartigimod group attained an MG-ADL score of 0 or 1 (minimal symptom expression) in cycle 1 versus 11% of the placebo group (P < .0001).
Nearly two-thirds (63%) of AChR-Ab+ patients responded to the first cycle of efgartigimod, and most of these patients (83%) responded to treatment within the first 2 weeks. Among the AChR-Ab+ participants who responded to efgartigimod in cycle 1, the duration of responder status was 6 to 7 weeks in 32% of patients, 8 to 11 weeks in 23% of patients, and 12 weeks or more in 34% of patients.
Safety profile
“Some patients never required retreatment over the 26-week period that they were under observation,” Dr. Howard said. “Patients want to be individuals. They don’t want to be assigned to a regimented therapy, and I think these results show that this therapy can be tailored to the individual patient, rather than simply giving it to them in a cookbook fashion,” he added.
The safety profile of efgartigimod was comparable to placebo. Most adverse events were mild or moderate in severity. The most commonly reported adverse events were headache, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, and urinary tract infection.
Four (5%) efgartigimod-treated patients had a serious adverse event, which included thrombocytosis, rectal adenocarcinoma, worsening MG, and depression.
The novel agent is currently under review with the U.S. Food and Drug Administration for the treatment of gMG, with a Prescription Drug User Fee Act target action date of Dec. 17. If approved, it would become the first FDA-approved FcRn antagonist.
Expanding therapeutic landscape
In a linked commentary, Shigeaki Suzuki, MD, PhD, department of neurology, Keio University School of Medicine, Tokyo, noted that the therapeutic landscape for patients with MG is “expanding year by year,” with several additional complement inhibitors and FcRn antagonists now in phase 3 testing.
“Biological drugs should be preferentially used as the treatment for patients with refractory myasthenia gravis, although the definition of refractory myasthenia gravis is different depending on the criteria used,” Dr. Suzuki wrote.
He noted that when “cost-effectiveness is not taken into account, targeted molecular therapy might be used widely” in patients with MG.
“Risks of myasthenic exacerbation and crises should be substantially decreased, particularly in patients with refractory myasthenia gravis,” Dr. Suzuki added.
The ADAPT study was supported by argenx. Dr. Howard has reported receiving research support from argenx, Alexion Pharmaceuticals, the Centers for Disease Control and Prevention, the Muscular Dystrophy Association, the National Institutes of Health, Patient-Centered Outcomes Research Institute, and Ra Pharmaceuticals; honoraria from argenx, Alexion, Immunovant, Ra, Regeneron Pharmaceuticals, and Viela Bio; and nonfinancial support from argenx, Alexion, Ra, and Toleranzia. Disclosures for the other investigators are listed in the original article. Dr. Suzuki has reported relationships with Alexion Pharmaceuticals, Japan Blood Products Organization, and Asahi Kasei Medical.
A version of this article first appeared on Medscape.com.
(gMG), new research suggests. Results from the phase 3, randomized, placebo-controlled ADAPT trial showed that reduction in disease burden and improvement in strength and quality of life in patients with gMG were consistent across four MG-specific scales for those receiving the novel treatment. In addition, these benefits were observed early and were reproducible and durable, the researchers noted.
Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work, and the side effect profile is much like placebo,” said principal investigator James Howard, Jr., MD, Distinguished Professor of Neuromuscular Disease, department of neurology, University of North Carolina at Chapel Hill.
The ADAPT results are “important for the MG community, and I am hopeful efgartigimod will provide a first-in-class targeted therapy that can be dosed in an individual way for people living with this chronic autoimmune disease,” Dr. Howard added in a news release.
The findings were published online June 17 in Lancet Neurology.
Targeted molecular therapy
The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have immunoglobulin G (IgG) antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.
Efgartigimod is an investigational antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.
The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.
The ADAPT trial was conducted at 56 neuromuscular academic and community centers in 15 countries in North America, Europe, and Japan. The study included 167 adults with gMG, regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (greater than 50% non-ocular) on a background of a stable dose of at least one MG drug.
For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.
ADAPT was designed to allow an individualized treatment approach with an initial treatment cycle followed by a variable number of subsequent treatment cycles, the investigators noted.
Primary endpoint met
The primary efficacy endpoint was number of acetylcholine receptor antibody-positive (AChR-Ab+) patients who achieved a clinically meaningful response on the MG-ADL score. This was defined as at least a 2-point improvement from baseline for 4 or more consecutive weeks. Forty-four (68%) of 65 AChR-Ab+ patients treated with efgartigimod met this endpoint versus 19 (30%) of 64 patients treated with placebo (odds ratio, 4.95; 95% confidence interval, 2.21-11.53; P < .0001).
Many of the patients treated with efgartigimod showed improvement “beyond the clinically meaningful threshold, achieving up to 9-point reductions in MG-ADL,” the investigators reported. In addition, 40% of the efgartigimod group attained an MG-ADL score of 0 or 1 (minimal symptom expression) in cycle 1 versus 11% of the placebo group (P < .0001).
Nearly two-thirds (63%) of AChR-Ab+ patients responded to the first cycle of efgartigimod, and most of these patients (83%) responded to treatment within the first 2 weeks. Among the AChR-Ab+ participants who responded to efgartigimod in cycle 1, the duration of responder status was 6 to 7 weeks in 32% of patients, 8 to 11 weeks in 23% of patients, and 12 weeks or more in 34% of patients.
Safety profile
“Some patients never required retreatment over the 26-week period that they were under observation,” Dr. Howard said. “Patients want to be individuals. They don’t want to be assigned to a regimented therapy, and I think these results show that this therapy can be tailored to the individual patient, rather than simply giving it to them in a cookbook fashion,” he added.
The safety profile of efgartigimod was comparable to placebo. Most adverse events were mild or moderate in severity. The most commonly reported adverse events were headache, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, and urinary tract infection.
Four (5%) efgartigimod-treated patients had a serious adverse event, which included thrombocytosis, rectal adenocarcinoma, worsening MG, and depression.
The novel agent is currently under review with the U.S. Food and Drug Administration for the treatment of gMG, with a Prescription Drug User Fee Act target action date of Dec. 17. If approved, it would become the first FDA-approved FcRn antagonist.
Expanding therapeutic landscape
In a linked commentary, Shigeaki Suzuki, MD, PhD, department of neurology, Keio University School of Medicine, Tokyo, noted that the therapeutic landscape for patients with MG is “expanding year by year,” with several additional complement inhibitors and FcRn antagonists now in phase 3 testing.
“Biological drugs should be preferentially used as the treatment for patients with refractory myasthenia gravis, although the definition of refractory myasthenia gravis is different depending on the criteria used,” Dr. Suzuki wrote.
He noted that when “cost-effectiveness is not taken into account, targeted molecular therapy might be used widely” in patients with MG.
“Risks of myasthenic exacerbation and crises should be substantially decreased, particularly in patients with refractory myasthenia gravis,” Dr. Suzuki added.
The ADAPT study was supported by argenx. Dr. Howard has reported receiving research support from argenx, Alexion Pharmaceuticals, the Centers for Disease Control and Prevention, the Muscular Dystrophy Association, the National Institutes of Health, Patient-Centered Outcomes Research Institute, and Ra Pharmaceuticals; honoraria from argenx, Alexion, Immunovant, Ra, Regeneron Pharmaceuticals, and Viela Bio; and nonfinancial support from argenx, Alexion, Ra, and Toleranzia. Disclosures for the other investigators are listed in the original article. Dr. Suzuki has reported relationships with Alexion Pharmaceuticals, Japan Blood Products Organization, and Asahi Kasei Medical.
A version of this article first appeared on Medscape.com.
From Lancet Neurology
Experimental antibody-drug conjugate shown active against r/r DLBCL
Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.
Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.
“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).
Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.
CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.
In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.
“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.
He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
DLBCL and others
The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.
Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.
The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.
All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.
The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
DLBCL efficacy
A total of 76 patients with DLBCL were evaluable for efficacy.
The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.
Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.
Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.
In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.
The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.
There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.
Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
Q 3 weeks suffices
In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.
“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.
Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.
“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.
The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.
Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.
Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.
“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).
Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.
CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.
In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.
“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.
He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
DLBCL and others
The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.
Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.
The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.
All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.
The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
DLBCL efficacy
A total of 76 patients with DLBCL were evaluable for efficacy.
The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.
Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.
Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.
In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.
The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.
There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.
Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
Q 3 weeks suffices
In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.
“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.
Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.
“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.
The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.
Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.
Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.
“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).
Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.
CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.
In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.
“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.
He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
DLBCL and others
The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.
Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.
The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.
All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.
The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
DLBCL efficacy
A total of 76 patients with DLBCL were evaluable for efficacy.
The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.
Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.
Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.
In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.
The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.
There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.
Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
Q 3 weeks suffices
In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.
“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.
Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.
“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.
The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.
FROM EHA 2021
Many comatose TBI patients recover consciousness during rehab
according to a study of 3 decades of TBI survivors.
“Caution is warranted in consideration of withdrawing or withholding life-sustaining therapies in patients with severe TBI and DoC,” wrote Robert G. Kowalski, MBBCh, MS, of the department of neurology at the University of Colorado at Denver, Aurora, and colleagues. The study was published in JAMA Neurology.
To determine the likelihood of returning to consciousness in the weeks that follow a serious brain injury, along with any notable contributing factors, the researchers launched a retrospective analysis of 17,470 patients with moderate to severe TBI. All participants had been enrolled in the Traumatic Brain Injury Model Systems database from January 1989 to June 2019 after being admitted to any 1 of 23 inpatient rehabilitation centers. The cohort had a median age of 39 (interquartile range, 25-56), with 74% being male and 66% being white. Their median duration of acute hospital care was 16 days (IQR, 9-26).
Unconsciousness was defined by the researchers as not being able to follow commands or having a Glasgow Coma Scale motor score in the ED of lower than 6 or a Disability Rating Scale motor score greater than 0. Of the overall cohort, 7,547 (57%) patients initially lost consciousness and 2,058 (12%) remained unconscious as they were admitted to rehab. Of that subgroup, 1,674 (82%) recovered consciousness during rehab. The 414 patients who still had a DoC at completion of rehab had a longer median stay (37 days; IQR, 22-65), compared with the patients who recovered consciousness (19 days; IQR, 12-30; P < .001). After multivariable analysis, the factors most associated with recovery of consciousness were the absence of intraventricular hemorrhage (adjusted odds ratio, 0.678; 95% confidence interval, 0.532-0.863; P = .002) and the absence of intracranial mass effect (aOR, 0.759; 95% CI, 0.595-0.968; P = .03).
Though all patients experienced an improvement in functional status during rehabilitation, patients with DoC had an increase in median Functional Independence Measure total score from 19 to 71 while patients without DoC increased from 54 to 96 (change in total score, +43 versus +37; P = .002). After multivariate analysis, younger age and male sex were both associated with better functional outcomes during rehab and at discharge.
When it comes to TBI patients, don’t give up hope
The choice to withdraw care in TBI patients is a complicated and daunting one, and this study is further evidence that physicians should delay that decision in many scenarios, wrote Jennifer A. Kim, MD, PhD, and Kevin N. Sheth, MD, of Yale University, New Haven, Conn., in an accompanying editorial.
“By showing that a large proportion of patients with persistent DoC recover during acute rehabilitation, this article further challenges our potential toward overly nihilistic notions of who may or may not ultimately recover consciousness long term,” they added.
That said, they also recognized the questions that still persist: What are the reasons for late-stage withdrawal of lifesaving therapy? What is the recovery rate of all hospitalized patients with TBI, not just those in rehabilitation facilities? And is it possible to detect covert consciousness using MRI and electroencephalography, which this study did not include?
“Defining both good and poor prognostic risk factors is critical to portending recovery,” they wrote, emphasizing the need for physicians to rely on scientifically based predictions when making such important assessments.
Patience is a virtue for TBI specialists
“A lot of people write notes on hospital charts, ‘poor prognosis.’ You don’t know, that early in the game, in the acute care setting, how TBI patients are going to do,” said Jamie S. Ullman, MD, of the department of neurosurgery at Hofstra University, Hempstead, N.Y., in an interview. “It’s over the long term that we really have to judge that.”
“Of course, there may be some characteristics that patients might have that may portend for a worse outcome, like brain stem damage,” she added. “But in general, there is plenty of literature to suggest that not only can even the worst-looking patients have some kind of functional outcome but that it takes 18 months or more to actually realize an outcome from a traumatic brain injury.”
She emphasized that each patient with TBI is unique; beyond their current status, you have to consider the significance of their injury, the thoughts of their families or partner, and their own previously stated wishes and willingness to tolerate disability. Nonetheless, this study is another step toward distilling the “nihilistic thinking” that can lead physicians to expect the worst regarding patients who may still have a path toward a functional life.
“As traumatic brain injury specialists,” she said, “we need to see what we can do to give patients as good a chance as possible at a recovery.”
The authors acknowledged their study’s limitations, including an inability to account for 3 decades of variations in treatment regimens and its limited generalizability because of the cohort being composed of only TBI survivors admitted to inpatient rehab. In addition, they noted a possible referential bias for the study’s mostly young TBI patients in rehab facilities, another reason why these findings “may not be directly applicable to the overall population of patients with moderate or severe TBI.”
The study was funded by grants from the National Institute on Disability, Independent Living, and Rehabilitation Research; the Department of Health & Human Services; and the Veterans Health Administration Central Office VA TBI Model Systems Program of Research. The authors reported several potential conflicts of interest, including receiving grants and support from various government agencies and pharmaceutical companies.
according to a study of 3 decades of TBI survivors.
“Caution is warranted in consideration of withdrawing or withholding life-sustaining therapies in patients with severe TBI and DoC,” wrote Robert G. Kowalski, MBBCh, MS, of the department of neurology at the University of Colorado at Denver, Aurora, and colleagues. The study was published in JAMA Neurology.
To determine the likelihood of returning to consciousness in the weeks that follow a serious brain injury, along with any notable contributing factors, the researchers launched a retrospective analysis of 17,470 patients with moderate to severe TBI. All participants had been enrolled in the Traumatic Brain Injury Model Systems database from January 1989 to June 2019 after being admitted to any 1 of 23 inpatient rehabilitation centers. The cohort had a median age of 39 (interquartile range, 25-56), with 74% being male and 66% being white. Their median duration of acute hospital care was 16 days (IQR, 9-26).
Unconsciousness was defined by the researchers as not being able to follow commands or having a Glasgow Coma Scale motor score in the ED of lower than 6 or a Disability Rating Scale motor score greater than 0. Of the overall cohort, 7,547 (57%) patients initially lost consciousness and 2,058 (12%) remained unconscious as they were admitted to rehab. Of that subgroup, 1,674 (82%) recovered consciousness during rehab. The 414 patients who still had a DoC at completion of rehab had a longer median stay (37 days; IQR, 22-65), compared with the patients who recovered consciousness (19 days; IQR, 12-30; P < .001). After multivariable analysis, the factors most associated with recovery of consciousness were the absence of intraventricular hemorrhage (adjusted odds ratio, 0.678; 95% confidence interval, 0.532-0.863; P = .002) and the absence of intracranial mass effect (aOR, 0.759; 95% CI, 0.595-0.968; P = .03).
Though all patients experienced an improvement in functional status during rehabilitation, patients with DoC had an increase in median Functional Independence Measure total score from 19 to 71 while patients without DoC increased from 54 to 96 (change in total score, +43 versus +37; P = .002). After multivariate analysis, younger age and male sex were both associated with better functional outcomes during rehab and at discharge.
When it comes to TBI patients, don’t give up hope
The choice to withdraw care in TBI patients is a complicated and daunting one, and this study is further evidence that physicians should delay that decision in many scenarios, wrote Jennifer A. Kim, MD, PhD, and Kevin N. Sheth, MD, of Yale University, New Haven, Conn., in an accompanying editorial.
“By showing that a large proportion of patients with persistent DoC recover during acute rehabilitation, this article further challenges our potential toward overly nihilistic notions of who may or may not ultimately recover consciousness long term,” they added.
That said, they also recognized the questions that still persist: What are the reasons for late-stage withdrawal of lifesaving therapy? What is the recovery rate of all hospitalized patients with TBI, not just those in rehabilitation facilities? And is it possible to detect covert consciousness using MRI and electroencephalography, which this study did not include?
“Defining both good and poor prognostic risk factors is critical to portending recovery,” they wrote, emphasizing the need for physicians to rely on scientifically based predictions when making such important assessments.
Patience is a virtue for TBI specialists
“A lot of people write notes on hospital charts, ‘poor prognosis.’ You don’t know, that early in the game, in the acute care setting, how TBI patients are going to do,” said Jamie S. Ullman, MD, of the department of neurosurgery at Hofstra University, Hempstead, N.Y., in an interview. “It’s over the long term that we really have to judge that.”
“Of course, there may be some characteristics that patients might have that may portend for a worse outcome, like brain stem damage,” she added. “But in general, there is plenty of literature to suggest that not only can even the worst-looking patients have some kind of functional outcome but that it takes 18 months or more to actually realize an outcome from a traumatic brain injury.”
She emphasized that each patient with TBI is unique; beyond their current status, you have to consider the significance of their injury, the thoughts of their families or partner, and their own previously stated wishes and willingness to tolerate disability. Nonetheless, this study is another step toward distilling the “nihilistic thinking” that can lead physicians to expect the worst regarding patients who may still have a path toward a functional life.
“As traumatic brain injury specialists,” she said, “we need to see what we can do to give patients as good a chance as possible at a recovery.”
The authors acknowledged their study’s limitations, including an inability to account for 3 decades of variations in treatment regimens and its limited generalizability because of the cohort being composed of only TBI survivors admitted to inpatient rehab. In addition, they noted a possible referential bias for the study’s mostly young TBI patients in rehab facilities, another reason why these findings “may not be directly applicable to the overall population of patients with moderate or severe TBI.”
The study was funded by grants from the National Institute on Disability, Independent Living, and Rehabilitation Research; the Department of Health & Human Services; and the Veterans Health Administration Central Office VA TBI Model Systems Program of Research. The authors reported several potential conflicts of interest, including receiving grants and support from various government agencies and pharmaceutical companies.
according to a study of 3 decades of TBI survivors.
“Caution is warranted in consideration of withdrawing or withholding life-sustaining therapies in patients with severe TBI and DoC,” wrote Robert G. Kowalski, MBBCh, MS, of the department of neurology at the University of Colorado at Denver, Aurora, and colleagues. The study was published in JAMA Neurology.
To determine the likelihood of returning to consciousness in the weeks that follow a serious brain injury, along with any notable contributing factors, the researchers launched a retrospective analysis of 17,470 patients with moderate to severe TBI. All participants had been enrolled in the Traumatic Brain Injury Model Systems database from January 1989 to June 2019 after being admitted to any 1 of 23 inpatient rehabilitation centers. The cohort had a median age of 39 (interquartile range, 25-56), with 74% being male and 66% being white. Their median duration of acute hospital care was 16 days (IQR, 9-26).
Unconsciousness was defined by the researchers as not being able to follow commands or having a Glasgow Coma Scale motor score in the ED of lower than 6 or a Disability Rating Scale motor score greater than 0. Of the overall cohort, 7,547 (57%) patients initially lost consciousness and 2,058 (12%) remained unconscious as they were admitted to rehab. Of that subgroup, 1,674 (82%) recovered consciousness during rehab. The 414 patients who still had a DoC at completion of rehab had a longer median stay (37 days; IQR, 22-65), compared with the patients who recovered consciousness (19 days; IQR, 12-30; P < .001). After multivariable analysis, the factors most associated with recovery of consciousness were the absence of intraventricular hemorrhage (adjusted odds ratio, 0.678; 95% confidence interval, 0.532-0.863; P = .002) and the absence of intracranial mass effect (aOR, 0.759; 95% CI, 0.595-0.968; P = .03).
Though all patients experienced an improvement in functional status during rehabilitation, patients with DoC had an increase in median Functional Independence Measure total score from 19 to 71 while patients without DoC increased from 54 to 96 (change in total score, +43 versus +37; P = .002). After multivariate analysis, younger age and male sex were both associated with better functional outcomes during rehab and at discharge.
When it comes to TBI patients, don’t give up hope
The choice to withdraw care in TBI patients is a complicated and daunting one, and this study is further evidence that physicians should delay that decision in many scenarios, wrote Jennifer A. Kim, MD, PhD, and Kevin N. Sheth, MD, of Yale University, New Haven, Conn., in an accompanying editorial.
“By showing that a large proportion of patients with persistent DoC recover during acute rehabilitation, this article further challenges our potential toward overly nihilistic notions of who may or may not ultimately recover consciousness long term,” they added.
That said, they also recognized the questions that still persist: What are the reasons for late-stage withdrawal of lifesaving therapy? What is the recovery rate of all hospitalized patients with TBI, not just those in rehabilitation facilities? And is it possible to detect covert consciousness using MRI and electroencephalography, which this study did not include?
“Defining both good and poor prognostic risk factors is critical to portending recovery,” they wrote, emphasizing the need for physicians to rely on scientifically based predictions when making such important assessments.
Patience is a virtue for TBI specialists
“A lot of people write notes on hospital charts, ‘poor prognosis.’ You don’t know, that early in the game, in the acute care setting, how TBI patients are going to do,” said Jamie S. Ullman, MD, of the department of neurosurgery at Hofstra University, Hempstead, N.Y., in an interview. “It’s over the long term that we really have to judge that.”
“Of course, there may be some characteristics that patients might have that may portend for a worse outcome, like brain stem damage,” she added. “But in general, there is plenty of literature to suggest that not only can even the worst-looking patients have some kind of functional outcome but that it takes 18 months or more to actually realize an outcome from a traumatic brain injury.”
She emphasized that each patient with TBI is unique; beyond their current status, you have to consider the significance of their injury, the thoughts of their families or partner, and their own previously stated wishes and willingness to tolerate disability. Nonetheless, this study is another step toward distilling the “nihilistic thinking” that can lead physicians to expect the worst regarding patients who may still have a path toward a functional life.
“As traumatic brain injury specialists,” she said, “we need to see what we can do to give patients as good a chance as possible at a recovery.”
The authors acknowledged their study’s limitations, including an inability to account for 3 decades of variations in treatment regimens and its limited generalizability because of the cohort being composed of only TBI survivors admitted to inpatient rehab. In addition, they noted a possible referential bias for the study’s mostly young TBI patients in rehab facilities, another reason why these findings “may not be directly applicable to the overall population of patients with moderate or severe TBI.”
The study was funded by grants from the National Institute on Disability, Independent Living, and Rehabilitation Research; the Department of Health & Human Services; and the Veterans Health Administration Central Office VA TBI Model Systems Program of Research. The authors reported several potential conflicts of interest, including receiving grants and support from various government agencies and pharmaceutical companies.
FROM JAMA NEUROLOGY
GLOW: Ibrutinib+venetoclax shines in first line for CLL/SLL
For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.
Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.
The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).
“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
A low bar
But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.
“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.
“This is like comparing a mule cart to a Tesla,” he said.
Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.
“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.
Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.
“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.
Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”
But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.
“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
GLOW details
Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.
The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.
The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.
After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.
About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
Superior PFS
As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).
PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).
IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).
Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.
Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259).
One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
Safety
In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.
There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.
Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.
Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.
In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.
The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.
For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.
Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.
The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).
“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
A low bar
But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.
“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.
“This is like comparing a mule cart to a Tesla,” he said.
Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.
“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.
Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.
“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.
Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”
But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.
“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
GLOW details
Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.
The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.
The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.
After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.
About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
Superior PFS
As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).
PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).
IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).
Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.
Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259).
One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
Safety
In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.
There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.
Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.
Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.
In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.
The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.
For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.
Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.
The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).
“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
A low bar
But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.
“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.
“This is like comparing a mule cart to a Tesla,” he said.
Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.
“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.
Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.
“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.
Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”
But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.
“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
GLOW details
Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.
The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.
The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.
After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.
About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
Superior PFS
As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).
PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).
IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).
Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.
Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259).
One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
Safety
In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.
There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.
Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.
Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.
In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.
The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.
FROM EHA 2021
Choosing the right R-CHOP dosage for elderly patients with DLBCL
Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.
To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).
Cutoff at 80 years of age
Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.
However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.
“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.
However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”
Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.
Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.
To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).
Cutoff at 80 years of age
Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.
However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.
“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.
However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”
Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.
Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.
To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).
Cutoff at 80 years of age
Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.
However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.
“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.
However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”
Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.
FROM BLOOD ADVANCES
Deep brain stimulation is effective over the long haul
, new research indicates.
“Subthalamic nucleus stimulation is a well recognized treatment used for improving motor conditions and quality of life in people with Parkinson’s disease. Our study, for the first time, supports its efficacy in the very long term – 15 years after surgery and 25 years since the Parkinson’s disease diagnosis,” said Elena Moro, MD, PhD, Grenoble Alpes University, Grenoble, France.
“This information is relevant for physicians, patients, and their families when they need to decide about the surgical option to deal with Parkinson’s disease,” said Dr. Moro.
The study was published online June 2 in Neurology.
‘Don’t delay’
The findings are based on 51 patients with Parkinson’s disease who underwent treatment with bilateral STN-DBS for an average of 17 years (range, 15-24 years). Their average age at diagnosis was 40 years, and the average age at device implantation was 51 years.
The results demonstrate that STN-DBS continues to be effective for motor complications for longer than 15 years, reducing time spent with dyskinesia by 75% and time spent in the off-state by 58.7%. This is similar to the amount of improvement seen 1 year after surgery.
Doses of dopaminergic medications continued to be low at long-term follow-up; dosing was reduced by 50.6% compared with baseline.
There was also continued improvement in quality of life. Scores on the Parkinson’s Disease Quality of Life Questionnaire in the very long term were 13.8% better compared with baseline.
“Few and mostly manageable device-related adverse events were observed during the follow-up,” the authors reported in their article.
“Deep brain stimulation is already recommended when a patient’s conditions are not optimized by medical treatment. Patients with Parkinson’s disease without dementia and in good general health conditions are the best candidates for this surgery,” said Dr. Moro.
“Taking into account our results and the data available in the literature, DBS surgery should not be delayed when motor conditions and quality of life decline despite medical treatment, if patients meet the inclusion criteria,” she added.
A revolutionary treatment
The authors of an accompanying editorial say these results, which indicate better motor outcomes with less medication, “reinforce why STN-DBS has revolutionized treatment for advanced Parkinson’s disease.”
Kelvin Chou, MD, of the University of Michigan, Ann Arbor, and David Charles, MD, of Vanderbilt University, Nashville, Tenn., pointed out that longer disease duration is associated with an increase in the likelihood of cognitive impairment and psychosis, both of which are risk factors for nursing home placement, and they limit the ability to use dopaminergic medications.
Although many of the patients in this cohort experienced hallucinations and psychosis over the long follow-up period, “one can imagine that the number and severity would be higher without DBS therapy,” they wrote.
Key caveats, said Dr. Chou and Dr. Charles, are that the results are based on a highly selected cohort and that the patients were managed by experts in the field of movement disorders and DBS.
Additionally, the patients’ conditions were highly responsive to levodopa; there was a 75.3% baseline improvement in Unified Parkinson’s Disease Rating Scale motor scores from the off-state to the on-state. In general, most DBS centers consider a levodopa response of approximately 30% as an acceptable cutoff for moving forward with STN-DBS, they noted.
Despite these caveats and limitations, the results of the study are important with respect to counseling potential candidates for DBS, Dr. Chou and Dr. Charles said.
“A common question that patients have is, ‘How long do the benefits of DBS last?’ We can now reassure them that, at least for STN-DBS, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life. In other words, with STN-DBS, we can uncomplicate their motor complications for the long haul,” the editorial writers concluded.
The research had no targeted funding. Moro has received honoraria from Medtronic and Abbott for consulting and lecturing and an educational grant from Boston and Newronika. A complete list of disclosures is available with the original articles.
A version of this article first appeared on Medscape.com.
, new research indicates.
“Subthalamic nucleus stimulation is a well recognized treatment used for improving motor conditions and quality of life in people with Parkinson’s disease. Our study, for the first time, supports its efficacy in the very long term – 15 years after surgery and 25 years since the Parkinson’s disease diagnosis,” said Elena Moro, MD, PhD, Grenoble Alpes University, Grenoble, France.
“This information is relevant for physicians, patients, and their families when they need to decide about the surgical option to deal with Parkinson’s disease,” said Dr. Moro.
The study was published online June 2 in Neurology.
‘Don’t delay’
The findings are based on 51 patients with Parkinson’s disease who underwent treatment with bilateral STN-DBS for an average of 17 years (range, 15-24 years). Their average age at diagnosis was 40 years, and the average age at device implantation was 51 years.
The results demonstrate that STN-DBS continues to be effective for motor complications for longer than 15 years, reducing time spent with dyskinesia by 75% and time spent in the off-state by 58.7%. This is similar to the amount of improvement seen 1 year after surgery.
Doses of dopaminergic medications continued to be low at long-term follow-up; dosing was reduced by 50.6% compared with baseline.
There was also continued improvement in quality of life. Scores on the Parkinson’s Disease Quality of Life Questionnaire in the very long term were 13.8% better compared with baseline.
“Few and mostly manageable device-related adverse events were observed during the follow-up,” the authors reported in their article.
“Deep brain stimulation is already recommended when a patient’s conditions are not optimized by medical treatment. Patients with Parkinson’s disease without dementia and in good general health conditions are the best candidates for this surgery,” said Dr. Moro.
“Taking into account our results and the data available in the literature, DBS surgery should not be delayed when motor conditions and quality of life decline despite medical treatment, if patients meet the inclusion criteria,” she added.
A revolutionary treatment
The authors of an accompanying editorial say these results, which indicate better motor outcomes with less medication, “reinforce why STN-DBS has revolutionized treatment for advanced Parkinson’s disease.”
Kelvin Chou, MD, of the University of Michigan, Ann Arbor, and David Charles, MD, of Vanderbilt University, Nashville, Tenn., pointed out that longer disease duration is associated with an increase in the likelihood of cognitive impairment and psychosis, both of which are risk factors for nursing home placement, and they limit the ability to use dopaminergic medications.
Although many of the patients in this cohort experienced hallucinations and psychosis over the long follow-up period, “one can imagine that the number and severity would be higher without DBS therapy,” they wrote.
Key caveats, said Dr. Chou and Dr. Charles, are that the results are based on a highly selected cohort and that the patients were managed by experts in the field of movement disorders and DBS.
Additionally, the patients’ conditions were highly responsive to levodopa; there was a 75.3% baseline improvement in Unified Parkinson’s Disease Rating Scale motor scores from the off-state to the on-state. In general, most DBS centers consider a levodopa response of approximately 30% as an acceptable cutoff for moving forward with STN-DBS, they noted.
Despite these caveats and limitations, the results of the study are important with respect to counseling potential candidates for DBS, Dr. Chou and Dr. Charles said.
“A common question that patients have is, ‘How long do the benefits of DBS last?’ We can now reassure them that, at least for STN-DBS, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life. In other words, with STN-DBS, we can uncomplicate their motor complications for the long haul,” the editorial writers concluded.
The research had no targeted funding. Moro has received honoraria from Medtronic and Abbott for consulting and lecturing and an educational grant from Boston and Newronika. A complete list of disclosures is available with the original articles.
A version of this article first appeared on Medscape.com.
, new research indicates.
“Subthalamic nucleus stimulation is a well recognized treatment used for improving motor conditions and quality of life in people with Parkinson’s disease. Our study, for the first time, supports its efficacy in the very long term – 15 years after surgery and 25 years since the Parkinson’s disease diagnosis,” said Elena Moro, MD, PhD, Grenoble Alpes University, Grenoble, France.
“This information is relevant for physicians, patients, and their families when they need to decide about the surgical option to deal with Parkinson’s disease,” said Dr. Moro.
The study was published online June 2 in Neurology.
‘Don’t delay’
The findings are based on 51 patients with Parkinson’s disease who underwent treatment with bilateral STN-DBS for an average of 17 years (range, 15-24 years). Their average age at diagnosis was 40 years, and the average age at device implantation was 51 years.
The results demonstrate that STN-DBS continues to be effective for motor complications for longer than 15 years, reducing time spent with dyskinesia by 75% and time spent in the off-state by 58.7%. This is similar to the amount of improvement seen 1 year after surgery.
Doses of dopaminergic medications continued to be low at long-term follow-up; dosing was reduced by 50.6% compared with baseline.
There was also continued improvement in quality of life. Scores on the Parkinson’s Disease Quality of Life Questionnaire in the very long term were 13.8% better compared with baseline.
“Few and mostly manageable device-related adverse events were observed during the follow-up,” the authors reported in their article.
“Deep brain stimulation is already recommended when a patient’s conditions are not optimized by medical treatment. Patients with Parkinson’s disease without dementia and in good general health conditions are the best candidates for this surgery,” said Dr. Moro.
“Taking into account our results and the data available in the literature, DBS surgery should not be delayed when motor conditions and quality of life decline despite medical treatment, if patients meet the inclusion criteria,” she added.
A revolutionary treatment
The authors of an accompanying editorial say these results, which indicate better motor outcomes with less medication, “reinforce why STN-DBS has revolutionized treatment for advanced Parkinson’s disease.”
Kelvin Chou, MD, of the University of Michigan, Ann Arbor, and David Charles, MD, of Vanderbilt University, Nashville, Tenn., pointed out that longer disease duration is associated with an increase in the likelihood of cognitive impairment and psychosis, both of which are risk factors for nursing home placement, and they limit the ability to use dopaminergic medications.
Although many of the patients in this cohort experienced hallucinations and psychosis over the long follow-up period, “one can imagine that the number and severity would be higher without DBS therapy,” they wrote.
Key caveats, said Dr. Chou and Dr. Charles, are that the results are based on a highly selected cohort and that the patients were managed by experts in the field of movement disorders and DBS.
Additionally, the patients’ conditions were highly responsive to levodopa; there was a 75.3% baseline improvement in Unified Parkinson’s Disease Rating Scale motor scores from the off-state to the on-state. In general, most DBS centers consider a levodopa response of approximately 30% as an acceptable cutoff for moving forward with STN-DBS, they noted.
Despite these caveats and limitations, the results of the study are important with respect to counseling potential candidates for DBS, Dr. Chou and Dr. Charles said.
“A common question that patients have is, ‘How long do the benefits of DBS last?’ We can now reassure them that, at least for STN-DBS, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life. In other words, with STN-DBS, we can uncomplicate their motor complications for the long haul,” the editorial writers concluded.
The research had no targeted funding. Moro has received honoraria from Medtronic and Abbott for consulting and lecturing and an educational grant from Boston and Newronika. A complete list of disclosures is available with the original articles.
A version of this article first appeared on Medscape.com.
From Neurology
Neurologists brace and prepare for long-COVID fallout
“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” said Greg Vanichkachorn, MD, MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).
Take a nap. Tough it out. Push through it. Dr. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.
Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.
PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared.
A total of 33.6% (95% confidence interval, 11.17-34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36-13.33) represented first-time diagnoses.
“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg chair of neurology at University of Miami, and past president of the American Academy of Neurology.
Neurologic detritus
Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms. “What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.
“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.
Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.
Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery. Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.
Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection. Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.
Debilitating, pervasive symptoms
Findings from an international survey of 3,762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40-49 years; 25.0% were aged 50-59 years). For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.
Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.
In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.
Reports of even more severe neurologic first-time diagnoses are emerging. Findings from the Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10-0.20), ischemic stroke (0.43%; 95% CI, 0.36-0.52), parkinsonism (0.07%; 95% CI, 0.05-0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51-2.89).
Dr. Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.
In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0-3 [median, 0]; cardiovagal, 0-3 [median, 0]; cardiovascular adrenergic, 0-4 [median, 0]).
“The pattern that’s emerging is consistent with deconditioning,” Dr. Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”
Proliferation of long-COVID clinics
A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. “These post-viral, autonomic neuropathies tend to be self-limiting, but we’re starting to see different levels of involvement,” Dr. Toledano explained. At present, causality and/or underlying mechanisms are unclear.
Speaking on behalf of the American Academy of Neurology, Dr. Sacco acknowledged the challenges that lie ahead. “Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.
On the flip side, he pointed to the lessons of the past year and how quickly health care systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.
Across the nation, numerous hospitals and health care systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.
The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that under-resourced populations can access needed care and assistance.
“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Dr. Toledano. During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges. Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.
An uphill battle
Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work. “The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Dr. Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”
Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Dr. Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.
He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression. “This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”
The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.
Despite the challenges, Dr. Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.
The interviewees have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” said Greg Vanichkachorn, MD, MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).
Take a nap. Tough it out. Push through it. Dr. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.
Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.
PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared.
A total of 33.6% (95% confidence interval, 11.17-34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36-13.33) represented first-time diagnoses.
“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg chair of neurology at University of Miami, and past president of the American Academy of Neurology.
Neurologic detritus
Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms. “What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.
“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.
Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.
Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery. Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.
Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection. Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.
Debilitating, pervasive symptoms
Findings from an international survey of 3,762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40-49 years; 25.0% were aged 50-59 years). For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.
Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.
In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.
Reports of even more severe neurologic first-time diagnoses are emerging. Findings from the Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10-0.20), ischemic stroke (0.43%; 95% CI, 0.36-0.52), parkinsonism (0.07%; 95% CI, 0.05-0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51-2.89).
Dr. Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.
In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0-3 [median, 0]; cardiovagal, 0-3 [median, 0]; cardiovascular adrenergic, 0-4 [median, 0]).
“The pattern that’s emerging is consistent with deconditioning,” Dr. Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”
Proliferation of long-COVID clinics
A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. “These post-viral, autonomic neuropathies tend to be self-limiting, but we’re starting to see different levels of involvement,” Dr. Toledano explained. At present, causality and/or underlying mechanisms are unclear.
Speaking on behalf of the American Academy of Neurology, Dr. Sacco acknowledged the challenges that lie ahead. “Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.
On the flip side, he pointed to the lessons of the past year and how quickly health care systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.
Across the nation, numerous hospitals and health care systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.
The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that under-resourced populations can access needed care and assistance.
“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Dr. Toledano. During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges. Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.
An uphill battle
Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work. “The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Dr. Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”
Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Dr. Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.
He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression. “This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”
The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.
Despite the challenges, Dr. Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.
The interviewees have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” said Greg Vanichkachorn, MD, MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).
Take a nap. Tough it out. Push through it. Dr. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.
Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.
PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared.
A total of 33.6% (95% confidence interval, 11.17-34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36-13.33) represented first-time diagnoses.
“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg chair of neurology at University of Miami, and past president of the American Academy of Neurology.
Neurologic detritus
Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms. “What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.
“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.
Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.
Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery. Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.
Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection. Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.
Debilitating, pervasive symptoms
Findings from an international survey of 3,762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40-49 years; 25.0% were aged 50-59 years). For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.
Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.
In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.
Reports of even more severe neurologic first-time diagnoses are emerging. Findings from the Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10-0.20), ischemic stroke (0.43%; 95% CI, 0.36-0.52), parkinsonism (0.07%; 95% CI, 0.05-0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51-2.89).
Dr. Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.
In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0-3 [median, 0]; cardiovagal, 0-3 [median, 0]; cardiovascular adrenergic, 0-4 [median, 0]).
“The pattern that’s emerging is consistent with deconditioning,” Dr. Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”
Proliferation of long-COVID clinics
A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. “These post-viral, autonomic neuropathies tend to be self-limiting, but we’re starting to see different levels of involvement,” Dr. Toledano explained. At present, causality and/or underlying mechanisms are unclear.
Speaking on behalf of the American Academy of Neurology, Dr. Sacco acknowledged the challenges that lie ahead. “Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.
On the flip side, he pointed to the lessons of the past year and how quickly health care systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.
Across the nation, numerous hospitals and health care systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.
The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that under-resourced populations can access needed care and assistance.
“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Dr. Toledano. During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges. Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.
An uphill battle
Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work. “The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Dr. Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”
Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Dr. Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.
He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression. “This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”
The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.
Despite the challenges, Dr. Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.
The interviewees have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FDA expands rimegepant indication to include migraine prevention
Last year, rimegepant became the first calcitonin gene-related peptide (CGRP) receptor antagonist, available in a fast-acting orally disintegrating tablet, to be approved for the acute treatment of migraine with or without aura in adults.
Rimegepant is currently the only migraine medication approved to both treat acute migraine attacks and help prevent future migraine attacks.
The new indication allows for use of rimegepant for preventive treatment in adults with episodic migraine (more than 15 migraine days per month). Rimegepant may be used for up to 18 doses per month, which includes both acute and preventive therapy.
In a phase 2/3 study, oral rimegepant was superior to placebo in reducing monthly migraine days. About half of adults who took rimegepant experienced a 50% or greater reduction in the number of days of moderate to severe migraines per month.
The most common adverse effects of rimegepant therapy were nausea (2.7%) and stomach pain or indigestion (2.4%).
The FDA approval of rimegepant for the preventive treatment of migraine, along with its acute treatment indication, is “one of the most ground-breaking things to happen to migraine treatment in my 40 years of practicing headache medicine,” Peter J. Goadsby, MD, PhD, an investigator in the prevention study, said in a company news release.
“To have one medication patients can use to treat and prevent migraine will likely change the treatment paradigm for many of the millions of people who live with migraine,” said Dr. Goadsby, professor of neurology, University of California, Los Angeles and King’s College, London.
A version of this article first appeared on Medscape.com.
Last year, rimegepant became the first calcitonin gene-related peptide (CGRP) receptor antagonist, available in a fast-acting orally disintegrating tablet, to be approved for the acute treatment of migraine with or without aura in adults.
Rimegepant is currently the only migraine medication approved to both treat acute migraine attacks and help prevent future migraine attacks.
The new indication allows for use of rimegepant for preventive treatment in adults with episodic migraine (more than 15 migraine days per month). Rimegepant may be used for up to 18 doses per month, which includes both acute and preventive therapy.
In a phase 2/3 study, oral rimegepant was superior to placebo in reducing monthly migraine days. About half of adults who took rimegepant experienced a 50% or greater reduction in the number of days of moderate to severe migraines per month.
The most common adverse effects of rimegepant therapy were nausea (2.7%) and stomach pain or indigestion (2.4%).
The FDA approval of rimegepant for the preventive treatment of migraine, along with its acute treatment indication, is “one of the most ground-breaking things to happen to migraine treatment in my 40 years of practicing headache medicine,” Peter J. Goadsby, MD, PhD, an investigator in the prevention study, said in a company news release.
“To have one medication patients can use to treat and prevent migraine will likely change the treatment paradigm for many of the millions of people who live with migraine,” said Dr. Goadsby, professor of neurology, University of California, Los Angeles and King’s College, London.
A version of this article first appeared on Medscape.com.
Last year, rimegepant became the first calcitonin gene-related peptide (CGRP) receptor antagonist, available in a fast-acting orally disintegrating tablet, to be approved for the acute treatment of migraine with or without aura in adults.
Rimegepant is currently the only migraine medication approved to both treat acute migraine attacks and help prevent future migraine attacks.
The new indication allows for use of rimegepant for preventive treatment in adults with episodic migraine (more than 15 migraine days per month). Rimegepant may be used for up to 18 doses per month, which includes both acute and preventive therapy.
In a phase 2/3 study, oral rimegepant was superior to placebo in reducing monthly migraine days. About half of adults who took rimegepant experienced a 50% or greater reduction in the number of days of moderate to severe migraines per month.
The most common adverse effects of rimegepant therapy were nausea (2.7%) and stomach pain or indigestion (2.4%).
The FDA approval of rimegepant for the preventive treatment of migraine, along with its acute treatment indication, is “one of the most ground-breaking things to happen to migraine treatment in my 40 years of practicing headache medicine,” Peter J. Goadsby, MD, PhD, an investigator in the prevention study, said in a company news release.
“To have one medication patients can use to treat and prevent migraine will likely change the treatment paradigm for many of the millions of people who live with migraine,” said Dr. Goadsby, professor of neurology, University of California, Los Angeles and King’s College, London.
A version of this article first appeared on Medscape.com.