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Efficacy of postvenetoclax therapy may depend on prior agent exposure in CLL
ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.
If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.
“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”
The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.
All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.
“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.
While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.
“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.
Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.
“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.
They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.
In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.
PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.
However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.
Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”
Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract 502.
ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.
If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.
“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”
The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.
All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.
“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.
While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.
“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.
Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.
“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.
They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.
In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.
PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.
However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.
Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”
Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract 502.
ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.
If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.
“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”
The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.
All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.
“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.
While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.
“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.
Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.
“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.
They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.
In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.
PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.
However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.
Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”
Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract 502.
REPORTING FROM ASH 2019
Reduction in convulsive seizure frequency is associated with improved executive function in Dravet syndrome
BALTIMORE – according to data presented at the annual meeting of the American Epilepsy Society. Large reductions in convulsive seizure frequency for prolonged periods may improve everyday deficits in executive function in these patients, according to the investigators.
Dravet syndrome often entails cognitive impairment, including deficits in executive function. The frequency and severity of convulsive seizures are believed to worsen cognitive impairment over time, but few researchers have conducted long-term studies to test this hypothesis. Adjunctive fenfluramine significantly reduced the frequency of convulsive seizures and improved executive function after 14 weeks in a phase 3 study of patients with Dravet syndrome.
An open-label extension of a phase 3 study
In an open-label extension of this study, Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco, Benioff Children’s Hospital, and colleagues analyzed the relationship between changes in convulsive seizure frequency and executive function. The investigators also examined the effect of reducing convulsive seizure frequency by comparing patients with profound reductions (greater than 75%) versus patients with minimal reductions (less than 25%).
Patients aged 2-18 years entered the open-label study and received adjunctive fenfluramine for 1 year. At the beginning of the open-label phase, the dose was titrated to effect. The dose ranged from 0.2 mg/kg per day to 0.7 mg/kg per day and was administered as 2.5 mg/mL of fenfluramine. The maximum dose was 17 mg with stiripentol or 26 mg without.
The investigators calculated the percent difference in convulsive seizure frequency per 28 days from baseline to the end of the open-label study. They evaluated executive function using the Behavior Rating Inventory of Executive Function (BRIEF), which caregivers completed at baseline and year 1 for patients aged 5-18 years. Scores on the BRIEF were updated to the newer version: BRIEF2. Dr. Sullivan and colleagues calculated Spearman’s rho correlation coefficients to evaluate the association between BRIEF2 Behavior Regulation Index, Emotion Regulation Index, Cognitive Regulation Index, and Global Executive Composite scores. Lower scores on the BRIEF2 indexes and composite indicate better executive functioning. In addition, the researchers compared clinically meaningful change in BRIEF2 indexes and composite scores from baseline to year 1 between patients with minimal and profound reductions in convulsive seizure frequency using Fisher’s exact test. They defined a clinically meaningful change as an improvement in the Reliable Change Index of greater than 95%.
Profound reduction in seizure frequency was common
At the time of analysis, 53 patients had completed at least 1 year of open-label fenfluramine and had baseline and year 1 BRIEF2 data. Patients’ median age was 10 years, and 57% of patients were male. The median reduction from prerandomization baseline in convulsive seizure frequency was 71%. The reduction ranged from 99.7% to 55.0%.
Twenty-four (45%) patients had a reduction in convulsive seizure frequency of greater than 75%, and 11 (21%) had a reduction of less than 25%. Change in convulsive seizure frequency correlated significantly with Emotion Regulation Index and Global Executive Composite. Change in seizure frequency tended to correlate with Cognitive Regulation Index, but the result was not statistically significant. Change in convulsive seizure frequency was not significantly associated with Behavior Regulation Index. A significantly higher percentage of patients in the profound responder group had significant, clinically meaningful improvements on Emotion Regulation Index and Global Executive Composite, compared with minimal responders.
Zogenix, the company that is developing fenfluramine as a treatment for Dravet syndrome, funded the study. Several investigators are employees of Zogenix.
SOURCE: Bishop KI et al. AES 2019, Abstract 2.438.
BALTIMORE – according to data presented at the annual meeting of the American Epilepsy Society. Large reductions in convulsive seizure frequency for prolonged periods may improve everyday deficits in executive function in these patients, according to the investigators.
Dravet syndrome often entails cognitive impairment, including deficits in executive function. The frequency and severity of convulsive seizures are believed to worsen cognitive impairment over time, but few researchers have conducted long-term studies to test this hypothesis. Adjunctive fenfluramine significantly reduced the frequency of convulsive seizures and improved executive function after 14 weeks in a phase 3 study of patients with Dravet syndrome.
An open-label extension of a phase 3 study
In an open-label extension of this study, Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco, Benioff Children’s Hospital, and colleagues analyzed the relationship between changes in convulsive seizure frequency and executive function. The investigators also examined the effect of reducing convulsive seizure frequency by comparing patients with profound reductions (greater than 75%) versus patients with minimal reductions (less than 25%).
Patients aged 2-18 years entered the open-label study and received adjunctive fenfluramine for 1 year. At the beginning of the open-label phase, the dose was titrated to effect. The dose ranged from 0.2 mg/kg per day to 0.7 mg/kg per day and was administered as 2.5 mg/mL of fenfluramine. The maximum dose was 17 mg with stiripentol or 26 mg without.
The investigators calculated the percent difference in convulsive seizure frequency per 28 days from baseline to the end of the open-label study. They evaluated executive function using the Behavior Rating Inventory of Executive Function (BRIEF), which caregivers completed at baseline and year 1 for patients aged 5-18 years. Scores on the BRIEF were updated to the newer version: BRIEF2. Dr. Sullivan and colleagues calculated Spearman’s rho correlation coefficients to evaluate the association between BRIEF2 Behavior Regulation Index, Emotion Regulation Index, Cognitive Regulation Index, and Global Executive Composite scores. Lower scores on the BRIEF2 indexes and composite indicate better executive functioning. In addition, the researchers compared clinically meaningful change in BRIEF2 indexes and composite scores from baseline to year 1 between patients with minimal and profound reductions in convulsive seizure frequency using Fisher’s exact test. They defined a clinically meaningful change as an improvement in the Reliable Change Index of greater than 95%.
Profound reduction in seizure frequency was common
At the time of analysis, 53 patients had completed at least 1 year of open-label fenfluramine and had baseline and year 1 BRIEF2 data. Patients’ median age was 10 years, and 57% of patients were male. The median reduction from prerandomization baseline in convulsive seizure frequency was 71%. The reduction ranged from 99.7% to 55.0%.
Twenty-four (45%) patients had a reduction in convulsive seizure frequency of greater than 75%, and 11 (21%) had a reduction of less than 25%. Change in convulsive seizure frequency correlated significantly with Emotion Regulation Index and Global Executive Composite. Change in seizure frequency tended to correlate with Cognitive Regulation Index, but the result was not statistically significant. Change in convulsive seizure frequency was not significantly associated with Behavior Regulation Index. A significantly higher percentage of patients in the profound responder group had significant, clinically meaningful improvements on Emotion Regulation Index and Global Executive Composite, compared with minimal responders.
Zogenix, the company that is developing fenfluramine as a treatment for Dravet syndrome, funded the study. Several investigators are employees of Zogenix.
SOURCE: Bishop KI et al. AES 2019, Abstract 2.438.
BALTIMORE – according to data presented at the annual meeting of the American Epilepsy Society. Large reductions in convulsive seizure frequency for prolonged periods may improve everyday deficits in executive function in these patients, according to the investigators.
Dravet syndrome often entails cognitive impairment, including deficits in executive function. The frequency and severity of convulsive seizures are believed to worsen cognitive impairment over time, but few researchers have conducted long-term studies to test this hypothesis. Adjunctive fenfluramine significantly reduced the frequency of convulsive seizures and improved executive function after 14 weeks in a phase 3 study of patients with Dravet syndrome.
An open-label extension of a phase 3 study
In an open-label extension of this study, Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco, Benioff Children’s Hospital, and colleagues analyzed the relationship between changes in convulsive seizure frequency and executive function. The investigators also examined the effect of reducing convulsive seizure frequency by comparing patients with profound reductions (greater than 75%) versus patients with minimal reductions (less than 25%).
Patients aged 2-18 years entered the open-label study and received adjunctive fenfluramine for 1 year. At the beginning of the open-label phase, the dose was titrated to effect. The dose ranged from 0.2 mg/kg per day to 0.7 mg/kg per day and was administered as 2.5 mg/mL of fenfluramine. The maximum dose was 17 mg with stiripentol or 26 mg without.
The investigators calculated the percent difference in convulsive seizure frequency per 28 days from baseline to the end of the open-label study. They evaluated executive function using the Behavior Rating Inventory of Executive Function (BRIEF), which caregivers completed at baseline and year 1 for patients aged 5-18 years. Scores on the BRIEF were updated to the newer version: BRIEF2. Dr. Sullivan and colleagues calculated Spearman’s rho correlation coefficients to evaluate the association between BRIEF2 Behavior Regulation Index, Emotion Regulation Index, Cognitive Regulation Index, and Global Executive Composite scores. Lower scores on the BRIEF2 indexes and composite indicate better executive functioning. In addition, the researchers compared clinically meaningful change in BRIEF2 indexes and composite scores from baseline to year 1 between patients with minimal and profound reductions in convulsive seizure frequency using Fisher’s exact test. They defined a clinically meaningful change as an improvement in the Reliable Change Index of greater than 95%.
Profound reduction in seizure frequency was common
At the time of analysis, 53 patients had completed at least 1 year of open-label fenfluramine and had baseline and year 1 BRIEF2 data. Patients’ median age was 10 years, and 57% of patients were male. The median reduction from prerandomization baseline in convulsive seizure frequency was 71%. The reduction ranged from 99.7% to 55.0%.
Twenty-four (45%) patients had a reduction in convulsive seizure frequency of greater than 75%, and 11 (21%) had a reduction of less than 25%. Change in convulsive seizure frequency correlated significantly with Emotion Regulation Index and Global Executive Composite. Change in seizure frequency tended to correlate with Cognitive Regulation Index, but the result was not statistically significant. Change in convulsive seizure frequency was not significantly associated with Behavior Regulation Index. A significantly higher percentage of patients in the profound responder group had significant, clinically meaningful improvements on Emotion Regulation Index and Global Executive Composite, compared with minimal responders.
Zogenix, the company that is developing fenfluramine as a treatment for Dravet syndrome, funded the study. Several investigators are employees of Zogenix.
SOURCE: Bishop KI et al. AES 2019, Abstract 2.438.
REPORTING FROM AES 2019
Myeloma patients over age 70 can benefit from auto-HC transplant
ORLANDO – Age 70 may be the new 60, at least when it comes to outcomes following autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma.
A large-scale study looking at transplant outcomes across age groups in multiple myeloma patients found similar rates of nonrelapse mortality, relapse/progression, progression-free survival, and overall survival between patients who were aged 70 years and older and those who were aged 60-69 years.
“Age has no implication in terms of the antimyeloma effect of transplant,” Anita D’Souza, MD, of the Medical College of Wisconsin, Milwaukee, said at the annual meeting of the American Society of Hematology.
The study analyzed outcomes from 15,999 multiple myeloma patients aged 20 years or older in the United States who received a single auto-HCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017. Within that dataset, the researchers compared outcomes from 7,032 patients aged 60-69 years and 2,092 patients aged 70 years and older.
This is the largest study of auto-HCT in older adults with multiple myeloma, the researchers said, and provides important data about the benefit of transplant at any age.
Univariate analysis showed that 100-day nonrelapse mortality was higher in patients aged 70 years and older – at 1% – compared with younger patients (P less than .01). Also, 2-year overall survival was lower in older adults – at 86% – compared with 60- to 69-year-olds (P less than .01).
However, on multivariate analysis with 60- to 69-year-olds as the reference group, patients older than age 70 years had similar nonrelapse mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1, 1.7, P = .06). The same trends were seen for relapse/progression (HR 1.0, 95% CI, 0.9-1, P = .6), progression-free survival (HR 1.1, 95% CI 1-1.2, P = .2), and overall survival (HR 1.2, 95% CI 1-1.4, P = .03). Given the large sample size, a P value of .01 was considered statistically significant.
Over the course of the study period, the percentage of patients aged 70 and older who received a transplant grew each year, rising to 28% by 2017. But Dr. D’Souza said that number is still too low given the safety and efficacy of auto-HCT in these patients.
“Every patient with myeloma should be referred to a transplant center,” she said.
Dr. D’Souza reported financial disclosures related to EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio, Prothena, Pfizer, Imbrium, and Akcea. Other study authors reported financial relationships with multiple companies including Celgene, Takeda, BMS, and Janssen.
SOURCE: Munshi PN et al. ASH 2019, Abstract 782.
ORLANDO – Age 70 may be the new 60, at least when it comes to outcomes following autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma.
A large-scale study looking at transplant outcomes across age groups in multiple myeloma patients found similar rates of nonrelapse mortality, relapse/progression, progression-free survival, and overall survival between patients who were aged 70 years and older and those who were aged 60-69 years.
“Age has no implication in terms of the antimyeloma effect of transplant,” Anita D’Souza, MD, of the Medical College of Wisconsin, Milwaukee, said at the annual meeting of the American Society of Hematology.
The study analyzed outcomes from 15,999 multiple myeloma patients aged 20 years or older in the United States who received a single auto-HCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017. Within that dataset, the researchers compared outcomes from 7,032 patients aged 60-69 years and 2,092 patients aged 70 years and older.
This is the largest study of auto-HCT in older adults with multiple myeloma, the researchers said, and provides important data about the benefit of transplant at any age.
Univariate analysis showed that 100-day nonrelapse mortality was higher in patients aged 70 years and older – at 1% – compared with younger patients (P less than .01). Also, 2-year overall survival was lower in older adults – at 86% – compared with 60- to 69-year-olds (P less than .01).
However, on multivariate analysis with 60- to 69-year-olds as the reference group, patients older than age 70 years had similar nonrelapse mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1, 1.7, P = .06). The same trends were seen for relapse/progression (HR 1.0, 95% CI, 0.9-1, P = .6), progression-free survival (HR 1.1, 95% CI 1-1.2, P = .2), and overall survival (HR 1.2, 95% CI 1-1.4, P = .03). Given the large sample size, a P value of .01 was considered statistically significant.
Over the course of the study period, the percentage of patients aged 70 and older who received a transplant grew each year, rising to 28% by 2017. But Dr. D’Souza said that number is still too low given the safety and efficacy of auto-HCT in these patients.
“Every patient with myeloma should be referred to a transplant center,” she said.
Dr. D’Souza reported financial disclosures related to EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio, Prothena, Pfizer, Imbrium, and Akcea. Other study authors reported financial relationships with multiple companies including Celgene, Takeda, BMS, and Janssen.
SOURCE: Munshi PN et al. ASH 2019, Abstract 782.
ORLANDO – Age 70 may be the new 60, at least when it comes to outcomes following autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma.
A large-scale study looking at transplant outcomes across age groups in multiple myeloma patients found similar rates of nonrelapse mortality, relapse/progression, progression-free survival, and overall survival between patients who were aged 70 years and older and those who were aged 60-69 years.
“Age has no implication in terms of the antimyeloma effect of transplant,” Anita D’Souza, MD, of the Medical College of Wisconsin, Milwaukee, said at the annual meeting of the American Society of Hematology.
The study analyzed outcomes from 15,999 multiple myeloma patients aged 20 years or older in the United States who received a single auto-HCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017. Within that dataset, the researchers compared outcomes from 7,032 patients aged 60-69 years and 2,092 patients aged 70 years and older.
This is the largest study of auto-HCT in older adults with multiple myeloma, the researchers said, and provides important data about the benefit of transplant at any age.
Univariate analysis showed that 100-day nonrelapse mortality was higher in patients aged 70 years and older – at 1% – compared with younger patients (P less than .01). Also, 2-year overall survival was lower in older adults – at 86% – compared with 60- to 69-year-olds (P less than .01).
However, on multivariate analysis with 60- to 69-year-olds as the reference group, patients older than age 70 years had similar nonrelapse mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1, 1.7, P = .06). The same trends were seen for relapse/progression (HR 1.0, 95% CI, 0.9-1, P = .6), progression-free survival (HR 1.1, 95% CI 1-1.2, P = .2), and overall survival (HR 1.2, 95% CI 1-1.4, P = .03). Given the large sample size, a P value of .01 was considered statistically significant.
Over the course of the study period, the percentage of patients aged 70 and older who received a transplant grew each year, rising to 28% by 2017. But Dr. D’Souza said that number is still too low given the safety and efficacy of auto-HCT in these patients.
“Every patient with myeloma should be referred to a transplant center,” she said.
Dr. D’Souza reported financial disclosures related to EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio, Prothena, Pfizer, Imbrium, and Akcea. Other study authors reported financial relationships with multiple companies including Celgene, Takeda, BMS, and Janssen.
SOURCE: Munshi PN et al. ASH 2019, Abstract 782.
REPORTING FROM ASH 2019
High complete response rate seen with novel CAR-T for myeloma
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
REPORTING FROM ASH 2019
Don’t Forget These 5 Things When Treating Hidradenitis Suppurativa
Hidradenitis suppurativa (HS) is a common and debilitating inflammatory disorder of the pilosebaceous unit that presents with recurrent scarring inflammatory nodules and sinus tracts in the intertriginous folds of the body. It is a complex condition that requires multimodal management to address the medical, surgical, and psychosocial needs of affected patients. However, it can be difficult to coordinate all that goes into HS management beyond the standard therapeutic ladder of topical and oral antimicrobials, intralesional corticosteroids, biologics, and surgery. In this article, I will outline 5 important aspects of HS treatment that often are overlooked.
Talk About Pathophysiology
Patients with HS often have limited understanding of their condition. One common misperception is that HS is an infectious disease and that disease activity is associated with poor hygiene.1 Dispelling this myth may help patients avoid unnecessary hygiene practices, decrease perceived stigma, and enhance your therapeutic alliance.
The current model of HS pathophysiology implicates an aberrant inflammatory response to the cutaneous bacterial microbiome, which leads to follicular occlusion and then rupture of debris and bacteria into the surrounding dermis. Immune cells and inflammatory mediators such as nuclear factor κB and tumor necrosis factor α respond to the disruption. Chronic lesions develop due to tissue repair with scarring and re-epithelialization.2,3 Although most patients probably are not interested in the esoteric details, I typically make a point of explaining to patients that HS is a chronic inflammatory disease and provide reassurance that it is not a sign of poor hygiene.
Counsel on Smoking Cessation
Most HS patients use tobacco. As many as 75% of HS patients are active smokers and another 10% to 15% are former smokers. Although there is mixed evidence that disease activity correlates with smoking status, the Hidradenitis Suppurativa Foundation in the United States and Canada concluded in the 2019 North American Clinical Management Guidelines for Hidradenitis Suppurativa that due to the overall health risks of smoking, we should recommend cessation to our patients.4
Laser Hair Removal Works
Don’t forget about laser hair removal! Evidence from randomized controlled trials supports the use of the Nd:YAG laser in the treatment of HS. Treat the entire affected anatomic area and use stacked double pulses on active nodules (typical settings: 10-mm spot size; 10-millisecond pulse duration and 35–50 J/cm2 in Fitzpatrick skin types I–III; 20-millisecond pulse duration and 25–40 J/cm2 in Fitzpatrick skin types IV–VI).4 Especially if it is covered by your patient’s insurance, Nd:YAG is a great adjunctive treatment to consider. The guidelines also recommend long-pulsed alexandrite and diode lasers as well as intense pulsed light, all of which result in follicular destruction, though these treatments have less supporting evidence.4
Have a Plan for Flares
Intralesional injection of triamcinolone is a mainstay of HS treatment and provides patients with rapid relief of symptoms during a flare.5 One case series found that there was a notable decrease in pain, size, and drainage after just 1 day of treatment with intralesional triamcinolone 10 mg/mL (0.2–2.0 mL).6
Intralesional steroid injection is a great tool for quieting an active disease flare while simultaneously instating ongoing treatment for preventive management. However, even when disease control is optimized, patients may still experience intermittent flares of disease. For some patients, it may be appropriate to have a plan in place for a return to clinic during the beginning of a flare to obtain intralesional steroids. The ability to come in on short notice may help avoid visits to the emergency department and urgent care where your patients may receive treatments such as short courses of antibiotics or incision and drainage that may deviate from your overall treatment plan.
Consider Childbearing Status
Don’t forget to consider childbearing plans and childbearing potential when treating female patients with HS. Pregnancy is a frequent consideration in HS patients, as HS affects 3 to 4 times more women than men and typically presents after puberty (second or third decades of life). Many of the medications in the HS armamentarium are contraindicated in pregnancy including tetracyclines, retinoids, and hormonal agents. Surgery should be avoided in pregnant patients whenever possible, particularly in the first trimester. Relatively safe options include topical antibiotics such as clindamycin and metronidazole, as well as tumor necrosis factor α inhibitors, which are classified as category B in pregnancy.5
Before making treatment decisions in pregnant and breastfeeding patients, consult the US Food and Drug Administration recommendations. Perng et al7 reviewed current management strategies for HS in pregnant and breastfeeding women, and their review article in the Journal of the American Academy of Dermatology is an excellent resource.
Final Thoughts
Comprehensive management of HS may include a combination of medication and procedures, lifestyle modification, management of comorbidities, and social support. Formulating a good treatment plan may be a challenge but can drastically improve your patient’s quality of life.
- What is hidradenitis suppurativa? Hidradenitis Suppurativa Foundation website. https://www.hs-foundation.org/what-is-hs. Accessed October 9, 2019.
- Frew JW, Hawkes JE, Krueger JG. Topical, systemic and biologic therapies in hidradenitis suppurativa: pathogenic insights by examining therapeutic mechanisms. Ther Adv Chronic Dis. 2019;10:2040622319830646. doi:10.1177/2040622319830646
- Lacarrubba F, Musumeci ML, Nasca MR, et al. Double-ended pseudocomedones in hidradenitis suppurativa: clinical, dermoscopic, and histopathological correlation. Acta Derm Venereol. 2017;97:763-764.
- Alikhan A, Sayed C, Alavi A, et al. North American Clinical Management Guidelines for Hidradenitis Suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations. part I: diagnosis, evaluation, and the use of complementary and procedural management. J Am Acad Dermatol. 2019;81:76-90.
- Alikhan A, Sayed C, Alavi A, et al. North American Clinical Management Guidelines for Hidradenitis Suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations. part II: topical, intralesional, and systemic medical management. J Am Acad Dermatol. 2019;81:91-101.
- Riis PT, Boer J, Prens EP, et al. Intralesional triamcinolone for flares of hidradenitis suppurativa (HS): a case series. J Am Acad Dermatol. 2016;75:1151-1155.
- Perng P, Zampella JG, Okoye GA. Management of hidradenitis suppurativa in pregnancy. J Am Acad Dermatol. 2017;76:979-989.
Hidradenitis suppurativa (HS) is a common and debilitating inflammatory disorder of the pilosebaceous unit that presents with recurrent scarring inflammatory nodules and sinus tracts in the intertriginous folds of the body. It is a complex condition that requires multimodal management to address the medical, surgical, and psychosocial needs of affected patients. However, it can be difficult to coordinate all that goes into HS management beyond the standard therapeutic ladder of topical and oral antimicrobials, intralesional corticosteroids, biologics, and surgery. In this article, I will outline 5 important aspects of HS treatment that often are overlooked.
Talk About Pathophysiology
Patients with HS often have limited understanding of their condition. One common misperception is that HS is an infectious disease and that disease activity is associated with poor hygiene.1 Dispelling this myth may help patients avoid unnecessary hygiene practices, decrease perceived stigma, and enhance your therapeutic alliance.
The current model of HS pathophysiology implicates an aberrant inflammatory response to the cutaneous bacterial microbiome, which leads to follicular occlusion and then rupture of debris and bacteria into the surrounding dermis. Immune cells and inflammatory mediators such as nuclear factor κB and tumor necrosis factor α respond to the disruption. Chronic lesions develop due to tissue repair with scarring and re-epithelialization.2,3 Although most patients probably are not interested in the esoteric details, I typically make a point of explaining to patients that HS is a chronic inflammatory disease and provide reassurance that it is not a sign of poor hygiene.
Counsel on Smoking Cessation
Most HS patients use tobacco. As many as 75% of HS patients are active smokers and another 10% to 15% are former smokers. Although there is mixed evidence that disease activity correlates with smoking status, the Hidradenitis Suppurativa Foundation in the United States and Canada concluded in the 2019 North American Clinical Management Guidelines for Hidradenitis Suppurativa that due to the overall health risks of smoking, we should recommend cessation to our patients.4
Laser Hair Removal Works
Don’t forget about laser hair removal! Evidence from randomized controlled trials supports the use of the Nd:YAG laser in the treatment of HS. Treat the entire affected anatomic area and use stacked double pulses on active nodules (typical settings: 10-mm spot size; 10-millisecond pulse duration and 35–50 J/cm2 in Fitzpatrick skin types I–III; 20-millisecond pulse duration and 25–40 J/cm2 in Fitzpatrick skin types IV–VI).4 Especially if it is covered by your patient’s insurance, Nd:YAG is a great adjunctive treatment to consider. The guidelines also recommend long-pulsed alexandrite and diode lasers as well as intense pulsed light, all of which result in follicular destruction, though these treatments have less supporting evidence.4
Have a Plan for Flares
Intralesional injection of triamcinolone is a mainstay of HS treatment and provides patients with rapid relief of symptoms during a flare.5 One case series found that there was a notable decrease in pain, size, and drainage after just 1 day of treatment with intralesional triamcinolone 10 mg/mL (0.2–2.0 mL).6
Intralesional steroid injection is a great tool for quieting an active disease flare while simultaneously instating ongoing treatment for preventive management. However, even when disease control is optimized, patients may still experience intermittent flares of disease. For some patients, it may be appropriate to have a plan in place for a return to clinic during the beginning of a flare to obtain intralesional steroids. The ability to come in on short notice may help avoid visits to the emergency department and urgent care where your patients may receive treatments such as short courses of antibiotics or incision and drainage that may deviate from your overall treatment plan.
Consider Childbearing Status
Don’t forget to consider childbearing plans and childbearing potential when treating female patients with HS. Pregnancy is a frequent consideration in HS patients, as HS affects 3 to 4 times more women than men and typically presents after puberty (second or third decades of life). Many of the medications in the HS armamentarium are contraindicated in pregnancy including tetracyclines, retinoids, and hormonal agents. Surgery should be avoided in pregnant patients whenever possible, particularly in the first trimester. Relatively safe options include topical antibiotics such as clindamycin and metronidazole, as well as tumor necrosis factor α inhibitors, which are classified as category B in pregnancy.5
Before making treatment decisions in pregnant and breastfeeding patients, consult the US Food and Drug Administration recommendations. Perng et al7 reviewed current management strategies for HS in pregnant and breastfeeding women, and their review article in the Journal of the American Academy of Dermatology is an excellent resource.
Final Thoughts
Comprehensive management of HS may include a combination of medication and procedures, lifestyle modification, management of comorbidities, and social support. Formulating a good treatment plan may be a challenge but can drastically improve your patient’s quality of life.
Hidradenitis suppurativa (HS) is a common and debilitating inflammatory disorder of the pilosebaceous unit that presents with recurrent scarring inflammatory nodules and sinus tracts in the intertriginous folds of the body. It is a complex condition that requires multimodal management to address the medical, surgical, and psychosocial needs of affected patients. However, it can be difficult to coordinate all that goes into HS management beyond the standard therapeutic ladder of topical and oral antimicrobials, intralesional corticosteroids, biologics, and surgery. In this article, I will outline 5 important aspects of HS treatment that often are overlooked.
Talk About Pathophysiology
Patients with HS often have limited understanding of their condition. One common misperception is that HS is an infectious disease and that disease activity is associated with poor hygiene.1 Dispelling this myth may help patients avoid unnecessary hygiene practices, decrease perceived stigma, and enhance your therapeutic alliance.
The current model of HS pathophysiology implicates an aberrant inflammatory response to the cutaneous bacterial microbiome, which leads to follicular occlusion and then rupture of debris and bacteria into the surrounding dermis. Immune cells and inflammatory mediators such as nuclear factor κB and tumor necrosis factor α respond to the disruption. Chronic lesions develop due to tissue repair with scarring and re-epithelialization.2,3 Although most patients probably are not interested in the esoteric details, I typically make a point of explaining to patients that HS is a chronic inflammatory disease and provide reassurance that it is not a sign of poor hygiene.
Counsel on Smoking Cessation
Most HS patients use tobacco. As many as 75% of HS patients are active smokers and another 10% to 15% are former smokers. Although there is mixed evidence that disease activity correlates with smoking status, the Hidradenitis Suppurativa Foundation in the United States and Canada concluded in the 2019 North American Clinical Management Guidelines for Hidradenitis Suppurativa that due to the overall health risks of smoking, we should recommend cessation to our patients.4
Laser Hair Removal Works
Don’t forget about laser hair removal! Evidence from randomized controlled trials supports the use of the Nd:YAG laser in the treatment of HS. Treat the entire affected anatomic area and use stacked double pulses on active nodules (typical settings: 10-mm spot size; 10-millisecond pulse duration and 35–50 J/cm2 in Fitzpatrick skin types I–III; 20-millisecond pulse duration and 25–40 J/cm2 in Fitzpatrick skin types IV–VI).4 Especially if it is covered by your patient’s insurance, Nd:YAG is a great adjunctive treatment to consider. The guidelines also recommend long-pulsed alexandrite and diode lasers as well as intense pulsed light, all of which result in follicular destruction, though these treatments have less supporting evidence.4
Have a Plan for Flares
Intralesional injection of triamcinolone is a mainstay of HS treatment and provides patients with rapid relief of symptoms during a flare.5 One case series found that there was a notable decrease in pain, size, and drainage after just 1 day of treatment with intralesional triamcinolone 10 mg/mL (0.2–2.0 mL).6
Intralesional steroid injection is a great tool for quieting an active disease flare while simultaneously instating ongoing treatment for preventive management. However, even when disease control is optimized, patients may still experience intermittent flares of disease. For some patients, it may be appropriate to have a plan in place for a return to clinic during the beginning of a flare to obtain intralesional steroids. The ability to come in on short notice may help avoid visits to the emergency department and urgent care where your patients may receive treatments such as short courses of antibiotics or incision and drainage that may deviate from your overall treatment plan.
Consider Childbearing Status
Don’t forget to consider childbearing plans and childbearing potential when treating female patients with HS. Pregnancy is a frequent consideration in HS patients, as HS affects 3 to 4 times more women than men and typically presents after puberty (second or third decades of life). Many of the medications in the HS armamentarium are contraindicated in pregnancy including tetracyclines, retinoids, and hormonal agents. Surgery should be avoided in pregnant patients whenever possible, particularly in the first trimester. Relatively safe options include topical antibiotics such as clindamycin and metronidazole, as well as tumor necrosis factor α inhibitors, which are classified as category B in pregnancy.5
Before making treatment decisions in pregnant and breastfeeding patients, consult the US Food and Drug Administration recommendations. Perng et al7 reviewed current management strategies for HS in pregnant and breastfeeding women, and their review article in the Journal of the American Academy of Dermatology is an excellent resource.
Final Thoughts
Comprehensive management of HS may include a combination of medication and procedures, lifestyle modification, management of comorbidities, and social support. Formulating a good treatment plan may be a challenge but can drastically improve your patient’s quality of life.
- What is hidradenitis suppurativa? Hidradenitis Suppurativa Foundation website. https://www.hs-foundation.org/what-is-hs. Accessed October 9, 2019.
- Frew JW, Hawkes JE, Krueger JG. Topical, systemic and biologic therapies in hidradenitis suppurativa: pathogenic insights by examining therapeutic mechanisms. Ther Adv Chronic Dis. 2019;10:2040622319830646. doi:10.1177/2040622319830646
- Lacarrubba F, Musumeci ML, Nasca MR, et al. Double-ended pseudocomedones in hidradenitis suppurativa: clinical, dermoscopic, and histopathological correlation. Acta Derm Venereol. 2017;97:763-764.
- Alikhan A, Sayed C, Alavi A, et al. North American Clinical Management Guidelines for Hidradenitis Suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations. part I: diagnosis, evaluation, and the use of complementary and procedural management. J Am Acad Dermatol. 2019;81:76-90.
- Alikhan A, Sayed C, Alavi A, et al. North American Clinical Management Guidelines for Hidradenitis Suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations. part II: topical, intralesional, and systemic medical management. J Am Acad Dermatol. 2019;81:91-101.
- Riis PT, Boer J, Prens EP, et al. Intralesional triamcinolone for flares of hidradenitis suppurativa (HS): a case series. J Am Acad Dermatol. 2016;75:1151-1155.
- Perng P, Zampella JG, Okoye GA. Management of hidradenitis suppurativa in pregnancy. J Am Acad Dermatol. 2017;76:979-989.
- What is hidradenitis suppurativa? Hidradenitis Suppurativa Foundation website. https://www.hs-foundation.org/what-is-hs. Accessed October 9, 2019.
- Frew JW, Hawkes JE, Krueger JG. Topical, systemic and biologic therapies in hidradenitis suppurativa: pathogenic insights by examining therapeutic mechanisms. Ther Adv Chronic Dis. 2019;10:2040622319830646. doi:10.1177/2040622319830646
- Lacarrubba F, Musumeci ML, Nasca MR, et al. Double-ended pseudocomedones in hidradenitis suppurativa: clinical, dermoscopic, and histopathological correlation. Acta Derm Venereol. 2017;97:763-764.
- Alikhan A, Sayed C, Alavi A, et al. North American Clinical Management Guidelines for Hidradenitis Suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations. part I: diagnosis, evaluation, and the use of complementary and procedural management. J Am Acad Dermatol. 2019;81:76-90.
- Alikhan A, Sayed C, Alavi A, et al. North American Clinical Management Guidelines for Hidradenitis Suppurativa: a publication from the United States and Canadian Hidradenitis Suppurativa Foundations. part II: topical, intralesional, and systemic medical management. J Am Acad Dermatol. 2019;81:91-101.
- Riis PT, Boer J, Prens EP, et al. Intralesional triamcinolone for flares of hidradenitis suppurativa (HS): a case series. J Am Acad Dermatol. 2016;75:1151-1155.
- Perng P, Zampella JG, Okoye GA. Management of hidradenitis suppurativa in pregnancy. J Am Acad Dermatol. 2017;76:979-989.
Resident Pearls
- Medical treatment of hidradenitis suppurativa (HS) can be relatively straightforward, but optimal comprehensive management is multifaceted.
- Educate patients about pathophysiology, counsel on smoking cessation, remember laser hair removal, consider an ongoing plan for addressing flares, and think about childbearing status when treating HS patients.
FDA approves Givlaari for treatment of acute hepatic porphyria
The Food and Drug Administration has approved givosiran (Givlaari) for the treatment of adult patients with acute hepatic porphyria, a genetic disorder that causes buildup of porphyrin molecules.
“This buildup can cause acute attacks, known as porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures, and mental status changes. These attacks occur suddenly and can produce permanent neurological damage and death. Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in a statement.
Approval for givosiran is based on results from a clinical trial of 94 patients with acute hepatic porphyria. Patients who received givosiran experienced 70% fewer porphyria attacks that required hospitalization, urgent health care visits, or home intravenous hemin injections compared with patients who received a placebo.
The most common adverse events associated with givosiran were nausea and injection site reactions. Patients receiving the medication should be monitored for anaphylactic reaction and renal function, and liver function should be tested before and periodically during treatment.
“The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients,” said Dr. Pazdur, acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
The Food and Drug Administration has approved givosiran (Givlaari) for the treatment of adult patients with acute hepatic porphyria, a genetic disorder that causes buildup of porphyrin molecules.
“This buildup can cause acute attacks, known as porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures, and mental status changes. These attacks occur suddenly and can produce permanent neurological damage and death. Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in a statement.
Approval for givosiran is based on results from a clinical trial of 94 patients with acute hepatic porphyria. Patients who received givosiran experienced 70% fewer porphyria attacks that required hospitalization, urgent health care visits, or home intravenous hemin injections compared with patients who received a placebo.
The most common adverse events associated with givosiran were nausea and injection site reactions. Patients receiving the medication should be monitored for anaphylactic reaction and renal function, and liver function should be tested before and periodically during treatment.
“The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients,” said Dr. Pazdur, acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
The Food and Drug Administration has approved givosiran (Givlaari) for the treatment of adult patients with acute hepatic porphyria, a genetic disorder that causes buildup of porphyrin molecules.
“This buildup can cause acute attacks, known as porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures, and mental status changes. These attacks occur suddenly and can produce permanent neurological damage and death. Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in a statement.
Approval for givosiran is based on results from a clinical trial of 94 patients with acute hepatic porphyria. Patients who received givosiran experienced 70% fewer porphyria attacks that required hospitalization, urgent health care visits, or home intravenous hemin injections compared with patients who received a placebo.
The most common adverse events associated with givosiran were nausea and injection site reactions. Patients receiving the medication should be monitored for anaphylactic reaction and renal function, and liver function should be tested before and periodically during treatment.
“The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients,” said Dr. Pazdur, acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
Fewer people are dying from systemic sclerosis at younger ages
ATLANTA – Patients with systemic sclerosis aged 44 years and younger in the United States now have mortality comparable to that of the general population in that age group, according to recent results presented at the annual meeting of the American College of Rheumatology.
“Mortality for scleroderma has steadily decreased in younger ages for the last 5 decades,” Ram R. Singh, MD, professor of medicine, pathology, and laboratory medicine at the University of California, Los Angeles, said in his presentation.
Using the Centers for Disease Control and Prevention’s National Vital Statistics System database, Dr. Singh and colleagues analyzed data of adults with systemic sclerosis (SSc) and identified 46,798 adults who died between 1968 and 2015. They divided the adults with and without SSc into three different age groups: 44 and younger, 45-64, and 65 and older. The researchers performed a joinpoint trend analysis, calculating the annual percent change (APC) and average APC as well as the age-standardized mortality rate (ASMR) in each age group.
In 1968, 466 deaths were attributed to SSc, compared with 1,195 deaths in 2015. Between 1968 and 2015, there was a 19% cumulative percentage increase in SSc-related deaths, compared with a 44% decrease in mortality not attributed to SSc; when the researchers analyzed the ratio of SSc-related ASMR to non-SSc-related ASMR, there was an increase of 112%, Dr. Singh said.
When analyzing the mortality of adults with SSc by age group during 1968-2015 using the CDC’s database, Dr. Singh and colleagues found 5,457 deaths in adults 44 and younger (11.7%), 18,395 deaths in adults aged 45-64 (39.3%), and 22,946 deaths in adults aged 65 and older (49.0%), compared with totals for the general population of 10.3 million deaths in adults aged 44 and younger (9.7%), 20.8 million deaths in adults 45-64 years (19.6%), and 74.8 million deaths in adults aged 65 and older (70.6%).
Over the 48-year period, there were three major trends in SSc-related ASMR, Dr. Singh noted. In the first trend period between 1968 and 1988, there was a 1.0% increase per year (95% confidence interval, 0.6%-1.4%). The second trend period, lasting until 2000, saw a 2.2% increase per year (95% CI, 1.6%-2.7%), while the SSc-related ASMR declined by 2.6% per year in the third trend period from 2001 to 2015 (95% CI, –3.1% to –2.2%).
The percentage of annual deaths for adults with SSc decreased between 1968 and 2015, from 23.4% to 5.7%, and the average APC was greater among adults aged 44 and younger with SSc (–2.2%; 95% CI, –2.4% to –2.0%) than for adults without SSc in the same age group (–1.5%; 95% CI, –1.9% to –1.1%).
There was a cumulative 60% decrease in the ASMR of adults with SSc aged 44 and younger between 1968 and 2015 from an ASMR of 1.0 per million (95% CI, 0.8%-1.2%) to an ASMR of 0.4 per million (0.3-0.5). Adults aged 45-64 years with SSc had a cumulative 20.3% decrease in ASMR over the same time period, with an ASMR of 5.9 per million in 1968 (95% CI, 5.2-6.7) and an ASMR of 4.7 per million in 2015 (95% CI, 4.2-5.2). However, adults aged 65 and older with SSc had a 187% cumulative increase in ASMR, with an ASMR of 5.4 per million in 1968 (95% CI, 4.4-6.5) and an ASMR of 15.5 per million in 2015 (95% CI, 14.3-16.6). Adults with non-SSc-related deaths between 1968 and 2015 had a 50.0% cumulative decrease in ASMR in the group aged 44 and under, a 48.0% cumulative decrease in the 45-year to 64-year-old group, and a 42.1% decrease in the 65-year-old or older group.
The ratio of SSc to non-SSc ASMRs between 1968 and 2015 in the group aged 44 and younger declined 20.0%, whereas there was a 53.1% cumulative increase in the 45- to 64-year-old group and a 395.4% cumulative increase in the 65-year-old and older group. In the oldest group, the APC increased by 3.9% each year for 33 years (95% CI, 3.7%-4.1%) before declining by 1.6% until 2015 (95% CI, –2.0 to –1.3). In contrast, the APC for adults 44 and younger never significantly increased over the 48 years, Dr. Singh noted.
“Increasing scleroderma mortality in older age could be due to improving survival and/or increasing age of onset of scleroderma,” he said.
Dr. Singh reported no conflicts of interest.
SOURCE: Yen E et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 825.
ATLANTA – Patients with systemic sclerosis aged 44 years and younger in the United States now have mortality comparable to that of the general population in that age group, according to recent results presented at the annual meeting of the American College of Rheumatology.
“Mortality for scleroderma has steadily decreased in younger ages for the last 5 decades,” Ram R. Singh, MD, professor of medicine, pathology, and laboratory medicine at the University of California, Los Angeles, said in his presentation.
Using the Centers for Disease Control and Prevention’s National Vital Statistics System database, Dr. Singh and colleagues analyzed data of adults with systemic sclerosis (SSc) and identified 46,798 adults who died between 1968 and 2015. They divided the adults with and without SSc into three different age groups: 44 and younger, 45-64, and 65 and older. The researchers performed a joinpoint trend analysis, calculating the annual percent change (APC) and average APC as well as the age-standardized mortality rate (ASMR) in each age group.
In 1968, 466 deaths were attributed to SSc, compared with 1,195 deaths in 2015. Between 1968 and 2015, there was a 19% cumulative percentage increase in SSc-related deaths, compared with a 44% decrease in mortality not attributed to SSc; when the researchers analyzed the ratio of SSc-related ASMR to non-SSc-related ASMR, there was an increase of 112%, Dr. Singh said.
When analyzing the mortality of adults with SSc by age group during 1968-2015 using the CDC’s database, Dr. Singh and colleagues found 5,457 deaths in adults 44 and younger (11.7%), 18,395 deaths in adults aged 45-64 (39.3%), and 22,946 deaths in adults aged 65 and older (49.0%), compared with totals for the general population of 10.3 million deaths in adults aged 44 and younger (9.7%), 20.8 million deaths in adults 45-64 years (19.6%), and 74.8 million deaths in adults aged 65 and older (70.6%).
Over the 48-year period, there were three major trends in SSc-related ASMR, Dr. Singh noted. In the first trend period between 1968 and 1988, there was a 1.0% increase per year (95% confidence interval, 0.6%-1.4%). The second trend period, lasting until 2000, saw a 2.2% increase per year (95% CI, 1.6%-2.7%), while the SSc-related ASMR declined by 2.6% per year in the third trend period from 2001 to 2015 (95% CI, –3.1% to –2.2%).
The percentage of annual deaths for adults with SSc decreased between 1968 and 2015, from 23.4% to 5.7%, and the average APC was greater among adults aged 44 and younger with SSc (–2.2%; 95% CI, –2.4% to –2.0%) than for adults without SSc in the same age group (–1.5%; 95% CI, –1.9% to –1.1%).
There was a cumulative 60% decrease in the ASMR of adults with SSc aged 44 and younger between 1968 and 2015 from an ASMR of 1.0 per million (95% CI, 0.8%-1.2%) to an ASMR of 0.4 per million (0.3-0.5). Adults aged 45-64 years with SSc had a cumulative 20.3% decrease in ASMR over the same time period, with an ASMR of 5.9 per million in 1968 (95% CI, 5.2-6.7) and an ASMR of 4.7 per million in 2015 (95% CI, 4.2-5.2). However, adults aged 65 and older with SSc had a 187% cumulative increase in ASMR, with an ASMR of 5.4 per million in 1968 (95% CI, 4.4-6.5) and an ASMR of 15.5 per million in 2015 (95% CI, 14.3-16.6). Adults with non-SSc-related deaths between 1968 and 2015 had a 50.0% cumulative decrease in ASMR in the group aged 44 and under, a 48.0% cumulative decrease in the 45-year to 64-year-old group, and a 42.1% decrease in the 65-year-old or older group.
The ratio of SSc to non-SSc ASMRs between 1968 and 2015 in the group aged 44 and younger declined 20.0%, whereas there was a 53.1% cumulative increase in the 45- to 64-year-old group and a 395.4% cumulative increase in the 65-year-old and older group. In the oldest group, the APC increased by 3.9% each year for 33 years (95% CI, 3.7%-4.1%) before declining by 1.6% until 2015 (95% CI, –2.0 to –1.3). In contrast, the APC for adults 44 and younger never significantly increased over the 48 years, Dr. Singh noted.
“Increasing scleroderma mortality in older age could be due to improving survival and/or increasing age of onset of scleroderma,” he said.
Dr. Singh reported no conflicts of interest.
SOURCE: Yen E et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 825.
ATLANTA – Patients with systemic sclerosis aged 44 years and younger in the United States now have mortality comparable to that of the general population in that age group, according to recent results presented at the annual meeting of the American College of Rheumatology.
“Mortality for scleroderma has steadily decreased in younger ages for the last 5 decades,” Ram R. Singh, MD, professor of medicine, pathology, and laboratory medicine at the University of California, Los Angeles, said in his presentation.
Using the Centers for Disease Control and Prevention’s National Vital Statistics System database, Dr. Singh and colleagues analyzed data of adults with systemic sclerosis (SSc) and identified 46,798 adults who died between 1968 and 2015. They divided the adults with and without SSc into three different age groups: 44 and younger, 45-64, and 65 and older. The researchers performed a joinpoint trend analysis, calculating the annual percent change (APC) and average APC as well as the age-standardized mortality rate (ASMR) in each age group.
In 1968, 466 deaths were attributed to SSc, compared with 1,195 deaths in 2015. Between 1968 and 2015, there was a 19% cumulative percentage increase in SSc-related deaths, compared with a 44% decrease in mortality not attributed to SSc; when the researchers analyzed the ratio of SSc-related ASMR to non-SSc-related ASMR, there was an increase of 112%, Dr. Singh said.
When analyzing the mortality of adults with SSc by age group during 1968-2015 using the CDC’s database, Dr. Singh and colleagues found 5,457 deaths in adults 44 and younger (11.7%), 18,395 deaths in adults aged 45-64 (39.3%), and 22,946 deaths in adults aged 65 and older (49.0%), compared with totals for the general population of 10.3 million deaths in adults aged 44 and younger (9.7%), 20.8 million deaths in adults 45-64 years (19.6%), and 74.8 million deaths in adults aged 65 and older (70.6%).
Over the 48-year period, there were three major trends in SSc-related ASMR, Dr. Singh noted. In the first trend period between 1968 and 1988, there was a 1.0% increase per year (95% confidence interval, 0.6%-1.4%). The second trend period, lasting until 2000, saw a 2.2% increase per year (95% CI, 1.6%-2.7%), while the SSc-related ASMR declined by 2.6% per year in the third trend period from 2001 to 2015 (95% CI, –3.1% to –2.2%).
The percentage of annual deaths for adults with SSc decreased between 1968 and 2015, from 23.4% to 5.7%, and the average APC was greater among adults aged 44 and younger with SSc (–2.2%; 95% CI, –2.4% to –2.0%) than for adults without SSc in the same age group (–1.5%; 95% CI, –1.9% to –1.1%).
There was a cumulative 60% decrease in the ASMR of adults with SSc aged 44 and younger between 1968 and 2015 from an ASMR of 1.0 per million (95% CI, 0.8%-1.2%) to an ASMR of 0.4 per million (0.3-0.5). Adults aged 45-64 years with SSc had a cumulative 20.3% decrease in ASMR over the same time period, with an ASMR of 5.9 per million in 1968 (95% CI, 5.2-6.7) and an ASMR of 4.7 per million in 2015 (95% CI, 4.2-5.2). However, adults aged 65 and older with SSc had a 187% cumulative increase in ASMR, with an ASMR of 5.4 per million in 1968 (95% CI, 4.4-6.5) and an ASMR of 15.5 per million in 2015 (95% CI, 14.3-16.6). Adults with non-SSc-related deaths between 1968 and 2015 had a 50.0% cumulative decrease in ASMR in the group aged 44 and under, a 48.0% cumulative decrease in the 45-year to 64-year-old group, and a 42.1% decrease in the 65-year-old or older group.
The ratio of SSc to non-SSc ASMRs between 1968 and 2015 in the group aged 44 and younger declined 20.0%, whereas there was a 53.1% cumulative increase in the 45- to 64-year-old group and a 395.4% cumulative increase in the 65-year-old and older group. In the oldest group, the APC increased by 3.9% each year for 33 years (95% CI, 3.7%-4.1%) before declining by 1.6% until 2015 (95% CI, –2.0 to –1.3). In contrast, the APC for adults 44 and younger never significantly increased over the 48 years, Dr. Singh noted.
“Increasing scleroderma mortality in older age could be due to improving survival and/or increasing age of onset of scleroderma,” he said.
Dr. Singh reported no conflicts of interest.
SOURCE: Yen E et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 825.
REPORTING FROM ACR 2019
RNA inhibitors silence two new targets in dyslipidemia
PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.
ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.
Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.
The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.
Gerald F. Watts, MBBS, DM, DSc, PhD, presented a separate phase 1/2a, 16-week study of a single dose of ARO-ANG3 at 35, 100, 200, or 300 mg in 40 dyslipidemic subjects who were not on background lipid-lowering therapy. The impact on lipids was similar to that achieved by silencing apolipoprotein C-III, except that the reduction in LDL cholesterol was larger and ARO-ANG3 reduced HDL cholesterol in dose-dependent fashion by up to 26%. As in the ARO-APOC3 study, the safety profile of the ANG3 RNA inhibitor raised no concerns, with no study dropouts and no serious adverse events, added Dr. Watts, professor of medicine at the University of Western Australia, Perth.
Discussant Daniel J. Rader, MD, noted that there is an unmet need for hypertriglyceridemia-lowering therapies, because elevated triglycerides can cause pancreatitis as well as coronary disease.
“These siRNA molecules are catalytic: They can go around and destroy multiple aspects of the target RNAs in a way that provides substantial longevity of effect, which is quite remarkable,” explained Dr. Rader, professor of molecular medicine and director of the preventive cardiology program at the University of Pennsylvania, Philadelphia.
Hypertriglyceridemia is often a challenge to treat successfully in clinical practice, so the siRNA studies drew considerable attention, not only for the impressive size and durability of the lipid changes, but also because of the way in which the target genes were identified, a process that began by genetic analysis of individuals with inherently low levels of APOC3 and ANG3.
“One of the really interesting parts of this story is the rapidity with which we went from target identification to therapeutics, now moving into phase 1 and 2 trials. It’s happening much more rapidly than we’ve ever seen before,” commented AHA scientific sessions program chair Donald Lloyd-Jones, MD, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
Still, he was quick to inject a cautionary note. “These genomic studies can show us that having lower levels of these proteins is associated with lower risk. But that doesn’t necessarily mean that lowering levels of these proteins will lower risk, and it certainly doesn’t tell us anything about potential safety concerns.”
In an interview, AHA spokesperson Jennifer Robinson, MD, made a similar point: “We have had lots of fibrate trials in which we’ve lowered triglycerides, and they didn’t really work.”
Yet she, too, was clearly caught up in the thrill of the early evidence of a novel means of treating new targets in dyslipidemia.
“We’re on the cusp of the genetic revolution,” declared Dr. Robinson, professor of epidemiology and director of the preventive and intervention center at the University of Iowa, Iowa City. “For us science nerds, this is so exciting. It’s so cool. The brilliance of these compounds is they have a very focused target in a very focused organ. If you’re just in the liver, you’re limiting off-target effects, so the safety issue should be better than with what we have now.”
Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.
Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.
PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.
ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.
Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.
The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.
Gerald F. Watts, MBBS, DM, DSc, PhD, presented a separate phase 1/2a, 16-week study of a single dose of ARO-ANG3 at 35, 100, 200, or 300 mg in 40 dyslipidemic subjects who were not on background lipid-lowering therapy. The impact on lipids was similar to that achieved by silencing apolipoprotein C-III, except that the reduction in LDL cholesterol was larger and ARO-ANG3 reduced HDL cholesterol in dose-dependent fashion by up to 26%. As in the ARO-APOC3 study, the safety profile of the ANG3 RNA inhibitor raised no concerns, with no study dropouts and no serious adverse events, added Dr. Watts, professor of medicine at the University of Western Australia, Perth.
Discussant Daniel J. Rader, MD, noted that there is an unmet need for hypertriglyceridemia-lowering therapies, because elevated triglycerides can cause pancreatitis as well as coronary disease.
“These siRNA molecules are catalytic: They can go around and destroy multiple aspects of the target RNAs in a way that provides substantial longevity of effect, which is quite remarkable,” explained Dr. Rader, professor of molecular medicine and director of the preventive cardiology program at the University of Pennsylvania, Philadelphia.
Hypertriglyceridemia is often a challenge to treat successfully in clinical practice, so the siRNA studies drew considerable attention, not only for the impressive size and durability of the lipid changes, but also because of the way in which the target genes were identified, a process that began by genetic analysis of individuals with inherently low levels of APOC3 and ANG3.
“One of the really interesting parts of this story is the rapidity with which we went from target identification to therapeutics, now moving into phase 1 and 2 trials. It’s happening much more rapidly than we’ve ever seen before,” commented AHA scientific sessions program chair Donald Lloyd-Jones, MD, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
Still, he was quick to inject a cautionary note. “These genomic studies can show us that having lower levels of these proteins is associated with lower risk. But that doesn’t necessarily mean that lowering levels of these proteins will lower risk, and it certainly doesn’t tell us anything about potential safety concerns.”
In an interview, AHA spokesperson Jennifer Robinson, MD, made a similar point: “We have had lots of fibrate trials in which we’ve lowered triglycerides, and they didn’t really work.”
Yet she, too, was clearly caught up in the thrill of the early evidence of a novel means of treating new targets in dyslipidemia.
“We’re on the cusp of the genetic revolution,” declared Dr. Robinson, professor of epidemiology and director of the preventive and intervention center at the University of Iowa, Iowa City. “For us science nerds, this is so exciting. It’s so cool. The brilliance of these compounds is they have a very focused target in a very focused organ. If you’re just in the liver, you’re limiting off-target effects, so the safety issue should be better than with what we have now.”
Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.
Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.
PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.
ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.
Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.
The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.
Gerald F. Watts, MBBS, DM, DSc, PhD, presented a separate phase 1/2a, 16-week study of a single dose of ARO-ANG3 at 35, 100, 200, or 300 mg in 40 dyslipidemic subjects who were not on background lipid-lowering therapy. The impact on lipids was similar to that achieved by silencing apolipoprotein C-III, except that the reduction in LDL cholesterol was larger and ARO-ANG3 reduced HDL cholesterol in dose-dependent fashion by up to 26%. As in the ARO-APOC3 study, the safety profile of the ANG3 RNA inhibitor raised no concerns, with no study dropouts and no serious adverse events, added Dr. Watts, professor of medicine at the University of Western Australia, Perth.
Discussant Daniel J. Rader, MD, noted that there is an unmet need for hypertriglyceridemia-lowering therapies, because elevated triglycerides can cause pancreatitis as well as coronary disease.
“These siRNA molecules are catalytic: They can go around and destroy multiple aspects of the target RNAs in a way that provides substantial longevity of effect, which is quite remarkable,” explained Dr. Rader, professor of molecular medicine and director of the preventive cardiology program at the University of Pennsylvania, Philadelphia.
Hypertriglyceridemia is often a challenge to treat successfully in clinical practice, so the siRNA studies drew considerable attention, not only for the impressive size and durability of the lipid changes, but also because of the way in which the target genes were identified, a process that began by genetic analysis of individuals with inherently low levels of APOC3 and ANG3.
“One of the really interesting parts of this story is the rapidity with which we went from target identification to therapeutics, now moving into phase 1 and 2 trials. It’s happening much more rapidly than we’ve ever seen before,” commented AHA scientific sessions program chair Donald Lloyd-Jones, MD, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
Still, he was quick to inject a cautionary note. “These genomic studies can show us that having lower levels of these proteins is associated with lower risk. But that doesn’t necessarily mean that lowering levels of these proteins will lower risk, and it certainly doesn’t tell us anything about potential safety concerns.”
In an interview, AHA spokesperson Jennifer Robinson, MD, made a similar point: “We have had lots of fibrate trials in which we’ve lowered triglycerides, and they didn’t really work.”
Yet she, too, was clearly caught up in the thrill of the early evidence of a novel means of treating new targets in dyslipidemia.
“We’re on the cusp of the genetic revolution,” declared Dr. Robinson, professor of epidemiology and director of the preventive and intervention center at the University of Iowa, Iowa City. “For us science nerds, this is so exciting. It’s so cool. The brilliance of these compounds is they have a very focused target in a very focused organ. If you’re just in the liver, you’re limiting off-target effects, so the safety issue should be better than with what we have now.”
Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.
Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.
REPORTING FROM AHA 2019
Apremilast for Behçet’s oral ulcers: Benefits maintained at 64 weeks
MADRID – of the long-term extension phase of the pivotal RELIEF trial, Alfred Mahr, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“We now have strong evidence that apremilast is an effective and safe therapy to treat oral ulcers in patients with Behçet’s syndrome. I think this is a major advance in the field,” declared Dr. Mahr, a rheumatologist at St. Gallen (Switzerland) Cantonal Hospital.
Based largely upon the results of the 12-week, double-blind portion of the phase 3 RELIEF trial, the Food and Drug Administration approved apremilast (Otezla) for the treatment of oral ulcers in patients with Behçet’s disease in the summer of 2019.
The safety profile of the oral phosphodiesterase-4 inhibitor was as seen in other studies, including in patients with psoriatic arthritis, an FDA-approved indication for the drug since 2014. The main side effects in the long-term extension of RELIEF were diarrhea and nausea, typically mild or moderate in nature and roughly twice as frequent as in placebo-treated controls in the double-blind study phase.
“At the end of the day, at week 64, only 12% of patients treated with apremilast during the entire 64 weeks discontinued the drug due to a treatment-emergent adverse event, which I believe is a good indicator of the safety of this medication,” the rheumatologist said. “The overall feeling is that the benefit-to-risk ratio is very good and it’s a safe drug to prescribe.”
At the close of the initial 12-week, double-blind phase of RELIEF, 178 of the original 207 participants elected to enter the long-term extension, either staying on apremilast at 30 mg twice a day for an additional 52 weeks or switching to that regimen from placebo.
The focus of the long-term extension was on disease activity and quality of life outcomes. The results in patients who had switched from placebo to apremilast after 12 weeks proved to be reassuringly similar to outcomes in patients on the drug for the full duration. For example, the mean improvement on the patient-reported Behçet’s Syndrome Activity Scale was 18.6 points after 12 weeks of double-blind apremilast, 16.9 points after 64 weeks of continuous apremilast, and 16.8 points with 12 weeks of placebo followed by 52 weeks of active therapy.
After 12 weeks of double-blind apremilast, patients averaged a 3.4-point improvement on the Behçet’s Disease Quality of Life measure. After 64 weeks on the drug, the improvement over baseline was 3.6 points, while in the switch group it was 3.4 points. Similarly, on all three components of the SF-36 quality of life metric, the continuous apremilast group showed maintenance of effect from week 12 to week 64, while the placebo-to-apremilast group caught up. The same was true with regards to the Behçet’s Disease Current Activity Index, which encompasses measures of both the patient’s and clinician’s perception of disease activity.
At the outset of the RELIEF trial, participants averaged four oral ulcers. At week 64, the continuous apremilast group averaged 1.4 and the switch group 0.8, a nonsignificant difference.
Asked if apremilast had a favorable impact upon other manifestations of Behçet’s disease besides the oral ulcers, Dr. Mahr replied, “This is a very good question. People often wonder about it. We do, too. But this trial was not designed to capture less common manifestations of Behçet’s syndrome, such as genital ulcers. There have been some analyses done, but the number of patients who had genital ulcers at 12 weeks were very few. The same was true for eye manifestations. There was sort of a signal that it works, but we can’t prove it in a placebo-controlled trial.”
Dr. Mahr reported receiving research funding from and serving as a consultant to Celgene, the study sponsor.
MADRID – of the long-term extension phase of the pivotal RELIEF trial, Alfred Mahr, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“We now have strong evidence that apremilast is an effective and safe therapy to treat oral ulcers in patients with Behçet’s syndrome. I think this is a major advance in the field,” declared Dr. Mahr, a rheumatologist at St. Gallen (Switzerland) Cantonal Hospital.
Based largely upon the results of the 12-week, double-blind portion of the phase 3 RELIEF trial, the Food and Drug Administration approved apremilast (Otezla) for the treatment of oral ulcers in patients with Behçet’s disease in the summer of 2019.
The safety profile of the oral phosphodiesterase-4 inhibitor was as seen in other studies, including in patients with psoriatic arthritis, an FDA-approved indication for the drug since 2014. The main side effects in the long-term extension of RELIEF were diarrhea and nausea, typically mild or moderate in nature and roughly twice as frequent as in placebo-treated controls in the double-blind study phase.
“At the end of the day, at week 64, only 12% of patients treated with apremilast during the entire 64 weeks discontinued the drug due to a treatment-emergent adverse event, which I believe is a good indicator of the safety of this medication,” the rheumatologist said. “The overall feeling is that the benefit-to-risk ratio is very good and it’s a safe drug to prescribe.”
At the close of the initial 12-week, double-blind phase of RELIEF, 178 of the original 207 participants elected to enter the long-term extension, either staying on apremilast at 30 mg twice a day for an additional 52 weeks or switching to that regimen from placebo.
The focus of the long-term extension was on disease activity and quality of life outcomes. The results in patients who had switched from placebo to apremilast after 12 weeks proved to be reassuringly similar to outcomes in patients on the drug for the full duration. For example, the mean improvement on the patient-reported Behçet’s Syndrome Activity Scale was 18.6 points after 12 weeks of double-blind apremilast, 16.9 points after 64 weeks of continuous apremilast, and 16.8 points with 12 weeks of placebo followed by 52 weeks of active therapy.
After 12 weeks of double-blind apremilast, patients averaged a 3.4-point improvement on the Behçet’s Disease Quality of Life measure. After 64 weeks on the drug, the improvement over baseline was 3.6 points, while in the switch group it was 3.4 points. Similarly, on all three components of the SF-36 quality of life metric, the continuous apremilast group showed maintenance of effect from week 12 to week 64, while the placebo-to-apremilast group caught up. The same was true with regards to the Behçet’s Disease Current Activity Index, which encompasses measures of both the patient’s and clinician’s perception of disease activity.
At the outset of the RELIEF trial, participants averaged four oral ulcers. At week 64, the continuous apremilast group averaged 1.4 and the switch group 0.8, a nonsignificant difference.
Asked if apremilast had a favorable impact upon other manifestations of Behçet’s disease besides the oral ulcers, Dr. Mahr replied, “This is a very good question. People often wonder about it. We do, too. But this trial was not designed to capture less common manifestations of Behçet’s syndrome, such as genital ulcers. There have been some analyses done, but the number of patients who had genital ulcers at 12 weeks were very few. The same was true for eye manifestations. There was sort of a signal that it works, but we can’t prove it in a placebo-controlled trial.”
Dr. Mahr reported receiving research funding from and serving as a consultant to Celgene, the study sponsor.
MADRID – of the long-term extension phase of the pivotal RELIEF trial, Alfred Mahr, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“We now have strong evidence that apremilast is an effective and safe therapy to treat oral ulcers in patients with Behçet’s syndrome. I think this is a major advance in the field,” declared Dr. Mahr, a rheumatologist at St. Gallen (Switzerland) Cantonal Hospital.
Based largely upon the results of the 12-week, double-blind portion of the phase 3 RELIEF trial, the Food and Drug Administration approved apremilast (Otezla) for the treatment of oral ulcers in patients with Behçet’s disease in the summer of 2019.
The safety profile of the oral phosphodiesterase-4 inhibitor was as seen in other studies, including in patients with psoriatic arthritis, an FDA-approved indication for the drug since 2014. The main side effects in the long-term extension of RELIEF were diarrhea and nausea, typically mild or moderate in nature and roughly twice as frequent as in placebo-treated controls in the double-blind study phase.
“At the end of the day, at week 64, only 12% of patients treated with apremilast during the entire 64 weeks discontinued the drug due to a treatment-emergent adverse event, which I believe is a good indicator of the safety of this medication,” the rheumatologist said. “The overall feeling is that the benefit-to-risk ratio is very good and it’s a safe drug to prescribe.”
At the close of the initial 12-week, double-blind phase of RELIEF, 178 of the original 207 participants elected to enter the long-term extension, either staying on apremilast at 30 mg twice a day for an additional 52 weeks or switching to that regimen from placebo.
The focus of the long-term extension was on disease activity and quality of life outcomes. The results in patients who had switched from placebo to apremilast after 12 weeks proved to be reassuringly similar to outcomes in patients on the drug for the full duration. For example, the mean improvement on the patient-reported Behçet’s Syndrome Activity Scale was 18.6 points after 12 weeks of double-blind apremilast, 16.9 points after 64 weeks of continuous apremilast, and 16.8 points with 12 weeks of placebo followed by 52 weeks of active therapy.
After 12 weeks of double-blind apremilast, patients averaged a 3.4-point improvement on the Behçet’s Disease Quality of Life measure. After 64 weeks on the drug, the improvement over baseline was 3.6 points, while in the switch group it was 3.4 points. Similarly, on all three components of the SF-36 quality of life metric, the continuous apremilast group showed maintenance of effect from week 12 to week 64, while the placebo-to-apremilast group caught up. The same was true with regards to the Behçet’s Disease Current Activity Index, which encompasses measures of both the patient’s and clinician’s perception of disease activity.
At the outset of the RELIEF trial, participants averaged four oral ulcers. At week 64, the continuous apremilast group averaged 1.4 and the switch group 0.8, a nonsignificant difference.
Asked if apremilast had a favorable impact upon other manifestations of Behçet’s disease besides the oral ulcers, Dr. Mahr replied, “This is a very good question. People often wonder about it. We do, too. But this trial was not designed to capture less common manifestations of Behçet’s syndrome, such as genital ulcers. There have been some analyses done, but the number of patients who had genital ulcers at 12 weeks were very few. The same was true for eye manifestations. There was sort of a signal that it works, but we can’t prove it in a placebo-controlled trial.”
Dr. Mahr reported receiving research funding from and serving as a consultant to Celgene, the study sponsor.
REPORTING FROM EADV 2019
Will TP53-mutated AML respond to immunotherapy?
NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).
Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.
These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.
Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.
He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*
With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.
Discovery cohort
The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.
The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.
The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).
The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).
Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).
Validation cohort and bone marrow samples
The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.
Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).
Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.
Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.
The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.
Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.
“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.
“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”
Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.
SOURCE: Rutella S et al. SITC 2019. Abstract O3.
*This article was updated on 11/19/2019.
NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).
Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.
These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.
Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.
He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*
With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.
Discovery cohort
The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.
The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.
The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).
The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).
Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).
Validation cohort and bone marrow samples
The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.
Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).
Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.
Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.
The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.
Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.
“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.
“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”
Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.
SOURCE: Rutella S et al. SITC 2019. Abstract O3.
*This article was updated on 11/19/2019.
NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).
Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.
These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.
Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.
He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*
With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.
Discovery cohort
The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.
The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.
The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).
The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).
Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).
Validation cohort and bone marrow samples
The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.
Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).
Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.
Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.
The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.
Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.
“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.
“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”
Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.
SOURCE: Rutella S et al. SITC 2019. Abstract O3.
*This article was updated on 11/19/2019.
REPORTING FROM SITC 2019