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a team of European and U.S. investigators reported.
The four-gene signature could be used to screen patients who are currently taking or are candidates for drugs know to increase risk for PML, a rare but frequently lethal demyelinating disorder of the central nervous system, according to Eli Hatchwell, MD, PhD, from Population BIO UK in Oxfordshire, England, and colleagues.
“Due to the seriousness of a PML diagnosis – particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops – it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they wrote in a study published in Frontiers in Neurology.
Benign virus, bad disease
PML is caused by reactivation of the otherwise benign JC virus (JCV), also known as human polyomavirus 2. (The “J” and “C” in the virus’ common name stand for John Cunningham, a man with Hodgkin lymphoma from whose brain the virus was first isolated, in 1971.)
The estimated prevalence of JCV infection ranges from 40% to 70% of the population worldwide, although PML itself is rare, with an incidence of approximately 1 in 200,000.
PML is a complication of treatment with targeted monoclonal antibodies, such as natalizumab (Tysabri), rituximab (Rituxan), alemtuzumab (Campath; Lemtrada), and other agents with immunosuppressive properties, such as dimethyl fumarate and mycophenolate mofetil.
In addition, PML can occur among patients with diseases that disrupt or inhibit natural immunity, such as HIV/AIDS, hematologic cancers, and autoimmune diseases.
Predisposing variants suspected
Dr. Hatchwell and colleagues hypothesized that some patients may have rare genetic variants in immune-system genes that predispose them to increased risk for PML. The researchers had previously shown an association between PML and 19 genetic risk variants among 184 patients with PML.
In the current study, they looked at variants in an additional 152 patients with PML who served as a validation sample. Of the 19 risk variants they had previously identified, the investigators narrowed the field down to 4 variants in both population controls and in a matched control set consisting of patients with multiple sclerosis (MS) who were positive for JCV and who were on therapy with a PML-linked drug for at least 2 years.
The four variants they identified, all linked to immune viral defense, were C8B, 1-57409459-C-A, rs139498867; LY9 (a checkpoint regulator also known as SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; and STXBP2, 19-7712287-G-C, rs35490401.
In all, 10.9% of patients with PML carried at least one of the variants.
The investigators reported that carriers of any one of the variants has a nearly ninefold risk for developing PML after exposure to a PML-linked drug compared with non-carriers with similar drug exposures (odds ratio, 8.7; P < .001).
“Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B_15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson syndrome and toxic epidermal necrolysis,” the authors noted.
Screening? Maybe
In a press release, Lawrence Steinman, MD, from Stanford (Calif.) University, who was not involved in the study, stated that “preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”
But another neurologist who was not involved in the study commented that the finding, while “exciting” as a confirmation study, is not as yet practice changing.
“It does give us very good confidence that these four genes are indeed risk factors that increase the risk of this brain infection by quite a bit, so that makes it very exciting,” said Robert Fox, MD, from the Neurological Institute at the Cleveland Clinic.
“Indeed, we are trying to risk-stratify patients to try to reduce the risk of PML in the patients treated with our MS drugs. So for natalizumab we risk stratify by testing them for JC virus serology. Half of people don’t have it and we say ‘OK, you’re good to go.’ With other drugs like Tecfidera – dimethyl fumarate – we follow their lymphocyte counts, so when their lymphocyte counts drop too low we say ‘OK, you need to come off the drug because of the risk of PML,’ ” he said in an interview.
The four-gene signature, however, only identifies about 11% of patients with PML, which is not a sufficiently large enough effect to be clinically useful. For example, the risk for PML in patients treated with natalizumab is about 1%, and if the test can only detect enhanced risk in about 11% of those patients, the risk would drop from 1% to 0.9%, which “doesn’t really the move needle much,” he pointed out.
Dr. Fox also noted that neurologists now have a large formulary of drugs to offer their patients, including agents (such as interferon-beta and corticosteroids that are not associated with increased risk for PML).
The study was funded by Emerald Lake Safety and Population Bio. Dr. Hatchwell and several coauthors are employees of the respective companies, and several are inventors of genetic screening methods for PML. Dr. Steiman has disclosed consulting for TG Therapeutics. Dr. Fox reported consulting for manufacturers of MS therapies.
a team of European and U.S. investigators reported.
The four-gene signature could be used to screen patients who are currently taking or are candidates for drugs know to increase risk for PML, a rare but frequently lethal demyelinating disorder of the central nervous system, according to Eli Hatchwell, MD, PhD, from Population BIO UK in Oxfordshire, England, and colleagues.
“Due to the seriousness of a PML diagnosis – particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops – it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they wrote in a study published in Frontiers in Neurology.
Benign virus, bad disease
PML is caused by reactivation of the otherwise benign JC virus (JCV), also known as human polyomavirus 2. (The “J” and “C” in the virus’ common name stand for John Cunningham, a man with Hodgkin lymphoma from whose brain the virus was first isolated, in 1971.)
The estimated prevalence of JCV infection ranges from 40% to 70% of the population worldwide, although PML itself is rare, with an incidence of approximately 1 in 200,000.
PML is a complication of treatment with targeted monoclonal antibodies, such as natalizumab (Tysabri), rituximab (Rituxan), alemtuzumab (Campath; Lemtrada), and other agents with immunosuppressive properties, such as dimethyl fumarate and mycophenolate mofetil.
In addition, PML can occur among patients with diseases that disrupt or inhibit natural immunity, such as HIV/AIDS, hematologic cancers, and autoimmune diseases.
Predisposing variants suspected
Dr. Hatchwell and colleagues hypothesized that some patients may have rare genetic variants in immune-system genes that predispose them to increased risk for PML. The researchers had previously shown an association between PML and 19 genetic risk variants among 184 patients with PML.
In the current study, they looked at variants in an additional 152 patients with PML who served as a validation sample. Of the 19 risk variants they had previously identified, the investigators narrowed the field down to 4 variants in both population controls and in a matched control set consisting of patients with multiple sclerosis (MS) who were positive for JCV and who were on therapy with a PML-linked drug for at least 2 years.
The four variants they identified, all linked to immune viral defense, were C8B, 1-57409459-C-A, rs139498867; LY9 (a checkpoint regulator also known as SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; and STXBP2, 19-7712287-G-C, rs35490401.
In all, 10.9% of patients with PML carried at least one of the variants.
The investigators reported that carriers of any one of the variants has a nearly ninefold risk for developing PML after exposure to a PML-linked drug compared with non-carriers with similar drug exposures (odds ratio, 8.7; P < .001).
“Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B_15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson syndrome and toxic epidermal necrolysis,” the authors noted.
Screening? Maybe
In a press release, Lawrence Steinman, MD, from Stanford (Calif.) University, who was not involved in the study, stated that “preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”
But another neurologist who was not involved in the study commented that the finding, while “exciting” as a confirmation study, is not as yet practice changing.
“It does give us very good confidence that these four genes are indeed risk factors that increase the risk of this brain infection by quite a bit, so that makes it very exciting,” said Robert Fox, MD, from the Neurological Institute at the Cleveland Clinic.
“Indeed, we are trying to risk-stratify patients to try to reduce the risk of PML in the patients treated with our MS drugs. So for natalizumab we risk stratify by testing them for JC virus serology. Half of people don’t have it and we say ‘OK, you’re good to go.’ With other drugs like Tecfidera – dimethyl fumarate – we follow their lymphocyte counts, so when their lymphocyte counts drop too low we say ‘OK, you need to come off the drug because of the risk of PML,’ ” he said in an interview.
The four-gene signature, however, only identifies about 11% of patients with PML, which is not a sufficiently large enough effect to be clinically useful. For example, the risk for PML in patients treated with natalizumab is about 1%, and if the test can only detect enhanced risk in about 11% of those patients, the risk would drop from 1% to 0.9%, which “doesn’t really the move needle much,” he pointed out.
Dr. Fox also noted that neurologists now have a large formulary of drugs to offer their patients, including agents (such as interferon-beta and corticosteroids that are not associated with increased risk for PML).
The study was funded by Emerald Lake Safety and Population Bio. Dr. Hatchwell and several coauthors are employees of the respective companies, and several are inventors of genetic screening methods for PML. Dr. Steiman has disclosed consulting for TG Therapeutics. Dr. Fox reported consulting for manufacturers of MS therapies.
a team of European and U.S. investigators reported.
The four-gene signature could be used to screen patients who are currently taking or are candidates for drugs know to increase risk for PML, a rare but frequently lethal demyelinating disorder of the central nervous system, according to Eli Hatchwell, MD, PhD, from Population BIO UK in Oxfordshire, England, and colleagues.
“Due to the seriousness of a PML diagnosis – particularly because it often leads to life-threatening outcomes and the lack of treatment options once it develops – it would seem unethical not to test individuals considering immunosuppressive therapies with PML risk for our top four variants, and advising those with a positive result to consider an alternative therapy or treatment strategy,” they wrote in a study published in Frontiers in Neurology.
Benign virus, bad disease
PML is caused by reactivation of the otherwise benign JC virus (JCV), also known as human polyomavirus 2. (The “J” and “C” in the virus’ common name stand for John Cunningham, a man with Hodgkin lymphoma from whose brain the virus was first isolated, in 1971.)
The estimated prevalence of JCV infection ranges from 40% to 70% of the population worldwide, although PML itself is rare, with an incidence of approximately 1 in 200,000.
PML is a complication of treatment with targeted monoclonal antibodies, such as natalizumab (Tysabri), rituximab (Rituxan), alemtuzumab (Campath; Lemtrada), and other agents with immunosuppressive properties, such as dimethyl fumarate and mycophenolate mofetil.
In addition, PML can occur among patients with diseases that disrupt or inhibit natural immunity, such as HIV/AIDS, hematologic cancers, and autoimmune diseases.
Predisposing variants suspected
Dr. Hatchwell and colleagues hypothesized that some patients may have rare genetic variants in immune-system genes that predispose them to increased risk for PML. The researchers had previously shown an association between PML and 19 genetic risk variants among 184 patients with PML.
In the current study, they looked at variants in an additional 152 patients with PML who served as a validation sample. Of the 19 risk variants they had previously identified, the investigators narrowed the field down to 4 variants in both population controls and in a matched control set consisting of patients with multiple sclerosis (MS) who were positive for JCV and who were on therapy with a PML-linked drug for at least 2 years.
The four variants they identified, all linked to immune viral defense, were C8B, 1-57409459-C-A, rs139498867; LY9 (a checkpoint regulator also known as SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; and STXBP2, 19-7712287-G-C, rs35490401.
In all, 10.9% of patients with PML carried at least one of the variants.
The investigators reported that carriers of any one of the variants has a nearly ninefold risk for developing PML after exposure to a PML-linked drug compared with non-carriers with similar drug exposures (odds ratio, 8.7; P < .001).
“Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B_15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson syndrome and toxic epidermal necrolysis,” the authors noted.
Screening? Maybe
In a press release, Lawrence Steinman, MD, from Stanford (Calif.) University, who was not involved in the study, stated that “preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.”
But another neurologist who was not involved in the study commented that the finding, while “exciting” as a confirmation study, is not as yet practice changing.
“It does give us very good confidence that these four genes are indeed risk factors that increase the risk of this brain infection by quite a bit, so that makes it very exciting,” said Robert Fox, MD, from the Neurological Institute at the Cleveland Clinic.
“Indeed, we are trying to risk-stratify patients to try to reduce the risk of PML in the patients treated with our MS drugs. So for natalizumab we risk stratify by testing them for JC virus serology. Half of people don’t have it and we say ‘OK, you’re good to go.’ With other drugs like Tecfidera – dimethyl fumarate – we follow their lymphocyte counts, so when their lymphocyte counts drop too low we say ‘OK, you need to come off the drug because of the risk of PML,’ ” he said in an interview.
The four-gene signature, however, only identifies about 11% of patients with PML, which is not a sufficiently large enough effect to be clinically useful. For example, the risk for PML in patients treated with natalizumab is about 1%, and if the test can only detect enhanced risk in about 11% of those patients, the risk would drop from 1% to 0.9%, which “doesn’t really the move needle much,” he pointed out.
Dr. Fox also noted that neurologists now have a large formulary of drugs to offer their patients, including agents (such as interferon-beta and corticosteroids that are not associated with increased risk for PML).
The study was funded by Emerald Lake Safety and Population Bio. Dr. Hatchwell and several coauthors are employees of the respective companies, and several are inventors of genetic screening methods for PML. Dr. Steiman has disclosed consulting for TG Therapeutics. Dr. Fox reported consulting for manufacturers of MS therapies.
FROM FRONTIERS IN NEUROLOGY