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Some MS treatments may heighten COVID risk
, according to a new analysis of an Italian cohort of patients with MS. The study confirmed that steroid exposure in the month before COVID-19 symptom onset is tied to more severe disease, and anti-CD20 therapy poses similar risks. But the researchers noted that interferon and possibly teriflunomide were associated with a protective effect in the multivariate analysis.
Maria Pia Sormani, PhD, who is a professor of biostatistics at the University of Genoa, presented the study at the 2021 annual meeting of the American Academy of Neurology.
The results confirm some previous analyses, and add to the body of evidence clinicians rely on, according to Jiwon Oh, MD, PhD, who moderated the session. “These data about the risk with the anti-CD20 therapies have been around for a while, but it seems that risk is pretty apparent, with this registry and other registries around the world. It affects counseling to patients on anti-CD20 therapies. We would counsel them to be cautious, obviously, follow public health precautions, but maybe be even more cautious. It affects our recommendations about the urgency of vaccination in these folks, how high priority they should be,” Dr. Oh said in an interview. She is the clinical director of the Barlo MS Center at St. Michael’s Unity Health in Toronto.
The analysis also hinted at complexities within demographics that might help explain some of the differing outcomes of infections. “We have learned that the course of the viral infection per se may not be the cause of severe outcomes, but the exaggerated inflammatory response to the virus is mainly responsible for intubations and deaths. The hypothesis we are investigating is whether anti-CD20 therapies can cause a more severe viral infection (that is something already known for other viral infections) but do not play a crucial role in causing the explosion of the inflammatory process,” said Dr. Sormani in an email.
The group plans to look at the risk of anti-CD20 therapies in different age groups, “to try to understand the underlying mechanism through which anti-CD20 increases the risk of more severe outcome,” she said.
Dr. Sormani presented an analysis of 3,274 patients with MS who contracted COVID-19 in Italy. The mean age was 44, the median Expanded Disability Status Scale (EDSS) score was 2, Among the study cohort, 68.6% were female; 14% had progressive MS and 26 patients died. Patients who died had a mean age of 63, 48% were female, 73% had progressive MS, and 50% were not on any DMT.
The researchers used ordinal logistic regression that “orders” outcome on a severity scale of 0 (mild disease, no pneumonia or hospitalization), 1 (pneumonia or hospitalization, n = 184), or 2 (ICU admission or death, n = 36). They calculated the odds ratio of moving from 0 to 1, or 1 to 2, and carried the assumption that the risk is the same. For example, an odds ratio of 2 for males versus females would mean that males are twice as likely to be hospitalized and twice as likely to go from being hospitalized to going to the ICU or dying.
The researchers found that older age, male sex, and comorbidities increase risk of worse COVID-19 outcomes. Exposure to methylprednisolone 1 month before COVID-19 symptom onset carried an increased risk (OR, 2.33; P = .03). Compared with no therapy, receiving interferon was associated with lower risk (OR, 0.34; P = .009) and teriflunomide trended towards an association with better outcomes (OR, 0.49; P = .054). Anti-CD20 treatment (ocrelizumab or rituximab) was linked to worse outcomes (OR, 1.89; P = .012) overall, which held up when ocrelizumab (OR, 1.71; P = .04) and rituximab (OR, 2.77; P = .03) were considered separately.
To understand why the risk of ocrelizumab might be lower, the researchers examined risk by duration of anti-CD20 treatment, and found that risk increased with increased duration of treatment, with the lowest risk at treatment duration less than 6 months (OR, 1.56; 95% CI, 0.65-3.77; not significant), followed by 6 months to 1 year (OR, 1.68; 95% CI, 0.69-4.03; P < .001), 1-2 years (OR, 1.74; 95% CI, 0.83-3.64; trend), and the highest risk at more than 2 years (OR, 2.75; 95% CI, 1.28-5.88).
Dr. Sormani suggested that the greater risk associated with rituximab may be because of a tendency towards longer treatment length, since patients treated with rituximab were more often treated for greater lengths of time; 11% had been treated for 6 months or less (vs. 24% of ocrelizumab patients); 26%, 6-12 months (vs. 18% ocrelizumab); 19%, 1-2 years (vs. 37% ocrelizumab); and 44%, 2 years or longer (vs. 21% ocrelizumab).
Dr. Sormani has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA, Novartis, Roche, and Immunic. The platform for data collection was donated by Merck. Dr. Oh has consulted for Roche, Celgene, Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Novartis, Alexion. She has been on a scientific advisory or data safety monitoring board for Roche, Biogen-Idec, and Sanofi-Genzyme.
, according to a new analysis of an Italian cohort of patients with MS. The study confirmed that steroid exposure in the month before COVID-19 symptom onset is tied to more severe disease, and anti-CD20 therapy poses similar risks. But the researchers noted that interferon and possibly teriflunomide were associated with a protective effect in the multivariate analysis.
Maria Pia Sormani, PhD, who is a professor of biostatistics at the University of Genoa, presented the study at the 2021 annual meeting of the American Academy of Neurology.
The results confirm some previous analyses, and add to the body of evidence clinicians rely on, according to Jiwon Oh, MD, PhD, who moderated the session. “These data about the risk with the anti-CD20 therapies have been around for a while, but it seems that risk is pretty apparent, with this registry and other registries around the world. It affects counseling to patients on anti-CD20 therapies. We would counsel them to be cautious, obviously, follow public health precautions, but maybe be even more cautious. It affects our recommendations about the urgency of vaccination in these folks, how high priority they should be,” Dr. Oh said in an interview. She is the clinical director of the Barlo MS Center at St. Michael’s Unity Health in Toronto.
The analysis also hinted at complexities within demographics that might help explain some of the differing outcomes of infections. “We have learned that the course of the viral infection per se may not be the cause of severe outcomes, but the exaggerated inflammatory response to the virus is mainly responsible for intubations and deaths. The hypothesis we are investigating is whether anti-CD20 therapies can cause a more severe viral infection (that is something already known for other viral infections) but do not play a crucial role in causing the explosion of the inflammatory process,” said Dr. Sormani in an email.
The group plans to look at the risk of anti-CD20 therapies in different age groups, “to try to understand the underlying mechanism through which anti-CD20 increases the risk of more severe outcome,” she said.
Dr. Sormani presented an analysis of 3,274 patients with MS who contracted COVID-19 in Italy. The mean age was 44, the median Expanded Disability Status Scale (EDSS) score was 2, Among the study cohort, 68.6% were female; 14% had progressive MS and 26 patients died. Patients who died had a mean age of 63, 48% were female, 73% had progressive MS, and 50% were not on any DMT.
The researchers used ordinal logistic regression that “orders” outcome on a severity scale of 0 (mild disease, no pneumonia or hospitalization), 1 (pneumonia or hospitalization, n = 184), or 2 (ICU admission or death, n = 36). They calculated the odds ratio of moving from 0 to 1, or 1 to 2, and carried the assumption that the risk is the same. For example, an odds ratio of 2 for males versus females would mean that males are twice as likely to be hospitalized and twice as likely to go from being hospitalized to going to the ICU or dying.
The researchers found that older age, male sex, and comorbidities increase risk of worse COVID-19 outcomes. Exposure to methylprednisolone 1 month before COVID-19 symptom onset carried an increased risk (OR, 2.33; P = .03). Compared with no therapy, receiving interferon was associated with lower risk (OR, 0.34; P = .009) and teriflunomide trended towards an association with better outcomes (OR, 0.49; P = .054). Anti-CD20 treatment (ocrelizumab or rituximab) was linked to worse outcomes (OR, 1.89; P = .012) overall, which held up when ocrelizumab (OR, 1.71; P = .04) and rituximab (OR, 2.77; P = .03) were considered separately.
To understand why the risk of ocrelizumab might be lower, the researchers examined risk by duration of anti-CD20 treatment, and found that risk increased with increased duration of treatment, with the lowest risk at treatment duration less than 6 months (OR, 1.56; 95% CI, 0.65-3.77; not significant), followed by 6 months to 1 year (OR, 1.68; 95% CI, 0.69-4.03; P < .001), 1-2 years (OR, 1.74; 95% CI, 0.83-3.64; trend), and the highest risk at more than 2 years (OR, 2.75; 95% CI, 1.28-5.88).
Dr. Sormani suggested that the greater risk associated with rituximab may be because of a tendency towards longer treatment length, since patients treated with rituximab were more often treated for greater lengths of time; 11% had been treated for 6 months or less (vs. 24% of ocrelizumab patients); 26%, 6-12 months (vs. 18% ocrelizumab); 19%, 1-2 years (vs. 37% ocrelizumab); and 44%, 2 years or longer (vs. 21% ocrelizumab).
Dr. Sormani has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA, Novartis, Roche, and Immunic. The platform for data collection was donated by Merck. Dr. Oh has consulted for Roche, Celgene, Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Novartis, Alexion. She has been on a scientific advisory or data safety monitoring board for Roche, Biogen-Idec, and Sanofi-Genzyme.
, according to a new analysis of an Italian cohort of patients with MS. The study confirmed that steroid exposure in the month before COVID-19 symptom onset is tied to more severe disease, and anti-CD20 therapy poses similar risks. But the researchers noted that interferon and possibly teriflunomide were associated with a protective effect in the multivariate analysis.
Maria Pia Sormani, PhD, who is a professor of biostatistics at the University of Genoa, presented the study at the 2021 annual meeting of the American Academy of Neurology.
The results confirm some previous analyses, and add to the body of evidence clinicians rely on, according to Jiwon Oh, MD, PhD, who moderated the session. “These data about the risk with the anti-CD20 therapies have been around for a while, but it seems that risk is pretty apparent, with this registry and other registries around the world. It affects counseling to patients on anti-CD20 therapies. We would counsel them to be cautious, obviously, follow public health precautions, but maybe be even more cautious. It affects our recommendations about the urgency of vaccination in these folks, how high priority they should be,” Dr. Oh said in an interview. She is the clinical director of the Barlo MS Center at St. Michael’s Unity Health in Toronto.
The analysis also hinted at complexities within demographics that might help explain some of the differing outcomes of infections. “We have learned that the course of the viral infection per se may not be the cause of severe outcomes, but the exaggerated inflammatory response to the virus is mainly responsible for intubations and deaths. The hypothesis we are investigating is whether anti-CD20 therapies can cause a more severe viral infection (that is something already known for other viral infections) but do not play a crucial role in causing the explosion of the inflammatory process,” said Dr. Sormani in an email.
The group plans to look at the risk of anti-CD20 therapies in different age groups, “to try to understand the underlying mechanism through which anti-CD20 increases the risk of more severe outcome,” she said.
Dr. Sormani presented an analysis of 3,274 patients with MS who contracted COVID-19 in Italy. The mean age was 44, the median Expanded Disability Status Scale (EDSS) score was 2, Among the study cohort, 68.6% were female; 14% had progressive MS and 26 patients died. Patients who died had a mean age of 63, 48% were female, 73% had progressive MS, and 50% were not on any DMT.
The researchers used ordinal logistic regression that “orders” outcome on a severity scale of 0 (mild disease, no pneumonia or hospitalization), 1 (pneumonia or hospitalization, n = 184), or 2 (ICU admission or death, n = 36). They calculated the odds ratio of moving from 0 to 1, or 1 to 2, and carried the assumption that the risk is the same. For example, an odds ratio of 2 for males versus females would mean that males are twice as likely to be hospitalized and twice as likely to go from being hospitalized to going to the ICU or dying.
The researchers found that older age, male sex, and comorbidities increase risk of worse COVID-19 outcomes. Exposure to methylprednisolone 1 month before COVID-19 symptom onset carried an increased risk (OR, 2.33; P = .03). Compared with no therapy, receiving interferon was associated with lower risk (OR, 0.34; P = .009) and teriflunomide trended towards an association with better outcomes (OR, 0.49; P = .054). Anti-CD20 treatment (ocrelizumab or rituximab) was linked to worse outcomes (OR, 1.89; P = .012) overall, which held up when ocrelizumab (OR, 1.71; P = .04) and rituximab (OR, 2.77; P = .03) were considered separately.
To understand why the risk of ocrelizumab might be lower, the researchers examined risk by duration of anti-CD20 treatment, and found that risk increased with increased duration of treatment, with the lowest risk at treatment duration less than 6 months (OR, 1.56; 95% CI, 0.65-3.77; not significant), followed by 6 months to 1 year (OR, 1.68; 95% CI, 0.69-4.03; P < .001), 1-2 years (OR, 1.74; 95% CI, 0.83-3.64; trend), and the highest risk at more than 2 years (OR, 2.75; 95% CI, 1.28-5.88).
Dr. Sormani suggested that the greater risk associated with rituximab may be because of a tendency towards longer treatment length, since patients treated with rituximab were more often treated for greater lengths of time; 11% had been treated for 6 months or less (vs. 24% of ocrelizumab patients); 26%, 6-12 months (vs. 18% ocrelizumab); 19%, 1-2 years (vs. 37% ocrelizumab); and 44%, 2 years or longer (vs. 21% ocrelizumab).
Dr. Sormani has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA, Novartis, Roche, and Immunic. The platform for data collection was donated by Merck. Dr. Oh has consulted for Roche, Celgene, Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Novartis, Alexion. She has been on a scientific advisory or data safety monitoring board for Roche, Biogen-Idec, and Sanofi-Genzyme.
FROM AAN 2021
Line of therapy matters for assessing biologic’s serious infection risk in RA
The order in which tocilizumab (Actemra) is used in the sequence of treatments for rheumatoid arthritis could be muddying the waters when it comes to evaluating patients’ risk for serious infection.
According to new data emerging from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA), the line of therapy is a confounding factor when examining the risk for serious infection with not only tocilizumab but also other biologic agents.
The good news for patients, however, is that there doesn’t appear to be any overall greater risk for serious infection with one biologic over another when the line of therapy is taken into account.
“We don’t have any strong signal that there is an increased risk of serious infections with tocilizumab, compared to TNF inhibitors,” rheumatologist Kim Lauper, MD, of Geneva University Hospitals, said in an interview after presenting the data at the annual conference of the British Society for Rheumatology.
This is in contrast to studies where an increased risk of infections with tocilizumab has been seen when compared to TNF inhibitors. However, those studies did not account for the line of therapy, explained Dr. Lauper, who is also a clinical research fellow in the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), where the BSRBR-RA is managed.
“Tocilizumab is a treatment that we often give to patients after several other treatments, so they’re really different patients,” Dr. Lauper observed. Indeed, in the “real-world” setting, patients taking tocilizumab tend to be older, have longer disease duration, and have worse functional status than do those who might receive other biologics.
To look at the effect of line of therapy on the serious infection risk associated with commonly used biologic drugs, Dr. Lauper and associates examined data on more than 33,000 treatment courses, representing more than 62,500 patient-years.
Using etanercept as the comparator – because it represents the largest group of patients in the BSRBR-RA – the serious infection risk for tocilizumab, rituximab, adalimumab, infliximab, certolizumab pegol, and abatacept were calculated as an overall rate, and for their use as first-, second-, third-, fourth-, or fifth-line therapy.
The researchers adjusted their analysis for some clear baseline differences between the treatment groups, including age, prior treatment, disease duration, and comorbidities. Seropositivity, smoking status, general health status, and disease activity scores were also adjusted for in the analysis.
Crude hazard ratios (HRs), compared with etanercept, before and after adjusting for these already-known confounding factors were 1.0 and 1.2 for tocilizumab, 1.1 and 1.1 for adalimumab, 1.4 and 1.3 for infliximab, 0.6 and 0.8 for certolizumab pegol, 0.9 and 1.0 for rituximab, and 0.9 and 1.2 for abatacept.
Stratifying by line of therapy, however, changed the results: HRs were no longer significantly different, compared with etanercept, for tocilizumab, adalimumab, and infliximab for most lines of therapy.
Indeed, while the risk for serious infection occurring with tocilizumab was 20% higher overall, compared with etanercept, that risk was actually lower if tocilizumab had been used as first- or fifth-line therapy (HRs for both, 0.9) but higher if it had been used as a third- or fourth-line therapy (HR of 1.4 for both).
“We often use tocilizumab as a second-line, third-line, or even fourth-line therapy, and if we don’t adjust for anything, we can have the impression that there are more infections with tocilizumab. But then, when we adjust for confounding factors and the line of therapy, we don’t have this anymore,” Dr. Lauper said.
“Line of therapy in itself is not a risk for serious infections,” she said in qualifying the conclusions that could be drawn from the study. “It may be a marker of the disease or some patient characteristic that is associated with a higher risk of infections.” Nevertheless, it should be taken into account when evaluating serious outcomes and possibly other safety and effectiveness outcomes.
“I understand concentrating on the hospitalized infections because the data are so much more robust,” observed consultant rheumatologist Jon Packham, BM, DM, of Haywood Hospital in Stoke-on-Trent, England, who chaired the session. He queried if there were any data on milder or just antibiotic-treated infections. At present, there aren’t those data to look at, Dr. Lauper responded, as this is something that’s difficult for registers to capture because doctors often do not log them in the databases.
There are also too few data on Janus kinase (JAK) inhibitors currently in the BSRBR-RA at present to be able to look at their rate of serious infection by line of therapy, Dr. Lauper noted. Because JAK inhibitors act on cytokines different from those affected by biologics for RA, there may be a difference there, but more data are needed on the JAK inhibitors before that question can be analyzed.
Dr. Lauper did not state having any disclosures. The BSRBR-RA is funded by the BSR via restricted income grants from several U.K. pharmaceutical companies, which has included or currently includes AbbVie, Celltrion, Hospira, Pfizer, UCB, Roche, Swedish Orphan Biovitrum, and Merck.
The order in which tocilizumab (Actemra) is used in the sequence of treatments for rheumatoid arthritis could be muddying the waters when it comes to evaluating patients’ risk for serious infection.
According to new data emerging from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA), the line of therapy is a confounding factor when examining the risk for serious infection with not only tocilizumab but also other biologic agents.
The good news for patients, however, is that there doesn’t appear to be any overall greater risk for serious infection with one biologic over another when the line of therapy is taken into account.
“We don’t have any strong signal that there is an increased risk of serious infections with tocilizumab, compared to TNF inhibitors,” rheumatologist Kim Lauper, MD, of Geneva University Hospitals, said in an interview after presenting the data at the annual conference of the British Society for Rheumatology.
This is in contrast to studies where an increased risk of infections with tocilizumab has been seen when compared to TNF inhibitors. However, those studies did not account for the line of therapy, explained Dr. Lauper, who is also a clinical research fellow in the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), where the BSRBR-RA is managed.
“Tocilizumab is a treatment that we often give to patients after several other treatments, so they’re really different patients,” Dr. Lauper observed. Indeed, in the “real-world” setting, patients taking tocilizumab tend to be older, have longer disease duration, and have worse functional status than do those who might receive other biologics.
To look at the effect of line of therapy on the serious infection risk associated with commonly used biologic drugs, Dr. Lauper and associates examined data on more than 33,000 treatment courses, representing more than 62,500 patient-years.
Using etanercept as the comparator – because it represents the largest group of patients in the BSRBR-RA – the serious infection risk for tocilizumab, rituximab, adalimumab, infliximab, certolizumab pegol, and abatacept were calculated as an overall rate, and for their use as first-, second-, third-, fourth-, or fifth-line therapy.
The researchers adjusted their analysis for some clear baseline differences between the treatment groups, including age, prior treatment, disease duration, and comorbidities. Seropositivity, smoking status, general health status, and disease activity scores were also adjusted for in the analysis.
Crude hazard ratios (HRs), compared with etanercept, before and after adjusting for these already-known confounding factors were 1.0 and 1.2 for tocilizumab, 1.1 and 1.1 for adalimumab, 1.4 and 1.3 for infliximab, 0.6 and 0.8 for certolizumab pegol, 0.9 and 1.0 for rituximab, and 0.9 and 1.2 for abatacept.
Stratifying by line of therapy, however, changed the results: HRs were no longer significantly different, compared with etanercept, for tocilizumab, adalimumab, and infliximab for most lines of therapy.
Indeed, while the risk for serious infection occurring with tocilizumab was 20% higher overall, compared with etanercept, that risk was actually lower if tocilizumab had been used as first- or fifth-line therapy (HRs for both, 0.9) but higher if it had been used as a third- or fourth-line therapy (HR of 1.4 for both).
“We often use tocilizumab as a second-line, third-line, or even fourth-line therapy, and if we don’t adjust for anything, we can have the impression that there are more infections with tocilizumab. But then, when we adjust for confounding factors and the line of therapy, we don’t have this anymore,” Dr. Lauper said.
“Line of therapy in itself is not a risk for serious infections,” she said in qualifying the conclusions that could be drawn from the study. “It may be a marker of the disease or some patient characteristic that is associated with a higher risk of infections.” Nevertheless, it should be taken into account when evaluating serious outcomes and possibly other safety and effectiveness outcomes.
“I understand concentrating on the hospitalized infections because the data are so much more robust,” observed consultant rheumatologist Jon Packham, BM, DM, of Haywood Hospital in Stoke-on-Trent, England, who chaired the session. He queried if there were any data on milder or just antibiotic-treated infections. At present, there aren’t those data to look at, Dr. Lauper responded, as this is something that’s difficult for registers to capture because doctors often do not log them in the databases.
There are also too few data on Janus kinase (JAK) inhibitors currently in the BSRBR-RA at present to be able to look at their rate of serious infection by line of therapy, Dr. Lauper noted. Because JAK inhibitors act on cytokines different from those affected by biologics for RA, there may be a difference there, but more data are needed on the JAK inhibitors before that question can be analyzed.
Dr. Lauper did not state having any disclosures. The BSRBR-RA is funded by the BSR via restricted income grants from several U.K. pharmaceutical companies, which has included or currently includes AbbVie, Celltrion, Hospira, Pfizer, UCB, Roche, Swedish Orphan Biovitrum, and Merck.
The order in which tocilizumab (Actemra) is used in the sequence of treatments for rheumatoid arthritis could be muddying the waters when it comes to evaluating patients’ risk for serious infection.
According to new data emerging from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA), the line of therapy is a confounding factor when examining the risk for serious infection with not only tocilizumab but also other biologic agents.
The good news for patients, however, is that there doesn’t appear to be any overall greater risk for serious infection with one biologic over another when the line of therapy is taken into account.
“We don’t have any strong signal that there is an increased risk of serious infections with tocilizumab, compared to TNF inhibitors,” rheumatologist Kim Lauper, MD, of Geneva University Hospitals, said in an interview after presenting the data at the annual conference of the British Society for Rheumatology.
This is in contrast to studies where an increased risk of infections with tocilizumab has been seen when compared to TNF inhibitors. However, those studies did not account for the line of therapy, explained Dr. Lauper, who is also a clinical research fellow in the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), where the BSRBR-RA is managed.
“Tocilizumab is a treatment that we often give to patients after several other treatments, so they’re really different patients,” Dr. Lauper observed. Indeed, in the “real-world” setting, patients taking tocilizumab tend to be older, have longer disease duration, and have worse functional status than do those who might receive other biologics.
To look at the effect of line of therapy on the serious infection risk associated with commonly used biologic drugs, Dr. Lauper and associates examined data on more than 33,000 treatment courses, representing more than 62,500 patient-years.
Using etanercept as the comparator – because it represents the largest group of patients in the BSRBR-RA – the serious infection risk for tocilizumab, rituximab, adalimumab, infliximab, certolizumab pegol, and abatacept were calculated as an overall rate, and for their use as first-, second-, third-, fourth-, or fifth-line therapy.
The researchers adjusted their analysis for some clear baseline differences between the treatment groups, including age, prior treatment, disease duration, and comorbidities. Seropositivity, smoking status, general health status, and disease activity scores were also adjusted for in the analysis.
Crude hazard ratios (HRs), compared with etanercept, before and after adjusting for these already-known confounding factors were 1.0 and 1.2 for tocilizumab, 1.1 and 1.1 for adalimumab, 1.4 and 1.3 for infliximab, 0.6 and 0.8 for certolizumab pegol, 0.9 and 1.0 for rituximab, and 0.9 and 1.2 for abatacept.
Stratifying by line of therapy, however, changed the results: HRs were no longer significantly different, compared with etanercept, for tocilizumab, adalimumab, and infliximab for most lines of therapy.
Indeed, while the risk for serious infection occurring with tocilizumab was 20% higher overall, compared with etanercept, that risk was actually lower if tocilizumab had been used as first- or fifth-line therapy (HRs for both, 0.9) but higher if it had been used as a third- or fourth-line therapy (HR of 1.4 for both).
“We often use tocilizumab as a second-line, third-line, or even fourth-line therapy, and if we don’t adjust for anything, we can have the impression that there are more infections with tocilizumab. But then, when we adjust for confounding factors and the line of therapy, we don’t have this anymore,” Dr. Lauper said.
“Line of therapy in itself is not a risk for serious infections,” she said in qualifying the conclusions that could be drawn from the study. “It may be a marker of the disease or some patient characteristic that is associated with a higher risk of infections.” Nevertheless, it should be taken into account when evaluating serious outcomes and possibly other safety and effectiveness outcomes.
“I understand concentrating on the hospitalized infections because the data are so much more robust,” observed consultant rheumatologist Jon Packham, BM, DM, of Haywood Hospital in Stoke-on-Trent, England, who chaired the session. He queried if there were any data on milder or just antibiotic-treated infections. At present, there aren’t those data to look at, Dr. Lauper responded, as this is something that’s difficult for registers to capture because doctors often do not log them in the databases.
There are also too few data on Janus kinase (JAK) inhibitors currently in the BSRBR-RA at present to be able to look at their rate of serious infection by line of therapy, Dr. Lauper noted. Because JAK inhibitors act on cytokines different from those affected by biologics for RA, there may be a difference there, but more data are needed on the JAK inhibitors before that question can be analyzed.
Dr. Lauper did not state having any disclosures. The BSRBR-RA is funded by the BSR via restricted income grants from several U.K. pharmaceutical companies, which has included or currently includes AbbVie, Celltrion, Hospira, Pfizer, UCB, Roche, Swedish Orphan Biovitrum, and Merck.
FROM BSR 2021
Survival benefit with nivolumab extends to 5 years in NSCLC
Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m2 once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.
At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.
The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.
There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.
According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”
“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.
Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”
No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.
The optimal duration of nivolumab treatment beyond 1 year is also uncertain.
The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.
The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.
They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.
Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.
This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.
Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m2 once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.
At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.
The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.
There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.
According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”
“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.
Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”
No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.
The optimal duration of nivolumab treatment beyond 1 year is also uncertain.
The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.
The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.
They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.
Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.
This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.
Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m2 once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.
At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.
The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.
There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.
According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”
“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.
Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”
No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.
The optimal duration of nivolumab treatment beyond 1 year is also uncertain.
The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.
The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.
They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.
Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.
This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Psilocybin matches SSRI for moderate to severe depression in phase 2 study
The psychedelic drug psilocybin performed just as well as a widely used antidepressant in easing the symptoms of major depression, and outperformed the selective serotonin reuptake inhibitor on a range of secondary measures, results of a small-scale, phase 2 study show.
In a 6-week trial that included 59 patients with moderate to severe depression, there was no significant difference between the impact of high-dose psilocybin on the study’s primary yardstick – the 16-item Quick Inventory of Depressive Symptomatology–Self-Report – and that of the SSRI escitalopram.
Patients in the psilocybin cohort did show a much more rapid improvement in the main measure than those taking escitalopram, but this gap narrowed over the span of the trial until it was no longer statistically significant.
“It’s very clear that psilocybin therapy has a faster antidepressant onset than escitalopram. And psilocybin was consistently superior on the ancillary outcomes, but it wasn’t different on the primary,” the study’s lead author Robin Carhart-Harris, PhD, head of the Centre for Psychedelic Research at Imperial College London, told reporters attending a news briefing.
Results of the phase 2, double-blind, randomized study were published online April 15, 2021, in the New England Journal of Medicine.
Secondary outcomes
Investigators found that psilocybin bested escitalopram in several secondary outcomes, including feelings of well-being, the ability to express emotion, and social functioning.
Still, Larger and longer trials are required.
“But the secondaries were highly suggestive – tantalizingly suggestive – of the potential superiority of psilocybin therapy to treat not just depression, but these ancillary symptoms,” Dr. Carhart-Harris said.
After they were selected from 1000 screening calls, the 59 patients were randomly assigned to receive psilocybin and 29 patients to receive escitalopram. Every procedure was mirrored in both groups.
At the 2 “dosing days” scheduled during the 6-week trial, all patients received an oral dose of psilocybin in a clinical setting. However, the escitalopram group received 1 mg versus 25 mg for the psilocybin group.
“And the reason why we did that is because we can standardize expectation. We say to everyone, you will receive psilocybin. It’s just the dosage might differ,” Dr. Carhart-Harris said.
He conceded that most patients – though not all – were able to determine which group they were in following the first dosing day based on the drugs’ effects.
Supportive therapy
Following the oral dose, volunteers would spend 6 hours reclining on a bed, surrounded by pillows and a curated selection of music and supported by two “guides” or therapists. The guides were on hand to support patients through their psychedelic experience but did not chat or otherwise interfere.
The next day, patients attended a session with their two therapists to talk through their experiences.
Between dosing days, patients in the high-dose psilocybin group would take daily capsules containing a placebo. The low-dose group received a course of escitalopram.
The incidence of adverse effects was similar in each group. None was serious.
The study’s principal investigator David Nutt, DM, FRCP, FRCPsych, FSB, FMedSci, the Edmond J. Safra Chair in Neuropsychopharmacology at Imperial College London, said that many patients in the psilocybin group reported revelatory insights during dosing days.
“Very often, for the first time, people have actually come to understand why they’re depressed,” he said.
The word psychedelic, coined in 1957 by psychiatrist Humphry Osmond, derives from the Greek words “psyche,” which means “soul” or “mind,” and “delos,” which means “reveal.”
'Profound experiences'
Certainly, patients in the psilocybin group received enough of the compound to induce what Dr. Carhart-Harris called “very profound experiences.”
The researchers said that the results, while promising, should not encourage anyone to self-medicate with psychedelic substances, which are still illegal in most jurisdictions.
“I view this very much – and I think most colleagues do as well – as a combination treatment,” Dr. Carhart-Harris said. “And we strongly believe that the psychotherapy component is as important as the drug action.”
He said the study was inspired by his earlier research into the effects of psilocybin on brain function along with a small open-label trial of the compound’s effects on treatment-resistant depression published in The Lancet Psychiatry in July 2016.
The team stressed that the cohort and the absence of an entirely placebo group limit conclusions that can be drawn about either treatment.
Dr. Carhart-Harris also said he would have liked a more diverse group of patients. Participants were mostly White and mostly male, with a mean age of 41, and a high educational attainment. Of the 59 enrolled, only 34% were women.
Volunteers underwent functional MRI scans at the start and end of the trial. The team will now analyze these results to gain insight into impact on brain function and will gather and assess follow-up data. They also plan a trial examining the effect of psilocybin on anorexia.
“I think it’s fair to say the results signal hope that we may be looking at a promising alternative treatment for depression,” Dr. Carhart-Harris said. “It’s often said that we need novel treatments to treat depression because too many new drugs are what [are] sometimes called ‘me too’ drugs: They work in the same way as drugs that have preceded them. Psilocybin therapy seems to work fundamentally in a different way to SSRIs.”
Unanswered questions
In an accompanying editorial, Jeffrey A. Lieberman, MD, Lawrence C. Kolb Professor and chairman of the department of psychiatry at Columbia University, New York, warned that there remain many unanswered questions about using psychedelics for medical purposes.
They were considered potential miracle cures for a range of mental disorders in the 1960s, only to be banned in 1970s America because of “the perceived dangers and corrosive effects” on society, he wrote.
“The Carhart-Harris study notwithstanding, we are still awaiting definitive proof of the therapeutic efficacy of psychedelics and their capacity to improve the human condition,” Dr. Lieberman wrote. “Should the mind-bending properties of the psychedelics prove to be the panacea their proponents professed, informed consent and safety standards must be established. How do we explain mystical, ineffable, and potentially transformative experiences to patients, particularly if they are in a vulnerable state of mind? What is their potential for addiction?”
David Owens, MD, PhD, professor emeritus of clinical psychiatry at the University of Edinburgh, described Lieberman’s comments as “spot on.”
“This is a small, exploratory study with numbers too small to analyze fully,” he said. “The population is not recruited randomly from, for example, consecutive admissions or presentations, and screening of volunteers was by telephone, not face to face. One might say this is an ‘interested’ population, willing to go for novel approaches and with no placebo group, the extent of the placebo response cannot be assessed.”
The study was funded by the Alexander Mosley Charitable Trust and the founders of the Centre for Psychedelic Research. Infrastructure support was provided by the National Institute for Health Research Imperial Biomedical Research Centre and NIHR Imperial Clinical Research Facility.
A version of this article first appeared on Medscape.com.
The psychedelic drug psilocybin performed just as well as a widely used antidepressant in easing the symptoms of major depression, and outperformed the selective serotonin reuptake inhibitor on a range of secondary measures, results of a small-scale, phase 2 study show.
In a 6-week trial that included 59 patients with moderate to severe depression, there was no significant difference between the impact of high-dose psilocybin on the study’s primary yardstick – the 16-item Quick Inventory of Depressive Symptomatology–Self-Report – and that of the SSRI escitalopram.
Patients in the psilocybin cohort did show a much more rapid improvement in the main measure than those taking escitalopram, but this gap narrowed over the span of the trial until it was no longer statistically significant.
“It’s very clear that psilocybin therapy has a faster antidepressant onset than escitalopram. And psilocybin was consistently superior on the ancillary outcomes, but it wasn’t different on the primary,” the study’s lead author Robin Carhart-Harris, PhD, head of the Centre for Psychedelic Research at Imperial College London, told reporters attending a news briefing.
Results of the phase 2, double-blind, randomized study were published online April 15, 2021, in the New England Journal of Medicine.
Secondary outcomes
Investigators found that psilocybin bested escitalopram in several secondary outcomes, including feelings of well-being, the ability to express emotion, and social functioning.
Still, Larger and longer trials are required.
“But the secondaries were highly suggestive – tantalizingly suggestive – of the potential superiority of psilocybin therapy to treat not just depression, but these ancillary symptoms,” Dr. Carhart-Harris said.
After they were selected from 1000 screening calls, the 59 patients were randomly assigned to receive psilocybin and 29 patients to receive escitalopram. Every procedure was mirrored in both groups.
At the 2 “dosing days” scheduled during the 6-week trial, all patients received an oral dose of psilocybin in a clinical setting. However, the escitalopram group received 1 mg versus 25 mg for the psilocybin group.
“And the reason why we did that is because we can standardize expectation. We say to everyone, you will receive psilocybin. It’s just the dosage might differ,” Dr. Carhart-Harris said.
He conceded that most patients – though not all – were able to determine which group they were in following the first dosing day based on the drugs’ effects.
Supportive therapy
Following the oral dose, volunteers would spend 6 hours reclining on a bed, surrounded by pillows and a curated selection of music and supported by two “guides” or therapists. The guides were on hand to support patients through their psychedelic experience but did not chat or otherwise interfere.
The next day, patients attended a session with their two therapists to talk through their experiences.
Between dosing days, patients in the high-dose psilocybin group would take daily capsules containing a placebo. The low-dose group received a course of escitalopram.
The incidence of adverse effects was similar in each group. None was serious.
The study’s principal investigator David Nutt, DM, FRCP, FRCPsych, FSB, FMedSci, the Edmond J. Safra Chair in Neuropsychopharmacology at Imperial College London, said that many patients in the psilocybin group reported revelatory insights during dosing days.
“Very often, for the first time, people have actually come to understand why they’re depressed,” he said.
The word psychedelic, coined in 1957 by psychiatrist Humphry Osmond, derives from the Greek words “psyche,” which means “soul” or “mind,” and “delos,” which means “reveal.”
'Profound experiences'
Certainly, patients in the psilocybin group received enough of the compound to induce what Dr. Carhart-Harris called “very profound experiences.”
The researchers said that the results, while promising, should not encourage anyone to self-medicate with psychedelic substances, which are still illegal in most jurisdictions.
“I view this very much – and I think most colleagues do as well – as a combination treatment,” Dr. Carhart-Harris said. “And we strongly believe that the psychotherapy component is as important as the drug action.”
He said the study was inspired by his earlier research into the effects of psilocybin on brain function along with a small open-label trial of the compound’s effects on treatment-resistant depression published in The Lancet Psychiatry in July 2016.
The team stressed that the cohort and the absence of an entirely placebo group limit conclusions that can be drawn about either treatment.
Dr. Carhart-Harris also said he would have liked a more diverse group of patients. Participants were mostly White and mostly male, with a mean age of 41, and a high educational attainment. Of the 59 enrolled, only 34% were women.
Volunteers underwent functional MRI scans at the start and end of the trial. The team will now analyze these results to gain insight into impact on brain function and will gather and assess follow-up data. They also plan a trial examining the effect of psilocybin on anorexia.
“I think it’s fair to say the results signal hope that we may be looking at a promising alternative treatment for depression,” Dr. Carhart-Harris said. “It’s often said that we need novel treatments to treat depression because too many new drugs are what [are] sometimes called ‘me too’ drugs: They work in the same way as drugs that have preceded them. Psilocybin therapy seems to work fundamentally in a different way to SSRIs.”
Unanswered questions
In an accompanying editorial, Jeffrey A. Lieberman, MD, Lawrence C. Kolb Professor and chairman of the department of psychiatry at Columbia University, New York, warned that there remain many unanswered questions about using psychedelics for medical purposes.
They were considered potential miracle cures for a range of mental disorders in the 1960s, only to be banned in 1970s America because of “the perceived dangers and corrosive effects” on society, he wrote.
“The Carhart-Harris study notwithstanding, we are still awaiting definitive proof of the therapeutic efficacy of psychedelics and their capacity to improve the human condition,” Dr. Lieberman wrote. “Should the mind-bending properties of the psychedelics prove to be the panacea their proponents professed, informed consent and safety standards must be established. How do we explain mystical, ineffable, and potentially transformative experiences to patients, particularly if they are in a vulnerable state of mind? What is their potential for addiction?”
David Owens, MD, PhD, professor emeritus of clinical psychiatry at the University of Edinburgh, described Lieberman’s comments as “spot on.”
“This is a small, exploratory study with numbers too small to analyze fully,” he said. “The population is not recruited randomly from, for example, consecutive admissions or presentations, and screening of volunteers was by telephone, not face to face. One might say this is an ‘interested’ population, willing to go for novel approaches and with no placebo group, the extent of the placebo response cannot be assessed.”
The study was funded by the Alexander Mosley Charitable Trust and the founders of the Centre for Psychedelic Research. Infrastructure support was provided by the National Institute for Health Research Imperial Biomedical Research Centre and NIHR Imperial Clinical Research Facility.
A version of this article first appeared on Medscape.com.
The psychedelic drug psilocybin performed just as well as a widely used antidepressant in easing the symptoms of major depression, and outperformed the selective serotonin reuptake inhibitor on a range of secondary measures, results of a small-scale, phase 2 study show.
In a 6-week trial that included 59 patients with moderate to severe depression, there was no significant difference between the impact of high-dose psilocybin on the study’s primary yardstick – the 16-item Quick Inventory of Depressive Symptomatology–Self-Report – and that of the SSRI escitalopram.
Patients in the psilocybin cohort did show a much more rapid improvement in the main measure than those taking escitalopram, but this gap narrowed over the span of the trial until it was no longer statistically significant.
“It’s very clear that psilocybin therapy has a faster antidepressant onset than escitalopram. And psilocybin was consistently superior on the ancillary outcomes, but it wasn’t different on the primary,” the study’s lead author Robin Carhart-Harris, PhD, head of the Centre for Psychedelic Research at Imperial College London, told reporters attending a news briefing.
Results of the phase 2, double-blind, randomized study were published online April 15, 2021, in the New England Journal of Medicine.
Secondary outcomes
Investigators found that psilocybin bested escitalopram in several secondary outcomes, including feelings of well-being, the ability to express emotion, and social functioning.
Still, Larger and longer trials are required.
“But the secondaries were highly suggestive – tantalizingly suggestive – of the potential superiority of psilocybin therapy to treat not just depression, but these ancillary symptoms,” Dr. Carhart-Harris said.
After they were selected from 1000 screening calls, the 59 patients were randomly assigned to receive psilocybin and 29 patients to receive escitalopram. Every procedure was mirrored in both groups.
At the 2 “dosing days” scheduled during the 6-week trial, all patients received an oral dose of psilocybin in a clinical setting. However, the escitalopram group received 1 mg versus 25 mg for the psilocybin group.
“And the reason why we did that is because we can standardize expectation. We say to everyone, you will receive psilocybin. It’s just the dosage might differ,” Dr. Carhart-Harris said.
He conceded that most patients – though not all – were able to determine which group they were in following the first dosing day based on the drugs’ effects.
Supportive therapy
Following the oral dose, volunteers would spend 6 hours reclining on a bed, surrounded by pillows and a curated selection of music and supported by two “guides” or therapists. The guides were on hand to support patients through their psychedelic experience but did not chat or otherwise interfere.
The next day, patients attended a session with their two therapists to talk through their experiences.
Between dosing days, patients in the high-dose psilocybin group would take daily capsules containing a placebo. The low-dose group received a course of escitalopram.
The incidence of adverse effects was similar in each group. None was serious.
The study’s principal investigator David Nutt, DM, FRCP, FRCPsych, FSB, FMedSci, the Edmond J. Safra Chair in Neuropsychopharmacology at Imperial College London, said that many patients in the psilocybin group reported revelatory insights during dosing days.
“Very often, for the first time, people have actually come to understand why they’re depressed,” he said.
The word psychedelic, coined in 1957 by psychiatrist Humphry Osmond, derives from the Greek words “psyche,” which means “soul” or “mind,” and “delos,” which means “reveal.”
'Profound experiences'
Certainly, patients in the psilocybin group received enough of the compound to induce what Dr. Carhart-Harris called “very profound experiences.”
The researchers said that the results, while promising, should not encourage anyone to self-medicate with psychedelic substances, which are still illegal in most jurisdictions.
“I view this very much – and I think most colleagues do as well – as a combination treatment,” Dr. Carhart-Harris said. “And we strongly believe that the psychotherapy component is as important as the drug action.”
He said the study was inspired by his earlier research into the effects of psilocybin on brain function along with a small open-label trial of the compound’s effects on treatment-resistant depression published in The Lancet Psychiatry in July 2016.
The team stressed that the cohort and the absence of an entirely placebo group limit conclusions that can be drawn about either treatment.
Dr. Carhart-Harris also said he would have liked a more diverse group of patients. Participants were mostly White and mostly male, with a mean age of 41, and a high educational attainment. Of the 59 enrolled, only 34% were women.
Volunteers underwent functional MRI scans at the start and end of the trial. The team will now analyze these results to gain insight into impact on brain function and will gather and assess follow-up data. They also plan a trial examining the effect of psilocybin on anorexia.
“I think it’s fair to say the results signal hope that we may be looking at a promising alternative treatment for depression,” Dr. Carhart-Harris said. “It’s often said that we need novel treatments to treat depression because too many new drugs are what [are] sometimes called ‘me too’ drugs: They work in the same way as drugs that have preceded them. Psilocybin therapy seems to work fundamentally in a different way to SSRIs.”
Unanswered questions
In an accompanying editorial, Jeffrey A. Lieberman, MD, Lawrence C. Kolb Professor and chairman of the department of psychiatry at Columbia University, New York, warned that there remain many unanswered questions about using psychedelics for medical purposes.
They were considered potential miracle cures for a range of mental disorders in the 1960s, only to be banned in 1970s America because of “the perceived dangers and corrosive effects” on society, he wrote.
“The Carhart-Harris study notwithstanding, we are still awaiting definitive proof of the therapeutic efficacy of psychedelics and their capacity to improve the human condition,” Dr. Lieberman wrote. “Should the mind-bending properties of the psychedelics prove to be the panacea their proponents professed, informed consent and safety standards must be established. How do we explain mystical, ineffable, and potentially transformative experiences to patients, particularly if they are in a vulnerable state of mind? What is their potential for addiction?”
David Owens, MD, PhD, professor emeritus of clinical psychiatry at the University of Edinburgh, described Lieberman’s comments as “spot on.”
“This is a small, exploratory study with numbers too small to analyze fully,” he said. “The population is not recruited randomly from, for example, consecutive admissions or presentations, and screening of volunteers was by telephone, not face to face. One might say this is an ‘interested’ population, willing to go for novel approaches and with no placebo group, the extent of the placebo response cannot be assessed.”
The study was funded by the Alexander Mosley Charitable Trust and the founders of the Centre for Psychedelic Research. Infrastructure support was provided by the National Institute for Health Research Imperial Biomedical Research Centre and NIHR Imperial Clinical Research Facility.
A version of this article first appeared on Medscape.com.
Transgender hormone therapy linked to blood pressure changes
Transgender people treated with gender-affirming hormone therapy show distinctive changes in blood pressure that begin soon after treatment initiation and do not subside over years of treatment, according to the largest and longest observational study to date to look at the issue.
“Many physicians may not be aware of the changes to blood pressure in trans patients who start hormone therapy,” senior author Michael S. Irwig, MD, director of transgender medicine at Beth Israel Deaconess Medical Center in Boston, told this news organization.
“The take-away message for physicians is to monitor blood pressure both before and after starting hormone therapy in transgender patients, as over a third of transgender individuals had stage 1 hypertension before starting hormone therapy, and many had their blood pressure increase after starting hormone therapy.”
Mean blood pressure increases in transgender males, decreases in females
In the study, published in Hypertension, Katherine Banks, MD, George Washington University, Washington, and colleagues, followed 470 transgender adult patients for up to 5 years.
The mean systolic blood pressure levels in transgender female patients (male at birth) significantly decreased compared with baseline within a few months of them starting gender-affirming hormone treatment.
Conversely, the systolic blood pressure levels in transgender males (females at birth) who were treated with testosterone increased over the same period.
There were no significant changes in the groups in terms of diastolic blood pressure, consistent with other studies.
“Our study is the first to describe the time course of the blood pressure effects of gender-affirming hormone therapy and to compare the rates of elevated blood pressure and stage 1 and stage 2 hypertension using blood pressure readings from gender-diverse individuals pre- and post–gender-affirming hormone therapy,” the authors note.
Gender-affirming hormone therapy – which has been prescribed to transgender patients for more than 25 years – typically involves a combination of estrogen and an anti-androgen for males transitioning to female, while the therapy for those transitioning to male generally only involves testosterone.
The therapy has previously been linked to various cardiac effects, with evidence showing transgender men have as much as a 5-times greater risk of heart attack versus cisgender women, the authors note.
Although the American Heart Association issued a 2020 Scientific Statement addressing the cardiovascular disease risk, evidence on the effects specifically on blood pressure in transgender patients has been inconsistent.
For the new study, Dr. Banks and colleagues enrolled 247 transgender females and 223 transgender males who were treated between 2007 and 2015 at two medical centers in Washington, D.C. Of the individuals, who had a mean age of 27.8, about 27% were non-White and 16% were Latinx.
They had blood pressure measurements taken at baseline and at follow-up clinical visits for up to 57 months following the initiation of gender-affirming hormone therapy.
Over the follow-up period, the transgender females had decreases in mean systolic blood pressure of 4.0 mm Hg within 2 to 4 months of starting hormone therapy (P < .0001) and mean declines of 6.0 mm Hg were further observed at 11 to 21 months compared with baseline.
In transgender males, the mean systolic blood pressure increased by 2.6 mm Hg at 2 to 4 months (P = .02), and by 2.9 mm Hg at 11 to 21 months after starting therapy.
Furthermore, “although the average increase in systolic blood pressure was 2.6 mm Hg in transgender men within 2 to 4 months, some patients had much higher increases,” Dr. Irwig noted.
As many as 40% of transgender men had stage 1 hypertension after 11 to 21 months of hormone therapy.
The blood pressure changes in transgender males and females were observed across all three racial ethnic groups of Whites, Blacks, and Latinx, and the changes remained consistent throughout the entire follow-up period of approximately 5 years while hormone therapy was continued.
In addition to the changes after therapy initiation, the researchers note that more than one-third of individuals in both groups had stage 1 hypertension even before starting hormone therapy.
The findings are a concern in light of “clear evidence linking hypertension and higher blood pressure with cardiovascular events such as stroke and heart attacks,” Dr. Irwig said.
Protective effects for transgender females?
Transgender females showed as much as a 47% decrease in the prevalence of stage 2 hypertension, from 19% to 10%, within 2 to 4 months of treatment with gender-affirming hormone therapy (P = .001), and the rate declined further to 8% at 11 to 21 months, suggesting a protective effect of the treatment.
“The rate of stage 2 hypertension did drop in transgender feminine individuals, which could be protective and lower their risk for cardiovascular events,” Dr. Irwig said.
“This was not a surprise, as lowering testosterone and the use of spironolactone can lower blood pressure,” he noted.
Exceptions in both groups
Of note, a sizable proportion of patients had blood pressure changes that were in fact the opposite of the patterns seen in the majority of their gender group.
Specifically, while 42% to 53% of the transgender females had systolic blood pressure readings of at least 5 mm Hg lower than their baseline readings, up to 32% had increases of at least 5 mm Hg compared to baseline readings.
Likewise, whereas 41% to 59% of transgender males had increases of at least 5 mm Hg compared with baseline, up to 35% had levels that were at least 5 mm Hg lower than baseline.
“It was a surprise that over a quarter of individuals had changes opposite to the mean changes,” Dr. Irwig said.
The differing blood pressure changes underscore that “more research is needed to determine which formulations of estrogen, testosterone, and antiandrogens are optimal regarding blood pressure and cardiovascular health, especially in older individuals,” the authors note.
Gender-affirming hormone therapy formulations differ
Various formulations for gender-affirming hormone regimens are available, including oral, transdermal, sublingual, and intramuscular preparations.
In the study, 77% to 91% of transgender males were on intramuscular testosterone injections, with the rest on transdermal formulations, and 92% of transgender female patients were started on oral estradiol, with mean doses generally increasing over time.
The study’s results are consistent with evidence from other studies, with 7 of 8 involving transgender males showing mean increases in systolic blood pressure ranging from 1 to 14 mm Hg.
Previous research supports cardiovascular risk
As reported by this news organization, other emerging research on cardiovascular risks to transgender people include a recent study showing more than 10% of transgender males were found to have hematocrit levels that could put them at risk for blood clots.
And further research on transgender youth also shows concerning elevations in lipids and other cardiovascular risks.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Transgender people treated with gender-affirming hormone therapy show distinctive changes in blood pressure that begin soon after treatment initiation and do not subside over years of treatment, according to the largest and longest observational study to date to look at the issue.
“Many physicians may not be aware of the changes to blood pressure in trans patients who start hormone therapy,” senior author Michael S. Irwig, MD, director of transgender medicine at Beth Israel Deaconess Medical Center in Boston, told this news organization.
“The take-away message for physicians is to monitor blood pressure both before and after starting hormone therapy in transgender patients, as over a third of transgender individuals had stage 1 hypertension before starting hormone therapy, and many had their blood pressure increase after starting hormone therapy.”
Mean blood pressure increases in transgender males, decreases in females
In the study, published in Hypertension, Katherine Banks, MD, George Washington University, Washington, and colleagues, followed 470 transgender adult patients for up to 5 years.
The mean systolic blood pressure levels in transgender female patients (male at birth) significantly decreased compared with baseline within a few months of them starting gender-affirming hormone treatment.
Conversely, the systolic blood pressure levels in transgender males (females at birth) who were treated with testosterone increased over the same period.
There were no significant changes in the groups in terms of diastolic blood pressure, consistent with other studies.
“Our study is the first to describe the time course of the blood pressure effects of gender-affirming hormone therapy and to compare the rates of elevated blood pressure and stage 1 and stage 2 hypertension using blood pressure readings from gender-diverse individuals pre- and post–gender-affirming hormone therapy,” the authors note.
Gender-affirming hormone therapy – which has been prescribed to transgender patients for more than 25 years – typically involves a combination of estrogen and an anti-androgen for males transitioning to female, while the therapy for those transitioning to male generally only involves testosterone.
The therapy has previously been linked to various cardiac effects, with evidence showing transgender men have as much as a 5-times greater risk of heart attack versus cisgender women, the authors note.
Although the American Heart Association issued a 2020 Scientific Statement addressing the cardiovascular disease risk, evidence on the effects specifically on blood pressure in transgender patients has been inconsistent.
For the new study, Dr. Banks and colleagues enrolled 247 transgender females and 223 transgender males who were treated between 2007 and 2015 at two medical centers in Washington, D.C. Of the individuals, who had a mean age of 27.8, about 27% were non-White and 16% were Latinx.
They had blood pressure measurements taken at baseline and at follow-up clinical visits for up to 57 months following the initiation of gender-affirming hormone therapy.
Over the follow-up period, the transgender females had decreases in mean systolic blood pressure of 4.0 mm Hg within 2 to 4 months of starting hormone therapy (P < .0001) and mean declines of 6.0 mm Hg were further observed at 11 to 21 months compared with baseline.
In transgender males, the mean systolic blood pressure increased by 2.6 mm Hg at 2 to 4 months (P = .02), and by 2.9 mm Hg at 11 to 21 months after starting therapy.
Furthermore, “although the average increase in systolic blood pressure was 2.6 mm Hg in transgender men within 2 to 4 months, some patients had much higher increases,” Dr. Irwig noted.
As many as 40% of transgender men had stage 1 hypertension after 11 to 21 months of hormone therapy.
The blood pressure changes in transgender males and females were observed across all three racial ethnic groups of Whites, Blacks, and Latinx, and the changes remained consistent throughout the entire follow-up period of approximately 5 years while hormone therapy was continued.
In addition to the changes after therapy initiation, the researchers note that more than one-third of individuals in both groups had stage 1 hypertension even before starting hormone therapy.
The findings are a concern in light of “clear evidence linking hypertension and higher blood pressure with cardiovascular events such as stroke and heart attacks,” Dr. Irwig said.
Protective effects for transgender females?
Transgender females showed as much as a 47% decrease in the prevalence of stage 2 hypertension, from 19% to 10%, within 2 to 4 months of treatment with gender-affirming hormone therapy (P = .001), and the rate declined further to 8% at 11 to 21 months, suggesting a protective effect of the treatment.
“The rate of stage 2 hypertension did drop in transgender feminine individuals, which could be protective and lower their risk for cardiovascular events,” Dr. Irwig said.
“This was not a surprise, as lowering testosterone and the use of spironolactone can lower blood pressure,” he noted.
Exceptions in both groups
Of note, a sizable proportion of patients had blood pressure changes that were in fact the opposite of the patterns seen in the majority of their gender group.
Specifically, while 42% to 53% of the transgender females had systolic blood pressure readings of at least 5 mm Hg lower than their baseline readings, up to 32% had increases of at least 5 mm Hg compared to baseline readings.
Likewise, whereas 41% to 59% of transgender males had increases of at least 5 mm Hg compared with baseline, up to 35% had levels that were at least 5 mm Hg lower than baseline.
“It was a surprise that over a quarter of individuals had changes opposite to the mean changes,” Dr. Irwig said.
The differing blood pressure changes underscore that “more research is needed to determine which formulations of estrogen, testosterone, and antiandrogens are optimal regarding blood pressure and cardiovascular health, especially in older individuals,” the authors note.
Gender-affirming hormone therapy formulations differ
Various formulations for gender-affirming hormone regimens are available, including oral, transdermal, sublingual, and intramuscular preparations.
In the study, 77% to 91% of transgender males were on intramuscular testosterone injections, with the rest on transdermal formulations, and 92% of transgender female patients were started on oral estradiol, with mean doses generally increasing over time.
The study’s results are consistent with evidence from other studies, with 7 of 8 involving transgender males showing mean increases in systolic blood pressure ranging from 1 to 14 mm Hg.
Previous research supports cardiovascular risk
As reported by this news organization, other emerging research on cardiovascular risks to transgender people include a recent study showing more than 10% of transgender males were found to have hematocrit levels that could put them at risk for blood clots.
And further research on transgender youth also shows concerning elevations in lipids and other cardiovascular risks.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Transgender people treated with gender-affirming hormone therapy show distinctive changes in blood pressure that begin soon after treatment initiation and do not subside over years of treatment, according to the largest and longest observational study to date to look at the issue.
“Many physicians may not be aware of the changes to blood pressure in trans patients who start hormone therapy,” senior author Michael S. Irwig, MD, director of transgender medicine at Beth Israel Deaconess Medical Center in Boston, told this news organization.
“The take-away message for physicians is to monitor blood pressure both before and after starting hormone therapy in transgender patients, as over a third of transgender individuals had stage 1 hypertension before starting hormone therapy, and many had their blood pressure increase after starting hormone therapy.”
Mean blood pressure increases in transgender males, decreases in females
In the study, published in Hypertension, Katherine Banks, MD, George Washington University, Washington, and colleagues, followed 470 transgender adult patients for up to 5 years.
The mean systolic blood pressure levels in transgender female patients (male at birth) significantly decreased compared with baseline within a few months of them starting gender-affirming hormone treatment.
Conversely, the systolic blood pressure levels in transgender males (females at birth) who were treated with testosterone increased over the same period.
There were no significant changes in the groups in terms of diastolic blood pressure, consistent with other studies.
“Our study is the first to describe the time course of the blood pressure effects of gender-affirming hormone therapy and to compare the rates of elevated blood pressure and stage 1 and stage 2 hypertension using blood pressure readings from gender-diverse individuals pre- and post–gender-affirming hormone therapy,” the authors note.
Gender-affirming hormone therapy – which has been prescribed to transgender patients for more than 25 years – typically involves a combination of estrogen and an anti-androgen for males transitioning to female, while the therapy for those transitioning to male generally only involves testosterone.
The therapy has previously been linked to various cardiac effects, with evidence showing transgender men have as much as a 5-times greater risk of heart attack versus cisgender women, the authors note.
Although the American Heart Association issued a 2020 Scientific Statement addressing the cardiovascular disease risk, evidence on the effects specifically on blood pressure in transgender patients has been inconsistent.
For the new study, Dr. Banks and colleagues enrolled 247 transgender females and 223 transgender males who were treated between 2007 and 2015 at two medical centers in Washington, D.C. Of the individuals, who had a mean age of 27.8, about 27% were non-White and 16% were Latinx.
They had blood pressure measurements taken at baseline and at follow-up clinical visits for up to 57 months following the initiation of gender-affirming hormone therapy.
Over the follow-up period, the transgender females had decreases in mean systolic blood pressure of 4.0 mm Hg within 2 to 4 months of starting hormone therapy (P < .0001) and mean declines of 6.0 mm Hg were further observed at 11 to 21 months compared with baseline.
In transgender males, the mean systolic blood pressure increased by 2.6 mm Hg at 2 to 4 months (P = .02), and by 2.9 mm Hg at 11 to 21 months after starting therapy.
Furthermore, “although the average increase in systolic blood pressure was 2.6 mm Hg in transgender men within 2 to 4 months, some patients had much higher increases,” Dr. Irwig noted.
As many as 40% of transgender men had stage 1 hypertension after 11 to 21 months of hormone therapy.
The blood pressure changes in transgender males and females were observed across all three racial ethnic groups of Whites, Blacks, and Latinx, and the changes remained consistent throughout the entire follow-up period of approximately 5 years while hormone therapy was continued.
In addition to the changes after therapy initiation, the researchers note that more than one-third of individuals in both groups had stage 1 hypertension even before starting hormone therapy.
The findings are a concern in light of “clear evidence linking hypertension and higher blood pressure with cardiovascular events such as stroke and heart attacks,” Dr. Irwig said.
Protective effects for transgender females?
Transgender females showed as much as a 47% decrease in the prevalence of stage 2 hypertension, from 19% to 10%, within 2 to 4 months of treatment with gender-affirming hormone therapy (P = .001), and the rate declined further to 8% at 11 to 21 months, suggesting a protective effect of the treatment.
“The rate of stage 2 hypertension did drop in transgender feminine individuals, which could be protective and lower their risk for cardiovascular events,” Dr. Irwig said.
“This was not a surprise, as lowering testosterone and the use of spironolactone can lower blood pressure,” he noted.
Exceptions in both groups
Of note, a sizable proportion of patients had blood pressure changes that were in fact the opposite of the patterns seen in the majority of their gender group.
Specifically, while 42% to 53% of the transgender females had systolic blood pressure readings of at least 5 mm Hg lower than their baseline readings, up to 32% had increases of at least 5 mm Hg compared to baseline readings.
Likewise, whereas 41% to 59% of transgender males had increases of at least 5 mm Hg compared with baseline, up to 35% had levels that were at least 5 mm Hg lower than baseline.
“It was a surprise that over a quarter of individuals had changes opposite to the mean changes,” Dr. Irwig said.
The differing blood pressure changes underscore that “more research is needed to determine which formulations of estrogen, testosterone, and antiandrogens are optimal regarding blood pressure and cardiovascular health, especially in older individuals,” the authors note.
Gender-affirming hormone therapy formulations differ
Various formulations for gender-affirming hormone regimens are available, including oral, transdermal, sublingual, and intramuscular preparations.
In the study, 77% to 91% of transgender males were on intramuscular testosterone injections, with the rest on transdermal formulations, and 92% of transgender female patients were started on oral estradiol, with mean doses generally increasing over time.
The study’s results are consistent with evidence from other studies, with 7 of 8 involving transgender males showing mean increases in systolic blood pressure ranging from 1 to 14 mm Hg.
Previous research supports cardiovascular risk
As reported by this news organization, other emerging research on cardiovascular risks to transgender people include a recent study showing more than 10% of transgender males were found to have hematocrit levels that could put them at risk for blood clots.
And further research on transgender youth also shows concerning elevations in lipids and other cardiovascular risks.
The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
GENUINE improvements: Ublituximab plus ibrutinib for CLL
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.
This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
What type of patients were treated in the GENUINE trial?
Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.
What were the main outcomes of the trial?
Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.
IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.
After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).
Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
What types of adverse events were found in the trial?
The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.
Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
What about serious adverse events?
Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.
Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?
In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.
Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?
I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.
Are there any other implications of the GENUINE trial?
I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.
Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).
Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.
A version of this article first appeared on Medscape.com.
Study shows how COVID-19 disrupted RA meds
During the first 3 months of the COVID-19 pandemic last year, about one-third of people with rheumatoid arthritis in the United States made changes in their RA medications, and, before the American College of Rheumatology tweaked its guidelines midway through that period, they were about twice as likely to make medication changes on their own than before the pandemic, according to an analysis of data in FORWARD, the National Databank for Rheumatic Diseases.
The study, published in Arthritis Care & Research, also found that about 10% of RA patients on hydroxychloroquine lost access to the drug at a time it was drawing interest as a treatment for COVID-19. Another finding was that a high percentage of patients on non–tumor necrosis factor biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors canceled or postponed appointments.
“Our results show that persons with RA who had medication changes in the first 3 months of the COVID-19 pandemic in the U.S. were more likely to have worse disease activity and higher exposure to prior DMARDs, but no statistical difference was found in terms of comorbidities,” first author Kaleb Michaud, PhD, and coauthors wrote. Dr. Michaud is with the National Databank for Rheumatic Diseases, Wichita, Kan., and the University of Nebraska Medical Center, Omaha.
The study evaluated responses from 734 adults who participated in FORWARD, an observational, multidisease registry. They answered online surveys about COVID-19 in May 2020 and had provided data on their medication use before the pandemic. A total of 30% (n = 221) reported medication changes in that period.
Details on medication changes
Medication changers were more likely to use glucocorticoids (GCs) (32.6% vs. 18.1%) and less likely to use nonhydroxychloroquine conventional DMARDs (49.3% vs. 62%) pre-COVID. Changers also reported higher rates of economic hardship during the pandemic (22.6% vs. 14.6%).
In the midst of the study period, the ACR issued a clinical guideline for treatment of rheumatic and musculoskeletal diseases (RMDs), emphasizing the need to maintain DMARD therapy, control disease activity, and reduce prednisone/GC use. The guideline advised continuing hydroxychloroquine and interleukin-6 inhibitor biologics in people with suspected or confirmed COVID-19.
Dr. Michaud and coauthors acknowledged the ongoing lack of knowledge about real-world treatment patterns for RA during the pandemic. They set out with this study to fill those knowledge gaps.
They noted that patients on bDMARDs (17.6%) and JAK inhibitors (17.1%) were more than twice as likely to discontinue medications than were those on conventional DMARDs (8.2%).
Switching to telehealth was the most common pandemic-related behavior change among patients in all DMARD groups, with rates ranging from 31% to 47.1%, followed by canceling or postponing appointments, with rates ranging from 27.9% to 36.4% depending on the DMARD group.
The study also found that RA patients widely adopted the behavior changes that the Centers for Disease Control and Prevention recommended during the pandemic, although the rates of restricting social contacts were significantly lower than the 90% reported in an early Italian study.
Dr. Michaud and coauthors also provided some explanation of why people on GCs and DMARDs were more likely than others to change medication patterns. “This may reflect efforts to reduce the perceived risk of infections due to GCs as well as the likely less-controlled disease activity associated with GC use,” they wrote. While the ACR’s early pandemic guidance followed the 2015 guidelines – that patients should continue on GCs at the “lowest possible dose” and not stop them “abruptly” – most U.S. rheumatologists reported cutting back on GC use during the pandemic.
The researchers acknowledged that evidence linking GC use with hospitalization for COVID-19, which emerged after they had surveyed study participants, was consistent their findings, but that the overall risk of COVID-19 in RA patients still isn’t known.
Pfizer funded the analysis, and a coauthor is an employee of Pfizer.
During the first 3 months of the COVID-19 pandemic last year, about one-third of people with rheumatoid arthritis in the United States made changes in their RA medications, and, before the American College of Rheumatology tweaked its guidelines midway through that period, they were about twice as likely to make medication changes on their own than before the pandemic, according to an analysis of data in FORWARD, the National Databank for Rheumatic Diseases.
The study, published in Arthritis Care & Research, also found that about 10% of RA patients on hydroxychloroquine lost access to the drug at a time it was drawing interest as a treatment for COVID-19. Another finding was that a high percentage of patients on non–tumor necrosis factor biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors canceled or postponed appointments.
“Our results show that persons with RA who had medication changes in the first 3 months of the COVID-19 pandemic in the U.S. were more likely to have worse disease activity and higher exposure to prior DMARDs, but no statistical difference was found in terms of comorbidities,” first author Kaleb Michaud, PhD, and coauthors wrote. Dr. Michaud is with the National Databank for Rheumatic Diseases, Wichita, Kan., and the University of Nebraska Medical Center, Omaha.
The study evaluated responses from 734 adults who participated in FORWARD, an observational, multidisease registry. They answered online surveys about COVID-19 in May 2020 and had provided data on their medication use before the pandemic. A total of 30% (n = 221) reported medication changes in that period.
Details on medication changes
Medication changers were more likely to use glucocorticoids (GCs) (32.6% vs. 18.1%) and less likely to use nonhydroxychloroquine conventional DMARDs (49.3% vs. 62%) pre-COVID. Changers also reported higher rates of economic hardship during the pandemic (22.6% vs. 14.6%).
In the midst of the study period, the ACR issued a clinical guideline for treatment of rheumatic and musculoskeletal diseases (RMDs), emphasizing the need to maintain DMARD therapy, control disease activity, and reduce prednisone/GC use. The guideline advised continuing hydroxychloroquine and interleukin-6 inhibitor biologics in people with suspected or confirmed COVID-19.
Dr. Michaud and coauthors acknowledged the ongoing lack of knowledge about real-world treatment patterns for RA during the pandemic. They set out with this study to fill those knowledge gaps.
They noted that patients on bDMARDs (17.6%) and JAK inhibitors (17.1%) were more than twice as likely to discontinue medications than were those on conventional DMARDs (8.2%).
Switching to telehealth was the most common pandemic-related behavior change among patients in all DMARD groups, with rates ranging from 31% to 47.1%, followed by canceling or postponing appointments, with rates ranging from 27.9% to 36.4% depending on the DMARD group.
The study also found that RA patients widely adopted the behavior changes that the Centers for Disease Control and Prevention recommended during the pandemic, although the rates of restricting social contacts were significantly lower than the 90% reported in an early Italian study.
Dr. Michaud and coauthors also provided some explanation of why people on GCs and DMARDs were more likely than others to change medication patterns. “This may reflect efforts to reduce the perceived risk of infections due to GCs as well as the likely less-controlled disease activity associated with GC use,” they wrote. While the ACR’s early pandemic guidance followed the 2015 guidelines – that patients should continue on GCs at the “lowest possible dose” and not stop them “abruptly” – most U.S. rheumatologists reported cutting back on GC use during the pandemic.
The researchers acknowledged that evidence linking GC use with hospitalization for COVID-19, which emerged after they had surveyed study participants, was consistent their findings, but that the overall risk of COVID-19 in RA patients still isn’t known.
Pfizer funded the analysis, and a coauthor is an employee of Pfizer.
During the first 3 months of the COVID-19 pandemic last year, about one-third of people with rheumatoid arthritis in the United States made changes in their RA medications, and, before the American College of Rheumatology tweaked its guidelines midway through that period, they were about twice as likely to make medication changes on their own than before the pandemic, according to an analysis of data in FORWARD, the National Databank for Rheumatic Diseases.
The study, published in Arthritis Care & Research, also found that about 10% of RA patients on hydroxychloroquine lost access to the drug at a time it was drawing interest as a treatment for COVID-19. Another finding was that a high percentage of patients on non–tumor necrosis factor biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors canceled or postponed appointments.
“Our results show that persons with RA who had medication changes in the first 3 months of the COVID-19 pandemic in the U.S. were more likely to have worse disease activity and higher exposure to prior DMARDs, but no statistical difference was found in terms of comorbidities,” first author Kaleb Michaud, PhD, and coauthors wrote. Dr. Michaud is with the National Databank for Rheumatic Diseases, Wichita, Kan., and the University of Nebraska Medical Center, Omaha.
The study evaluated responses from 734 adults who participated in FORWARD, an observational, multidisease registry. They answered online surveys about COVID-19 in May 2020 and had provided data on their medication use before the pandemic. A total of 30% (n = 221) reported medication changes in that period.
Details on medication changes
Medication changers were more likely to use glucocorticoids (GCs) (32.6% vs. 18.1%) and less likely to use nonhydroxychloroquine conventional DMARDs (49.3% vs. 62%) pre-COVID. Changers also reported higher rates of economic hardship during the pandemic (22.6% vs. 14.6%).
In the midst of the study period, the ACR issued a clinical guideline for treatment of rheumatic and musculoskeletal diseases (RMDs), emphasizing the need to maintain DMARD therapy, control disease activity, and reduce prednisone/GC use. The guideline advised continuing hydroxychloroquine and interleukin-6 inhibitor biologics in people with suspected or confirmed COVID-19.
Dr. Michaud and coauthors acknowledged the ongoing lack of knowledge about real-world treatment patterns for RA during the pandemic. They set out with this study to fill those knowledge gaps.
They noted that patients on bDMARDs (17.6%) and JAK inhibitors (17.1%) were more than twice as likely to discontinue medications than were those on conventional DMARDs (8.2%).
Switching to telehealth was the most common pandemic-related behavior change among patients in all DMARD groups, with rates ranging from 31% to 47.1%, followed by canceling or postponing appointments, with rates ranging from 27.9% to 36.4% depending on the DMARD group.
The study also found that RA patients widely adopted the behavior changes that the Centers for Disease Control and Prevention recommended during the pandemic, although the rates of restricting social contacts were significantly lower than the 90% reported in an early Italian study.
Dr. Michaud and coauthors also provided some explanation of why people on GCs and DMARDs were more likely than others to change medication patterns. “This may reflect efforts to reduce the perceived risk of infections due to GCs as well as the likely less-controlled disease activity associated with GC use,” they wrote. While the ACR’s early pandemic guidance followed the 2015 guidelines – that patients should continue on GCs at the “lowest possible dose” and not stop them “abruptly” – most U.S. rheumatologists reported cutting back on GC use during the pandemic.
The researchers acknowledged that evidence linking GC use with hospitalization for COVID-19, which emerged after they had surveyed study participants, was consistent their findings, but that the overall risk of COVID-19 in RA patients still isn’t known.
Pfizer funded the analysis, and a coauthor is an employee of Pfizer.
FROM ARTHRITIS CARE & RESEARCH
Survey finds Mohs surgeons favor nicotinamide for chemoprevention
, in a survey of members of the American College of Mohs Surgeons.
Although nicotinamide, a vitamin B3 derivative, has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients, it is not approved by the Food and Drug Administration for chemoprevention, and no safe upper limit has been established in clinical trials to date, wrote Sheena Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues.
The investigators emailed an anonymous 12-question survey to 1,500 members of the American College of Mohs Surgeons. Of the 170 who responded, 10 were excluded for discordant responses, leaving 160 participants whose replies were included in a multiple logistic regression analysis. The respondents were mainly U.S. board-certified dermatologists and Mohs surgeons (99.4% for both); 86.9% were in clinical practice, including 78.8% in private practice, according to the report of the results, published in Dermatologic Surgery.
Overall, 76.9% of the respondents said they recommended nicotinamide for preventing KC, and 20% said they had recommended nicotinamide to more than 100 patients in the past year. In addition, 45% of respondents reported patients who had been taking nicotinamide for 2 years or more. Overall, 63.8% of the respondents expressed no concerns about long-term safety of nicotinamide, compared with 28.1% who said they were uncertain about long-term safety. Those who expressed concern or uncertainty about long-term safety were significantly less likely to recommend nicotinamide for KC prevention in the past year (odds ratio, 0.30; 95% confidence interval [CI] 0.13-0.71). Clinicians with more than 10 years in practice were significantly less likely to recommend nicotinamide for chemoprevention (OR, 0.20; 95% CI 0.05-0.82).
The study findings were limited by several factors, including the low number of responses and the potential lack of generalizability to clinicians other than Mohs surgeons, the researchers noted. “Additional studies on nicotinamide safety and use patterns, including cost-effectiveness analyses, are needed given the widespread use identified in this study,” they concluded.
Limited safety data highlight research gaps
The study is particularly important at this time because nicotinamide has been increasingly used for KC chemoprevention since a randomized, controlled trial published in 2015 in the New England Journal of Medicine showed benefits, corresponding author Rebecca I. Hartman, MD, of the department of dermatology, Brigham and Women’s Hospital and Harvard University, Boston, said in an interview. That study of high-risk patients found that nicotinamide, 500 mg twice a day, was safe and effective in lowering the rates of new nonmelanoma skin cancers and AKs after 12 months .
“However, because this is not a prescription medication, but rather an OTC vitamin supplement, data on its use are not available,” she said.
Dr. Hartman said she was not surprised that nicotinamide is being used frequently by a majority of the survey respondents. “Most are using this if someone has two KCs over 2 years, which is a quite common occurrence,” she noted. However, “I was a bit surprised that nearly two-thirds had no safety concerns with long-term use, even though this has not been well-studied,” she added.
“Like anything we recommend, we must consider the risks and benefits,” Dr. Hartman said of nicotinamide. “Unfortunately, we don’t know the risks well, since this hasn’t been well-characterized with regular long-term use in these doses,” and more research is needed, she said. “The risks are likely low, as this is a vitamin that has been used for years in various OTC supplements,” she added. “However, there are some data showing slightly increased all-cause mortality with similar doses of a related medicine, niacin, in cardiovascular patients. For this reason, I recommend the medication when a patient’s KCs are really becoming burdensome – several KCs in a year or two – or when they are high-risk due to immunosuppression,” she explained.
“We also must consider the individual patient. For a healthy younger patient who has a public-facing job and as a result is very averse to developing any KCs on his or her face and very motivated to try prevention, it may make sense to try nicotinamide,” Dr. Hartman said. But for an older patient with cardiovascular comorbidities who is not bothered by a KC on his or her back or extremities, “this medication may not have a favorable risk-benefit profile.”
To address safety concerns, “researchers need to examine whether there are any harms in long-term regular nicotinamide use for KC prevention,” Dr. Hartman said. “This is something we hope to do in our patients; however, it is challenging to study in a retrospective way since the harm is likely small and there are so many other features that influence mortality as an outcome,” she noted.
The study received no outside funding. The researchers had no financial conflicts to disclose.
, in a survey of members of the American College of Mohs Surgeons.
Although nicotinamide, a vitamin B3 derivative, has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients, it is not approved by the Food and Drug Administration for chemoprevention, and no safe upper limit has been established in clinical trials to date, wrote Sheena Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues.
The investigators emailed an anonymous 12-question survey to 1,500 members of the American College of Mohs Surgeons. Of the 170 who responded, 10 were excluded for discordant responses, leaving 160 participants whose replies were included in a multiple logistic regression analysis. The respondents were mainly U.S. board-certified dermatologists and Mohs surgeons (99.4% for both); 86.9% were in clinical practice, including 78.8% in private practice, according to the report of the results, published in Dermatologic Surgery.
Overall, 76.9% of the respondents said they recommended nicotinamide for preventing KC, and 20% said they had recommended nicotinamide to more than 100 patients in the past year. In addition, 45% of respondents reported patients who had been taking nicotinamide for 2 years or more. Overall, 63.8% of the respondents expressed no concerns about long-term safety of nicotinamide, compared with 28.1% who said they were uncertain about long-term safety. Those who expressed concern or uncertainty about long-term safety were significantly less likely to recommend nicotinamide for KC prevention in the past year (odds ratio, 0.30; 95% confidence interval [CI] 0.13-0.71). Clinicians with more than 10 years in practice were significantly less likely to recommend nicotinamide for chemoprevention (OR, 0.20; 95% CI 0.05-0.82).
The study findings were limited by several factors, including the low number of responses and the potential lack of generalizability to clinicians other than Mohs surgeons, the researchers noted. “Additional studies on nicotinamide safety and use patterns, including cost-effectiveness analyses, are needed given the widespread use identified in this study,” they concluded.
Limited safety data highlight research gaps
The study is particularly important at this time because nicotinamide has been increasingly used for KC chemoprevention since a randomized, controlled trial published in 2015 in the New England Journal of Medicine showed benefits, corresponding author Rebecca I. Hartman, MD, of the department of dermatology, Brigham and Women’s Hospital and Harvard University, Boston, said in an interview. That study of high-risk patients found that nicotinamide, 500 mg twice a day, was safe and effective in lowering the rates of new nonmelanoma skin cancers and AKs after 12 months .
“However, because this is not a prescription medication, but rather an OTC vitamin supplement, data on its use are not available,” she said.
Dr. Hartman said she was not surprised that nicotinamide is being used frequently by a majority of the survey respondents. “Most are using this if someone has two KCs over 2 years, which is a quite common occurrence,” she noted. However, “I was a bit surprised that nearly two-thirds had no safety concerns with long-term use, even though this has not been well-studied,” she added.
“Like anything we recommend, we must consider the risks and benefits,” Dr. Hartman said of nicotinamide. “Unfortunately, we don’t know the risks well, since this hasn’t been well-characterized with regular long-term use in these doses,” and more research is needed, she said. “The risks are likely low, as this is a vitamin that has been used for years in various OTC supplements,” she added. “However, there are some data showing slightly increased all-cause mortality with similar doses of a related medicine, niacin, in cardiovascular patients. For this reason, I recommend the medication when a patient’s KCs are really becoming burdensome – several KCs in a year or two – or when they are high-risk due to immunosuppression,” she explained.
“We also must consider the individual patient. For a healthy younger patient who has a public-facing job and as a result is very averse to developing any KCs on his or her face and very motivated to try prevention, it may make sense to try nicotinamide,” Dr. Hartman said. But for an older patient with cardiovascular comorbidities who is not bothered by a KC on his or her back or extremities, “this medication may not have a favorable risk-benefit profile.”
To address safety concerns, “researchers need to examine whether there are any harms in long-term regular nicotinamide use for KC prevention,” Dr. Hartman said. “This is something we hope to do in our patients; however, it is challenging to study in a retrospective way since the harm is likely small and there are so many other features that influence mortality as an outcome,” she noted.
The study received no outside funding. The researchers had no financial conflicts to disclose.
, in a survey of members of the American College of Mohs Surgeons.
Although nicotinamide, a vitamin B3 derivative, has been shown to reduce keratinocyte carcinoma (KC) in high-risk patients, it is not approved by the Food and Drug Administration for chemoprevention, and no safe upper limit has been established in clinical trials to date, wrote Sheena Desai of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues.
The investigators emailed an anonymous 12-question survey to 1,500 members of the American College of Mohs Surgeons. Of the 170 who responded, 10 were excluded for discordant responses, leaving 160 participants whose replies were included in a multiple logistic regression analysis. The respondents were mainly U.S. board-certified dermatologists and Mohs surgeons (99.4% for both); 86.9% were in clinical practice, including 78.8% in private practice, according to the report of the results, published in Dermatologic Surgery.
Overall, 76.9% of the respondents said they recommended nicotinamide for preventing KC, and 20% said they had recommended nicotinamide to more than 100 patients in the past year. In addition, 45% of respondents reported patients who had been taking nicotinamide for 2 years or more. Overall, 63.8% of the respondents expressed no concerns about long-term safety of nicotinamide, compared with 28.1% who said they were uncertain about long-term safety. Those who expressed concern or uncertainty about long-term safety were significantly less likely to recommend nicotinamide for KC prevention in the past year (odds ratio, 0.30; 95% confidence interval [CI] 0.13-0.71). Clinicians with more than 10 years in practice were significantly less likely to recommend nicotinamide for chemoprevention (OR, 0.20; 95% CI 0.05-0.82).
The study findings were limited by several factors, including the low number of responses and the potential lack of generalizability to clinicians other than Mohs surgeons, the researchers noted. “Additional studies on nicotinamide safety and use patterns, including cost-effectiveness analyses, are needed given the widespread use identified in this study,” they concluded.
Limited safety data highlight research gaps
The study is particularly important at this time because nicotinamide has been increasingly used for KC chemoprevention since a randomized, controlled trial published in 2015 in the New England Journal of Medicine showed benefits, corresponding author Rebecca I. Hartman, MD, of the department of dermatology, Brigham and Women’s Hospital and Harvard University, Boston, said in an interview. That study of high-risk patients found that nicotinamide, 500 mg twice a day, was safe and effective in lowering the rates of new nonmelanoma skin cancers and AKs after 12 months .
“However, because this is not a prescription medication, but rather an OTC vitamin supplement, data on its use are not available,” she said.
Dr. Hartman said she was not surprised that nicotinamide is being used frequently by a majority of the survey respondents. “Most are using this if someone has two KCs over 2 years, which is a quite common occurrence,” she noted. However, “I was a bit surprised that nearly two-thirds had no safety concerns with long-term use, even though this has not been well-studied,” she added.
“Like anything we recommend, we must consider the risks and benefits,” Dr. Hartman said of nicotinamide. “Unfortunately, we don’t know the risks well, since this hasn’t been well-characterized with regular long-term use in these doses,” and more research is needed, she said. “The risks are likely low, as this is a vitamin that has been used for years in various OTC supplements,” she added. “However, there are some data showing slightly increased all-cause mortality with similar doses of a related medicine, niacin, in cardiovascular patients. For this reason, I recommend the medication when a patient’s KCs are really becoming burdensome – several KCs in a year or two – or when they are high-risk due to immunosuppression,” she explained.
“We also must consider the individual patient. For a healthy younger patient who has a public-facing job and as a result is very averse to developing any KCs on his or her face and very motivated to try prevention, it may make sense to try nicotinamide,” Dr. Hartman said. But for an older patient with cardiovascular comorbidities who is not bothered by a KC on his or her back or extremities, “this medication may not have a favorable risk-benefit profile.”
To address safety concerns, “researchers need to examine whether there are any harms in long-term regular nicotinamide use for KC prevention,” Dr. Hartman said. “This is something we hope to do in our patients; however, it is challenging to study in a retrospective way since the harm is likely small and there are so many other features that influence mortality as an outcome,” she noted.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM DERMATOLOGIC SURGERY
FDA approves frontline immunotherapy for gastric cancers
This is the first immunotherapy approved for the frontline treatment of gastric cancers, the agency says in a press release.
The approval comes after nivolumab received Priority Review and Orphan Drug designations for this indication. There are approximately 28,000 new diagnoses of gastric cancer annually in the United States, and overall survival is generally poor with currently available therapy, points out the FDA.
“Today’s approval is the first treatment in more than a decade to show a survival benefit for patients with advanced or metastatic gastric cancer who are being treated for the first time,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, states in an FDA press release.
Efficacy in the gastric cancer setting was demonstrated in the randomized, phase 3, open-label CheckMate 649 study of 1,518 untreated patients. Median survival was 13.8 months among those treated with nivolumab, compared with 11.6 months with chemotherapy alone (hazard ratio, 0.80; P = .0002).
Common side effects experienced by patients in the nivolumab group included peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Nivolumab is also approved for numerous other cancers. Other known adverse effects include immune-mediated inflammation of the lungs, colon, liver, endocrine glands, and kidneys.
“Patients should tell their health care providers if they have immune system problems, lung or breathing problems, liver problems, have had an organ transplant, or are pregnant or plan to become pregnant before starting treatment,” the FDA states.
A version of this article first appeared on Medscape.com.
This is the first immunotherapy approved for the frontline treatment of gastric cancers, the agency says in a press release.
The approval comes after nivolumab received Priority Review and Orphan Drug designations for this indication. There are approximately 28,000 new diagnoses of gastric cancer annually in the United States, and overall survival is generally poor with currently available therapy, points out the FDA.
“Today’s approval is the first treatment in more than a decade to show a survival benefit for patients with advanced or metastatic gastric cancer who are being treated for the first time,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, states in an FDA press release.
Efficacy in the gastric cancer setting was demonstrated in the randomized, phase 3, open-label CheckMate 649 study of 1,518 untreated patients. Median survival was 13.8 months among those treated with nivolumab, compared with 11.6 months with chemotherapy alone (hazard ratio, 0.80; P = .0002).
Common side effects experienced by patients in the nivolumab group included peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Nivolumab is also approved for numerous other cancers. Other known adverse effects include immune-mediated inflammation of the lungs, colon, liver, endocrine glands, and kidneys.
“Patients should tell their health care providers if they have immune system problems, lung or breathing problems, liver problems, have had an organ transplant, or are pregnant or plan to become pregnant before starting treatment,” the FDA states.
A version of this article first appeared on Medscape.com.
This is the first immunotherapy approved for the frontline treatment of gastric cancers, the agency says in a press release.
The approval comes after nivolumab received Priority Review and Orphan Drug designations for this indication. There are approximately 28,000 new diagnoses of gastric cancer annually in the United States, and overall survival is generally poor with currently available therapy, points out the FDA.
“Today’s approval is the first treatment in more than a decade to show a survival benefit for patients with advanced or metastatic gastric cancer who are being treated for the first time,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, states in an FDA press release.
Efficacy in the gastric cancer setting was demonstrated in the randomized, phase 3, open-label CheckMate 649 study of 1,518 untreated patients. Median survival was 13.8 months among those treated with nivolumab, compared with 11.6 months with chemotherapy alone (hazard ratio, 0.80; P = .0002).
Common side effects experienced by patients in the nivolumab group included peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Nivolumab is also approved for numerous other cancers. Other known adverse effects include immune-mediated inflammation of the lungs, colon, liver, endocrine glands, and kidneys.
“Patients should tell their health care providers if they have immune system problems, lung or breathing problems, liver problems, have had an organ transplant, or are pregnant or plan to become pregnant before starting treatment,” the FDA states.
A version of this article first appeared on Medscape.com.
How some COVID-19 vaccines could cause rare blood clots
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.
on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.
This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.
According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.
On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.
In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.
“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness.
“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.
Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.
Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria.
This has experts questioning whether all vaccines of this type may cause these rare clots.
“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
Adenovirus vaccines scrutinized
Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.
Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses.
Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system.
The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.
There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.
The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.
Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans.
Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.
There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.
Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport.
But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.
The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1.
Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.
On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.
The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.
The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.
So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.
A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.
The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.
“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
Studies suggest possible mechanism
On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.
The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.
These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.
It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.
The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).
It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.
“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”
No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.
Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising.
Grappling with evidence
The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.
Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.
With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.
They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.
Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.
“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.
“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.
A version of this article first appeared on Medscape.com.