B-Cell Lymphoma ICYMI

The BALL score was able to identify a subset of patients with chronic lymphocytic leukemia (CLL) who particularly benefit from single-agent ibrutinib therapy, according to the results of a study of 111 patients followed from two different institutions.

The BALL model consists of four factors: serum beta₂-microglobulin at 5 mg/dL or greater, hemoglobin < 110 g/L for women or < 120 g/L for men, lactate dehydrogenase [LDH] > upper limit of normal [UNL], and time elapsed from last therapy less than 24 months. Each parameter was alloted 1 point, leading to a stratification of patients into three different prognostic groups: low risk (score 0-1), intermediate risk (2-3), and high risk (score 4), according to a report published online in Leukemia Research.

According to Stefano Molica, MD, of the Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues, the majority of patients (82%) were clinical Rai stage II-IV. The median patient age was 63 years and nearly 68% were men.

The researchers assessed four models for predicting overall survival. The modified version of CLL-International Prognostic Index (CLL-IPI) failed to provide prognostic information in relapsed/refractory (R/R) CLL (P = .77) as did the Ahn et al. model (P = .95) and a simplified BALL model (P = .09). In contrast, the full BALL score captured two groups of patients with significant differences in survival (hazard ratio, 0.240; 95 % confidence interval, 0.10-0.54; P = .0005); however, because of the low number of patients in the high-risk category, these cases were combined with the intermediate-risk group.

The BALL score identified a subset of patients, accounting for about 50% of the whole population, who particularly benefit from single-agent ibrutinib, according to Dr. Molica and his colleagues. These patients had a survival rate of 85% at 3 years.

“In contrast, the outcome of subjects with intermediate-high risk is disappointing. These patients should be considered for a combination of targeted drugs or cellular-based therapies,” the researchers concluded.

The authors reported that they had no conflicts.

[email protected]

SOURCE: Molica S et al. Leuk Res. 2020 Jun 10. https://doi.org/10.1016/j.leukres.2020.

The BALL score was able to identify a subset of patients with chronic lymphocytic leukemia (CLL) who particularly benefit from single-agent ibrutinib therapy, according to the results of a study of 111 patients followed from two different institutions.

The BALL model consists of four factors: serum beta₂-microglobulin at 5 mg/dL or greater, hemoglobin < 110 g/L for women or < 120 g/L for men, lactate dehydrogenase [LDH] > upper limit of normal [UNL], and time elapsed from last therapy less than 24 months. Each parameter was alloted 1 point, leading to a stratification of patients into three different prognostic groups: low risk (score 0-1), intermediate risk (2-3), and high risk (score 4), according to a report published online in Leukemia Research.

According to Stefano Molica, MD, of the Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues, the majority of patients (82%) were clinical Rai stage II-IV. The median patient age was 63 years and nearly 68% were men.

The researchers assessed four models for predicting overall survival. The modified version of CLL-International Prognostic Index (CLL-IPI) failed to provide prognostic information in relapsed/refractory (R/R) CLL (P = .77) as did the Ahn et al. model (P = .95) and a simplified BALL model (P = .09). In contrast, the full BALL score captured two groups of patients with significant differences in survival (hazard ratio, 0.240; 95 % confidence interval, 0.10-0.54; P = .0005); however, because of the low number of patients in the high-risk category, these cases were combined with the intermediate-risk group.

The BALL score identified a subset of patients, accounting for about 50% of the whole population, who particularly benefit from single-agent ibrutinib, according to Dr. Molica and his colleagues. These patients had a survival rate of 85% at 3 years.

“In contrast, the outcome of subjects with intermediate-high risk is disappointing. These patients should be considered for a combination of targeted drugs or cellular-based therapies,” the researchers concluded.

The authors reported that they had no conflicts.

[email protected]

SOURCE: Molica S et al. Leuk Res. 2020 Jun 10. https://doi.org/10.1016/j.leukres.2020.

The BALL score was able to identify a subset of patients with chronic lymphocytic leukemia (CLL) who particularly benefit from single-agent ibrutinib therapy, according to the results of a study of 111 patients followed from two different institutions.

The BALL model consists of four factors: serum beta₂-microglobulin at 5 mg/dL or greater, hemoglobin < 110 g/L for women or < 120 g/L for men, lactate dehydrogenase [LDH] > upper limit of normal [UNL], and time elapsed from last therapy less than 24 months. Each parameter was alloted 1 point, leading to a stratification of patients into three different prognostic groups: low risk (score 0-1), intermediate risk (2-3), and high risk (score 4), according to a report published online in Leukemia Research.

According to Stefano Molica, MD, of the Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues, the majority of patients (82%) were clinical Rai stage II-IV. The median patient age was 63 years and nearly 68% were men.

The researchers assessed four models for predicting overall survival. The modified version of CLL-International Prognostic Index (CLL-IPI) failed to provide prognostic information in relapsed/refractory (R/R) CLL (P = .77) as did the Ahn et al. model (P = .95) and a simplified BALL model (P = .09). In contrast, the full BALL score captured two groups of patients with significant differences in survival (hazard ratio, 0.240; 95 % confidence interval, 0.10-0.54; P = .0005); however, because of the low number of patients in the high-risk category, these cases were combined with the intermediate-risk group.

The BALL score identified a subset of patients, accounting for about 50% of the whole population, who particularly benefit from single-agent ibrutinib, according to Dr. Molica and his colleagues. These patients had a survival rate of 85% at 3 years.

“In contrast, the outcome of subjects with intermediate-high risk is disappointing. These patients should be considered for a combination of targeted drugs or cellular-based therapies,” the researchers concluded.

The authors reported that they had no conflicts.

[email protected]

SOURCE: Molica S et al. Leuk Res. 2020 Jun 10. https://doi.org/10.1016/j.leukres.2020.

A new study of hypertension treatment trends found that uncontrolled high blood pressure along with considerable undertreatment of the condition were prevalent in individuals with a history of both hypertension and stroke. “To our knowledge, the present study is the first to analyze and report national antihypertensive medication trends exclusively among individuals with a history of stroke in the United States,” wrote Daniel Santos, MD, and Mandip S. Dhamoon, MD, DrPH, of the Icahn School of Medicine at Mount Sinai, New York. Their study was published in JAMA Neurology.

To examine blood pressure control and treatment trends among stroke survivors, the researchers examined more than a decade of data from the National Health and Nutrition Examination Survey (NHANES). The cross-sectional survey is conducted in 2-year cycles; the authors analyzed the results from 2005 to 2016 and uncovered a total of 4,971,136 eligible individuals with a history of both stroke and hypertension.

The mean age of the study population was 67.1 (95% confidence interval, 66.1-68.1), and 2,790,518 (56.1%) were women. Their mean blood pressure was 134/68 mm Hg (95% CI, 133/67–136/69), and the average number of antihypertensive medications they were taking was 1.8 (95% CI, 1.7-1.9). Of the 4,971,136 analyzed individuals, 4,721,409 (95%) were aware of their hypertension diagnosis yet more than 10% of that group had not previously been prescribed an antihypertensive medication.

More than 37% (n = 1,846,470) of the participants had uncontrolled high blood pressure upon examination (95% CI, 33.5%-40.8%), and 15.3% (95% CI, 12.5%-18.0%) were not taking any medication for it at all. The most commonly used antihypertensive medications included ACE inhibitors or angiotensin receptor blockers (59.2%; 95% CI, 54.9%-63.4%), beta-blockers (43.8%; 95% CI, 40.3%-47.3%), diuretics (41.6%; 95% CI, 37.3%-45.9%) and calcium-channel blockers (31.5%; 95% CI, 28.2%-34.8%).* Roughly 57% of the sample was taking more than one antihypertensive medication (95% CI, 52.8%-60.6%) while 28% (95% CI, 24.6%-31.5%) were taking only one.
 

Continued surveillance is key

“All the studies that have ever been done show that hypertension is inadequately treated,” Louis Caplan, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center, both in Boston, said in an interview. “One of the reasons is that it can be hard to get some of the patients to seek treatment, particularly Black Americans. Also, a lot of the medicines to treat high blood pressure have side effects, so many patients don’t want to take the pills.

“Treating hypertension really requires continued surveillance,” he added. “It’s not one visit where the doctor gives you a pill. It’s taking the pill, following your blood pressure, and seeing if it works. If it doesn’t, then maybe you change the dose, get another pill, and are followed once again. That doesn’t happen as often as it should.”

In regard to next steps, Dr. Caplan urged that hypertension “be evaluated more seriously. Even as home blood pressure kits and monitoring become increasingly available, many doctors are still going by a casual blood pressure test in the office, which doesn’t tell you how serious the problem is. There needs to be more use of technology and more conditioning of patients to monitor their own blood pressure as a guide, and then we go from there.”

The authors acknowledged their study’s limitations, including the NHANES’s reliance on self-reporting a history of stroke and the inability to distinguish between subtypes of stroke. In addition, they noted that many antihypertensive medications have uses beyond treating hypertension, which introduces “another confounding factor to medication trends.”

The authors and Dr. Caplan reported no conflicts of interest.

SOURCE: Santos D et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2499.

Correction, 8/20/20: An earlier version of this article misstated the confidence interval for diuretics.

A new study of hypertension treatment trends found that uncontrolled high blood pressure along with considerable undertreatment of the condition were prevalent in individuals with a history of both hypertension and stroke. “To our knowledge, the present study is the first to analyze and report national antihypertensive medication trends exclusively among individuals with a history of stroke in the United States,” wrote Daniel Santos, MD, and Mandip S. Dhamoon, MD, DrPH, of the Icahn School of Medicine at Mount Sinai, New York. Their study was published in JAMA Neurology.

To examine blood pressure control and treatment trends among stroke survivors, the researchers examined more than a decade of data from the National Health and Nutrition Examination Survey (NHANES). The cross-sectional survey is conducted in 2-year cycles; the authors analyzed the results from 2005 to 2016 and uncovered a total of 4,971,136 eligible individuals with a history of both stroke and hypertension.

The mean age of the study population was 67.1 (95% confidence interval, 66.1-68.1), and 2,790,518 (56.1%) were women. Their mean blood pressure was 134/68 mm Hg (95% CI, 133/67–136/69), and the average number of antihypertensive medications they were taking was 1.8 (95% CI, 1.7-1.9). Of the 4,971,136 analyzed individuals, 4,721,409 (95%) were aware of their hypertension diagnosis yet more than 10% of that group had not previously been prescribed an antihypertensive medication.

More than 37% (n = 1,846,470) of the participants had uncontrolled high blood pressure upon examination (95% CI, 33.5%-40.8%), and 15.3% (95% CI, 12.5%-18.0%) were not taking any medication for it at all. The most commonly used antihypertensive medications included ACE inhibitors or angiotensin receptor blockers (59.2%; 95% CI, 54.9%-63.4%), beta-blockers (43.8%; 95% CI, 40.3%-47.3%), diuretics (41.6%; 95% CI, 37.3%-45.9%) and calcium-channel blockers (31.5%; 95% CI, 28.2%-34.8%).* Roughly 57% of the sample was taking more than one antihypertensive medication (95% CI, 52.8%-60.6%) while 28% (95% CI, 24.6%-31.5%) were taking only one.
 

Continued surveillance is key

“All the studies that have ever been done show that hypertension is inadequately treated,” Louis Caplan, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center, both in Boston, said in an interview. “One of the reasons is that it can be hard to get some of the patients to seek treatment, particularly Black Americans. Also, a lot of the medicines to treat high blood pressure have side effects, so many patients don’t want to take the pills.

“Treating hypertension really requires continued surveillance,” he added. “It’s not one visit where the doctor gives you a pill. It’s taking the pill, following your blood pressure, and seeing if it works. If it doesn’t, then maybe you change the dose, get another pill, and are followed once again. That doesn’t happen as often as it should.”

In regard to next steps, Dr. Caplan urged that hypertension “be evaluated more seriously. Even as home blood pressure kits and monitoring become increasingly available, many doctors are still going by a casual blood pressure test in the office, which doesn’t tell you how serious the problem is. There needs to be more use of technology and more conditioning of patients to monitor their own blood pressure as a guide, and then we go from there.”

The authors acknowledged their study’s limitations, including the NHANES’s reliance on self-reporting a history of stroke and the inability to distinguish between subtypes of stroke. In addition, they noted that many antihypertensive medications have uses beyond treating hypertension, which introduces “another confounding factor to medication trends.”

The authors and Dr. Caplan reported no conflicts of interest.

SOURCE: Santos D et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2499.

Correction, 8/20/20: An earlier version of this article misstated the confidence interval for diuretics.

A new study of hypertension treatment trends found that uncontrolled high blood pressure along with considerable undertreatment of the condition were prevalent in individuals with a history of both hypertension and stroke. “To our knowledge, the present study is the first to analyze and report national antihypertensive medication trends exclusively among individuals with a history of stroke in the United States,” wrote Daniel Santos, MD, and Mandip S. Dhamoon, MD, DrPH, of the Icahn School of Medicine at Mount Sinai, New York. Their study was published in JAMA Neurology.

To examine blood pressure control and treatment trends among stroke survivors, the researchers examined more than a decade of data from the National Health and Nutrition Examination Survey (NHANES). The cross-sectional survey is conducted in 2-year cycles; the authors analyzed the results from 2005 to 2016 and uncovered a total of 4,971,136 eligible individuals with a history of both stroke and hypertension.

The mean age of the study population was 67.1 (95% confidence interval, 66.1-68.1), and 2,790,518 (56.1%) were women. Their mean blood pressure was 134/68 mm Hg (95% CI, 133/67–136/69), and the average number of antihypertensive medications they were taking was 1.8 (95% CI, 1.7-1.9). Of the 4,971,136 analyzed individuals, 4,721,409 (95%) were aware of their hypertension diagnosis yet more than 10% of that group had not previously been prescribed an antihypertensive medication.

More than 37% (n = 1,846,470) of the participants had uncontrolled high blood pressure upon examination (95% CI, 33.5%-40.8%), and 15.3% (95% CI, 12.5%-18.0%) were not taking any medication for it at all. The most commonly used antihypertensive medications included ACE inhibitors or angiotensin receptor blockers (59.2%; 95% CI, 54.9%-63.4%), beta-blockers (43.8%; 95% CI, 40.3%-47.3%), diuretics (41.6%; 95% CI, 37.3%-45.9%) and calcium-channel blockers (31.5%; 95% CI, 28.2%-34.8%).* Roughly 57% of the sample was taking more than one antihypertensive medication (95% CI, 52.8%-60.6%) while 28% (95% CI, 24.6%-31.5%) were taking only one.
 

Continued surveillance is key

“All the studies that have ever been done show that hypertension is inadequately treated,” Louis Caplan, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center, both in Boston, said in an interview. “One of the reasons is that it can be hard to get some of the patients to seek treatment, particularly Black Americans. Also, a lot of the medicines to treat high blood pressure have side effects, so many patients don’t want to take the pills.

“Treating hypertension really requires continued surveillance,” he added. “It’s not one visit where the doctor gives you a pill. It’s taking the pill, following your blood pressure, and seeing if it works. If it doesn’t, then maybe you change the dose, get another pill, and are followed once again. That doesn’t happen as often as it should.”

In regard to next steps, Dr. Caplan urged that hypertension “be evaluated more seriously. Even as home blood pressure kits and monitoring become increasingly available, many doctors are still going by a casual blood pressure test in the office, which doesn’t tell you how serious the problem is. There needs to be more use of technology and more conditioning of patients to monitor their own blood pressure as a guide, and then we go from there.”

The authors acknowledged their study’s limitations, including the NHANES’s reliance on self-reporting a history of stroke and the inability to distinguish between subtypes of stroke. In addition, they noted that many antihypertensive medications have uses beyond treating hypertension, which introduces “another confounding factor to medication trends.”

The authors and Dr. Caplan reported no conflicts of interest.

SOURCE: Santos D et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2499.

Correction, 8/20/20: An earlier version of this article misstated the confidence interval for diuretics.

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

“This is a new approach [that] will actively take system changes ... but it will ultimately be safer for patients – and that is crucial,” commented Jessica P. Hwang, MD, MPH, cochair of the American Society of Clinical Oncology HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Dr. Hwang said in an interview.

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

“Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death,” Dr. Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

“This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, comanagement with specialists, and antiviral therapy and monitoring,” she added.

The updated opinion was published online July 27 in the Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed “to provide timely clinical guidance” on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides “a clinically pragmatic approach to HBV screening and management” that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Dr. Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening “inefficient and impractical,” she said.

“The results of these two studies suggest that a universal screening approach, its potential harms (e.g., patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment,” the authors comment.

The screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in implementing universal HBV screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple “sticky-note” alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a “comprehensive set of multimodal interventions,” including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

“Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems,” the panel says. The authors note that “[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation.”

The panel also identified a research gap related to HBV reactivation risks “for the growing list of agents that deplete or modulate B cells.” It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Dr. Hwang said that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

“That’s a really strong statement that insurance payers are accepting of this kind of preventative service,” she said.

Expert panel cochair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

“There’s growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment,” Dr. Artz said in an interview.

Dr. Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, California.

He suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies – and more lines of therapy – could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it. “There’s no question we will have to change practice,” Dr. Artz said in an interview. “But this is easier than the previous approach that essentially wasn’t being followed because it was too difficult to follow and patients were being missed.”

Most clinicians will appreciate having an approach that’s easier to follow, Dr. Artz predicted.

If there’s a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to “take some ownership of the issue,” as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as “strong,” with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as “moderate.” All were based on “informal consensus,” with the exception of the key recommendation for universal HBV screening – use of three specific tests – which was “evidence based.”

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Dr. Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Dr. Artz received research funding from Miltenyi Biotec. All expert panel members’ disclosures are available in the PCO update.

This article first appeared on Medscape.com.

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

“This is a new approach [that] will actively take system changes ... but it will ultimately be safer for patients – and that is crucial,” commented Jessica P. Hwang, MD, MPH, cochair of the American Society of Clinical Oncology HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Dr. Hwang said in an interview.

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

“Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death,” Dr. Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

“This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, comanagement with specialists, and antiviral therapy and monitoring,” she added.

The updated opinion was published online July 27 in the Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed “to provide timely clinical guidance” on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides “a clinically pragmatic approach to HBV screening and management” that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Dr. Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening “inefficient and impractical,” she said.

“The results of these two studies suggest that a universal screening approach, its potential harms (e.g., patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment,” the authors comment.

The screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in implementing universal HBV screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple “sticky-note” alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a “comprehensive set of multimodal interventions,” including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

“Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems,” the panel says. The authors note that “[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation.”

The panel also identified a research gap related to HBV reactivation risks “for the growing list of agents that deplete or modulate B cells.” It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Dr. Hwang said that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

“That’s a really strong statement that insurance payers are accepting of this kind of preventative service,” she said.

Expert panel cochair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

“There’s growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment,” Dr. Artz said in an interview.

Dr. Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, California.

He suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies – and more lines of therapy – could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it. “There’s no question we will have to change practice,” Dr. Artz said in an interview. “But this is easier than the previous approach that essentially wasn’t being followed because it was too difficult to follow and patients were being missed.”

Most clinicians will appreciate having an approach that’s easier to follow, Dr. Artz predicted.

If there’s a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to “take some ownership of the issue,” as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as “strong,” with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as “moderate.” All were based on “informal consensus,” with the exception of the key recommendation for universal HBV screening – use of three specific tests – which was “evidence based.”

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Dr. Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Dr. Artz received research funding from Miltenyi Biotec. All expert panel members’ disclosures are available in the PCO update.

This article first appeared on Medscape.com.

All patients with cancer who are candidates for systemic anticancer therapy should be screened for hepatitis B virus (HBV) infection prior to or at the start of therapy, according to an updated provisional clinical opinion (PCO) from the American Society of Clinical Oncology.

“This is a new approach [that] will actively take system changes ... but it will ultimately be safer for patients – and that is crucial,” commented Jessica P. Hwang, MD, MPH, cochair of the American Society of Clinical Oncology HBV Screening Expert Panel and the first author of the PCO.

Uptake of this universal screening approach would streamline testing protocols and identify more patients at risk for HBV reactivation who should receive prophylactic antiviral therapy, Dr. Hwang said in an interview.

The PCO calls for antiviral prophylaxis during and for at least 12 months after therapy for those with chronic HBV infection who are receiving any systemic anticancer treatment and for those with have had HBV in the past and are receiving any therapies that pose a risk for HBV reactivation.

“Hepatitis B reactivation can cause really terrible outcomes, like organ failure and even death,” Dr. Hwang, who is also a professor at the University of Texas MD Anderson Cancer Center, Houston, commented in an interview.

“This whole [issue of] reactivation and adverse outcomes with anticancer therapies is completely preventable with good planning, good communication, comanagement with specialists, and antiviral therapy and monitoring,” she added.

The updated opinion was published online July 27 in the Journal of Clinical Oncology.

It was developed in response to new data that call into question the previously recommended risk-adaptive approach to HBV screening of cancer patients, say the authors.

ASCO PCOs are developed “to provide timely clinical guidance” on the basis of emerging practice-changing information. This is the second update to follow the initial HBV screening PCO, published in 2010. In the absence of clear consensus because of limited data, the original PCO called for a risk-based approach to screening. A 2015 update extended the recommendation for screening to patients starting anti-CD20 therapy or who are to undergo stem cell transplant and to those with risk factors for HBV exposure.

The current update provides “a clinically pragmatic approach to HBV screening and management” that is based on the latest findings, say the authors. These include findings from a multicenter prospective cohort study of more than 3000 patients. In that study, 21% of patients with chronic HBV had no known risk factors for the infection. In another large prospective observational cohort study, led by Dr. Hwang, which included more than 2100 patients with cancer, 90% had one or more significant risk factors for HBV infection, making selective screening “inefficient and impractical,” she said.

“The results of these two studies suggest that a universal screening approach, its potential harms (e.g., patient and clinician anxiety about management, financial burden associated with antiviral therapy) notwithstanding, is the most efficient, clinically pragmatic approach to HBV screening in persons anticipating systemic anticancer treatment,” the authors comment.

The screening recommended in the PCO requires three tests: hepatitis B surface antigen (HBsAg), core antibody total immunoglobulin or IgG, and antibody to HBsAg tests.

Anticancer therapy should not be delayed pending the results, they write.

Planning for monitoring and long-term prophylaxis for chronic HBV infection should involve a clinician experienced in HBV management, the authors write. Management of those with past infection should be individualized. Alternatively, patients with past infection can be carefully monitored rather than given prophylactic treatment, as long as frequent and consistent follow-up is possible to allow for rapid initiation of antiviral therapy in the event of reactivation, they say.

Hormonal therapy without systemic anticancer therapy is not likely to lead to HBV reactivation in patients with chronic or past infection; antiviral therapy and management of these patients should follow relevant national HBV guidelines, they note.

Challenges in implementing universal HBV screening

The expert panel acknowledges the challenges associated with implementation of universal HBV screening as recommended in their report and notes that electronic health record–based approaches that use alerts to prompt screening have demonstrated success. In one study of high-risk primary care patients, an EHR alert system significantly increased testing rates (odds ratio, 2.64 in comparison with a control group without alerts), and another study that used a simple “sticky-note” alert system to promote referral of HBsAg patients to hepatologists increased referrals from 28% to 73%.

In a cancer population, a “comprehensive set of multimodal interventions,” including pharmacy staff checks for screening prior to anti-CD20 therapy administration and electronic medication order reviews to assess for appropriate testing and treatment before anti-CD20 therapy, increased testing rates to greater than 90% and antiviral prophylaxis rates to more than 80%.

A study of 965 patients in Taiwan showed that a computer-assisted reminder system that prompted for testing prior to ordering anticancer therapy increased screening from 8% to 86% but was less effective for improving the rates of antiviral prophylaxis for those who tested positive for HBV, particularly among physicians treating patients with nonhematologic malignancies.

“Future studies will be needed to make universal HBV screening and linkage to care efficient and systematic, likely based in EHR systems,” the panel says. The authors note that “[o]ngoing studies of HBV tests such as ultrasensitive HBsAg, HBV RNA, and hepatitis B core antigen are being studied and may be useful in predicting risk of HBV reactivation.”

The panel also identified a research gap related to HBV reactivation risks “for the growing list of agents that deplete or modulate B cells.” It notes a need for additional research on the cost-effectiveness of HBV screening. The results of prior cost analyses have been inconsistent and vary with respect to the population studied. For example, universal screening and antiviral prophylaxis approaches have been shown to be cost-effective for patients with hematologic malignancies and high HBV reactivation risk but are less so for patients with solid tumors and lower reactivation risk, they explain.

Dr. Hwang said that not one of the more than 2100 patients in her HBV screening cohort study encountered problems with receiving insurance payment for their HBV screening.

“That’s a really strong statement that insurance payers are accepting of this kind of preventative service,” she said.

Expert panel cochair Andrew Artz, MD, commented that there is now greater acceptance of the need for HBV screening across medical specialties.

“There’s growing consensus among hepatologists, infectious disease specialists, oncologists, and HBV specialists that we need to do a better job of finding patients with hepatitis B [who are] about to receive immunocompromising treatment,” Dr. Artz said in an interview.

Dr. Artz is director of the Program for Aging and Blood Cancers and deputy director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center, Duarte, California.

He suggested that the growing acceptance is due in part to the increasing number of anticancer therapies available and the resulting increase in the likelihood of patients receiving therapies that could cause reactivation.

More therapies – and more lines of therapy – could mean greater risk, he explained. He said that testing is easy and that universal screening is the simplest approach to determining who needs it. “There’s no question we will have to change practice,” Dr. Artz said in an interview. “But this is easier than the previous approach that essentially wasn’t being followed because it was too difficult to follow and patients were being missed.”

Most clinicians will appreciate having an approach that’s easier to follow, Dr. Artz predicted.

If there’s a challenge it will be in developing partnerships with HBV specialists, particularly in rural areas. In areas where there is a paucity of subspecialists, oncologists will have to “take some ownership of the issue,” as they often do in such settings, he said.

However, with support from pharmacists, administrators, and others in embracing this guidance, implementation can take place at a systems level rather than an individual clinician level, he added.

The recommendations in this updated PCO were all rated as “strong,” with the exception of the recommendation on hormonal therapy in the absence of systemic anticancer therapy, which was rated as “moderate.” All were based on “informal consensus,” with the exception of the key recommendation for universal HBV screening – use of three specific tests – which was “evidence based.”

The expert panel agreed that the benefits outweigh the harms for each recommendation in the update.

Dr. Hwang received research funding to her institution from Gilead Sciences and Merck Sharp & Dohme. She also has a relationship with the Asian Health Foundation. Dr. Artz received research funding from Miltenyi Biotec. All expert panel members’ disclosures are available in the PCO update.

This article first appeared on Medscape.com.

An observational cohort study of a prospective international database of patients with multiple sclerosis has reported that medical therapy can reduce disability progression in patients with active secondary progressive MS (SPMS) who are prone to inflammatory relapses.

Brian Hoyle/MDedge News

The international researchers, led by Nathanial Lizak, MMBS, of the University of Melbourne, conducted the cohort study of 1,621 patients with SPMS from the MSBase international registry, which prospectively collected the information from 1995 to 2018. Their findings were published in JAMA Neurology.

“Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent,” wrote Dr. Lizak and colleagues of the MSBase Study Group.
 

Therapy’s impact on disease progression

To ensure that they had timely data on the early disease course of all study patients, they researchers only included patients whose diagnosis and first documented Expanded Disability Status Scale (EDSS) score were no more than 24 months apart. At SPMS conversion, 1,494 patients had an EDSS score of less than 7 (on a scale of 0-10); during the follow-up period, 267 of them (17.9%) crossed over the threshold of 7.

Dr. Lizak and colleagues noted that early treatment during relapsing remitting MS didn’t impact outcomes after SPMS conversion.

For evaluating the MS Severity Score (MSSS), the study split the cohort into three groups depending on the efficacy of therapy: low-efficacy treatments, mostly consisting of interferon-beta and glatiramer acetate; medium-efficacy treatments, mostly fingolimod and dimethyl fumarate; and high-efficacy treatments, predominately natalizumab and mitoxantrone.

The MSSS progression slope in the cohort had an average reduction of 0.02 points per year. “For patients who experienced superimposed relapses during SPMS, a reduced MSSS progression slope during SPMS was observed among those who received disease-modifying therapies for a greater proportion of time during SPMS,” Dr. Lizak and colleagues wrote.

MSSS progression slope reduction was more pronounced in the medium- and high-efficacy groups, with a reduction of beta 0.22 (P = .06) and 0.034 (P = .002), respectively.

“Based on our models, the level of disability in patients with active SPMS who are continuously treated with high-efficacy immunotherapies would progress more slowly in comparison with the general population with MS by a mean (standard deviation) of 1.56 (4.60) deciles over 10 years,” Dr. Lizak and colleagues wrote.

While the researchers cited a number of studies that didn’t support immunotherapy for SPMS, they also did cite the EXPAND trial to support treatment with siponimod in SPMS patients (Lancet. 2018;391:1263-73). The ASCEND trial of natalizumab enrolled a largely relapse-free cohort and found no link between treatment and disability progression in SPMS (Lancet Neurol. 2018;17:405-15), and a previous report by the MSBase Study Group found no benefit of therapy when adjusted for SPMS relapse rates (Neurology. 2017;89:1050-9).

“Together with the present study, the existing data converge on the suggestion that relapses during SPMS provide a therapeutic target and a marker of future response to immunotherapy during SPMS,” Dr. Lizak and colleagues wrote.
 

Challenging dogma

Commenting on the research, Mark Freedman, HBSc, MSc, MD, said that the MSBase study makes an important contribution to the literature on management of SPMS. “Up until this point we’ve been basing our assumptions on secondary progressive MS on natural history studies, which are actually quite old, dating back 20-30 years.” Dr. Freedman is senior scientist in the Neuroscience Program at the Ottawa Hospital Research Institute and professor of medicine in neurology at the University of Ottawa.

He said “the most damaging” of those studies was by the late Christian Confavreaux, MD, and colleagues in Lyon, France (N Engl J Med. 2000;343:1430-8), that reported relapses didn’t alter the progression of disability. “In other words, once you’re in EDSS of 4, it’s a runaway train; it doesn’t matter what you do,” Dr. Freedman said.

“That was kind of dogma for years,” he said. “The reason this publication is important is because it’s suggesting that’s not the case.” In other words, the MSBase cohort study is validating what neurologists have been doing in the real world for years: treating patients with SPMS who have relapses.

Dr Lizak reported receiving travel compensation from Merck outside the scope of the study. His coauthors reported numerous financial relationships.

SOURCE: Lizak N et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2453

An observational cohort study of a prospective international database of patients with multiple sclerosis has reported that medical therapy can reduce disability progression in patients with active secondary progressive MS (SPMS) who are prone to inflammatory relapses.

Brian Hoyle/MDedge News

The international researchers, led by Nathanial Lizak, MMBS, of the University of Melbourne, conducted the cohort study of 1,621 patients with SPMS from the MSBase international registry, which prospectively collected the information from 1995 to 2018. Their findings were published in JAMA Neurology.

“Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent,” wrote Dr. Lizak and colleagues of the MSBase Study Group.
 

Therapy’s impact on disease progression

To ensure that they had timely data on the early disease course of all study patients, they researchers only included patients whose diagnosis and first documented Expanded Disability Status Scale (EDSS) score were no more than 24 months apart. At SPMS conversion, 1,494 patients had an EDSS score of less than 7 (on a scale of 0-10); during the follow-up period, 267 of them (17.9%) crossed over the threshold of 7.

Dr. Lizak and colleagues noted that early treatment during relapsing remitting MS didn’t impact outcomes after SPMS conversion.

For evaluating the MS Severity Score (MSSS), the study split the cohort into three groups depending on the efficacy of therapy: low-efficacy treatments, mostly consisting of interferon-beta and glatiramer acetate; medium-efficacy treatments, mostly fingolimod and dimethyl fumarate; and high-efficacy treatments, predominately natalizumab and mitoxantrone.

The MSSS progression slope in the cohort had an average reduction of 0.02 points per year. “For patients who experienced superimposed relapses during SPMS, a reduced MSSS progression slope during SPMS was observed among those who received disease-modifying therapies for a greater proportion of time during SPMS,” Dr. Lizak and colleagues wrote.

MSSS progression slope reduction was more pronounced in the medium- and high-efficacy groups, with a reduction of beta 0.22 (P = .06) and 0.034 (P = .002), respectively.

“Based on our models, the level of disability in patients with active SPMS who are continuously treated with high-efficacy immunotherapies would progress more slowly in comparison with the general population with MS by a mean (standard deviation) of 1.56 (4.60) deciles over 10 years,” Dr. Lizak and colleagues wrote.

While the researchers cited a number of studies that didn’t support immunotherapy for SPMS, they also did cite the EXPAND trial to support treatment with siponimod in SPMS patients (Lancet. 2018;391:1263-73). The ASCEND trial of natalizumab enrolled a largely relapse-free cohort and found no link between treatment and disability progression in SPMS (Lancet Neurol. 2018;17:405-15), and a previous report by the MSBase Study Group found no benefit of therapy when adjusted for SPMS relapse rates (Neurology. 2017;89:1050-9).

“Together with the present study, the existing data converge on the suggestion that relapses during SPMS provide a therapeutic target and a marker of future response to immunotherapy during SPMS,” Dr. Lizak and colleagues wrote.
 

Challenging dogma

Commenting on the research, Mark Freedman, HBSc, MSc, MD, said that the MSBase study makes an important contribution to the literature on management of SPMS. “Up until this point we’ve been basing our assumptions on secondary progressive MS on natural history studies, which are actually quite old, dating back 20-30 years.” Dr. Freedman is senior scientist in the Neuroscience Program at the Ottawa Hospital Research Institute and professor of medicine in neurology at the University of Ottawa.

He said “the most damaging” of those studies was by the late Christian Confavreaux, MD, and colleagues in Lyon, France (N Engl J Med. 2000;343:1430-8), that reported relapses didn’t alter the progression of disability. “In other words, once you’re in EDSS of 4, it’s a runaway train; it doesn’t matter what you do,” Dr. Freedman said.

“That was kind of dogma for years,” he said. “The reason this publication is important is because it’s suggesting that’s not the case.” In other words, the MSBase cohort study is validating what neurologists have been doing in the real world for years: treating patients with SPMS who have relapses.

Dr Lizak reported receiving travel compensation from Merck outside the scope of the study. His coauthors reported numerous financial relationships.

SOURCE: Lizak N et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2453

An observational cohort study of a prospective international database of patients with multiple sclerosis has reported that medical therapy can reduce disability progression in patients with active secondary progressive MS (SPMS) who are prone to inflammatory relapses.

Brian Hoyle/MDedge News

The international researchers, led by Nathanial Lizak, MMBS, of the University of Melbourne, conducted the cohort study of 1,621 patients with SPMS from the MSBase international registry, which prospectively collected the information from 1995 to 2018. Their findings were published in JAMA Neurology.

“Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent,” wrote Dr. Lizak and colleagues of the MSBase Study Group.
 

Therapy’s impact on disease progression

To ensure that they had timely data on the early disease course of all study patients, they researchers only included patients whose diagnosis and first documented Expanded Disability Status Scale (EDSS) score were no more than 24 months apart. At SPMS conversion, 1,494 patients had an EDSS score of less than 7 (on a scale of 0-10); during the follow-up period, 267 of them (17.9%) crossed over the threshold of 7.

Dr. Lizak and colleagues noted that early treatment during relapsing remitting MS didn’t impact outcomes after SPMS conversion.

For evaluating the MS Severity Score (MSSS), the study split the cohort into three groups depending on the efficacy of therapy: low-efficacy treatments, mostly consisting of interferon-beta and glatiramer acetate; medium-efficacy treatments, mostly fingolimod and dimethyl fumarate; and high-efficacy treatments, predominately natalizumab and mitoxantrone.

The MSSS progression slope in the cohort had an average reduction of 0.02 points per year. “For patients who experienced superimposed relapses during SPMS, a reduced MSSS progression slope during SPMS was observed among those who received disease-modifying therapies for a greater proportion of time during SPMS,” Dr. Lizak and colleagues wrote.

MSSS progression slope reduction was more pronounced in the medium- and high-efficacy groups, with a reduction of beta 0.22 (P = .06) and 0.034 (P = .002), respectively.

“Based on our models, the level of disability in patients with active SPMS who are continuously treated with high-efficacy immunotherapies would progress more slowly in comparison with the general population with MS by a mean (standard deviation) of 1.56 (4.60) deciles over 10 years,” Dr. Lizak and colleagues wrote.

While the researchers cited a number of studies that didn’t support immunotherapy for SPMS, they also did cite the EXPAND trial to support treatment with siponimod in SPMS patients (Lancet. 2018;391:1263-73). The ASCEND trial of natalizumab enrolled a largely relapse-free cohort and found no link between treatment and disability progression in SPMS (Lancet Neurol. 2018;17:405-15), and a previous report by the MSBase Study Group found no benefit of therapy when adjusted for SPMS relapse rates (Neurology. 2017;89:1050-9).

“Together with the present study, the existing data converge on the suggestion that relapses during SPMS provide a therapeutic target and a marker of future response to immunotherapy during SPMS,” Dr. Lizak and colleagues wrote.
 

Challenging dogma

Commenting on the research, Mark Freedman, HBSc, MSc, MD, said that the MSBase study makes an important contribution to the literature on management of SPMS. “Up until this point we’ve been basing our assumptions on secondary progressive MS on natural history studies, which are actually quite old, dating back 20-30 years.” Dr. Freedman is senior scientist in the Neuroscience Program at the Ottawa Hospital Research Institute and professor of medicine in neurology at the University of Ottawa.

He said “the most damaging” of those studies was by the late Christian Confavreaux, MD, and colleagues in Lyon, France (N Engl J Med. 2000;343:1430-8), that reported relapses didn’t alter the progression of disability. “In other words, once you’re in EDSS of 4, it’s a runaway train; it doesn’t matter what you do,” Dr. Freedman said.

“That was kind of dogma for years,” he said. “The reason this publication is important is because it’s suggesting that’s not the case.” In other words, the MSBase cohort study is validating what neurologists have been doing in the real world for years: treating patients with SPMS who have relapses.

Dr Lizak reported receiving travel compensation from Merck outside the scope of the study. His coauthors reported numerous financial relationships.

SOURCE: Lizak N et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2453

The cannabidiol (CBD) oral solution Epidiolex has been approved by the Food and Drug Administration for the new indication of treatment of seizures associated with tuberous sclerosis complex in patients 1 year of age and older.

The drug was approved by the FDA in 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, as reported by Medscape Medical News.

This is the only FDA-approved drug that contains a purified drug substance derived from cannabis. It is also the second FDA approval of a drug for the treatment of seizures associated with tuberous sclerosis complex.

CBD is a chemical component of the cannabis sativa plant, but it does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC), which is the primary psychoactive component of cannabis.

“The FDA continues to believe the drug approval process represents the best way to make new medicines, including any drugs derived from cannabis, available to patients in need of appropriate medical therapy such as the treatment of seizures associated with these rare conditions,” Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, said in an agency press release.

“This paradigm ensures new therapies are safe, effective, and manufactured to a high quality that provides uniform and reliable dosing for patients,” Dr. Throckmorton said.

He added that the FDA is committed to supporting research on the potential medical uses of cannabis-derived products.
 

Rare genetic disease

Tuberous sclerosis complex is a rare genetic disease that causes benign tumors to grow in the brain and other parts of the body, such as the eyes, heart, kidneys, lungs, and skin.

It usually affects the central nervous system and can result in a combination of symptoms, including seizures, developmental delay, and behavioral problems. The signs and symptoms of the condition, as well as the severity of symptoms, vary widely. The disease affects about 1 in 6,000 individuals.

The effectiveness of Epidiolex in the treatment of seizures associated with tuberous sclerosis complex was established in a randomized, double-blind, placebo-controlled trial in which 148 patients of a total of 224 in the study received the active drug, the FDA noted.

Results showed that for patients treated with CBD, there was a significantly greater reduction in seizure frequency during the treatment period than for patients who received placebo.

This effect was seen within 8 weeks and remained consistent throughout the 16-week treatment period.

The most common side effects that occurred in CBD-treated participants were diarrhea, elevated liver enzyme levels, decreased appetite, sleepiness, fever, and vomiting. Additional side effects that have been reported with the product include liver injury, decreased weight, anemia, and increased creatinine level.

As is true for all drugs that currently treat epilepsy, including Epidiolex, the most serious risks may include an increase in suicidal thoughts and behavior or thoughts of self-harm, the FDA reports.

Patients, their caregivers, and their families should be advised to monitor for any unusual changes in mood or behavior, such as worsening depression or suicidal thoughts or behavior. They should report behaviors of concern immediately to health care providers, the agency notes.

It also points out that Epidiolex can cause liver injury, of which most cases are generally mild. However, there is a risk for rare but more severe liver injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine.

A version of this story originally appeared on Medscape.com.

The cannabidiol (CBD) oral solution Epidiolex has been approved by the Food and Drug Administration for the new indication of treatment of seizures associated with tuberous sclerosis complex in patients 1 year of age and older.

The drug was approved by the FDA in 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, as reported by Medscape Medical News.

This is the only FDA-approved drug that contains a purified drug substance derived from cannabis. It is also the second FDA approval of a drug for the treatment of seizures associated with tuberous sclerosis complex.

CBD is a chemical component of the cannabis sativa plant, but it does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC), which is the primary psychoactive component of cannabis.

“The FDA continues to believe the drug approval process represents the best way to make new medicines, including any drugs derived from cannabis, available to patients in need of appropriate medical therapy such as the treatment of seizures associated with these rare conditions,” Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, said in an agency press release.

“This paradigm ensures new therapies are safe, effective, and manufactured to a high quality that provides uniform and reliable dosing for patients,” Dr. Throckmorton said.

He added that the FDA is committed to supporting research on the potential medical uses of cannabis-derived products.
 

Rare genetic disease

Tuberous sclerosis complex is a rare genetic disease that causes benign tumors to grow in the brain and other parts of the body, such as the eyes, heart, kidneys, lungs, and skin.

It usually affects the central nervous system and can result in a combination of symptoms, including seizures, developmental delay, and behavioral problems. The signs and symptoms of the condition, as well as the severity of symptoms, vary widely. The disease affects about 1 in 6,000 individuals.

The effectiveness of Epidiolex in the treatment of seizures associated with tuberous sclerosis complex was established in a randomized, double-blind, placebo-controlled trial in which 148 patients of a total of 224 in the study received the active drug, the FDA noted.

Results showed that for patients treated with CBD, there was a significantly greater reduction in seizure frequency during the treatment period than for patients who received placebo.

This effect was seen within 8 weeks and remained consistent throughout the 16-week treatment period.

The most common side effects that occurred in CBD-treated participants were diarrhea, elevated liver enzyme levels, decreased appetite, sleepiness, fever, and vomiting. Additional side effects that have been reported with the product include liver injury, decreased weight, anemia, and increased creatinine level.

As is true for all drugs that currently treat epilepsy, including Epidiolex, the most serious risks may include an increase in suicidal thoughts and behavior or thoughts of self-harm, the FDA reports.

Patients, their caregivers, and their families should be advised to monitor for any unusual changes in mood or behavior, such as worsening depression or suicidal thoughts or behavior. They should report behaviors of concern immediately to health care providers, the agency notes.

It also points out that Epidiolex can cause liver injury, of which most cases are generally mild. However, there is a risk for rare but more severe liver injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine.

A version of this story originally appeared on Medscape.com.

The cannabidiol (CBD) oral solution Epidiolex has been approved by the Food and Drug Administration for the new indication of treatment of seizures associated with tuberous sclerosis complex in patients 1 year of age and older.

The drug was approved by the FDA in 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, as reported by Medscape Medical News.

This is the only FDA-approved drug that contains a purified drug substance derived from cannabis. It is also the second FDA approval of a drug for the treatment of seizures associated with tuberous sclerosis complex.

CBD is a chemical component of the cannabis sativa plant, but it does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC), which is the primary psychoactive component of cannabis.

“The FDA continues to believe the drug approval process represents the best way to make new medicines, including any drugs derived from cannabis, available to patients in need of appropriate medical therapy such as the treatment of seizures associated with these rare conditions,” Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, said in an agency press release.

“This paradigm ensures new therapies are safe, effective, and manufactured to a high quality that provides uniform and reliable dosing for patients,” Dr. Throckmorton said.

He added that the FDA is committed to supporting research on the potential medical uses of cannabis-derived products.
 

Rare genetic disease

Tuberous sclerosis complex is a rare genetic disease that causes benign tumors to grow in the brain and other parts of the body, such as the eyes, heart, kidneys, lungs, and skin.

It usually affects the central nervous system and can result in a combination of symptoms, including seizures, developmental delay, and behavioral problems. The signs and symptoms of the condition, as well as the severity of symptoms, vary widely. The disease affects about 1 in 6,000 individuals.

The effectiveness of Epidiolex in the treatment of seizures associated with tuberous sclerosis complex was established in a randomized, double-blind, placebo-controlled trial in which 148 patients of a total of 224 in the study received the active drug, the FDA noted.

Results showed that for patients treated with CBD, there was a significantly greater reduction in seizure frequency during the treatment period than for patients who received placebo.

This effect was seen within 8 weeks and remained consistent throughout the 16-week treatment period.

The most common side effects that occurred in CBD-treated participants were diarrhea, elevated liver enzyme levels, decreased appetite, sleepiness, fever, and vomiting. Additional side effects that have been reported with the product include liver injury, decreased weight, anemia, and increased creatinine level.

As is true for all drugs that currently treat epilepsy, including Epidiolex, the most serious risks may include an increase in suicidal thoughts and behavior or thoughts of self-harm, the FDA reports.

Patients, their caregivers, and their families should be advised to monitor for any unusual changes in mood or behavior, such as worsening depression or suicidal thoughts or behavior. They should report behaviors of concern immediately to health care providers, the agency notes.

It also points out that Epidiolex can cause liver injury, of which most cases are generally mild. However, there is a risk for rare but more severe liver injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine.

A version of this story originally appeared on Medscape.com.

A novel drug, tafasitamab-cxix (Monjuvi, MorphoSys US), has been approved by the Food and Drug Administration for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The product is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. It mediates B-cell lysis through apoptosis and immune effector mechanism, including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

It is indicated for use in combination with lenalidomide for adult patients with relapsed/refractory DLBCL that is not otherwise specified, including DLBCL arising from low-grade lymphoma, and in patients who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab-cxix in combination with lenalidomide is the first treatment that approved by the FDA for second-line use for patients with relapsed or refractory DLBCL, notes the manufacturer.

The approval “brings a new treatment option to patients in dire need across the United States,” said Gilles Salles, MD, chair of the clinical hematology department at the University of Lyon (France), and lead investigator of the L-MIND study.

The FDA granted an accelerated approval on the basis of overall response rate from an open-label, single-arm, phase 2 trial in 81 patients (known as L-MIND). Further trials are underway to confirm clinical benefit.

The L-MIND trial was conducted in patients with relapsed or refractory DLBCL who had received at least one, but no more than three, prior lines of therapy, including an anti-CD20 targeting therapy (e.g., rituximab), who were not eligible for high-dose chemotherapy or who refused subsequent ASCT.

All patients received tafasitamab-cxix 12 mg/kg intravenously with lenalidomide (25 mg orally on days 1-21 of each 28-day cycle) for a maximum of 12 cycles, followed by tafasitamab-cxix as monotherapy.

The best ORR (defined as complete and partial responders) in 71 patients with a diagnosis of DLBCL confirmed by central pathology was 55%, with complete responses in 37% and partial responses in 18% of patients. The median response duration was 21.7 months (range, 0-24).

The most common adverse reactions (≥20%) were neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, fever, peripheral edema, respiratory tract infection, and decreased appetite.

Precautions and warnings include infusion-related reactions (6%), serious or severe myelosuppression (including neutropenia [50%], thrombocytopenia [18%], and anemia [7%]), infections (73%), and embryo-fetal toxicity.

DLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide, characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs. It is an aggressive disease with about one in three patients not responding to initial therapy or relapsing thereafter, notes the manufacturer. In the United States each year approximately 10,000 patients who are not eligible for ASCT are diagnosed with relapsed or refractory DLBCL.

This article first appeared on Medscape.com.

A novel drug, tafasitamab-cxix (Monjuvi, MorphoSys US), has been approved by the Food and Drug Administration for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The product is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. It mediates B-cell lysis through apoptosis and immune effector mechanism, including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

It is indicated for use in combination with lenalidomide for adult patients with relapsed/refractory DLBCL that is not otherwise specified, including DLBCL arising from low-grade lymphoma, and in patients who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab-cxix in combination with lenalidomide is the first treatment that approved by the FDA for second-line use for patients with relapsed or refractory DLBCL, notes the manufacturer.

The approval “brings a new treatment option to patients in dire need across the United States,” said Gilles Salles, MD, chair of the clinical hematology department at the University of Lyon (France), and lead investigator of the L-MIND study.

The FDA granted an accelerated approval on the basis of overall response rate from an open-label, single-arm, phase 2 trial in 81 patients (known as L-MIND). Further trials are underway to confirm clinical benefit.

The L-MIND trial was conducted in patients with relapsed or refractory DLBCL who had received at least one, but no more than three, prior lines of therapy, including an anti-CD20 targeting therapy (e.g., rituximab), who were not eligible for high-dose chemotherapy or who refused subsequent ASCT.

All patients received tafasitamab-cxix 12 mg/kg intravenously with lenalidomide (25 mg orally on days 1-21 of each 28-day cycle) for a maximum of 12 cycles, followed by tafasitamab-cxix as monotherapy.

The best ORR (defined as complete and partial responders) in 71 patients with a diagnosis of DLBCL confirmed by central pathology was 55%, with complete responses in 37% and partial responses in 18% of patients. The median response duration was 21.7 months (range, 0-24).

The most common adverse reactions (≥20%) were neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, fever, peripheral edema, respiratory tract infection, and decreased appetite.

Precautions and warnings include infusion-related reactions (6%), serious or severe myelosuppression (including neutropenia [50%], thrombocytopenia [18%], and anemia [7%]), infections (73%), and embryo-fetal toxicity.

DLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide, characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs. It is an aggressive disease with about one in three patients not responding to initial therapy or relapsing thereafter, notes the manufacturer. In the United States each year approximately 10,000 patients who are not eligible for ASCT are diagnosed with relapsed or refractory DLBCL.

This article first appeared on Medscape.com.

A novel drug, tafasitamab-cxix (Monjuvi, MorphoSys US), has been approved by the Food and Drug Administration for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The product is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. It mediates B-cell lysis through apoptosis and immune effector mechanism, including antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

It is indicated for use in combination with lenalidomide for adult patients with relapsed/refractory DLBCL that is not otherwise specified, including DLBCL arising from low-grade lymphoma, and in patients who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab-cxix in combination with lenalidomide is the first treatment that approved by the FDA for second-line use for patients with relapsed or refractory DLBCL, notes the manufacturer.

The approval “brings a new treatment option to patients in dire need across the United States,” said Gilles Salles, MD, chair of the clinical hematology department at the University of Lyon (France), and lead investigator of the L-MIND study.

The FDA granted an accelerated approval on the basis of overall response rate from an open-label, single-arm, phase 2 trial in 81 patients (known as L-MIND). Further trials are underway to confirm clinical benefit.

The L-MIND trial was conducted in patients with relapsed or refractory DLBCL who had received at least one, but no more than three, prior lines of therapy, including an anti-CD20 targeting therapy (e.g., rituximab), who were not eligible for high-dose chemotherapy or who refused subsequent ASCT.

All patients received tafasitamab-cxix 12 mg/kg intravenously with lenalidomide (25 mg orally on days 1-21 of each 28-day cycle) for a maximum of 12 cycles, followed by tafasitamab-cxix as monotherapy.

The best ORR (defined as complete and partial responders) in 71 patients with a diagnosis of DLBCL confirmed by central pathology was 55%, with complete responses in 37% and partial responses in 18% of patients. The median response duration was 21.7 months (range, 0-24).

The most common adverse reactions (≥20%) were neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, fever, peripheral edema, respiratory tract infection, and decreased appetite.

Precautions and warnings include infusion-related reactions (6%), serious or severe myelosuppression (including neutropenia [50%], thrombocytopenia [18%], and anemia [7%]), infections (73%), and embryo-fetal toxicity.

DLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide, characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs. It is an aggressive disease with about one in three patients not responding to initial therapy or relapsing thereafter, notes the manufacturer. In the United States each year approximately 10,000 patients who are not eligible for ASCT are diagnosed with relapsed or refractory DLBCL.

This article first appeared on Medscape.com.

The novel, orally administered calcitonin gene-related peptide (CGRP) antagonist atogepant has met the primary endpoint in a phase 3 trial for migraine prevention, AbbVie, the company developing the drug, has announced.

Top-line results from the ADVANCE trial, which evaluated atogepant 10, 30, and 60 mg, showed all three doses were associated with a significant reduction from baseline in mean monthly migraine days, compared with placebo.

There were also significant improvements in all six secondary endpoints with the two higher doses.

Data from the ADVANCE trial and a previous phase 2/3 trial will be the basis for regulatory submissions in the United States and other countries, AbbVie reported.

Decreased migraine days

The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was designed to evaluate the efficacy, safety, and tolerability of oral atogepant for the prevention of migraine in those who experienced 4-14 migraine days per month.

A total of 910 patients were randomized to one of four treatment groups: 10 mg, 30 mg, or 60 mg of atogepant once daily or placebo. Efficacy analyses were based on the modified intent-to-treat population of 873 patients.

The primary endpoint was change from baseline in mean monthly migraine days during the 12-week treatment period. All atogepant dose groups met the primary endpoint and demonstrated significantly greater decreases in mean monthly migraine days, compared with placebo.

Mean monthly migraine days were reduced by 3.69 days with the 10-mg dose, 3.86 days with the 30-mg dose, and 4.2 days with the 60-mg dose of atogepant, compared with a reduction of 2.48 migraine days in the placebo group (P < .0001, all dose groups vs. placebo).

A key secondary endpoint measured the proportion of patients who achieved at least a 50% reduction in mean monthly migraine days over 12 weeks. This outcome occurred in 55.6% of the 10-mg atogepant group, 58.7% of the 30-mg group, and 60.8% of the 60-mg group, compared with 29% of the placebo group (P < .0001, all dose groups vs. placebo).

Significant improvements

Additional secondary endpoints measured during the 12-week treatment period included change from baseline in mean monthly headache days, mean monthly acute–medication use days, mean monthly performance of daily activities and physical impairment domain scores on the Activity Impairment in Migraine-Diary, and change from baseline in the Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at week 12. Treatment with the 30-mg and 60-mg doses resulted in significant improvements in all secondary endpoints, and treatment with the 10-mg dose resulted in significant improvements in four of the six secondary endpoints.

No new safety risks were observed when compared with the safety profile of atogepant observed in previous trials, AbbVie said. Serious adverse events occurred in 0.9% of patients in the atogepant 10-mg group versus 0.9% of patients in the placebo group. No patients in the atogepant 30-mg or 60-mg groups experienced a serious adverse event. The most common adverse events (reported in at least 5% of patients and at least one atogepant group and at a rate greater than placebo), across all doses versus placebo, were constipation (6.9%-7.7% vs. 0.5%), nausea (4.4%-6.1% vs. 1.8%), and upper respiratory tract infection (3.9%-5.7% vs. 4.5%).

Most cases of constipation, nausea, and upper respiratory tract infection were mild or moderate in severity and did not lead to discontinuation. There were no hepatic safety issues identified in the trial.

Full data results will be presented at an upcoming medical congress and/or published in a peer-reviewed journal, the company said.
 

A version of this article originally appeared on Medscape.com.

The novel, orally administered calcitonin gene-related peptide (CGRP) antagonist atogepant has met the primary endpoint in a phase 3 trial for migraine prevention, AbbVie, the company developing the drug, has announced.

Top-line results from the ADVANCE trial, which evaluated atogepant 10, 30, and 60 mg, showed all three doses were associated with a significant reduction from baseline in mean monthly migraine days, compared with placebo.

There were also significant improvements in all six secondary endpoints with the two higher doses.

Data from the ADVANCE trial and a previous phase 2/3 trial will be the basis for regulatory submissions in the United States and other countries, AbbVie reported.

Decreased migraine days

The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was designed to evaluate the efficacy, safety, and tolerability of oral atogepant for the prevention of migraine in those who experienced 4-14 migraine days per month.

A total of 910 patients were randomized to one of four treatment groups: 10 mg, 30 mg, or 60 mg of atogepant once daily or placebo. Efficacy analyses were based on the modified intent-to-treat population of 873 patients.

The primary endpoint was change from baseline in mean monthly migraine days during the 12-week treatment period. All atogepant dose groups met the primary endpoint and demonstrated significantly greater decreases in mean monthly migraine days, compared with placebo.

Mean monthly migraine days were reduced by 3.69 days with the 10-mg dose, 3.86 days with the 30-mg dose, and 4.2 days with the 60-mg dose of atogepant, compared with a reduction of 2.48 migraine days in the placebo group (P < .0001, all dose groups vs. placebo).

A key secondary endpoint measured the proportion of patients who achieved at least a 50% reduction in mean monthly migraine days over 12 weeks. This outcome occurred in 55.6% of the 10-mg atogepant group, 58.7% of the 30-mg group, and 60.8% of the 60-mg group, compared with 29% of the placebo group (P < .0001, all dose groups vs. placebo).

Significant improvements

Additional secondary endpoints measured during the 12-week treatment period included change from baseline in mean monthly headache days, mean monthly acute–medication use days, mean monthly performance of daily activities and physical impairment domain scores on the Activity Impairment in Migraine-Diary, and change from baseline in the Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at week 12. Treatment with the 30-mg and 60-mg doses resulted in significant improvements in all secondary endpoints, and treatment with the 10-mg dose resulted in significant improvements in four of the six secondary endpoints.

No new safety risks were observed when compared with the safety profile of atogepant observed in previous trials, AbbVie said. Serious adverse events occurred in 0.9% of patients in the atogepant 10-mg group versus 0.9% of patients in the placebo group. No patients in the atogepant 30-mg or 60-mg groups experienced a serious adverse event. The most common adverse events (reported in at least 5% of patients and at least one atogepant group and at a rate greater than placebo), across all doses versus placebo, were constipation (6.9%-7.7% vs. 0.5%), nausea (4.4%-6.1% vs. 1.8%), and upper respiratory tract infection (3.9%-5.7% vs. 4.5%).

Most cases of constipation, nausea, and upper respiratory tract infection were mild or moderate in severity and did not lead to discontinuation. There were no hepatic safety issues identified in the trial.

Full data results will be presented at an upcoming medical congress and/or published in a peer-reviewed journal, the company said.
 

A version of this article originally appeared on Medscape.com.

The novel, orally administered calcitonin gene-related peptide (CGRP) antagonist atogepant has met the primary endpoint in a phase 3 trial for migraine prevention, AbbVie, the company developing the drug, has announced.

Top-line results from the ADVANCE trial, which evaluated atogepant 10, 30, and 60 mg, showed all three doses were associated with a significant reduction from baseline in mean monthly migraine days, compared with placebo.

There were also significant improvements in all six secondary endpoints with the two higher doses.

Data from the ADVANCE trial and a previous phase 2/3 trial will be the basis for regulatory submissions in the United States and other countries, AbbVie reported.

Decreased migraine days

The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was designed to evaluate the efficacy, safety, and tolerability of oral atogepant for the prevention of migraine in those who experienced 4-14 migraine days per month.

A total of 910 patients were randomized to one of four treatment groups: 10 mg, 30 mg, or 60 mg of atogepant once daily or placebo. Efficacy analyses were based on the modified intent-to-treat population of 873 patients.

The primary endpoint was change from baseline in mean monthly migraine days during the 12-week treatment period. All atogepant dose groups met the primary endpoint and demonstrated significantly greater decreases in mean monthly migraine days, compared with placebo.

Mean monthly migraine days were reduced by 3.69 days with the 10-mg dose, 3.86 days with the 30-mg dose, and 4.2 days with the 60-mg dose of atogepant, compared with a reduction of 2.48 migraine days in the placebo group (P < .0001, all dose groups vs. placebo).

A key secondary endpoint measured the proportion of patients who achieved at least a 50% reduction in mean monthly migraine days over 12 weeks. This outcome occurred in 55.6% of the 10-mg atogepant group, 58.7% of the 30-mg group, and 60.8% of the 60-mg group, compared with 29% of the placebo group (P < .0001, all dose groups vs. placebo).

Significant improvements

Additional secondary endpoints measured during the 12-week treatment period included change from baseline in mean monthly headache days, mean monthly acute–medication use days, mean monthly performance of daily activities and physical impairment domain scores on the Activity Impairment in Migraine-Diary, and change from baseline in the Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at week 12. Treatment with the 30-mg and 60-mg doses resulted in significant improvements in all secondary endpoints, and treatment with the 10-mg dose resulted in significant improvements in four of the six secondary endpoints.

No new safety risks were observed when compared with the safety profile of atogepant observed in previous trials, AbbVie said. Serious adverse events occurred in 0.9% of patients in the atogepant 10-mg group versus 0.9% of patients in the placebo group. No patients in the atogepant 30-mg or 60-mg groups experienced a serious adverse event. The most common adverse events (reported in at least 5% of patients and at least one atogepant group and at a rate greater than placebo), across all doses versus placebo, were constipation (6.9%-7.7% vs. 0.5%), nausea (4.4%-6.1% vs. 1.8%), and upper respiratory tract infection (3.9%-5.7% vs. 4.5%).

Most cases of constipation, nausea, and upper respiratory tract infection were mild or moderate in severity and did not lead to discontinuation. There were no hepatic safety issues identified in the trial.

Full data results will be presented at an upcoming medical congress and/or published in a peer-reviewed journal, the company said.
 

A version of this article originally appeared on Medscape.com.

Two new long-term studies, one an extension trial and the other an analysis of real-world experience, show that the RNS System direct brain responsive neurostimulator leads to reduction of seizure frequency in most epilepsy patients who had it implanted. Both studies showed that the benefit from the devices increased over time.

That accruing benefit may be because of improved protocols as clinicians gain experience with the device or because of network remodeling that occurs over time as seizures are controlled. “I think it’s both,” said Martha Morrell, MD, a clinical professor of neurology at Stanford (Calif.) University and chief medical officer at NeuroPace, the company that has marketed the device since it gained FDA approval in 2013.

In both studies, the slope of improvement over time was similar, but the real-world study showed greater improvement at the beginning of treatment. “I think the slopes represent physiological changes, but the fact that [the real-world study] starts with better outcomes is, I think, directly attributable to learning. When the long-term study was started in 2004, this had never been done before, and we had to make a highly educated guess about what we should do, and the initial stimulatory parameters were programmed in a way that’s very similar to what was used for movement disorders,” Dr. Morrell said in an interview.

The long-term treatment study appeared online July 20 in the journal Neurology, while the real-world analysis was published July 13 in Epilepsia.
 

An alternative option

Medications can effectively treat some seizures, but 30%-40% of patients must turn to other options for control. Surgery can sometimes be curative, but is not suitable for some patients. Other stimulation devices include vagus nerve stimulation (VNS), which sends pulses from a chest implant to the vagus nerve, reducing epileptic attacks through an unknown mechanism. Deep brain stimulation (DBS) places electrodes that deliver stimulation to the anterior nucleus of the thalamus, which can spread initially localized seizures.

The RNS device consists of a neurostimulator implanted cranially and connected to leads that are placed based on the individual patient’s seizure focus or foci. It also continuously monitors brain activity and delivers stimulation only when its signal suggests the beginning of a seizure.

That capacity for recording is a key benefit because the information can be stored and analyzed, according to Vikram Rao, MD, PhD, a coinvestigator in the real-world trial and an associate professor and the epilepsy division chief at the University of California, San Francisco, which was one of the trial centers. “You know more precisely than we previously did how many seizures a patient is having. Many of our patients are not able to quantify their seizures with perfect accuracy, so we’re better quantifying their seizure burden,” Dr. Rao said in an interview.

The ability to monitor patients can also improve clinical management. Dr. Morrell recounted an elderly patient who for many years has driven 5 hours for appointments. Recently she was able to review his data from the RNS System remotely. She determined that he was doing fine and, after a telephone consultation, told him he didn’t need to come in for a scheduled visit.
 

Real-world analysis

In the real-world analysis, researchers led by Babak Razavi, PhD, and Casey Halpern, MD, at Stanford University conducted a chart review of 150 patients at eight centers who underwent treatment with the RNS system between 2013 and 2018. All patients were followed at least 1 year, with a mean of 2.3 years. Patients had a median of 7.7 disabling seizures per month. The mean value was 52 and the numbers ranged from 0.1 to 3,000. A total of 60% had abnormal brain MRI findings.

At 1 year, subjects achieved a mean 67% decrease in seizure frequency (interquartile range, 50%-94%). At 2 years, that grew to 77%; at 3 or more years, 84%. There was no significant difference in seizure reduction at 1 year according to age, age at epilepsy onset, duration of epilepsy, location of seizure foci, presence of brain MRI abnormalities, prior intracranial monitoring, prior epilepsy surgery, or prior VNS treatment. When patients who underwent a resection at the time of RNS placement were excluded, the results were similar. There were no significant differences in outcome by center.

A total of 11.3% of patients experienced a device-related serious adverse event, and 4% developed infections. The rate of infection was not significantly different between patients who had the neurostimulator and leads implanted alone (3.0%) and patients who had intracranial EEG diagnostic monitoring (ICM) electrodes removed at the same time (6.1%; P = .38).

Although about one-third of the patients who started the long-term study dropped out before completion, most were because the participants moved away from treatment centers, according to Dr. Morrell, and other evidence points squarely to patient satisfaction. “At the end of the battery’s longevity, the neurostimulator needs to be replaced. It’s an outpatient, 45-minute procedure. Over 90% of patients chose to have it replaced. It’s not the answer for everybody, but the substantial majority of patients choose to continue,” she said.
 

Extension trial

The open-label extension trial, led by Dileep Nair, MD, of the Cleveland Clinic Foundation and Dr. Morrell, followed 230 of the 256 patients who participated in 2-year phase 3 study or feasibility studies, extending device usage to 9 years. A total of 162 completed follow-up (mean, 7.5 years). The median reduction of seizure frequency was 58% at the end of year 3, and 75% by year 9 (P < .0001; Wilcoxon signed rank). Although patient population enrichment could have explained this observation, other analyses confirmed that the improvement was real.

Nearly 75% had at least a 50% reduction in seizure frequency; 35% had a 90% or greater reduction in seizure frequency. Some patients (18.4%) had at least a full year with no seizures, and 62% who had a 1-year seizure-free period experienced no seizures at the latest follow-up. Overall, 21% had no seizures in the last 6 months of follow-up.

For those with a seizure-free period of more than 1 year, the average duration was 3.2 years (range, 1.04-9.6 years). There was no difference in response among patients based on previous antiseizure medication use or previous epilepsy surgery, VNS treatment, or intracranial monitoring, and there were no differences by patient age at enrollment, age of seizure onset, brain imaging abnormality, seizure onset locality, or number of foci.

The researchers noted improvement in overall Quality of Life in Epilepsy Inventory–89 scores at 1 year (mean, +3.2; P < .0001), which continued through year 9 (mean, +1.9; P < .05). Improvements were also seen in epilepsy targeted (mean, +4.5; P < .001) and cognitive domains (mean, +2.5; P = .005). Risk of infection was 4.1% per procedure, and 12.1% of subjects overall experienced a serious device-related implant infection. Of 35 infections, 16 led to device removal.

The extension study was funded by NeuroPace. NeuroPace supported data entry and institutional review board submission for the real-world trial. Dr. Morrell owns stock and is an employee of NeuroPace. Dr Rao has received support from and/or consulted for NeuroPace.

SOURCE: Nair DR et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010154. Razavi B et al. Epilepsia. 2020 Jul 13. doi: 10.1111/epi.16593.

Two new long-term studies, one an extension trial and the other an analysis of real-world experience, show that the RNS System direct brain responsive neurostimulator leads to reduction of seizure frequency in most epilepsy patients who had it implanted. Both studies showed that the benefit from the devices increased over time.

That accruing benefit may be because of improved protocols as clinicians gain experience with the device or because of network remodeling that occurs over time as seizures are controlled. “I think it’s both,” said Martha Morrell, MD, a clinical professor of neurology at Stanford (Calif.) University and chief medical officer at NeuroPace, the company that has marketed the device since it gained FDA approval in 2013.

In both studies, the slope of improvement over time was similar, but the real-world study showed greater improvement at the beginning of treatment. “I think the slopes represent physiological changes, but the fact that [the real-world study] starts with better outcomes is, I think, directly attributable to learning. When the long-term study was started in 2004, this had never been done before, and we had to make a highly educated guess about what we should do, and the initial stimulatory parameters were programmed in a way that’s very similar to what was used for movement disorders,” Dr. Morrell said in an interview.

The long-term treatment study appeared online July 20 in the journal Neurology, while the real-world analysis was published July 13 in Epilepsia.
 

An alternative option

Medications can effectively treat some seizures, but 30%-40% of patients must turn to other options for control. Surgery can sometimes be curative, but is not suitable for some patients. Other stimulation devices include vagus nerve stimulation (VNS), which sends pulses from a chest implant to the vagus nerve, reducing epileptic attacks through an unknown mechanism. Deep brain stimulation (DBS) places electrodes that deliver stimulation to the anterior nucleus of the thalamus, which can spread initially localized seizures.

The RNS device consists of a neurostimulator implanted cranially and connected to leads that are placed based on the individual patient’s seizure focus or foci. It also continuously monitors brain activity and delivers stimulation only when its signal suggests the beginning of a seizure.

That capacity for recording is a key benefit because the information can be stored and analyzed, according to Vikram Rao, MD, PhD, a coinvestigator in the real-world trial and an associate professor and the epilepsy division chief at the University of California, San Francisco, which was one of the trial centers. “You know more precisely than we previously did how many seizures a patient is having. Many of our patients are not able to quantify their seizures with perfect accuracy, so we’re better quantifying their seizure burden,” Dr. Rao said in an interview.

The ability to monitor patients can also improve clinical management. Dr. Morrell recounted an elderly patient who for many years has driven 5 hours for appointments. Recently she was able to review his data from the RNS System remotely. She determined that he was doing fine and, after a telephone consultation, told him he didn’t need to come in for a scheduled visit.
 

Real-world analysis

In the real-world analysis, researchers led by Babak Razavi, PhD, and Casey Halpern, MD, at Stanford University conducted a chart review of 150 patients at eight centers who underwent treatment with the RNS system between 2013 and 2018. All patients were followed at least 1 year, with a mean of 2.3 years. Patients had a median of 7.7 disabling seizures per month. The mean value was 52 and the numbers ranged from 0.1 to 3,000. A total of 60% had abnormal brain MRI findings.

At 1 year, subjects achieved a mean 67% decrease in seizure frequency (interquartile range, 50%-94%). At 2 years, that grew to 77%; at 3 or more years, 84%. There was no significant difference in seizure reduction at 1 year according to age, age at epilepsy onset, duration of epilepsy, location of seizure foci, presence of brain MRI abnormalities, prior intracranial monitoring, prior epilepsy surgery, or prior VNS treatment. When patients who underwent a resection at the time of RNS placement were excluded, the results were similar. There were no significant differences in outcome by center.

A total of 11.3% of patients experienced a device-related serious adverse event, and 4% developed infections. The rate of infection was not significantly different between patients who had the neurostimulator and leads implanted alone (3.0%) and patients who had intracranial EEG diagnostic monitoring (ICM) electrodes removed at the same time (6.1%; P = .38).

Although about one-third of the patients who started the long-term study dropped out before completion, most were because the participants moved away from treatment centers, according to Dr. Morrell, and other evidence points squarely to patient satisfaction. “At the end of the battery’s longevity, the neurostimulator needs to be replaced. It’s an outpatient, 45-minute procedure. Over 90% of patients chose to have it replaced. It’s not the answer for everybody, but the substantial majority of patients choose to continue,” she said.
 

Extension trial

The open-label extension trial, led by Dileep Nair, MD, of the Cleveland Clinic Foundation and Dr. Morrell, followed 230 of the 256 patients who participated in 2-year phase 3 study or feasibility studies, extending device usage to 9 years. A total of 162 completed follow-up (mean, 7.5 years). The median reduction of seizure frequency was 58% at the end of year 3, and 75% by year 9 (P < .0001; Wilcoxon signed rank). Although patient population enrichment could have explained this observation, other analyses confirmed that the improvement was real.

Nearly 75% had at least a 50% reduction in seizure frequency; 35% had a 90% or greater reduction in seizure frequency. Some patients (18.4%) had at least a full year with no seizures, and 62% who had a 1-year seizure-free period experienced no seizures at the latest follow-up. Overall, 21% had no seizures in the last 6 months of follow-up.

For those with a seizure-free period of more than 1 year, the average duration was 3.2 years (range, 1.04-9.6 years). There was no difference in response among patients based on previous antiseizure medication use or previous epilepsy surgery, VNS treatment, or intracranial monitoring, and there were no differences by patient age at enrollment, age of seizure onset, brain imaging abnormality, seizure onset locality, or number of foci.

The researchers noted improvement in overall Quality of Life in Epilepsy Inventory–89 scores at 1 year (mean, +3.2; P < .0001), which continued through year 9 (mean, +1.9; P < .05). Improvements were also seen in epilepsy targeted (mean, +4.5; P < .001) and cognitive domains (mean, +2.5; P = .005). Risk of infection was 4.1% per procedure, and 12.1% of subjects overall experienced a serious device-related implant infection. Of 35 infections, 16 led to device removal.

The extension study was funded by NeuroPace. NeuroPace supported data entry and institutional review board submission for the real-world trial. Dr. Morrell owns stock and is an employee of NeuroPace. Dr Rao has received support from and/or consulted for NeuroPace.

SOURCE: Nair DR et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010154. Razavi B et al. Epilepsia. 2020 Jul 13. doi: 10.1111/epi.16593.

Two new long-term studies, one an extension trial and the other an analysis of real-world experience, show that the RNS System direct brain responsive neurostimulator leads to reduction of seizure frequency in most epilepsy patients who had it implanted. Both studies showed that the benefit from the devices increased over time.

That accruing benefit may be because of improved protocols as clinicians gain experience with the device or because of network remodeling that occurs over time as seizures are controlled. “I think it’s both,” said Martha Morrell, MD, a clinical professor of neurology at Stanford (Calif.) University and chief medical officer at NeuroPace, the company that has marketed the device since it gained FDA approval in 2013.

In both studies, the slope of improvement over time was similar, but the real-world study showed greater improvement at the beginning of treatment. “I think the slopes represent physiological changes, but the fact that [the real-world study] starts with better outcomes is, I think, directly attributable to learning. When the long-term study was started in 2004, this had never been done before, and we had to make a highly educated guess about what we should do, and the initial stimulatory parameters were programmed in a way that’s very similar to what was used for movement disorders,” Dr. Morrell said in an interview.

The long-term treatment study appeared online July 20 in the journal Neurology, while the real-world analysis was published July 13 in Epilepsia.
 

An alternative option

Medications can effectively treat some seizures, but 30%-40% of patients must turn to other options for control. Surgery can sometimes be curative, but is not suitable for some patients. Other stimulation devices include vagus nerve stimulation (VNS), which sends pulses from a chest implant to the vagus nerve, reducing epileptic attacks through an unknown mechanism. Deep brain stimulation (DBS) places electrodes that deliver stimulation to the anterior nucleus of the thalamus, which can spread initially localized seizures.

The RNS device consists of a neurostimulator implanted cranially and connected to leads that are placed based on the individual patient’s seizure focus or foci. It also continuously monitors brain activity and delivers stimulation only when its signal suggests the beginning of a seizure.

That capacity for recording is a key benefit because the information can be stored and analyzed, according to Vikram Rao, MD, PhD, a coinvestigator in the real-world trial and an associate professor and the epilepsy division chief at the University of California, San Francisco, which was one of the trial centers. “You know more precisely than we previously did how many seizures a patient is having. Many of our patients are not able to quantify their seizures with perfect accuracy, so we’re better quantifying their seizure burden,” Dr. Rao said in an interview.

The ability to monitor patients can also improve clinical management. Dr. Morrell recounted an elderly patient who for many years has driven 5 hours for appointments. Recently she was able to review his data from the RNS System remotely. She determined that he was doing fine and, after a telephone consultation, told him he didn’t need to come in for a scheduled visit.
 

Real-world analysis

In the real-world analysis, researchers led by Babak Razavi, PhD, and Casey Halpern, MD, at Stanford University conducted a chart review of 150 patients at eight centers who underwent treatment with the RNS system between 2013 and 2018. All patients were followed at least 1 year, with a mean of 2.3 years. Patients had a median of 7.7 disabling seizures per month. The mean value was 52 and the numbers ranged from 0.1 to 3,000. A total of 60% had abnormal brain MRI findings.

At 1 year, subjects achieved a mean 67% decrease in seizure frequency (interquartile range, 50%-94%). At 2 years, that grew to 77%; at 3 or more years, 84%. There was no significant difference in seizure reduction at 1 year according to age, age at epilepsy onset, duration of epilepsy, location of seizure foci, presence of brain MRI abnormalities, prior intracranial monitoring, prior epilepsy surgery, or prior VNS treatment. When patients who underwent a resection at the time of RNS placement were excluded, the results were similar. There were no significant differences in outcome by center.

A total of 11.3% of patients experienced a device-related serious adverse event, and 4% developed infections. The rate of infection was not significantly different between patients who had the neurostimulator and leads implanted alone (3.0%) and patients who had intracranial EEG diagnostic monitoring (ICM) electrodes removed at the same time (6.1%; P = .38).

Although about one-third of the patients who started the long-term study dropped out before completion, most were because the participants moved away from treatment centers, according to Dr. Morrell, and other evidence points squarely to patient satisfaction. “At the end of the battery’s longevity, the neurostimulator needs to be replaced. It’s an outpatient, 45-minute procedure. Over 90% of patients chose to have it replaced. It’s not the answer for everybody, but the substantial majority of patients choose to continue,” she said.
 

Extension trial

The open-label extension trial, led by Dileep Nair, MD, of the Cleveland Clinic Foundation and Dr. Morrell, followed 230 of the 256 patients who participated in 2-year phase 3 study or feasibility studies, extending device usage to 9 years. A total of 162 completed follow-up (mean, 7.5 years). The median reduction of seizure frequency was 58% at the end of year 3, and 75% by year 9 (P < .0001; Wilcoxon signed rank). Although patient population enrichment could have explained this observation, other analyses confirmed that the improvement was real.

Nearly 75% had at least a 50% reduction in seizure frequency; 35% had a 90% or greater reduction in seizure frequency. Some patients (18.4%) had at least a full year with no seizures, and 62% who had a 1-year seizure-free period experienced no seizures at the latest follow-up. Overall, 21% had no seizures in the last 6 months of follow-up.

For those with a seizure-free period of more than 1 year, the average duration was 3.2 years (range, 1.04-9.6 years). There was no difference in response among patients based on previous antiseizure medication use or previous epilepsy surgery, VNS treatment, or intracranial monitoring, and there were no differences by patient age at enrollment, age of seizure onset, brain imaging abnormality, seizure onset locality, or number of foci.

The researchers noted improvement in overall Quality of Life in Epilepsy Inventory–89 scores at 1 year (mean, +3.2; P < .0001), which continued through year 9 (mean, +1.9; P < .05). Improvements were also seen in epilepsy targeted (mean, +4.5; P < .001) and cognitive domains (mean, +2.5; P = .005). Risk of infection was 4.1% per procedure, and 12.1% of subjects overall experienced a serious device-related implant infection. Of 35 infections, 16 led to device removal.

The extension study was funded by NeuroPace. NeuroPace supported data entry and institutional review board submission for the real-world trial. Dr. Morrell owns stock and is an employee of NeuroPace. Dr Rao has received support from and/or consulted for NeuroPace.

SOURCE: Nair DR et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010154. Razavi B et al. Epilepsia. 2020 Jul 13. doi: 10.1111/epi.16593.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has given a thumbs up to avapritinib and acalabrutinib, paving the way for the drugs’ approval in the European Union (EU). 

The CHMP recommended granting conditional marketing authorization for avapritinib (Ayvakit, Blueprint Medicines) for use in adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. About 6%-10% of GIST tumors harbor this mutation, and avapritinib is a selective and potent inhibitor of KIT and PDGFRA mutant kinases.

The CHMP also adopted a positive opinion for acalabrutinib (Calquence, AstraZeneca) for the treatment of chronic lymphocytic leukemia (CLL) as monotherapy in patients who are treatment-naive or have received at least one prior therapy.

The CHMP opinion on both drugs will be reviewed by the European Commission, which has the authority to grant marketing authorization for medicinal products in the EU.

Detailed recommendations for the use of both drugs will be provided in the summary of product characteristics, which will be published in the European public assessment report and made available in all official EU languages after the products receive marketing authorization by the European Commission.

First targeted therapy for mutation

If approved by the European Commission, avapritinib would be the first treatment in the EU indicated for patients with PDGFRA D842V-mutant GIST.

Avapritinib was approved by the US Food and Drug Administration (FDA) earlier this year for the aforementioned indication. The FDA approval was based on findings from the phase 1 NAVIGATOR trial, which included 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with the most common mutation, PDGFRA D842V.

For patients harboring a PDGFRA exon 18 mutation, the overall response rate (ORR) was 84%, with 7% having a complete response and 77% having a partial response. Patients with the PDGFRA D842V mutation achieved an ORR of 89%, with 8% having a complete response and 82% having a partial response.

“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies ... Today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, in a statement at the time of approval.

The most common side effects (≥ 20% of patients) observed in patients taking avapritinib include nausea, fatigue, anemia, periorbital edema, face edema, hyperbilirubinemia, diarrhea, vomiting, peripheral edema, increased lacrimation, decreased appetite, and memory impairment. There may also be a risk of intracranial hemorrhage, in which case the dose should be reduced or the drug should be discontinued.

In the EU, conditional marketing authorization is granted to a medicinal product that fulfills an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required, the CHMP notes on its website. 

Avapritinib had received an orphan medicine designation during development, which the EMA will review to determine if the designation can be maintained.

New treatment for CLL

Acalabrutinib is already approved in the United States, Canada, and Australia for the treatment of CLL and small lymphocytic lymphoma. The product was approved at the same time by all three regulatory authorities last year.  In the United States, acalabrutinib had previously been approved for use in mantle cell lymphoma.

The CHMP’s positive opinion of acalabrutinib is based on results from two phase 3 trials, ELEVATE TN and ASCEND.

In the ASCEND trial, acalabrutinib was compared with investigator’s choice of idelalisib or bendamustine with rituximab. The trial, which involved 310 patients with relapsed/refractory CLL, showed that acalabrutinib improved progression-free survival (PFS).

At a median follow-up of 16.1 months, the median PFS was not reached with acalabrutinib and was 16.5 months with investigator’s choice of therapy (P < .0001).

The most commonly reported adverse events seen with acalabrutinib were respiratory tract infections, headache, bruising, contusion, diarrhea, nausea, rash, musculoskeletal pain, fatigue, decreased hemoglobin, and decreased platelets.

In the ELEVATE TN trial, acalabrutinib was given alone or combined with obinutuzumab and compared to chlorambucil plus obinutuzumab in patients with previously untreated CLL. There were 535 patients randomized to receive acalabrutinib alone (n = 179), acalabrutinib plus obinutuzumab (n = 179), and chlorambucil plus obinutuzumab (n = 177).

At a median follow-up of 28 months, the median PFS was not reached with acalabrutinib alone or with acalabrutinib plus obinutuzumab, but the median PFS was 22.6 months in the chlorambucil-obinutuzumab arm (P < .0001 for both comparisons).

The most common adverse events in the acalabrutinib arms were headache, diarrhea, neutropenia, and nausea.
 

A version of this article first appeared on Medscape.com.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has given a thumbs up to avapritinib and acalabrutinib, paving the way for the drugs’ approval in the European Union (EU). 

The CHMP recommended granting conditional marketing authorization for avapritinib (Ayvakit, Blueprint Medicines) for use in adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. About 6%-10% of GIST tumors harbor this mutation, and avapritinib is a selective and potent inhibitor of KIT and PDGFRA mutant kinases.

The CHMP also adopted a positive opinion for acalabrutinib (Calquence, AstraZeneca) for the treatment of chronic lymphocytic leukemia (CLL) as monotherapy in patients who are treatment-naive or have received at least one prior therapy.

The CHMP opinion on both drugs will be reviewed by the European Commission, which has the authority to grant marketing authorization for medicinal products in the EU.

Detailed recommendations for the use of both drugs will be provided in the summary of product characteristics, which will be published in the European public assessment report and made available in all official EU languages after the products receive marketing authorization by the European Commission.

First targeted therapy for mutation

If approved by the European Commission, avapritinib would be the first treatment in the EU indicated for patients with PDGFRA D842V-mutant GIST.

Avapritinib was approved by the US Food and Drug Administration (FDA) earlier this year for the aforementioned indication. The FDA approval was based on findings from the phase 1 NAVIGATOR trial, which included 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with the most common mutation, PDGFRA D842V.

For patients harboring a PDGFRA exon 18 mutation, the overall response rate (ORR) was 84%, with 7% having a complete response and 77% having a partial response. Patients with the PDGFRA D842V mutation achieved an ORR of 89%, with 8% having a complete response and 82% having a partial response.

“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies ... Today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, in a statement at the time of approval.

The most common side effects (≥ 20% of patients) observed in patients taking avapritinib include nausea, fatigue, anemia, periorbital edema, face edema, hyperbilirubinemia, diarrhea, vomiting, peripheral edema, increased lacrimation, decreased appetite, and memory impairment. There may also be a risk of intracranial hemorrhage, in which case the dose should be reduced or the drug should be discontinued.

In the EU, conditional marketing authorization is granted to a medicinal product that fulfills an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required, the CHMP notes on its website. 

Avapritinib had received an orphan medicine designation during development, which the EMA will review to determine if the designation can be maintained.

New treatment for CLL

Acalabrutinib is already approved in the United States, Canada, and Australia for the treatment of CLL and small lymphocytic lymphoma. The product was approved at the same time by all three regulatory authorities last year.  In the United States, acalabrutinib had previously been approved for use in mantle cell lymphoma.

The CHMP’s positive opinion of acalabrutinib is based on results from two phase 3 trials, ELEVATE TN and ASCEND.

In the ASCEND trial, acalabrutinib was compared with investigator’s choice of idelalisib or bendamustine with rituximab. The trial, which involved 310 patients with relapsed/refractory CLL, showed that acalabrutinib improved progression-free survival (PFS).

At a median follow-up of 16.1 months, the median PFS was not reached with acalabrutinib and was 16.5 months with investigator’s choice of therapy (P < .0001).

The most commonly reported adverse events seen with acalabrutinib were respiratory tract infections, headache, bruising, contusion, diarrhea, nausea, rash, musculoskeletal pain, fatigue, decreased hemoglobin, and decreased platelets.

In the ELEVATE TN trial, acalabrutinib was given alone or combined with obinutuzumab and compared to chlorambucil plus obinutuzumab in patients with previously untreated CLL. There were 535 patients randomized to receive acalabrutinib alone (n = 179), acalabrutinib plus obinutuzumab (n = 179), and chlorambucil plus obinutuzumab (n = 177).

At a median follow-up of 28 months, the median PFS was not reached with acalabrutinib alone or with acalabrutinib plus obinutuzumab, but the median PFS was 22.6 months in the chlorambucil-obinutuzumab arm (P < .0001 for both comparisons).

The most common adverse events in the acalabrutinib arms were headache, diarrhea, neutropenia, and nausea.
 

A version of this article first appeared on Medscape.com.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has given a thumbs up to avapritinib and acalabrutinib, paving the way for the drugs’ approval in the European Union (EU). 

The CHMP recommended granting conditional marketing authorization for avapritinib (Ayvakit, Blueprint Medicines) for use in adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. About 6%-10% of GIST tumors harbor this mutation, and avapritinib is a selective and potent inhibitor of KIT and PDGFRA mutant kinases.

The CHMP also adopted a positive opinion for acalabrutinib (Calquence, AstraZeneca) for the treatment of chronic lymphocytic leukemia (CLL) as monotherapy in patients who are treatment-naive or have received at least one prior therapy.

The CHMP opinion on both drugs will be reviewed by the European Commission, which has the authority to grant marketing authorization for medicinal products in the EU.

Detailed recommendations for the use of both drugs will be provided in the summary of product characteristics, which will be published in the European public assessment report and made available in all official EU languages after the products receive marketing authorization by the European Commission.

First targeted therapy for mutation

If approved by the European Commission, avapritinib would be the first treatment in the EU indicated for patients with PDGFRA D842V-mutant GIST.

Avapritinib was approved by the US Food and Drug Administration (FDA) earlier this year for the aforementioned indication. The FDA approval was based on findings from the phase 1 NAVIGATOR trial, which included 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with the most common mutation, PDGFRA D842V.

For patients harboring a PDGFRA exon 18 mutation, the overall response rate (ORR) was 84%, with 7% having a complete response and 77% having a partial response. Patients with the PDGFRA D842V mutation achieved an ORR of 89%, with 8% having a complete response and 82% having a partial response.

“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies ... Today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, in a statement at the time of approval.

The most common side effects (≥ 20% of patients) observed in patients taking avapritinib include nausea, fatigue, anemia, periorbital edema, face edema, hyperbilirubinemia, diarrhea, vomiting, peripheral edema, increased lacrimation, decreased appetite, and memory impairment. There may also be a risk of intracranial hemorrhage, in which case the dose should be reduced or the drug should be discontinued.

In the EU, conditional marketing authorization is granted to a medicinal product that fulfills an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required, the CHMP notes on its website. 

Avapritinib had received an orphan medicine designation during development, which the EMA will review to determine if the designation can be maintained.

New treatment for CLL

Acalabrutinib is already approved in the United States, Canada, and Australia for the treatment of CLL and small lymphocytic lymphoma. The product was approved at the same time by all three regulatory authorities last year.  In the United States, acalabrutinib had previously been approved for use in mantle cell lymphoma.

The CHMP’s positive opinion of acalabrutinib is based on results from two phase 3 trials, ELEVATE TN and ASCEND.

In the ASCEND trial, acalabrutinib was compared with investigator’s choice of idelalisib or bendamustine with rituximab. The trial, which involved 310 patients with relapsed/refractory CLL, showed that acalabrutinib improved progression-free survival (PFS).

At a median follow-up of 16.1 months, the median PFS was not reached with acalabrutinib and was 16.5 months with investigator’s choice of therapy (P < .0001).

The most commonly reported adverse events seen with acalabrutinib were respiratory tract infections, headache, bruising, contusion, diarrhea, nausea, rash, musculoskeletal pain, fatigue, decreased hemoglobin, and decreased platelets.

In the ELEVATE TN trial, acalabrutinib was given alone or combined with obinutuzumab and compared to chlorambucil plus obinutuzumab in patients with previously untreated CLL. There were 535 patients randomized to receive acalabrutinib alone (n = 179), acalabrutinib plus obinutuzumab (n = 179), and chlorambucil plus obinutuzumab (n = 177).

At a median follow-up of 28 months, the median PFS was not reached with acalabrutinib alone or with acalabrutinib plus obinutuzumab, but the median PFS was 22.6 months in the chlorambucil-obinutuzumab arm (P < .0001 for both comparisons).

The most common adverse events in the acalabrutinib arms were headache, diarrhea, neutropenia, and nausea.
 

A version of this article first appeared on Medscape.com.

The Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma), the first approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

The new agent is the second approved CAR T cell product developed by Kite and follows the 2017 approval of axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma.

“Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy,” investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a company statement. “Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments.”

In the same press statement, Meghan Gutierrez, chief executive officer, Lymphoma Research Foundation, said: “This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease.”

The approval of the single-infusion therapy is based on efficacy and safety data from the ongoing, single-arm ZUMA-2 pivotal trial, which enrolled 74 adult patients. All patients had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib).

In the trial, there was an objective response rate, which was the primary outcome measure, of 87% among 60 patients who were evaluable for efficacy analysis; 62% had a complete response. 

Among all patients, follow-up was at least 6 months after their first objective disease response. Median duration of response has not yet been reached.

In terms of adverse events, 18% of the 82 patients evaluable for safety experienced > grade 3 cytokine release syndrome and 37% experienced neurologic events, per the company statement. The most common (≥ 10%) grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Brexucabtagene autoleucel will be manufactured in Kite’s facility in California. In the pivotal trial, there was a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery.  
 

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma), the first approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

The new agent is the second approved CAR T cell product developed by Kite and follows the 2017 approval of axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma.

“Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy,” investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a company statement. “Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments.”

In the same press statement, Meghan Gutierrez, chief executive officer, Lymphoma Research Foundation, said: “This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease.”

The approval of the single-infusion therapy is based on efficacy and safety data from the ongoing, single-arm ZUMA-2 pivotal trial, which enrolled 74 adult patients. All patients had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib).

In the trial, there was an objective response rate, which was the primary outcome measure, of 87% among 60 patients who were evaluable for efficacy analysis; 62% had a complete response. 

Among all patients, follow-up was at least 6 months after their first objective disease response. Median duration of response has not yet been reached.

In terms of adverse events, 18% of the 82 patients evaluable for safety experienced > grade 3 cytokine release syndrome and 37% experienced neurologic events, per the company statement. The most common (≥ 10%) grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Brexucabtagene autoleucel will be manufactured in Kite’s facility in California. In the pivotal trial, there was a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery.  
 

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel (Tecartus, Kite Pharma), the first approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

The new agent is the second approved CAR T cell product developed by Kite and follows the 2017 approval of axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma.

“Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy,” investigator Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, said in a company statement. “Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments.”

In the same press statement, Meghan Gutierrez, chief executive officer, Lymphoma Research Foundation, said: “This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease.”

The approval of the single-infusion therapy is based on efficacy and safety data from the ongoing, single-arm ZUMA-2 pivotal trial, which enrolled 74 adult patients. All patients had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib).

In the trial, there was an objective response rate, which was the primary outcome measure, of 87% among 60 patients who were evaluable for efficacy analysis; 62% had a complete response. 

Among all patients, follow-up was at least 6 months after their first objective disease response. Median duration of response has not yet been reached.

In terms of adverse events, 18% of the 82 patients evaluable for safety experienced > grade 3 cytokine release syndrome and 37% experienced neurologic events, per the company statement. The most common (≥ 10%) grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia.

Brexucabtagene autoleucel will be manufactured in Kite’s facility in California. In the pivotal trial, there was a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery.  
 

A version of this article originally appeared on Medscape.com.