User login
Maintenance lenalidomide prolongs progression-free survival in DLBCL
Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.
None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.
The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.
After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).
This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.
The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.
“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”
The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.
None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.
The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.
After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).
This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.
The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.
“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”
The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Maintenance therapy with lenalidomide significantly prolongs progression-free survival (PFS) in elderly patients with diffuse large B-cell lymphoma (DLBCL), according to findings from a phase III trial.
None of the previous trials assessing a maintenance drug in this patient population – including bevacizumab, rituximab, enzastaurin, or everolimus – have reported such a benefit, Catherine Thieblemont, MD, PhD, of the department of hematology-oncology, Hôpital Saint-Louis, Paris, and her associates, reported.
The standard regimen for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), but 30%-40% of patients have disease progression or relapse, usually during the first 2 years after diagnosis. Lenalidomide is an immunomodulator with antineoplastic activity and has shown activity in relapsed DLBCL. The investigators compared 24 months of lenalidomide maintenance therapy against a matching placebo in an international, randomized double-blind phase III trial involving 650 patients aged 60-80 years who showed either partial or complete responses to first-line R-CHOP.
After a median follow-up of 39 months (range, 0-74 months), median PFS was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide. This represents a statistically significant and clinically meaningful improvement in PFS, Dr. Thieblemont and her associates noted (J Clin Oncol. 2017 Apr 20. doi: 10.1200/JCO.2017.72.6984).
This survival benefit was consistent across all subgroups of patients. Most important, PFS was significantly prolonged regardless of whether patients had shown only a partial response or a complete response to R-CHOP, the investigators said.
The maintenance therapy did not appear to prolong overall survival, which was 87% for lenalidomide and 89% for placebo.
“We do not yet fully understand the basis for lack of an [overall survival] benefit despite the positive PFS data. Other than that, this is not due to excessive toxicity in the experimental arm,” they said. “We speculate the reason may be differences in the outcomes after progression or some other unrecognized reason.”
The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
Key clinical point:
Major finding: Median progression-free survival was not yet reached in the lenalidomide group and was estimated to be 58.9 months in the placebo group, for a hazard ratio of 0.708 favoring lenalidomide.
Data source: A 5-year international, randomized double-blind placebo-controlled phase III trial involving 650 patients aged 60-80 years.
Disclosures: The study was sponsored by the Lymphoma Academic Research Organisation of France and Celgene. Dr. Thieblemont reported ties to Celgene, Bayer, AbbVie, Janssen, and Roche. Her associates reported ties to numerous industry sources.
ASCO updates NSCLC guidelines for adjuvant therapy
Adjuvant cisplatin-based chemotherapy is recommended for routine use in non–small cell lung cancer patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections, according to updated guidelines from the American Society of Clinical Oncology.
In patients with stage IA disease, the guidelines recommend against cisplatin-based chemotherapy. The new guidelines are based on a systematic review current to January 2016 and an American Society for Radiation Oncology guideline and systematic review, which ASCO had already endorsed, which formed the basis for recommendations on adjuvant radiation therapy, Mark G. Kris, MD, and panel authors said (J Clin Oncol. 2017 April 26. doi: 10.1200/JCO.2017.72.4401).
The guidelines, available online, also recommend against routine cisplatin-based chemotherapy in patients with stage IB disease, but they suggest an evaluation of these patients to explore the pros and cons of adjuvant chemotherapy.
With respect to radiation, the authors recommend against it for patients with resected stage I or stage II disease, and they recommend against it for routine use in patients with stage IIIA. However, in patients with IIIA N2 disease, patients should be evaluated postoperatively, in consultation with a medical oncologist, for the potential risks and benefits of adjuvant radiation.
The authors also provide some recommendations for communicating with patients regarding treatment decisions. There are few studies examining this question, so the recommendations are based on low-quality evidence.
Non–small cell lung cancer patients may have complex social, psychological, and medical issues, and discussions should be carried out with this in mind. Pain, impaired breathing, and fatigue are common after surgery, and smoking cessation can lead to short-term stress as a result of nicotine withdrawal. Older patients may have a range of comorbidities.
Studies show that patients are most satisfied if they feel that physicians allow them to share in the decision making, and if they are given sufficient time to choose. To that end, the authors recommend a session dedicated to discussion of adjuvant therapy.
Communicating risk of death is challenging for many reasons. Patients should be asked how they would like to hear about their risks: some prefer general terms, while others may opt for numbers, charts, or graphs. The guidelines include a risk chart that can help patients understand the potential benefits and risks of chemotherapy.
The study authors report financial relationships with numerous pharmaceutical companies.
Adjuvant cisplatin-based chemotherapy is recommended for routine use in non–small cell lung cancer patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections, according to updated guidelines from the American Society of Clinical Oncology.
In patients with stage IA disease, the guidelines recommend against cisplatin-based chemotherapy. The new guidelines are based on a systematic review current to January 2016 and an American Society for Radiation Oncology guideline and systematic review, which ASCO had already endorsed, which formed the basis for recommendations on adjuvant radiation therapy, Mark G. Kris, MD, and panel authors said (J Clin Oncol. 2017 April 26. doi: 10.1200/JCO.2017.72.4401).
The guidelines, available online, also recommend against routine cisplatin-based chemotherapy in patients with stage IB disease, but they suggest an evaluation of these patients to explore the pros and cons of adjuvant chemotherapy.
With respect to radiation, the authors recommend against it for patients with resected stage I or stage II disease, and they recommend against it for routine use in patients with stage IIIA. However, in patients with IIIA N2 disease, patients should be evaluated postoperatively, in consultation with a medical oncologist, for the potential risks and benefits of adjuvant radiation.
The authors also provide some recommendations for communicating with patients regarding treatment decisions. There are few studies examining this question, so the recommendations are based on low-quality evidence.
Non–small cell lung cancer patients may have complex social, psychological, and medical issues, and discussions should be carried out with this in mind. Pain, impaired breathing, and fatigue are common after surgery, and smoking cessation can lead to short-term stress as a result of nicotine withdrawal. Older patients may have a range of comorbidities.
Studies show that patients are most satisfied if they feel that physicians allow them to share in the decision making, and if they are given sufficient time to choose. To that end, the authors recommend a session dedicated to discussion of adjuvant therapy.
Communicating risk of death is challenging for many reasons. Patients should be asked how they would like to hear about their risks: some prefer general terms, while others may opt for numbers, charts, or graphs. The guidelines include a risk chart that can help patients understand the potential benefits and risks of chemotherapy.
The study authors report financial relationships with numerous pharmaceutical companies.
Adjuvant cisplatin-based chemotherapy is recommended for routine use in non–small cell lung cancer patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections, according to updated guidelines from the American Society of Clinical Oncology.
In patients with stage IA disease, the guidelines recommend against cisplatin-based chemotherapy. The new guidelines are based on a systematic review current to January 2016 and an American Society for Radiation Oncology guideline and systematic review, which ASCO had already endorsed, which formed the basis for recommendations on adjuvant radiation therapy, Mark G. Kris, MD, and panel authors said (J Clin Oncol. 2017 April 26. doi: 10.1200/JCO.2017.72.4401).
The guidelines, available online, also recommend against routine cisplatin-based chemotherapy in patients with stage IB disease, but they suggest an evaluation of these patients to explore the pros and cons of adjuvant chemotherapy.
With respect to radiation, the authors recommend against it for patients with resected stage I or stage II disease, and they recommend against it for routine use in patients with stage IIIA. However, in patients with IIIA N2 disease, patients should be evaluated postoperatively, in consultation with a medical oncologist, for the potential risks and benefits of adjuvant radiation.
The authors also provide some recommendations for communicating with patients regarding treatment decisions. There are few studies examining this question, so the recommendations are based on low-quality evidence.
Non–small cell lung cancer patients may have complex social, psychological, and medical issues, and discussions should be carried out with this in mind. Pain, impaired breathing, and fatigue are common after surgery, and smoking cessation can lead to short-term stress as a result of nicotine withdrawal. Older patients may have a range of comorbidities.
Studies show that patients are most satisfied if they feel that physicians allow them to share in the decision making, and if they are given sufficient time to choose. To that end, the authors recommend a session dedicated to discussion of adjuvant therapy.
Communicating risk of death is challenging for many reasons. Patients should be asked how they would like to hear about their risks: some prefer general terms, while others may opt for numbers, charts, or graphs. The guidelines include a risk chart that can help patients understand the potential benefits and risks of chemotherapy.
The study authors report financial relationships with numerous pharmaceutical companies.
Genomic Variation May Reveal ‘Biological Pathway’ to Obesity
African-Americans have the highest age-adjusted rates of obesity in the U.S. Now, an NIH study is offering clues to why that is.
Researchers from the National Human Genome Research Institute (NHGRI), University of Lagos, University of Nigeria, Kwame Nkumrah University of Science and Technology, University of Ghana, and University of Maryland collaborated in a study and found about 1 % of West Africans, African-Americans, and others of African ancestry carry a genomic variant that increases their risk of obesity. People with the genomic differences were about 6 pounds heavier than those without the variant.
This is the first study to use a Genome-Wide Association Study (GWAS) to investigate the genomic basis of obesity in continental Africans. Most previous studies on obesity using a GWAS have examined people of European ancestry. Those studies would not have found the genomic variant for the African descendants which is absent in Europeans and Asians. “We wanted to close this unacceptable gap in genomics research,” said Charles Rotimi, PhD, chief of NHGRI’s Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch and director of the NIH Center for Research on Genomics and Global Health.
“By studying people of West Africa, the ancestral home of most African-Americans, and replicating our results in a large group of African-Americans,” said Ayo Doumatey, PhD, study co-lead and CRGGH staff scientist, “we are providing new insights into biological pathways for obesity that have not been previously explored.”
African-Americans have the highest age-adjusted rates of obesity in the U.S. Now, an NIH study is offering clues to why that is.
Researchers from the National Human Genome Research Institute (NHGRI), University of Lagos, University of Nigeria, Kwame Nkumrah University of Science and Technology, University of Ghana, and University of Maryland collaborated in a study and found about 1 % of West Africans, African-Americans, and others of African ancestry carry a genomic variant that increases their risk of obesity. People with the genomic differences were about 6 pounds heavier than those without the variant.
This is the first study to use a Genome-Wide Association Study (GWAS) to investigate the genomic basis of obesity in continental Africans. Most previous studies on obesity using a GWAS have examined people of European ancestry. Those studies would not have found the genomic variant for the African descendants which is absent in Europeans and Asians. “We wanted to close this unacceptable gap in genomics research,” said Charles Rotimi, PhD, chief of NHGRI’s Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch and director of the NIH Center for Research on Genomics and Global Health.
“By studying people of West Africa, the ancestral home of most African-Americans, and replicating our results in a large group of African-Americans,” said Ayo Doumatey, PhD, study co-lead and CRGGH staff scientist, “we are providing new insights into biological pathways for obesity that have not been previously explored.”
African-Americans have the highest age-adjusted rates of obesity in the U.S. Now, an NIH study is offering clues to why that is.
Researchers from the National Human Genome Research Institute (NHGRI), University of Lagos, University of Nigeria, Kwame Nkumrah University of Science and Technology, University of Ghana, and University of Maryland collaborated in a study and found about 1 % of West Africans, African-Americans, and others of African ancestry carry a genomic variant that increases their risk of obesity. People with the genomic differences were about 6 pounds heavier than those without the variant.
This is the first study to use a Genome-Wide Association Study (GWAS) to investigate the genomic basis of obesity in continental Africans. Most previous studies on obesity using a GWAS have examined people of European ancestry. Those studies would not have found the genomic variant for the African descendants which is absent in Europeans and Asians. “We wanted to close this unacceptable gap in genomics research,” said Charles Rotimi, PhD, chief of NHGRI’s Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch and director of the NIH Center for Research on Genomics and Global Health.
“By studying people of West Africa, the ancestral home of most African-Americans, and replicating our results in a large group of African-Americans,” said Ayo Doumatey, PhD, study co-lead and CRGGH staff scientist, “we are providing new insights into biological pathways for obesity that have not been previously explored.”
Hospital infections top WHO’s list of priority pathogens
The World Health Organization is urging governments to focus antibiotic research efforts on a list of urgent bacterial threats, topped by several increasingly powerful superbugs that cause hospital-based infections and other potentially deadly conditions.
The WHO listed the top 20 bacteria that it believes are most harmful to human health, other than mycobacteria such as Mycobacterium tuberculosis, which causes tuberculosis. The germ was not included in the list because it’s generally accepted to be the most urgent priority for new antibiotic research and development, Marie-Paule Kieny, PhD, a WHO assistant director, said at a press conference.
The priority list is needed because the antibiotic pipeline is “practically dry,” thanks to scientific research challenges and a lack of financial incentives, according to Dr. Kieny. “Antibiotics are generally used for the short term, unlike therapies for chronic diseases, which bring in much higher returns on investment,” she said. The list “is intended to signal to the scientific community and the pharmaceutical industry the areas they should focus on to address urgent public health threats.”
The WHO list begins with Priority 1/“Critical” pathogens that it believes most urgently need to be targeted through antibiotic research and development: Acinetobacter baumannii, carbapenem-resistant; Pseudomonas aeruginosa, carbapenem-resistant; and Enterobacteriaceae (including Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., and Morganella spp.), carbapenem-resistant, extended-spectrum beta-lactamase–producing.
“These bacteria are responsible for severe infections and high mortality rates, mostly in hospitalized patients, transplant recipients, those receiving chemotherapy, or patients in intensive care units,” Dr. Kieny said. “While these bacteria are not widespread and do not generally affect healthy individuals, the burden for patients and society is now alarming – and new, effective therapies are imperative.”
Priority 2/”High” pathogens are Enterococcus faecium, vancomycin-resistant; Staphylococcus aureus, methicillin-resistant, vancomycin intermediate and resistant; Helicobacter pylori, clarithromycin-resistant; Campylobacter, fluoroquinolone-resistant; Salmonella spp., fluoroquinolone-resistant; Neisseria gonorrhoeae, third-generation cephalosporin-resistant and fluoroquinolone-resistant.
Pathogens in this category can infect healthy individuals, Dr. Kieny noted. “These infections, although not associated with significant mortality, have a dramatic health and economic impact on communities and, in particular, in low-income countries.”
Priority 3/”Medium” pathogens are Streptococcus pneumoniae, penicillin–non-susceptible; Haemophilus influenzae, ampicillin-resistant; and Shigella spp., fluoroquinolone-resistant.
These pathogens “represent a threat because of increasing resistance but still have some effective antibiotic options available,” Dr. Kieny said.
According to a statement provided by the WHO, the priority list doesn’t include streptococcus A and B or chlamydia, because resistance hasn’t reached the level of a public health threat.
One goal of the list is to focus attention on the development of small-market, gram-negative drugs that combat hospital-based infections, explained Nicola Magrini, MD, a WHO scientist who also spoke at the press conference.
Over the last decade, he said, the pipeline has instead focused more on gram-positive agents – mostly linked to beta-lactamase – that have wider market potential and generate less resistance.
“From a clinical point of view, these multidrug-resistant gram-negative clinical trials are very difficult and expensive to do, more than for gram-positive,” noted Evelina Tacconelli, MD, PhD, a contributor to the WHO report. “Because when we talk about gram-negative, we need to cover multiple pathogens and not just one or two, as in the case of gram-positive.”
Dr. Magrini said he couldn’t provide estimates about how many people worldwide are affected by the listed pathogens. However, he said a full report with numbers will be released by June.
It does appear that patients with severe infection from antibiotic-resistant germs face a mortality rate of up to 60%, while extended-spectrum beta-lactamase–positive E. coli accounts for up to 70% of urinary tract infections in many countries, explained Dr. Tacconelli, head of the division of infectious diseases at the University of Tübingen, Germany.
“Even if we don’t know exactly how many,” she said, “we are talking about millions of people affected.”
The World Health Organization is urging governments to focus antibiotic research efforts on a list of urgent bacterial threats, topped by several increasingly powerful superbugs that cause hospital-based infections and other potentially deadly conditions.
The WHO listed the top 20 bacteria that it believes are most harmful to human health, other than mycobacteria such as Mycobacterium tuberculosis, which causes tuberculosis. The germ was not included in the list because it’s generally accepted to be the most urgent priority for new antibiotic research and development, Marie-Paule Kieny, PhD, a WHO assistant director, said at a press conference.
The priority list is needed because the antibiotic pipeline is “practically dry,” thanks to scientific research challenges and a lack of financial incentives, according to Dr. Kieny. “Antibiotics are generally used for the short term, unlike therapies for chronic diseases, which bring in much higher returns on investment,” she said. The list “is intended to signal to the scientific community and the pharmaceutical industry the areas they should focus on to address urgent public health threats.”
The WHO list begins with Priority 1/“Critical” pathogens that it believes most urgently need to be targeted through antibiotic research and development: Acinetobacter baumannii, carbapenem-resistant; Pseudomonas aeruginosa, carbapenem-resistant; and Enterobacteriaceae (including Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., and Morganella spp.), carbapenem-resistant, extended-spectrum beta-lactamase–producing.
“These bacteria are responsible for severe infections and high mortality rates, mostly in hospitalized patients, transplant recipients, those receiving chemotherapy, or patients in intensive care units,” Dr. Kieny said. “While these bacteria are not widespread and do not generally affect healthy individuals, the burden for patients and society is now alarming – and new, effective therapies are imperative.”
Priority 2/”High” pathogens are Enterococcus faecium, vancomycin-resistant; Staphylococcus aureus, methicillin-resistant, vancomycin intermediate and resistant; Helicobacter pylori, clarithromycin-resistant; Campylobacter, fluoroquinolone-resistant; Salmonella spp., fluoroquinolone-resistant; Neisseria gonorrhoeae, third-generation cephalosporin-resistant and fluoroquinolone-resistant.
Pathogens in this category can infect healthy individuals, Dr. Kieny noted. “These infections, although not associated with significant mortality, have a dramatic health and economic impact on communities and, in particular, in low-income countries.”
Priority 3/”Medium” pathogens are Streptococcus pneumoniae, penicillin–non-susceptible; Haemophilus influenzae, ampicillin-resistant; and Shigella spp., fluoroquinolone-resistant.
These pathogens “represent a threat because of increasing resistance but still have some effective antibiotic options available,” Dr. Kieny said.
According to a statement provided by the WHO, the priority list doesn’t include streptococcus A and B or chlamydia, because resistance hasn’t reached the level of a public health threat.
One goal of the list is to focus attention on the development of small-market, gram-negative drugs that combat hospital-based infections, explained Nicola Magrini, MD, a WHO scientist who also spoke at the press conference.
Over the last decade, he said, the pipeline has instead focused more on gram-positive agents – mostly linked to beta-lactamase – that have wider market potential and generate less resistance.
“From a clinical point of view, these multidrug-resistant gram-negative clinical trials are very difficult and expensive to do, more than for gram-positive,” noted Evelina Tacconelli, MD, PhD, a contributor to the WHO report. “Because when we talk about gram-negative, we need to cover multiple pathogens and not just one or two, as in the case of gram-positive.”
Dr. Magrini said he couldn’t provide estimates about how many people worldwide are affected by the listed pathogens. However, he said a full report with numbers will be released by June.
It does appear that patients with severe infection from antibiotic-resistant germs face a mortality rate of up to 60%, while extended-spectrum beta-lactamase–positive E. coli accounts for up to 70% of urinary tract infections in many countries, explained Dr. Tacconelli, head of the division of infectious diseases at the University of Tübingen, Germany.
“Even if we don’t know exactly how many,” she said, “we are talking about millions of people affected.”
The World Health Organization is urging governments to focus antibiotic research efforts on a list of urgent bacterial threats, topped by several increasingly powerful superbugs that cause hospital-based infections and other potentially deadly conditions.
The WHO listed the top 20 bacteria that it believes are most harmful to human health, other than mycobacteria such as Mycobacterium tuberculosis, which causes tuberculosis. The germ was not included in the list because it’s generally accepted to be the most urgent priority for new antibiotic research and development, Marie-Paule Kieny, PhD, a WHO assistant director, said at a press conference.
The priority list is needed because the antibiotic pipeline is “practically dry,” thanks to scientific research challenges and a lack of financial incentives, according to Dr. Kieny. “Antibiotics are generally used for the short term, unlike therapies for chronic diseases, which bring in much higher returns on investment,” she said. The list “is intended to signal to the scientific community and the pharmaceutical industry the areas they should focus on to address urgent public health threats.”
The WHO list begins with Priority 1/“Critical” pathogens that it believes most urgently need to be targeted through antibiotic research and development: Acinetobacter baumannii, carbapenem-resistant; Pseudomonas aeruginosa, carbapenem-resistant; and Enterobacteriaceae (including Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., and Morganella spp.), carbapenem-resistant, extended-spectrum beta-lactamase–producing.
“These bacteria are responsible for severe infections and high mortality rates, mostly in hospitalized patients, transplant recipients, those receiving chemotherapy, or patients in intensive care units,” Dr. Kieny said. “While these bacteria are not widespread and do not generally affect healthy individuals, the burden for patients and society is now alarming – and new, effective therapies are imperative.”
Priority 2/”High” pathogens are Enterococcus faecium, vancomycin-resistant; Staphylococcus aureus, methicillin-resistant, vancomycin intermediate and resistant; Helicobacter pylori, clarithromycin-resistant; Campylobacter, fluoroquinolone-resistant; Salmonella spp., fluoroquinolone-resistant; Neisseria gonorrhoeae, third-generation cephalosporin-resistant and fluoroquinolone-resistant.
Pathogens in this category can infect healthy individuals, Dr. Kieny noted. “These infections, although not associated with significant mortality, have a dramatic health and economic impact on communities and, in particular, in low-income countries.”
Priority 3/”Medium” pathogens are Streptococcus pneumoniae, penicillin–non-susceptible; Haemophilus influenzae, ampicillin-resistant; and Shigella spp., fluoroquinolone-resistant.
These pathogens “represent a threat because of increasing resistance but still have some effective antibiotic options available,” Dr. Kieny said.
According to a statement provided by the WHO, the priority list doesn’t include streptococcus A and B or chlamydia, because resistance hasn’t reached the level of a public health threat.
One goal of the list is to focus attention on the development of small-market, gram-negative drugs that combat hospital-based infections, explained Nicola Magrini, MD, a WHO scientist who also spoke at the press conference.
Over the last decade, he said, the pipeline has instead focused more on gram-positive agents – mostly linked to beta-lactamase – that have wider market potential and generate less resistance.
“From a clinical point of view, these multidrug-resistant gram-negative clinical trials are very difficult and expensive to do, more than for gram-positive,” noted Evelina Tacconelli, MD, PhD, a contributor to the WHO report. “Because when we talk about gram-negative, we need to cover multiple pathogens and not just one or two, as in the case of gram-positive.”
Dr. Magrini said he couldn’t provide estimates about how many people worldwide are affected by the listed pathogens. However, he said a full report with numbers will be released by June.
It does appear that patients with severe infection from antibiotic-resistant germs face a mortality rate of up to 60%, while extended-spectrum beta-lactamase–positive E. coli accounts for up to 70% of urinary tract infections in many countries, explained Dr. Tacconelli, head of the division of infectious diseases at the University of Tübingen, Germany.
“Even if we don’t know exactly how many,” she said, “we are talking about millions of people affected.”
Vaccine for Respiratory Syncytial Virus Enters Phase 1 Testing
A vaccine against respiratory syncytial virus (RSV) is entering a phase 1 safety and tolerability trial. The vaccine developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID) is badly needed, according to Anthony Fauci, MD, director of NIAID. Although common and causing usually mild symptoms RSV infection also can lead to severe lower respiratory tract diseases, such as pneumonia and bronchiolitis in infants, children, the elderly, and immune-compromised patients. Globally, RSV infections cause upwards of 250,000 deaths each year. “RSV is underappreciated as a major cause of illness and death,” Fauci said.
The vaccine (DS-Cav1) will fill a void. Currently no vaccine is available to prevent RSV infection, and no drug is available to treat it. The monoclonal antibody palivizumab is approved for preventing lower respiratory tract disease caused by RSV in high-risk children, but is not approved for use in the general population.
The study, VRC 317, will enroll healthy adults aged 18 to 50. Participants will be assigned randomly to receive 2 injections 12 weeks apart with the investigational vaccine or the investigational vaccine with alum, a compound commonly added to vaccines to enhance the immune response.
Participants also will be randomly assigned to receive 1 of 3 doses (50, 150, or 500 μg) at both time points. To start, 5 people will receive the 50-µg dose. If they experience no serious adverse reactions attributable to the vaccine the other participants will be vaccinated with the higher doses.
The participants will return for 12 clinic visits over 44 weeks when researchers will conduct physical exams, collect blood samples, and test mucous samples to measure the immune response.
DS-Cav1 is the result of “years of research” at the Vaccine Research Center, the NIH says. Traditionally a vaccine is derived from a weakened or inactivated whole virus. By contrast, DS-Cav1 is a single, structurally engineered protein from the surface of RSV. Co-lead investigator Barney Graham, MD, PhD, deputy VRC director, says, “This work represents how new biological insights from basic research can lead to candidate vaccines for diseases of public health importance.”
A vaccine against respiratory syncytial virus (RSV) is entering a phase 1 safety and tolerability trial. The vaccine developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID) is badly needed, according to Anthony Fauci, MD, director of NIAID. Although common and causing usually mild symptoms RSV infection also can lead to severe lower respiratory tract diseases, such as pneumonia and bronchiolitis in infants, children, the elderly, and immune-compromised patients. Globally, RSV infections cause upwards of 250,000 deaths each year. “RSV is underappreciated as a major cause of illness and death,” Fauci said.
The vaccine (DS-Cav1) will fill a void. Currently no vaccine is available to prevent RSV infection, and no drug is available to treat it. The monoclonal antibody palivizumab is approved for preventing lower respiratory tract disease caused by RSV in high-risk children, but is not approved for use in the general population.
The study, VRC 317, will enroll healthy adults aged 18 to 50. Participants will be assigned randomly to receive 2 injections 12 weeks apart with the investigational vaccine or the investigational vaccine with alum, a compound commonly added to vaccines to enhance the immune response.
Participants also will be randomly assigned to receive 1 of 3 doses (50, 150, or 500 μg) at both time points. To start, 5 people will receive the 50-µg dose. If they experience no serious adverse reactions attributable to the vaccine the other participants will be vaccinated with the higher doses.
The participants will return for 12 clinic visits over 44 weeks when researchers will conduct physical exams, collect blood samples, and test mucous samples to measure the immune response.
DS-Cav1 is the result of “years of research” at the Vaccine Research Center, the NIH says. Traditionally a vaccine is derived from a weakened or inactivated whole virus. By contrast, DS-Cav1 is a single, structurally engineered protein from the surface of RSV. Co-lead investigator Barney Graham, MD, PhD, deputy VRC director, says, “This work represents how new biological insights from basic research can lead to candidate vaccines for diseases of public health importance.”
A vaccine against respiratory syncytial virus (RSV) is entering a phase 1 safety and tolerability trial. The vaccine developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID) is badly needed, according to Anthony Fauci, MD, director of NIAID. Although common and causing usually mild symptoms RSV infection also can lead to severe lower respiratory tract diseases, such as pneumonia and bronchiolitis in infants, children, the elderly, and immune-compromised patients. Globally, RSV infections cause upwards of 250,000 deaths each year. “RSV is underappreciated as a major cause of illness and death,” Fauci said.
The vaccine (DS-Cav1) will fill a void. Currently no vaccine is available to prevent RSV infection, and no drug is available to treat it. The monoclonal antibody palivizumab is approved for preventing lower respiratory tract disease caused by RSV in high-risk children, but is not approved for use in the general population.
The study, VRC 317, will enroll healthy adults aged 18 to 50. Participants will be assigned randomly to receive 2 injections 12 weeks apart with the investigational vaccine or the investigational vaccine with alum, a compound commonly added to vaccines to enhance the immune response.
Participants also will be randomly assigned to receive 1 of 3 doses (50, 150, or 500 μg) at both time points. To start, 5 people will receive the 50-µg dose. If they experience no serious adverse reactions attributable to the vaccine the other participants will be vaccinated with the higher doses.
The participants will return for 12 clinic visits over 44 weeks when researchers will conduct physical exams, collect blood samples, and test mucous samples to measure the immune response.
DS-Cav1 is the result of “years of research” at the Vaccine Research Center, the NIH says. Traditionally a vaccine is derived from a weakened or inactivated whole virus. By contrast, DS-Cav1 is a single, structurally engineered protein from the surface of RSV. Co-lead investigator Barney Graham, MD, PhD, deputy VRC director, says, “This work represents how new biological insights from basic research can lead to candidate vaccines for diseases of public health importance.”
In mantle cell lymphoma, triple therapy proves too toxic
Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.
The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD, of the University of Chicago and her colleagues said in The Lancet Haematology.
In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.
The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred (Lancet Haematol. 2017 Apr;4:e176-82).
Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.
Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.
“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.
The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.
“Both ... trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.
Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.
“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.
The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.
“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.
The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.
The findings by Dr. Smith and her colleagues add to several other reported studies that involved unexpected toxicities with various combinations of targeted agents in lymphoid malignancies.
Combinations of B-cell receptor signaling inhibitors can lead to immune dysregulation, which can be acute and severe when combined with immunomodulatory agents.
While the study of rational targeted combinations continues to hold immense potential in both untreated and relapsed/refractory disease, the combination must be thoroughly studied in the context of carefully and conservatively designed clinical trials.
Given the unpredictable nature of adverse events, the use of novel combinations outside of a clinical trial should be strongly discouraged.
Patrick M. Reagan, MD , and Paul M. Barr, MD , are with the James P. Wilmot Cancer Institute, University of Rochester, New York. Dr. Reagan reported having no disclosures. Dr. Barr has consulted for Gilead, Pharmacyclics, AbbVie, and Celgene. They made their remarks in an editorial that accompanied the article.
The findings by Dr. Smith and her colleagues add to several other reported studies that involved unexpected toxicities with various combinations of targeted agents in lymphoid malignancies.
Combinations of B-cell receptor signaling inhibitors can lead to immune dysregulation, which can be acute and severe when combined with immunomodulatory agents.
While the study of rational targeted combinations continues to hold immense potential in both untreated and relapsed/refractory disease, the combination must be thoroughly studied in the context of carefully and conservatively designed clinical trials.
Given the unpredictable nature of adverse events, the use of novel combinations outside of a clinical trial should be strongly discouraged.
Patrick M. Reagan, MD , and Paul M. Barr, MD , are with the James P. Wilmot Cancer Institute, University of Rochester, New York. Dr. Reagan reported having no disclosures. Dr. Barr has consulted for Gilead, Pharmacyclics, AbbVie, and Celgene. They made their remarks in an editorial that accompanied the article.
The findings by Dr. Smith and her colleagues add to several other reported studies that involved unexpected toxicities with various combinations of targeted agents in lymphoid malignancies.
Combinations of B-cell receptor signaling inhibitors can lead to immune dysregulation, which can be acute and severe when combined with immunomodulatory agents.
While the study of rational targeted combinations continues to hold immense potential in both untreated and relapsed/refractory disease, the combination must be thoroughly studied in the context of carefully and conservatively designed clinical trials.
Given the unpredictable nature of adverse events, the use of novel combinations outside of a clinical trial should be strongly discouraged.
Patrick M. Reagan, MD , and Paul M. Barr, MD , are with the James P. Wilmot Cancer Institute, University of Rochester, New York. Dr. Reagan reported having no disclosures. Dr. Barr has consulted for Gilead, Pharmacyclics, AbbVie, and Celgene. They made their remarks in an editorial that accompanied the article.
Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.
The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD, of the University of Chicago and her colleagues said in The Lancet Haematology.
In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.
The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred (Lancet Haematol. 2017 Apr;4:e176-82).
Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.
Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.
“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.
The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.
“Both ... trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.
Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.
“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.
The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.
“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.
The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.
Combined idelalisib, lenalidomide, and rituximab proved excessively toxic for the treatment of relapsed and refractory mantle cell and follicular lymphoma in two phase I trials conducted by the Alliance for Clinical Trials in Oncology.
The unexpected outcome, which led to early study termination, underscores the need for caution as new treatment combinations are proposed, Sonali M. Smith, MD, of the University of Chicago and her colleagues said in The Lancet Haematology.
In four of the first eight patients enrolled in the mantle cell lymphoma (A051201) and follicular lymphoma (A051202) phase I trials between July 9, 2013, and Sept. 30, 2014, unexpected dose-limiting toxicities occurred, including grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash.
The adverse events occurred between 9 and 20 days after treatment initiation and coincided with rituximab infusions, the researchers said. No treatment-related deaths occurred (Lancet Haematol. 2017 Apr;4:e176-82).
Overall, 8 of 11 patients were removed from treatment because of an adverse event, and 3 of those required intensive care unit level of care.
Although rituximab was removed in both trials, two of the remaining three patients in the studies, including three with mantle cell lymphoma and eight with follicular lymphoma, experienced grade 3 rashes, and one had grade 3 AST elevations. In those with mantle cell lymphoma, the most common grade 3-4 adverse events were ALT elevations and rash. In those with follicular lymphoma, the most common grade 3-4 adverse events were neutropenia and rash.
“Given the inability to deliver treatment due to toxicity, both studies were permanently closed,” the researchers wrote, noting that the primary endpoint of safety and tolerability was not met.
The trials had the overall goal of developing targeted regimens to replace cytotoxic therapy.
“Both ... trials were designed to capitalize on the clinical synergy of lenalidomide and rituximab observed in previous trials by adding the highly specific PI3K delta inhibitor, idelalisib, for patients with relapsed mantle cell lymphoma and follicular lymphoma,” they said.
Previously available data implied that lenalidomide plus rituximab would be a safe backbone for therapy, and there was clinical rationale for adding idelalisib to that combination, they explained.
“Overall, our brief experience underscores the limited knowledge regarding drug interactions and off-target effects and serves as a cautionary note in developing biological agents in combination and against ad-hoc combinations outside of carefully monitored clinical trials,” they said.
The researchers noted that the nature of the toxicities observed in these trials supports an immune-activated state characterized by excessive inflammation.
“A more detailed assessment of effect on cytokines, T-cell subsets, natural killer cells, and clinical features predictive of toxicity and response should be included in any further testing of these classes of agents, and they should never be combined outside of a carefully designed and diligently monitored clinical trial setting,” they concluded.
The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.
Key clinical point:
Major finding: Of 11 patients, 8 were removed from treatment because of an adverse event, and 3 of those required intensive care unit–level care.
Data source: Two phase I trials involving 11 patients.
Disclosures: The study was funded by the National Cancer Institute. Dr. Smith received research funding and consulting fees from Gilead and Celgene.
New guideline: Address GTCS frequency to reduce SUDEP risk
BOSTON – Generalized tonic-clonic seizures (GTCS) are a major risk factor for sudden unexpected death in epilepsy (SUDEP), which underscores the importance of advising people with epilepsy about controlling such seizures, according to a new practice guideline from the American Academy of Neurology and the American Epilepsy Society.
Though SUDEP is rare, with an incidence rate of 0.22/1,000 patient-years in children with epilepsy and 1.2/1,000 patient-years in adults with epilepsy, the guideline committee found that people with three or more GTCS per year are 15 times more likely to die suddenly than are those without this seizure type. The risk increases with increasing GTCS frequency. This translates to an absolute risk of up to 18 deaths per 1,000 patient-years for people with epilepsy who have frequent GTCS.
Specifically, the guideline recommends that , she said, adding that the guideline shows that “being free of seizures, particularly tonic-clonic seizures, is strongly associated with a decreased risk.”
Guideline coauthor, Elizabeth Donner, MD, added that, for this reason, the guideline recommends “that health professionals work with people who continue to have, specifically, these kind of seizures to try and reduce them with medications or with epilepsy surgery, actively weighing the risks and benefits of any new approach to seizure management.”
The recommendations are based on moderate (Level B) evidence.
The team also looked at numerous other risk factors for SUDEP and found that the strength of the evidence was too weak to support additional recommendations, said Dr. Donner, director of the comprehensive epilepsy program at The Hospital for Sick Children in Toronto and chair of the American Epilepsy Society SUDEP Task Force.
“More research is now needed to identify other preventable risk factors for SUDEP so that we can focus future studies on finding ways to reduce how often SUDEP occurs,” she added.
While the message regarding the importance of reducing seizure frequency is not new, it is important that this message be reiterated in the context of SUDEP, Dr. Donner said.
“It’s very important for it to be clear that the risk of frequent generalized tonic-clonic seizures – and we’re not talking about really frequent here; we’re talking about significant increased risk of death with only three per year – is not related only to maintaining a driver’s license, maintaining work, or other outcomes like that. It’s actually related to risk of death,” she said, noting that she hopes this is a motivator for pursuing treatments beyond medication when medication isn’t successful for treating seizures.
The guideline, which is endorsed by the International Child Neurology Association, is available online and in print (Neurology. 2017;88:1674–80).
Dr. Harden receives royalties from Wiley and Up-to-Date. Dr. Donner has received research support from the Canadian Institutes of Health Research, Dravet Canada, and SUDEP Aware. Other guideline authors reported numerous disclosures, including many industry sources.
BOSTON – Generalized tonic-clonic seizures (GTCS) are a major risk factor for sudden unexpected death in epilepsy (SUDEP), which underscores the importance of advising people with epilepsy about controlling such seizures, according to a new practice guideline from the American Academy of Neurology and the American Epilepsy Society.
Though SUDEP is rare, with an incidence rate of 0.22/1,000 patient-years in children with epilepsy and 1.2/1,000 patient-years in adults with epilepsy, the guideline committee found that people with three or more GTCS per year are 15 times more likely to die suddenly than are those without this seizure type. The risk increases with increasing GTCS frequency. This translates to an absolute risk of up to 18 deaths per 1,000 patient-years for people with epilepsy who have frequent GTCS.
Specifically, the guideline recommends that , she said, adding that the guideline shows that “being free of seizures, particularly tonic-clonic seizures, is strongly associated with a decreased risk.”
Guideline coauthor, Elizabeth Donner, MD, added that, for this reason, the guideline recommends “that health professionals work with people who continue to have, specifically, these kind of seizures to try and reduce them with medications or with epilepsy surgery, actively weighing the risks and benefits of any new approach to seizure management.”
The recommendations are based on moderate (Level B) evidence.
The team also looked at numerous other risk factors for SUDEP and found that the strength of the evidence was too weak to support additional recommendations, said Dr. Donner, director of the comprehensive epilepsy program at The Hospital for Sick Children in Toronto and chair of the American Epilepsy Society SUDEP Task Force.
“More research is now needed to identify other preventable risk factors for SUDEP so that we can focus future studies on finding ways to reduce how often SUDEP occurs,” she added.
While the message regarding the importance of reducing seizure frequency is not new, it is important that this message be reiterated in the context of SUDEP, Dr. Donner said.
“It’s very important for it to be clear that the risk of frequent generalized tonic-clonic seizures – and we’re not talking about really frequent here; we’re talking about significant increased risk of death with only three per year – is not related only to maintaining a driver’s license, maintaining work, or other outcomes like that. It’s actually related to risk of death,” she said, noting that she hopes this is a motivator for pursuing treatments beyond medication when medication isn’t successful for treating seizures.
The guideline, which is endorsed by the International Child Neurology Association, is available online and in print (Neurology. 2017;88:1674–80).
Dr. Harden receives royalties from Wiley and Up-to-Date. Dr. Donner has received research support from the Canadian Institutes of Health Research, Dravet Canada, and SUDEP Aware. Other guideline authors reported numerous disclosures, including many industry sources.
BOSTON – Generalized tonic-clonic seizures (GTCS) are a major risk factor for sudden unexpected death in epilepsy (SUDEP), which underscores the importance of advising people with epilepsy about controlling such seizures, according to a new practice guideline from the American Academy of Neurology and the American Epilepsy Society.
Though SUDEP is rare, with an incidence rate of 0.22/1,000 patient-years in children with epilepsy and 1.2/1,000 patient-years in adults with epilepsy, the guideline committee found that people with three or more GTCS per year are 15 times more likely to die suddenly than are those without this seizure type. The risk increases with increasing GTCS frequency. This translates to an absolute risk of up to 18 deaths per 1,000 patient-years for people with epilepsy who have frequent GTCS.
Specifically, the guideline recommends that , she said, adding that the guideline shows that “being free of seizures, particularly tonic-clonic seizures, is strongly associated with a decreased risk.”
Guideline coauthor, Elizabeth Donner, MD, added that, for this reason, the guideline recommends “that health professionals work with people who continue to have, specifically, these kind of seizures to try and reduce them with medications or with epilepsy surgery, actively weighing the risks and benefits of any new approach to seizure management.”
The recommendations are based on moderate (Level B) evidence.
The team also looked at numerous other risk factors for SUDEP and found that the strength of the evidence was too weak to support additional recommendations, said Dr. Donner, director of the comprehensive epilepsy program at The Hospital for Sick Children in Toronto and chair of the American Epilepsy Society SUDEP Task Force.
“More research is now needed to identify other preventable risk factors for SUDEP so that we can focus future studies on finding ways to reduce how often SUDEP occurs,” she added.
While the message regarding the importance of reducing seizure frequency is not new, it is important that this message be reiterated in the context of SUDEP, Dr. Donner said.
“It’s very important for it to be clear that the risk of frequent generalized tonic-clonic seizures – and we’re not talking about really frequent here; we’re talking about significant increased risk of death with only three per year – is not related only to maintaining a driver’s license, maintaining work, or other outcomes like that. It’s actually related to risk of death,” she said, noting that she hopes this is a motivator for pursuing treatments beyond medication when medication isn’t successful for treating seizures.
The guideline, which is endorsed by the International Child Neurology Association, is available online and in print (Neurology. 2017;88:1674–80).
Dr. Harden receives royalties from Wiley and Up-to-Date. Dr. Donner has received research support from the Canadian Institutes of Health Research, Dravet Canada, and SUDEP Aware. Other guideline authors reported numerous disclosures, including many industry sources.
AT AAN 2017
Prognostic tool may allow tailored therapy for Hodgkin lymphoma
A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score (CHIPS), may allow better tailoring of therapy at the time of diagnosis for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Researchers in the Children’s Oncology Group first assessed 562 patients receiving uniform standard treatment to identify which risk factors present at diagnosis best predicted response to therapy, and used them to develop the prognostic score. They considered such factors as patient age, the number of involved sites, hemoglobin level, albumin level, erythrocyte sedimentation rate, the presence or absence of a large mediastinal mass, nodal involvement, the total bulk of disease, and the presence or absence of B symptoms (fever, weight loss, and/or night sweats). The final CHIPS prognostic tool included four predictors of poor event-free survival that are easily ascertained at diagnosis: stage IV disease, a large mediastinal mass (one with a tumor to thoracic diameter ratio over 0.33), the presence of fever, and hypoalbuminemia (a level of less than 3.5 g/dL).
The investigators then confirmed the accuracy of that score in a validation cohort of 541 patients from the United States, Canada, Switzerland, Australia, New Zealand, the Netherlands, and Israel. All the study participants received four cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) with prednisone and cyclophosphamide (PC), followed by involved-field radiation therapy, said Cindy L. Schwartz, MD, of the division of pediatrics, University of Texas MD Anderson Cancer Center, Houston, and her associates.
Patients who had low a CHIPS of 0 or 1 had excellent 4-year event-free survival (93% and 89%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (78% and 69%, respectively). These findings remained consistent across all subgroups of patients, regardless of whether the tumors had nodular sclerosis histology or mixed cellular histology (Pediatr Blood Cancer. 2017 Apr;64[4]).
The study results suggest that patients with CHIPS 2 or 3 could be considered for high-risk Hodgkin lymphoma treatment such as higher-dose cyclophosphamide or the addition of brentuximab vedotin, while those with a CHIPS 0 or 1 could be considered for less aggressive treatment such as foregoing or reducing radiation therapy, Dr. Schwartz and her associates said.
This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score (CHIPS), may allow better tailoring of therapy at the time of diagnosis for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Researchers in the Children’s Oncology Group first assessed 562 patients receiving uniform standard treatment to identify which risk factors present at diagnosis best predicted response to therapy, and used them to develop the prognostic score. They considered such factors as patient age, the number of involved sites, hemoglobin level, albumin level, erythrocyte sedimentation rate, the presence or absence of a large mediastinal mass, nodal involvement, the total bulk of disease, and the presence or absence of B symptoms (fever, weight loss, and/or night sweats). The final CHIPS prognostic tool included four predictors of poor event-free survival that are easily ascertained at diagnosis: stage IV disease, a large mediastinal mass (one with a tumor to thoracic diameter ratio over 0.33), the presence of fever, and hypoalbuminemia (a level of less than 3.5 g/dL).
The investigators then confirmed the accuracy of that score in a validation cohort of 541 patients from the United States, Canada, Switzerland, Australia, New Zealand, the Netherlands, and Israel. All the study participants received four cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) with prednisone and cyclophosphamide (PC), followed by involved-field radiation therapy, said Cindy L. Schwartz, MD, of the division of pediatrics, University of Texas MD Anderson Cancer Center, Houston, and her associates.
Patients who had low a CHIPS of 0 or 1 had excellent 4-year event-free survival (93% and 89%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (78% and 69%, respectively). These findings remained consistent across all subgroups of patients, regardless of whether the tumors had nodular sclerosis histology or mixed cellular histology (Pediatr Blood Cancer. 2017 Apr;64[4]).
The study results suggest that patients with CHIPS 2 or 3 could be considered for high-risk Hodgkin lymphoma treatment such as higher-dose cyclophosphamide or the addition of brentuximab vedotin, while those with a CHIPS 0 or 1 could be considered for less aggressive treatment such as foregoing or reducing radiation therapy, Dr. Schwartz and her associates said.
This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score (CHIPS), may allow better tailoring of therapy at the time of diagnosis for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Researchers in the Children’s Oncology Group first assessed 562 patients receiving uniform standard treatment to identify which risk factors present at diagnosis best predicted response to therapy, and used them to develop the prognostic score. They considered such factors as patient age, the number of involved sites, hemoglobin level, albumin level, erythrocyte sedimentation rate, the presence or absence of a large mediastinal mass, nodal involvement, the total bulk of disease, and the presence or absence of B symptoms (fever, weight loss, and/or night sweats). The final CHIPS prognostic tool included four predictors of poor event-free survival that are easily ascertained at diagnosis: stage IV disease, a large mediastinal mass (one with a tumor to thoracic diameter ratio over 0.33), the presence of fever, and hypoalbuminemia (a level of less than 3.5 g/dL).
The investigators then confirmed the accuracy of that score in a validation cohort of 541 patients from the United States, Canada, Switzerland, Australia, New Zealand, the Netherlands, and Israel. All the study participants received four cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) with prednisone and cyclophosphamide (PC), followed by involved-field radiation therapy, said Cindy L. Schwartz, MD, of the division of pediatrics, University of Texas MD Anderson Cancer Center, Houston, and her associates.
Patients who had low a CHIPS of 0 or 1 had excellent 4-year event-free survival (93% and 89%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (78% and 69%, respectively). These findings remained consistent across all subgroups of patients, regardless of whether the tumors had nodular sclerosis histology or mixed cellular histology (Pediatr Blood Cancer. 2017 Apr;64[4]).
The study results suggest that patients with CHIPS 2 or 3 could be considered for high-risk Hodgkin lymphoma treatment such as higher-dose cyclophosphamide or the addition of brentuximab vedotin, while those with a CHIPS 0 or 1 could be considered for less aggressive treatment such as foregoing or reducing radiation therapy, Dr. Schwartz and her associates said.
This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
Key clinical point: A newly developed “robust and inexpensive” prognostic tool, the Childhood Hodgkin International Prognostic Score, or CHIPS, may allow more tailored therapy for children and adolescents who have intermediate-risk Hodgkin lymphoma.
Major finding: Patients who had a low CHIPS of 0 or 1 had excellent 4-year event-free survival (93.1% and 88.5%, respectively), while patients with a high CHIPS of 2 or 3 had poorer 4-year event-free survival (77.6% and 69.2%).
Data source: A cohort study to develop (in 562 patients) and validate (in 541 patients) a score for predicting the response to standard treatment in pediatric Hodgkin lymphoma.
Disclosures: This study was supported by a grant from the National Cancer Institute to the Children’s Oncology Group. Dr. Schwartz and her associates reported having no relevant financial disclosures.
FDA warns against use of codeine, tramadol in children
The Food and Drug Administration is restricting the use of two opiates – codeine and tramadol – in children, and also warns they are potentially dangerous to infants of breastfeeding women.
Codeine is approved to treat pain and cough; tramadol is approved to treat pain.
“We understand that there are limited options when it comes to treating pain or cough in children, and that these changes may raise some questions for health care providers and parents. However, please know that our decision today was made based on the latest evidence and with this goal in mind: keeping our kids safe,” Douglas Throckmorton, MD, the deputy center director for regulatory programs at the FDA Center for Drug Evaluation and Research, said in a statement.
In 2013, the FDA updated prescription codeine labeling to contain a boxed warning and contraindication for children up to age 18 years regarding the risk of slowed breathing from codeine prescribed after tonsillectomy and/or adenoidectomy. And in 2015, the agency issued warnings about the risk of serious breathing problems in children who had ultrarapid metabolism of codeine and tramadol.
In the current safety statement, the FDA said it will require additional labeling changes, including contraindications for use of codeine or tramadol in all children younger than 12 years of age and a new contraindication for tramadol in children younger than 18 years being treated for pain after tonsillectomy and/or adenoidectomy, warnings about their use in children 12-18 years of age with certain medical conditions, and a stronger warning recommending against their use in nursing mothers.
Single-ingredient codeine and all tramadol-containing products are FDA-approved only for use in adults, the agency noted.
The agency cited particular concerns over those who are “ultra-rapid metabolizers” of substrates of the cytochrome P450 isoenzyme 2D6 (CYP2D6) genotype. These people more quickly convert codeine into potentially dangerously high levels of morphine, which can lead to fatal respiratory depression.
Supporting the restrictions and warning were data on 64 cases of respiratory depression that occurred worldwide between 1969 and 2015, when a codeine-based medicine was used in children younger than 18 years. Twenty-four of these children died.
The most frequently cited medicines in the cases were acetaminophen with codeine and promethazine with codeine with or without phenylephrine, either given to soothe postoperative pain, general pain, sore or strep throat pain, or cough and cold.
Ten of the 64 cases implicated the CYP2D6 genotype. Seven of the patients were “ultrarapid metabolizers,” five of whom died.
Data cited on tramadol included nine worldwide cases of tramadol-related respiratory depression occurring between 1969 and 2016, resulting in the deaths of three children, all under the age of 6 years, and all of whom were taking the drug for postoperative pain or fever.
All but one case of respiratory depression occurred within the first 24 hours of taking the drug. One of the patients was genotyped for CYP2D6, and found to have three functional alleles consistent with ultrarapid metabolism.
Mothers who are ultrarapid metabolizers of codeine can have high levels of morphine in their breast milk that are dangerous to their breastfed infants, whereas there is less of a threat posed by women with normal codeine metabolism because the amount of codeine secreted into the breast milk is low and dose dependent.
The FDA stated that data reveal numerous reports of respiratory depression and at least one death in infants of breastfeeding mothers taking these medicines, particularly mothers with the CYP2D6 genotype. Although there are FDA-cleared tests for ultrarapid metabolism, they are not commonly used.
The agency stated that breastfeeding women taking any opioid pain medicine, including codeine or tramadol should contact their health care provider if they notice the infant is sleeping more than 4 hours at a time, or if the infant is having difficulty breastfeeding or seems limp.
Clinicians are urged to report side effects that occur while using codeine or tramadol to the FDA’s MedWatch Adverse Event Reporting program.
The Food and Drug Administration is restricting the use of two opiates – codeine and tramadol – in children, and also warns they are potentially dangerous to infants of breastfeeding women.
Codeine is approved to treat pain and cough; tramadol is approved to treat pain.
“We understand that there are limited options when it comes to treating pain or cough in children, and that these changes may raise some questions for health care providers and parents. However, please know that our decision today was made based on the latest evidence and with this goal in mind: keeping our kids safe,” Douglas Throckmorton, MD, the deputy center director for regulatory programs at the FDA Center for Drug Evaluation and Research, said in a statement.
In 2013, the FDA updated prescription codeine labeling to contain a boxed warning and contraindication for children up to age 18 years regarding the risk of slowed breathing from codeine prescribed after tonsillectomy and/or adenoidectomy. And in 2015, the agency issued warnings about the risk of serious breathing problems in children who had ultrarapid metabolism of codeine and tramadol.
In the current safety statement, the FDA said it will require additional labeling changes, including contraindications for use of codeine or tramadol in all children younger than 12 years of age and a new contraindication for tramadol in children younger than 18 years being treated for pain after tonsillectomy and/or adenoidectomy, warnings about their use in children 12-18 years of age with certain medical conditions, and a stronger warning recommending against their use in nursing mothers.
Single-ingredient codeine and all tramadol-containing products are FDA-approved only for use in adults, the agency noted.
The agency cited particular concerns over those who are “ultra-rapid metabolizers” of substrates of the cytochrome P450 isoenzyme 2D6 (CYP2D6) genotype. These people more quickly convert codeine into potentially dangerously high levels of morphine, which can lead to fatal respiratory depression.
Supporting the restrictions and warning were data on 64 cases of respiratory depression that occurred worldwide between 1969 and 2015, when a codeine-based medicine was used in children younger than 18 years. Twenty-four of these children died.
The most frequently cited medicines in the cases were acetaminophen with codeine and promethazine with codeine with or without phenylephrine, either given to soothe postoperative pain, general pain, sore or strep throat pain, or cough and cold.
Ten of the 64 cases implicated the CYP2D6 genotype. Seven of the patients were “ultrarapid metabolizers,” five of whom died.
Data cited on tramadol included nine worldwide cases of tramadol-related respiratory depression occurring between 1969 and 2016, resulting in the deaths of three children, all under the age of 6 years, and all of whom were taking the drug for postoperative pain or fever.
All but one case of respiratory depression occurred within the first 24 hours of taking the drug. One of the patients was genotyped for CYP2D6, and found to have three functional alleles consistent with ultrarapid metabolism.
Mothers who are ultrarapid metabolizers of codeine can have high levels of morphine in their breast milk that are dangerous to their breastfed infants, whereas there is less of a threat posed by women with normal codeine metabolism because the amount of codeine secreted into the breast milk is low and dose dependent.
The FDA stated that data reveal numerous reports of respiratory depression and at least one death in infants of breastfeeding mothers taking these medicines, particularly mothers with the CYP2D6 genotype. Although there are FDA-cleared tests for ultrarapid metabolism, they are not commonly used.
The agency stated that breastfeeding women taking any opioid pain medicine, including codeine or tramadol should contact their health care provider if they notice the infant is sleeping more than 4 hours at a time, or if the infant is having difficulty breastfeeding or seems limp.
Clinicians are urged to report side effects that occur while using codeine or tramadol to the FDA’s MedWatch Adverse Event Reporting program.
The Food and Drug Administration is restricting the use of two opiates – codeine and tramadol – in children, and also warns they are potentially dangerous to infants of breastfeeding women.
Codeine is approved to treat pain and cough; tramadol is approved to treat pain.
“We understand that there are limited options when it comes to treating pain or cough in children, and that these changes may raise some questions for health care providers and parents. However, please know that our decision today was made based on the latest evidence and with this goal in mind: keeping our kids safe,” Douglas Throckmorton, MD, the deputy center director for regulatory programs at the FDA Center for Drug Evaluation and Research, said in a statement.
In 2013, the FDA updated prescription codeine labeling to contain a boxed warning and contraindication for children up to age 18 years regarding the risk of slowed breathing from codeine prescribed after tonsillectomy and/or adenoidectomy. And in 2015, the agency issued warnings about the risk of serious breathing problems in children who had ultrarapid metabolism of codeine and tramadol.
In the current safety statement, the FDA said it will require additional labeling changes, including contraindications for use of codeine or tramadol in all children younger than 12 years of age and a new contraindication for tramadol in children younger than 18 years being treated for pain after tonsillectomy and/or adenoidectomy, warnings about their use in children 12-18 years of age with certain medical conditions, and a stronger warning recommending against their use in nursing mothers.
Single-ingredient codeine and all tramadol-containing products are FDA-approved only for use in adults, the agency noted.
The agency cited particular concerns over those who are “ultra-rapid metabolizers” of substrates of the cytochrome P450 isoenzyme 2D6 (CYP2D6) genotype. These people more quickly convert codeine into potentially dangerously high levels of morphine, which can lead to fatal respiratory depression.
Supporting the restrictions and warning were data on 64 cases of respiratory depression that occurred worldwide between 1969 and 2015, when a codeine-based medicine was used in children younger than 18 years. Twenty-four of these children died.
The most frequently cited medicines in the cases were acetaminophen with codeine and promethazine with codeine with or without phenylephrine, either given to soothe postoperative pain, general pain, sore or strep throat pain, or cough and cold.
Ten of the 64 cases implicated the CYP2D6 genotype. Seven of the patients were “ultrarapid metabolizers,” five of whom died.
Data cited on tramadol included nine worldwide cases of tramadol-related respiratory depression occurring between 1969 and 2016, resulting in the deaths of three children, all under the age of 6 years, and all of whom were taking the drug for postoperative pain or fever.
All but one case of respiratory depression occurred within the first 24 hours of taking the drug. One of the patients was genotyped for CYP2D6, and found to have three functional alleles consistent with ultrarapid metabolism.
Mothers who are ultrarapid metabolizers of codeine can have high levels of morphine in their breast milk that are dangerous to their breastfed infants, whereas there is less of a threat posed by women with normal codeine metabolism because the amount of codeine secreted into the breast milk is low and dose dependent.
The FDA stated that data reveal numerous reports of respiratory depression and at least one death in infants of breastfeeding mothers taking these medicines, particularly mothers with the CYP2D6 genotype. Although there are FDA-cleared tests for ultrarapid metabolism, they are not commonly used.
The agency stated that breastfeeding women taking any opioid pain medicine, including codeine or tramadol should contact their health care provider if they notice the infant is sleeping more than 4 hours at a time, or if the infant is having difficulty breastfeeding or seems limp.
Clinicians are urged to report side effects that occur while using codeine or tramadol to the FDA’s MedWatch Adverse Event Reporting program.
Thousands expected to get CAR T-cells by 2018
NEW YORK – Should the first chimeric antigen receptor (CAR) T-cell treatment receive Food and Drug Administration approval for refractory, aggressive non-Hodgkin lymphoma, possibly before the end of 2017, several thousand U.S. patients will be potential candidates for the treatment, Jeremy S. Abramson, MD, predicted at a conference held by Imedex.
Dr. Abramson has led studies using a CAR T cell that differs from the one furthest along in development. He based his predicted timetable for an approved biologics license of the process, with which he can engineer patient-specific T cells that are under development by Kite Pharma, on the “remarkable” level of complete responses the intervention produced in a pivotal phase II study.
“Seeing a complete response rate of close to 40% that is sustained for more than 3 months and a complete response rate of close to a third at 6 months is light years beyond what is now available for patients” with these chemotherapy refractory B-cell lymphomas, said Dr. Abramson, clinical director of the Center for Lymphoma at Massachusetts General Hospital in Boston. “This is the first treatment to show a significant impact on large B-cell lymphoma, and that makes me optimistic” that the FDA will grant license approval later in 2017, he said in an interview.
Dr. Abramson acknowledged that some patients developed grade 3 or 4 cytokine-release syndrome and neurologic events, but the events were reversible and manageable if treated with the immunosuppressant tocilizumab (Actemra) or a corticosteroid.
At the end of March, Kite reported the completion of its FDA application, and, on April 2, the ZUMA-1 investigators presented an updated report on their results, with a 36% complete response rate across all enrolled patients at 6 month follow-up and a 39% complete response rate in all patients out to a median follow-up of 8.7 months.
Annually, in U.S. practice, perhaps 3,000 new patients with diffuse large B-cell lymphoma would meet the enrollment criteria for ZUMA-1, Dr. Abramson estimated. Once axicabtagene ciloleucel becomes commercially available in the United States, several thousand U.S. patients might initially seek the treatment.
Dr. Abramson has been a consultant to Kite Pharma and to AbbVie, Genentech, Gilead, and Seattle Genetics.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
NEW YORK – Should the first chimeric antigen receptor (CAR) T-cell treatment receive Food and Drug Administration approval for refractory, aggressive non-Hodgkin lymphoma, possibly before the end of 2017, several thousand U.S. patients will be potential candidates for the treatment, Jeremy S. Abramson, MD, predicted at a conference held by Imedex.
Dr. Abramson has led studies using a CAR T cell that differs from the one furthest along in development. He based his predicted timetable for an approved biologics license of the process, with which he can engineer patient-specific T cells that are under development by Kite Pharma, on the “remarkable” level of complete responses the intervention produced in a pivotal phase II study.
“Seeing a complete response rate of close to 40% that is sustained for more than 3 months and a complete response rate of close to a third at 6 months is light years beyond what is now available for patients” with these chemotherapy refractory B-cell lymphomas, said Dr. Abramson, clinical director of the Center for Lymphoma at Massachusetts General Hospital in Boston. “This is the first treatment to show a significant impact on large B-cell lymphoma, and that makes me optimistic” that the FDA will grant license approval later in 2017, he said in an interview.
Dr. Abramson acknowledged that some patients developed grade 3 or 4 cytokine-release syndrome and neurologic events, but the events were reversible and manageable if treated with the immunosuppressant tocilizumab (Actemra) or a corticosteroid.
At the end of March, Kite reported the completion of its FDA application, and, on April 2, the ZUMA-1 investigators presented an updated report on their results, with a 36% complete response rate across all enrolled patients at 6 month follow-up and a 39% complete response rate in all patients out to a median follow-up of 8.7 months.
Annually, in U.S. practice, perhaps 3,000 new patients with diffuse large B-cell lymphoma would meet the enrollment criteria for ZUMA-1, Dr. Abramson estimated. Once axicabtagene ciloleucel becomes commercially available in the United States, several thousand U.S. patients might initially seek the treatment.
Dr. Abramson has been a consultant to Kite Pharma and to AbbVie, Genentech, Gilead, and Seattle Genetics.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
NEW YORK – Should the first chimeric antigen receptor (CAR) T-cell treatment receive Food and Drug Administration approval for refractory, aggressive non-Hodgkin lymphoma, possibly before the end of 2017, several thousand U.S. patients will be potential candidates for the treatment, Jeremy S. Abramson, MD, predicted at a conference held by Imedex.
Dr. Abramson has led studies using a CAR T cell that differs from the one furthest along in development. He based his predicted timetable for an approved biologics license of the process, with which he can engineer patient-specific T cells that are under development by Kite Pharma, on the “remarkable” level of complete responses the intervention produced in a pivotal phase II study.
“Seeing a complete response rate of close to 40% that is sustained for more than 3 months and a complete response rate of close to a third at 6 months is light years beyond what is now available for patients” with these chemotherapy refractory B-cell lymphomas, said Dr. Abramson, clinical director of the Center for Lymphoma at Massachusetts General Hospital in Boston. “This is the first treatment to show a significant impact on large B-cell lymphoma, and that makes me optimistic” that the FDA will grant license approval later in 2017, he said in an interview.
Dr. Abramson acknowledged that some patients developed grade 3 or 4 cytokine-release syndrome and neurologic events, but the events were reversible and manageable if treated with the immunosuppressant tocilizumab (Actemra) or a corticosteroid.
At the end of March, Kite reported the completion of its FDA application, and, on April 2, the ZUMA-1 investigators presented an updated report on their results, with a 36% complete response rate across all enrolled patients at 6 month follow-up and a 39% complete response rate in all patients out to a median follow-up of 8.7 months.
Annually, in U.S. practice, perhaps 3,000 new patients with diffuse large B-cell lymphoma would meet the enrollment criteria for ZUMA-1, Dr. Abramson estimated. Once axicabtagene ciloleucel becomes commercially available in the United States, several thousand U.S. patients might initially seek the treatment.
Dr. Abramson has been a consultant to Kite Pharma and to AbbVie, Genentech, Gilead, and Seattle Genetics.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM A MEETING ON HEMATOLOGIC MALIGNANCIES