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Prescribe antibiotics wisely
Clinical question: What is the incidence of antibiotic-associated adverse drug events (ADEs) among adult inpatients?
Background: Antibiotics are used widely in the inpatient setting, although 20%-30% of inpatient antibiotic prescription are estimated to be unnecessary. Data are lacking on the rates of associated ADEs.
Study design: Retrospective cohort study.
Synopsis: Of the 5,579 patients admitted to four inpatient medicine services between September 2013 and June 2014, 1,488 (27%) received antibiotics for at least 24 hours. Patients were followed through admission and out to 90 days. A total of 324 unique antibiotic-associated ADEs occurred among 298 (20%) patients within 90 days of initial therapy. The overall rate of antibiotic-associated ADEs was 22.9/10,000 person-days. The investigators determined that 287 (19%) of antibiotic regimens were not clinically indicated, and among those, there were 56 (20%) ADEs. The most common 30-day ADEs were gastrointestinal, renal, and hematologic. The highest proportion of ADEs occurred with beta-lactams, fluoroquinolones, intravenous vancomycin, and trimethoprim-sulfamethoxazole, perhaps reflecting how commonly these agents are prescribed. Nearly all ADEs were considered clinically significant (97%). There were no deaths attributable to antibiotic-associated ADEs.
Bottom line: Antibiotic associated ADEs occur in about one in five inpatients, and about one in five antibiotic prescriptions may not be clinically indicated.
Citation: Tamma PD et al. Association of adverse events with antibiotic use in hospitalized patients. JAMA Intern Med. 2017 Sep 1;177(9):1308-15.
Dr. Anderson is an associate program director in the internal medicine residency training program at the University of Colorado School of Medicine and a hospitalist at the VA Eastern Colorado Health Care System in Denver.
Clinical question: What is the incidence of antibiotic-associated adverse drug events (ADEs) among adult inpatients?
Background: Antibiotics are used widely in the inpatient setting, although 20%-30% of inpatient antibiotic prescription are estimated to be unnecessary. Data are lacking on the rates of associated ADEs.
Study design: Retrospective cohort study.
Synopsis: Of the 5,579 patients admitted to four inpatient medicine services between September 2013 and June 2014, 1,488 (27%) received antibiotics for at least 24 hours. Patients were followed through admission and out to 90 days. A total of 324 unique antibiotic-associated ADEs occurred among 298 (20%) patients within 90 days of initial therapy. The overall rate of antibiotic-associated ADEs was 22.9/10,000 person-days. The investigators determined that 287 (19%) of antibiotic regimens were not clinically indicated, and among those, there were 56 (20%) ADEs. The most common 30-day ADEs were gastrointestinal, renal, and hematologic. The highest proportion of ADEs occurred with beta-lactams, fluoroquinolones, intravenous vancomycin, and trimethoprim-sulfamethoxazole, perhaps reflecting how commonly these agents are prescribed. Nearly all ADEs were considered clinically significant (97%). There were no deaths attributable to antibiotic-associated ADEs.
Bottom line: Antibiotic associated ADEs occur in about one in five inpatients, and about one in five antibiotic prescriptions may not be clinically indicated.
Citation: Tamma PD et al. Association of adverse events with antibiotic use in hospitalized patients. JAMA Intern Med. 2017 Sep 1;177(9):1308-15.
Dr. Anderson is an associate program director in the internal medicine residency training program at the University of Colorado School of Medicine and a hospitalist at the VA Eastern Colorado Health Care System in Denver.
Clinical question: What is the incidence of antibiotic-associated adverse drug events (ADEs) among adult inpatients?
Background: Antibiotics are used widely in the inpatient setting, although 20%-30% of inpatient antibiotic prescription are estimated to be unnecessary. Data are lacking on the rates of associated ADEs.
Study design: Retrospective cohort study.
Synopsis: Of the 5,579 patients admitted to four inpatient medicine services between September 2013 and June 2014, 1,488 (27%) received antibiotics for at least 24 hours. Patients were followed through admission and out to 90 days. A total of 324 unique antibiotic-associated ADEs occurred among 298 (20%) patients within 90 days of initial therapy. The overall rate of antibiotic-associated ADEs was 22.9/10,000 person-days. The investigators determined that 287 (19%) of antibiotic regimens were not clinically indicated, and among those, there were 56 (20%) ADEs. The most common 30-day ADEs were gastrointestinal, renal, and hematologic. The highest proportion of ADEs occurred with beta-lactams, fluoroquinolones, intravenous vancomycin, and trimethoprim-sulfamethoxazole, perhaps reflecting how commonly these agents are prescribed. Nearly all ADEs were considered clinically significant (97%). There were no deaths attributable to antibiotic-associated ADEs.
Bottom line: Antibiotic associated ADEs occur in about one in five inpatients, and about one in five antibiotic prescriptions may not be clinically indicated.
Citation: Tamma PD et al. Association of adverse events with antibiotic use in hospitalized patients. JAMA Intern Med. 2017 Sep 1;177(9):1308-15.
Dr. Anderson is an associate program director in the internal medicine residency training program at the University of Colorado School of Medicine and a hospitalist at the VA Eastern Colorado Health Care System in Denver.
Closing the Timing Gap Between HIV Infection and Diagnosis
In 2015, nearly 40,000 people were diagnosed with HIV infection. Half of those had been living with HIV for at least 3 years. One-quarter had been infected for ≥ 7 years.
But now HIV is being diagnosed sooner than before after infection. The estimated median time from infection to diagnosis in 2015 was 3 years compared with 3 years and 7 months in 2011, according to a CDC Vital Signs report.
Estimated median time from infection to diagnosis ranged from 5 years for heterosexual men to 2 and one-half for heterosexual women and women who inject drugs. The median time was 4 years for Asian Americans, 3 years for African Americans and Latinos, and 2 years for whites.
The percentage of people at high risk for HIV who report getting a test the previous year also has risen. Despite that progress, though, the CDC says “too few are tested.”
In 2015, nearly 40,000 people were diagnosed with HIV infection. Half of those had been living with HIV for at least 3 years. One-quarter had been infected for ≥ 7 years.
But now HIV is being diagnosed sooner than before after infection. The estimated median time from infection to diagnosis in 2015 was 3 years compared with 3 years and 7 months in 2011, according to a CDC Vital Signs report.
Estimated median time from infection to diagnosis ranged from 5 years for heterosexual men to 2 and one-half for heterosexual women and women who inject drugs. The median time was 4 years for Asian Americans, 3 years for African Americans and Latinos, and 2 years for whites.
The percentage of people at high risk for HIV who report getting a test the previous year also has risen. Despite that progress, though, the CDC says “too few are tested.”
In 2015, nearly 40,000 people were diagnosed with HIV infection. Half of those had been living with HIV for at least 3 years. One-quarter had been infected for ≥ 7 years.
But now HIV is being diagnosed sooner than before after infection. The estimated median time from infection to diagnosis in 2015 was 3 years compared with 3 years and 7 months in 2011, according to a CDC Vital Signs report.
Estimated median time from infection to diagnosis ranged from 5 years for heterosexual men to 2 and one-half for heterosexual women and women who inject drugs. The median time was 4 years for Asian Americans, 3 years for African Americans and Latinos, and 2 years for whites.
The percentage of people at high risk for HIV who report getting a test the previous year also has risen. Despite that progress, though, the CDC says “too few are tested.”
Clinical Trial Begins for Long-Acting Anti-HIV Injectable
A clinical trial to test a new, potentially more convenient HIV prophylaxis for women is starting in Africa. It is a long-acting form of the investigational drug cabotegravir and could give sexually active women a choice of biomedical HIV prevention tools for the first time, similar to the choices available for contraception, says Sinead Delany-Moretiwe, PhD, chair of the protocol.
The trial, HPTN 084, will enroll about 3,200 women aged 18 to 45 years at 20 sites in 7 countries. The women will be randomly assigned to either cabotegravir and a placebo pill or Truvada, which is a combination of emtricitabine and tenofovir disoproxil fumarate. Truvada, currently the only drug licensed for HIV pre-exposure prophylaxis, must be taken every day to achieve and maintain protective drug concentrations. The women will start with 2 cabotegravir injections 4 weeks apart, then receive injections once every 8 weeks for an average of 2.6 years. After completing the injections, participants will be offered 48 weeks of PrEP with daily oral Truvada.
The NIAID is sponsoring the phase 3 clinical trial and cofunding it in a unique partnership with ViiV Healthcare (which is providing the study medications with Gilead Sciences) and the Bill & Melinda Gates Foundation.
Participants will receive HIV prevention counseling, condoms and lubricant, and counseling to support adherence to the daily pill. Anyone who becomes HIV infected during the trial will stop receiving the study products and be referred to local medical providers for care and treatment.
The study also will evaluate how women experience long-acting injectable cabotegravir, the researchers say. They are hoping to get a better understanding of the types of safe and effective HIV prevention that also fit best in women’s lives.
A clinical trial to test a new, potentially more convenient HIV prophylaxis for women is starting in Africa. It is a long-acting form of the investigational drug cabotegravir and could give sexually active women a choice of biomedical HIV prevention tools for the first time, similar to the choices available for contraception, says Sinead Delany-Moretiwe, PhD, chair of the protocol.
The trial, HPTN 084, will enroll about 3,200 women aged 18 to 45 years at 20 sites in 7 countries. The women will be randomly assigned to either cabotegravir and a placebo pill or Truvada, which is a combination of emtricitabine and tenofovir disoproxil fumarate. Truvada, currently the only drug licensed for HIV pre-exposure prophylaxis, must be taken every day to achieve and maintain protective drug concentrations. The women will start with 2 cabotegravir injections 4 weeks apart, then receive injections once every 8 weeks for an average of 2.6 years. After completing the injections, participants will be offered 48 weeks of PrEP with daily oral Truvada.
The NIAID is sponsoring the phase 3 clinical trial and cofunding it in a unique partnership with ViiV Healthcare (which is providing the study medications with Gilead Sciences) and the Bill & Melinda Gates Foundation.
Participants will receive HIV prevention counseling, condoms and lubricant, and counseling to support adherence to the daily pill. Anyone who becomes HIV infected during the trial will stop receiving the study products and be referred to local medical providers for care and treatment.
The study also will evaluate how women experience long-acting injectable cabotegravir, the researchers say. They are hoping to get a better understanding of the types of safe and effective HIV prevention that also fit best in women’s lives.
A clinical trial to test a new, potentially more convenient HIV prophylaxis for women is starting in Africa. It is a long-acting form of the investigational drug cabotegravir and could give sexually active women a choice of biomedical HIV prevention tools for the first time, similar to the choices available for contraception, says Sinead Delany-Moretiwe, PhD, chair of the protocol.
The trial, HPTN 084, will enroll about 3,200 women aged 18 to 45 years at 20 sites in 7 countries. The women will be randomly assigned to either cabotegravir and a placebo pill or Truvada, which is a combination of emtricitabine and tenofovir disoproxil fumarate. Truvada, currently the only drug licensed for HIV pre-exposure prophylaxis, must be taken every day to achieve and maintain protective drug concentrations. The women will start with 2 cabotegravir injections 4 weeks apart, then receive injections once every 8 weeks for an average of 2.6 years. After completing the injections, participants will be offered 48 weeks of PrEP with daily oral Truvada.
The NIAID is sponsoring the phase 3 clinical trial and cofunding it in a unique partnership with ViiV Healthcare (which is providing the study medications with Gilead Sciences) and the Bill & Melinda Gates Foundation.
Participants will receive HIV prevention counseling, condoms and lubricant, and counseling to support adherence to the daily pill. Anyone who becomes HIV infected during the trial will stop receiving the study products and be referred to local medical providers for care and treatment.
The study also will evaluate how women experience long-acting injectable cabotegravir, the researchers say. They are hoping to get a better understanding of the types of safe and effective HIV prevention that also fit best in women’s lives.
Interventions can increase cord blood donations
Simple interventions can increase cord blood donations, according to research published in Scientific Reports.
Researchers saw a significant increase in cord blood donation when expectant mothers received information about the procedure and were asked to indicate their interest in donating at both early and late stages of their pregnancies.
“We more than doubled the number of cord blood units that were collected,” said study author Nicola Lacetera, PhD, of the University of Toronto Mississauga in Ontario, Canada.
“We learned a lot, and we did a little bit of good too, so that feels nice.”
Dr Lacetera and his colleagues conducted this study in Milan, Italy, where private cord blood banking is banned.
The team set out to determine if providing expectant mothers with information about cord blood donation and prompting them to consider the procedure would increase donations to a public cord blood bank.
Interventions
The researchers enrolled 850 expectant mothers and divided them into 6 treatment cohorts.
The T0 cohort included 217 control subjects who did not receive any information on cord blood donation.
The T1 cohort included 64 subjects who received information on cord blood donation during their first trimester.
The T2 cohort included 88 subjects who were given information on cord blood donation and asked about their intentions to donate in their first trimester.
The T3 cohort included 197 subjects who received information on cord blood donation in their third trimester.
The T4 cohort included 249 subjects who were given information on cord blood donation and asked about their intentions to donate during their third trimester.
The T5 cohort included 35 subjects who were given information on cord blood donation and asked about their intentions to donate during the first trimester and the third trimester.
Results
The researchers found that T5 subjects had the highest donation rate.
In the entire study sample, the donation rate was 2.3% (5/217) in controls, 6.3% (4/64) in T1 subjects, 1.1% (1/88) in T2, 8.1% (16/197) in T3, 10.0% (25/249) in T4, and 17.1% in T5 (6/35).
These results may not be entirely accurate, however, because the researchers could only confirm patients’ donation status if mothers delivered their babies at the study hospital, Ospedale dei Bambini Vittore Buzzi (also known as Buzzi Hospital, BH).
Among women who delivered at BH, donation rates were 2.7% (5/183) in controls, 11.7% (4/34) in T1, 2.2% (1/45) in T2, 8.9% (16/179) in T3, 11.4% (25/42) in T4, and 21.4% (6/28) in T5.
Though these data suggest the various interventions tested can increase cord blood donations, donation rates in this study could have been even higher, according to the researchers.
There were 197 women who submitted consent forms to donate cord blood, were medically eligible to donate, and delivered their babies at BH. However, only 57 of these women successfully donated cord blood.
There were 62 women (56.9%) who could not donate because of medical complications during delivery.
Thirty-three women (30.3%) failed to donate because of organizational reasons, including overcrowding of the delivery room and the absence of obstetric nurses certified to collect and process cord blood at the time of delivery.
There were 14 women (7.1%) who did not donate for institution-related reasons. For example, the women gave birth when the Milan Cord Blood Bank was closed.
There were no details on the remaining 31 women who failed to donate. 
Simple interventions can increase cord blood donations, according to research published in Scientific Reports.
Researchers saw a significant increase in cord blood donation when expectant mothers received information about the procedure and were asked to indicate their interest in donating at both early and late stages of their pregnancies.
“We more than doubled the number of cord blood units that were collected,” said study author Nicola Lacetera, PhD, of the University of Toronto Mississauga in Ontario, Canada.
“We learned a lot, and we did a little bit of good too, so that feels nice.”
Dr Lacetera and his colleagues conducted this study in Milan, Italy, where private cord blood banking is banned.
The team set out to determine if providing expectant mothers with information about cord blood donation and prompting them to consider the procedure would increase donations to a public cord blood bank.
Interventions
The researchers enrolled 850 expectant mothers and divided them into 6 treatment cohorts.
The T0 cohort included 217 control subjects who did not receive any information on cord blood donation.
The T1 cohort included 64 subjects who received information on cord blood donation during their first trimester.
The T2 cohort included 88 subjects who were given information on cord blood donation and asked about their intentions to donate in their first trimester.
The T3 cohort included 197 subjects who received information on cord blood donation in their third trimester.
The T4 cohort included 249 subjects who were given information on cord blood donation and asked about their intentions to donate during their third trimester.
The T5 cohort included 35 subjects who were given information on cord blood donation and asked about their intentions to donate during the first trimester and the third trimester.
Results
The researchers found that T5 subjects had the highest donation rate.
In the entire study sample, the donation rate was 2.3% (5/217) in controls, 6.3% (4/64) in T1 subjects, 1.1% (1/88) in T2, 8.1% (16/197) in T3, 10.0% (25/249) in T4, and 17.1% in T5 (6/35).
These results may not be entirely accurate, however, because the researchers could only confirm patients’ donation status if mothers delivered their babies at the study hospital, Ospedale dei Bambini Vittore Buzzi (also known as Buzzi Hospital, BH).
Among women who delivered at BH, donation rates were 2.7% (5/183) in controls, 11.7% (4/34) in T1, 2.2% (1/45) in T2, 8.9% (16/179) in T3, 11.4% (25/42) in T4, and 21.4% (6/28) in T5.
Though these data suggest the various interventions tested can increase cord blood donations, donation rates in this study could have been even higher, according to the researchers.
There were 197 women who submitted consent forms to donate cord blood, were medically eligible to donate, and delivered their babies at BH. However, only 57 of these women successfully donated cord blood.
There were 62 women (56.9%) who could not donate because of medical complications during delivery.
Thirty-three women (30.3%) failed to donate because of organizational reasons, including overcrowding of the delivery room and the absence of obstetric nurses certified to collect and process cord blood at the time of delivery.
There were 14 women (7.1%) who did not donate for institution-related reasons. For example, the women gave birth when the Milan Cord Blood Bank was closed.
There were no details on the remaining 31 women who failed to donate.
Simple interventions can increase cord blood donations, according to research published in Scientific Reports.
Researchers saw a significant increase in cord blood donation when expectant mothers received information about the procedure and were asked to indicate their interest in donating at both early and late stages of their pregnancies.
“We more than doubled the number of cord blood units that were collected,” said study author Nicola Lacetera, PhD, of the University of Toronto Mississauga in Ontario, Canada.
“We learned a lot, and we did a little bit of good too, so that feels nice.”
Dr Lacetera and his colleagues conducted this study in Milan, Italy, where private cord blood banking is banned.
The team set out to determine if providing expectant mothers with information about cord blood donation and prompting them to consider the procedure would increase donations to a public cord blood bank.
Interventions
The researchers enrolled 850 expectant mothers and divided them into 6 treatment cohorts.
The T0 cohort included 217 control subjects who did not receive any information on cord blood donation.
The T1 cohort included 64 subjects who received information on cord blood donation during their first trimester.
The T2 cohort included 88 subjects who were given information on cord blood donation and asked about their intentions to donate in their first trimester.
The T3 cohort included 197 subjects who received information on cord blood donation in their third trimester.
The T4 cohort included 249 subjects who were given information on cord blood donation and asked about their intentions to donate during their third trimester.
The T5 cohort included 35 subjects who were given information on cord blood donation and asked about their intentions to donate during the first trimester and the third trimester.
Results
The researchers found that T5 subjects had the highest donation rate.
In the entire study sample, the donation rate was 2.3% (5/217) in controls, 6.3% (4/64) in T1 subjects, 1.1% (1/88) in T2, 8.1% (16/197) in T3, 10.0% (25/249) in T4, and 17.1% in T5 (6/35).
These results may not be entirely accurate, however, because the researchers could only confirm patients’ donation status if mothers delivered their babies at the study hospital, Ospedale dei Bambini Vittore Buzzi (also known as Buzzi Hospital, BH).
Among women who delivered at BH, donation rates were 2.7% (5/183) in controls, 11.7% (4/34) in T1, 2.2% (1/45) in T2, 8.9% (16/179) in T3, 11.4% (25/42) in T4, and 21.4% (6/28) in T5.
Though these data suggest the various interventions tested can increase cord blood donations, donation rates in this study could have been even higher, according to the researchers.
There were 197 women who submitted consent forms to donate cord blood, were medically eligible to donate, and delivered their babies at BH. However, only 57 of these women successfully donated cord blood.
There were 62 women (56.9%) who could not donate because of medical complications during delivery.
Thirty-three women (30.3%) failed to donate because of organizational reasons, including overcrowding of the delivery room and the absence of obstetric nurses certified to collect and process cord blood at the time of delivery.
There were 14 women (7.1%) who did not donate for institution-related reasons. For example, the women gave birth when the Milan Cord Blood Bank was closed.
There were no details on the remaining 31 women who failed to donate.
EMA recommends orphan designation for pracinostat
The European Medicines Agency (EMA) has recommended that pracinostat receive orphan drug designation.
Pracinostat is an oral histone deacetylase inhibitor currently under investigation in a phase 3 study in combination with azacitidine for the treatment of acute myeloid leukemia (AML) in adult patients unfit to receive induction chemotherapy.
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure. The designation also provides a 10-year period of marketing exclusivity if a therapy receives regulatory approval.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
Phase 2 study
The EMA’s recommendation that pracinostat receive orphan drug designation is based on results of a phase 2 study, which were presented at the 2016 ASH Annual Meeting.
The study included 50 patients who had a median age of 75 (range, 66-84). Sixty-six percent of patients had de novo AML, and 34% had secondary AML.
The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine at 75 mg/m2 subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.
As of October 15, 2016, 90% of patients had discontinued treatment, 42% due to progressive disease, 28% due to adverse events (AEs), 14% due to patient decision, and 6% due to investigator decision.
Fifty-two percent of patients (n=26) achieved the primary endpoint of complete response (CR) plus CR with incomplete count recovery (CRi) plus morphologic leukemia-free state (MLFS).
Forty-two percent of patients had a CR, 4% had a CRi, and 6% achieved MLFS. The median duration of CR/CRi/MLFS was 13.2 months. The median duration of CR/CRi was 17.2 months.
The median overall survival was 19.1 months. The 1-year survival rate was 62%, and the 2-year survival rate was 41%.
The most common treatment-emergent AEs were nausea (78%), constipation (70%), fatigue (62%), decreased appetite (56%), diarrhea (50%), vomiting (40%), cough (36%), dyspnea (34%), hypokalemia (34%), peripheral edema (34%), pyrexia (34%), dizziness (32%), back pain (28%), insomnia (28%), febrile neutropenia (48%), thrombocytopenia (46%), anemia (38%), and neutropenia (38%).
Treatment-emergent AEs led to discontinuation in 14 patients. Three of these patients developed sepsis that proved fatal.
The other AEs leading to discontinuation included grade 3 acute axonal neuropathy, grade 3 parainfluenza, grade 3 prolonged QTc/atrial fibrillation, grade 1 acute kidney injury, grade 3 diverticulitis, grade 3 supraglottic ulcer, grade 2 upper respiratory infection, grade 3 fatigue (n=2), and grades 1 and 3 intermittent fatigue (n=2).
The European Medicines Agency (EMA) has recommended that pracinostat receive orphan drug designation.
Pracinostat is an oral histone deacetylase inhibitor currently under investigation in a phase 3 study in combination with azacitidine for the treatment of acute myeloid leukemia (AML) in adult patients unfit to receive induction chemotherapy.
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure. The designation also provides a 10-year period of marketing exclusivity if a therapy receives regulatory approval.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
Phase 2 study
The EMA’s recommendation that pracinostat receive orphan drug designation is based on results of a phase 2 study, which were presented at the 2016 ASH Annual Meeting.
The study included 50 patients who had a median age of 75 (range, 66-84). Sixty-six percent of patients had de novo AML, and 34% had secondary AML.
The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine at 75 mg/m2 subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.
As of October 15, 2016, 90% of patients had discontinued treatment, 42% due to progressive disease, 28% due to adverse events (AEs), 14% due to patient decision, and 6% due to investigator decision.
Fifty-two percent of patients (n=26) achieved the primary endpoint of complete response (CR) plus CR with incomplete count recovery (CRi) plus morphologic leukemia-free state (MLFS).
Forty-two percent of patients had a CR, 4% had a CRi, and 6% achieved MLFS. The median duration of CR/CRi/MLFS was 13.2 months. The median duration of CR/CRi was 17.2 months.
The median overall survival was 19.1 months. The 1-year survival rate was 62%, and the 2-year survival rate was 41%.
The most common treatment-emergent AEs were nausea (78%), constipation (70%), fatigue (62%), decreased appetite (56%), diarrhea (50%), vomiting (40%), cough (36%), dyspnea (34%), hypokalemia (34%), peripheral edema (34%), pyrexia (34%), dizziness (32%), back pain (28%), insomnia (28%), febrile neutropenia (48%), thrombocytopenia (46%), anemia (38%), and neutropenia (38%).
Treatment-emergent AEs led to discontinuation in 14 patients. Three of these patients developed sepsis that proved fatal.
The other AEs leading to discontinuation included grade 3 acute axonal neuropathy, grade 3 parainfluenza, grade 3 prolonged QTc/atrial fibrillation, grade 1 acute kidney injury, grade 3 diverticulitis, grade 3 supraglottic ulcer, grade 2 upper respiratory infection, grade 3 fatigue (n=2), and grades 1 and 3 intermittent fatigue (n=2).
The European Medicines Agency (EMA) has recommended that pracinostat receive orphan drug designation.
Pracinostat is an oral histone deacetylase inhibitor currently under investigation in a phase 3 study in combination with azacitidine for the treatment of acute myeloid leukemia (AML) in adult patients unfit to receive induction chemotherapy.
Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.
Orphan designation provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure. The designation also provides a 10-year period of marketing exclusivity if a therapy receives regulatory approval.
The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.
Phase 2 study
The EMA’s recommendation that pracinostat receive orphan drug designation is based on results of a phase 2 study, which were presented at the 2016 ASH Annual Meeting.
The study included 50 patients who had a median age of 75 (range, 66-84). Sixty-six percent of patients had de novo AML, and 34% had secondary AML.
The patients received pracinostat at 60 mg orally on days 1, 3, and 5 of each week for 21 days of each 28-day cycle. They received azacitidine at 75 mg/m2 subcutaneously or intravenously on days 1-7 or days 1-5 and 8-9 (per site preference) of each 28-day cycle.
As of October 15, 2016, 90% of patients had discontinued treatment, 42% due to progressive disease, 28% due to adverse events (AEs), 14% due to patient decision, and 6% due to investigator decision.
Fifty-two percent of patients (n=26) achieved the primary endpoint of complete response (CR) plus CR with incomplete count recovery (CRi) plus morphologic leukemia-free state (MLFS).
Forty-two percent of patients had a CR, 4% had a CRi, and 6% achieved MLFS. The median duration of CR/CRi/MLFS was 13.2 months. The median duration of CR/CRi was 17.2 months.
The median overall survival was 19.1 months. The 1-year survival rate was 62%, and the 2-year survival rate was 41%.
The most common treatment-emergent AEs were nausea (78%), constipation (70%), fatigue (62%), decreased appetite (56%), diarrhea (50%), vomiting (40%), cough (36%), dyspnea (34%), hypokalemia (34%), peripheral edema (34%), pyrexia (34%), dizziness (32%), back pain (28%), insomnia (28%), febrile neutropenia (48%), thrombocytopenia (46%), anemia (38%), and neutropenia (38%).
Treatment-emergent AEs led to discontinuation in 14 patients. Three of these patients developed sepsis that proved fatal.
The other AEs leading to discontinuation included grade 3 acute axonal neuropathy, grade 3 parainfluenza, grade 3 prolonged QTc/atrial fibrillation, grade 1 acute kidney injury, grade 3 diverticulitis, grade 3 supraglottic ulcer, grade 2 upper respiratory infection, grade 3 fatigue (n=2), and grades 1 and 3 intermittent fatigue (n=2).
Dental Health: What It Means in Kidney Disease
Q) I teach nephrology at a local PA program, and they want us to integrate dental care into each module. What’s the connection between the two?
Dental health is frequently overlooked in the medical realm, as many clinicians feel that dental issues are out of our purview. Hematuria worries us, but bleeding gums and other signs of periodontal disease are often ignored. Surprisingly, many patients don’t seem to mind when their gums bleed every time they brush; they believe that this is normal, when really, it’s not.
Growing evidence supports associations between dental health and multiple medical issues—chronic kidney disease (CKD) among them. Periodontal disease is one of several inflammatory diseases caused by an interaction between gram-negative periodontal bacterial species and the immune system. It manifests with sore, red, bleeding gums and can lead to tooth loss if left untreated.
Chronic inflammation in the gums is a good indicator of inflammation elsewhere in the body. In and of itself, periodontitis can set off an inflammatory cascade in the body. Poor dentition can also lead to poor nutrition, which then causes a feedback loop, leading to even more inflammation.
Patients with periodontal disease have higher levels of C-reactive protein and a higher erythrocyte sedimentation rate than those without the disease.1 And a recent study by Zhang et al showed that periodontal disease increased risk for all-cause mortality in patients with CKD.2
The high cost of CKD from both a financial and personal view makes any intervention worth exploring, as the risk factors are difficult to modify and the CKD population is growing worldwide. We, as medical providers, should reiterate what our dental colleagues have been saying for years: Encourage patients with CKD to practice good dental hygiene by brushing twice a day and flossing daily, in an attempt to improve their overall outcomes.
LCDR Julie Taylor, PA-C
United States Public Health Service, Boston
1. Zhang J, Jiang H, Sun M, Chen J. Association between periodontal disease and mortality in people with CKD: a meta-analysis of cohort studies. BMC Nephrol. 2017;18(1):269.
2. Chen YT, Shin CJ, Ou SM, et al; Taiwan Geriatric Kidney Disease (TGKD) Research Group. Periodontal disease and risks of kidney function decline and mortality in older people: a community-based cohort study. Am J Kidney Dis. 2015; 66(2):223-230.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Nicole DeFeo McCormick, DNP, MBA, NP-C, CCTC, who is an Assistant Professor in the School of Medicine at the University of Colorado, and LCDR Julie Cure, PA-C, who is with the United States Public Health Service in Boston.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Nicole DeFeo McCormick, DNP, MBA, NP-C, CCTC, who is an Assistant Professor in the School of Medicine at the University of Colorado, and LCDR Julie Cure, PA-C, who is with the United States Public Health Service in Boston.
Clinician Reviews in partnership with
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation's Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a semi-retired PA who works with the American Academy of Nephrology PAs and is a past chair of the NKF-CAP. This month's responses were authored by Nicole DeFeo McCormick, DNP, MBA, NP-C, CCTC, who is an Assistant Professor in the School of Medicine at the University of Colorado, and LCDR Julie Cure, PA-C, who is with the United States Public Health Service in Boston.
Q) I teach nephrology at a local PA program, and they want us to integrate dental care into each module. What’s the connection between the two?
Dental health is frequently overlooked in the medical realm, as many clinicians feel that dental issues are out of our purview. Hematuria worries us, but bleeding gums and other signs of periodontal disease are often ignored. Surprisingly, many patients don’t seem to mind when their gums bleed every time they brush; they believe that this is normal, when really, it’s not.
Growing evidence supports associations between dental health and multiple medical issues—chronic kidney disease (CKD) among them. Periodontal disease is one of several inflammatory diseases caused by an interaction between gram-negative periodontal bacterial species and the immune system. It manifests with sore, red, bleeding gums and can lead to tooth loss if left untreated.
Chronic inflammation in the gums is a good indicator of inflammation elsewhere in the body. In and of itself, periodontitis can set off an inflammatory cascade in the body. Poor dentition can also lead to poor nutrition, which then causes a feedback loop, leading to even more inflammation.
Patients with periodontal disease have higher levels of C-reactive protein and a higher erythrocyte sedimentation rate than those without the disease.1 And a recent study by Zhang et al showed that periodontal disease increased risk for all-cause mortality in patients with CKD.2
The high cost of CKD from both a financial and personal view makes any intervention worth exploring, as the risk factors are difficult to modify and the CKD population is growing worldwide. We, as medical providers, should reiterate what our dental colleagues have been saying for years: Encourage patients with CKD to practice good dental hygiene by brushing twice a day and flossing daily, in an attempt to improve their overall outcomes.
LCDR Julie Taylor, PA-C
United States Public Health Service, Boston
Q) I teach nephrology at a local PA program, and they want us to integrate dental care into each module. What’s the connection between the two?
Dental health is frequently overlooked in the medical realm, as many clinicians feel that dental issues are out of our purview. Hematuria worries us, but bleeding gums and other signs of periodontal disease are often ignored. Surprisingly, many patients don’t seem to mind when their gums bleed every time they brush; they believe that this is normal, when really, it’s not.
Growing evidence supports associations between dental health and multiple medical issues—chronic kidney disease (CKD) among them. Periodontal disease is one of several inflammatory diseases caused by an interaction between gram-negative periodontal bacterial species and the immune system. It manifests with sore, red, bleeding gums and can lead to tooth loss if left untreated.
Chronic inflammation in the gums is a good indicator of inflammation elsewhere in the body. In and of itself, periodontitis can set off an inflammatory cascade in the body. Poor dentition can also lead to poor nutrition, which then causes a feedback loop, leading to even more inflammation.
Patients with periodontal disease have higher levels of C-reactive protein and a higher erythrocyte sedimentation rate than those without the disease.1 And a recent study by Zhang et al showed that periodontal disease increased risk for all-cause mortality in patients with CKD.2
The high cost of CKD from both a financial and personal view makes any intervention worth exploring, as the risk factors are difficult to modify and the CKD population is growing worldwide. We, as medical providers, should reiterate what our dental colleagues have been saying for years: Encourage patients with CKD to practice good dental hygiene by brushing twice a day and flossing daily, in an attempt to improve their overall outcomes.
LCDR Julie Taylor, PA-C
United States Public Health Service, Boston
1. Zhang J, Jiang H, Sun M, Chen J. Association between periodontal disease and mortality in people with CKD: a meta-analysis of cohort studies. BMC Nephrol. 2017;18(1):269.
2. Chen YT, Shin CJ, Ou SM, et al; Taiwan Geriatric Kidney Disease (TGKD) Research Group. Periodontal disease and risks of kidney function decline and mortality in older people: a community-based cohort study. Am J Kidney Dis. 2015; 66(2):223-230.
1. Zhang J, Jiang H, Sun M, Chen J. Association between periodontal disease and mortality in people with CKD: a meta-analysis of cohort studies. BMC Nephrol. 2017;18(1):269.
2. Chen YT, Shin CJ, Ou SM, et al; Taiwan Geriatric Kidney Disease (TGKD) Research Group. Periodontal disease and risks of kidney function decline and mortality in older people: a community-based cohort study. Am J Kidney Dis. 2015; 66(2):223-230.
FDA: No more codeine or hydrocodone cold medicines for children
New safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone limit their use to adults 18 years or older.
The Food and Drug Administration took this action after “conducting an extensive review and convening a panel of outside experts,” which determined that the risks of these medicines outweigh their benefits in children younger than 18 years. The agency also is requiring companies to add a boxed warning to drug labels for prescription cough and cold medicines containing codeine or hydrocodone about the “risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing,” according to an FDA safety announcement.
Common side effects of opioids include drowsiness, dizziness, nausea, vomiting, constipation, shortness of breath, and headache, according to the press release.
Reassure parents that cough because of a cold or upper respiratory infection is self-limited and generally does not need to be treated, the FDA advised. If children do need cough treatment, there are over-the-counter products such as dextromethorphan, as well as prescription benzonatate products, the FDA said. Encourage parents to check labels of nonprescription cough and cold products.
In a few states, some codeine cough medicines are available OTC. The FDA is considering regulatory action for these products, according to the safety announcement.
New safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone limit their use to adults 18 years or older.
The Food and Drug Administration took this action after “conducting an extensive review and convening a panel of outside experts,” which determined that the risks of these medicines outweigh their benefits in children younger than 18 years. The agency also is requiring companies to add a boxed warning to drug labels for prescription cough and cold medicines containing codeine or hydrocodone about the “risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing,” according to an FDA safety announcement.
Common side effects of opioids include drowsiness, dizziness, nausea, vomiting, constipation, shortness of breath, and headache, according to the press release.
Reassure parents that cough because of a cold or upper respiratory infection is self-limited and generally does not need to be treated, the FDA advised. If children do need cough treatment, there are over-the-counter products such as dextromethorphan, as well as prescription benzonatate products, the FDA said. Encourage parents to check labels of nonprescription cough and cold products.
In a few states, some codeine cough medicines are available OTC. The FDA is considering regulatory action for these products, according to the safety announcement.
New safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone limit their use to adults 18 years or older.
The Food and Drug Administration took this action after “conducting an extensive review and convening a panel of outside experts,” which determined that the risks of these medicines outweigh their benefits in children younger than 18 years. The agency also is requiring companies to add a boxed warning to drug labels for prescription cough and cold medicines containing codeine or hydrocodone about the “risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing,” according to an FDA safety announcement.
Common side effects of opioids include drowsiness, dizziness, nausea, vomiting, constipation, shortness of breath, and headache, according to the press release.
Reassure parents that cough because of a cold or upper respiratory infection is self-limited and generally does not need to be treated, the FDA advised. If children do need cough treatment, there are over-the-counter products such as dextromethorphan, as well as prescription benzonatate products, the FDA said. Encourage parents to check labels of nonprescription cough and cold products.
In a few states, some codeine cough medicines are available OTC. The FDA is considering regulatory action for these products, according to the safety announcement.
AUDIO: Immunotherapy’s role in NHL
ATLANTA – The use of immune checkpoint blockade is increasingly becoming standard therapy in Hodgkin lymphoma, but this approach has so far garnered mixed results in non-Hodgkin lymphoma, Stephen Ansell, MD, PhD, said at the annual meeting of the American Society of Hematology.
In an interview, Dr. Ansell, professor of medicine and chair of the lymphoma group at the Mayo Clinic, Rochester, Minn., said responses have been variable with promising results from immune checkpoint inhibitors in primary mediastinal large B-cell lymphoma, some NK/T-cell lymphomas, and primary CNS lymphoma. However, responses have been modest in low-grade lymphoma.
Dr. Ansell, who chaired a session at ASH 2017 on immunotherapy’s expanding role in non-Hodgkin lymphoma, said one of the major challenges of using immune checkpoint blockade in non-Hodgkin lymphoma is the complicated biology. For example, there are a lot of regulatory T cells that actually inhibit the immune response, and many of the T cells that are present within the tumor have an exhausted phenotype and are poorly functioning. Additionally, some of the cytokines that would seem to be stimulating the immune system can, over time, slowly produce T-cell exhaustion.
“Sort of like too much of a good thing ends up being a bad thing,” he said.
These are the issues that are fueling research today, Dr. Ansell said. Going forward he said he expects to see more combination approaches to therapy, such as using an agonistic positive signal plus the blocking of an inhibitory signal with chemotherapy.
Dr. Ansell reported that Mayo Clinic receives clinical trial support from Merck, Bristol-Myers Squibb, Seattle Genetics, Trillium, and Affimed.
ATLANTA – The use of immune checkpoint blockade is increasingly becoming standard therapy in Hodgkin lymphoma, but this approach has so far garnered mixed results in non-Hodgkin lymphoma, Stephen Ansell, MD, PhD, said at the annual meeting of the American Society of Hematology.
In an interview, Dr. Ansell, professor of medicine and chair of the lymphoma group at the Mayo Clinic, Rochester, Minn., said responses have been variable with promising results from immune checkpoint inhibitors in primary mediastinal large B-cell lymphoma, some NK/T-cell lymphomas, and primary CNS lymphoma. However, responses have been modest in low-grade lymphoma.
Dr. Ansell, who chaired a session at ASH 2017 on immunotherapy’s expanding role in non-Hodgkin lymphoma, said one of the major challenges of using immune checkpoint blockade in non-Hodgkin lymphoma is the complicated biology. For example, there are a lot of regulatory T cells that actually inhibit the immune response, and many of the T cells that are present within the tumor have an exhausted phenotype and are poorly functioning. Additionally, some of the cytokines that would seem to be stimulating the immune system can, over time, slowly produce T-cell exhaustion.
“Sort of like too much of a good thing ends up being a bad thing,” he said.
These are the issues that are fueling research today, Dr. Ansell said. Going forward he said he expects to see more combination approaches to therapy, such as using an agonistic positive signal plus the blocking of an inhibitory signal with chemotherapy.
Dr. Ansell reported that Mayo Clinic receives clinical trial support from Merck, Bristol-Myers Squibb, Seattle Genetics, Trillium, and Affimed.
ATLANTA – The use of immune checkpoint blockade is increasingly becoming standard therapy in Hodgkin lymphoma, but this approach has so far garnered mixed results in non-Hodgkin lymphoma, Stephen Ansell, MD, PhD, said at the annual meeting of the American Society of Hematology.
In an interview, Dr. Ansell, professor of medicine and chair of the lymphoma group at the Mayo Clinic, Rochester, Minn., said responses have been variable with promising results from immune checkpoint inhibitors in primary mediastinal large B-cell lymphoma, some NK/T-cell lymphomas, and primary CNS lymphoma. However, responses have been modest in low-grade lymphoma.
Dr. Ansell, who chaired a session at ASH 2017 on immunotherapy’s expanding role in non-Hodgkin lymphoma, said one of the major challenges of using immune checkpoint blockade in non-Hodgkin lymphoma is the complicated biology. For example, there are a lot of regulatory T cells that actually inhibit the immune response, and many of the T cells that are present within the tumor have an exhausted phenotype and are poorly functioning. Additionally, some of the cytokines that would seem to be stimulating the immune system can, over time, slowly produce T-cell exhaustion.
“Sort of like too much of a good thing ends up being a bad thing,” he said.
These are the issues that are fueling research today, Dr. Ansell said. Going forward he said he expects to see more combination approaches to therapy, such as using an agonistic positive signal plus the blocking of an inhibitory signal with chemotherapy.
Dr. Ansell reported that Mayo Clinic receives clinical trial support from Merck, Bristol-Myers Squibb, Seattle Genetics, Trillium, and Affimed.
EXPERT ANALYSIS FROM ASH 2017
Novel herpes zoster vaccine is more cost effective than old vaccine
The novel herpes zoster subunit vaccine (HZ/su) is more effective and less expensive than the currently used live attenuated virus (ZVL), according to a study from the Center for Value-Based Research.
Phuc Le, PhD, of the Cleveland Clinic and her colleague Michael Rothberg, MD, conducted an economic analysis of vaccine strategies from the societal perspective. This included the direct medical costs and productivity losses associated with HZ disease and complications.
The one-, two-, and three-way sensitivity analyses examined how different variables affected the cost-effectiveness of different vaccine strategies. The one-way analysis examined the association of input variables and cost-effectiveness. This included HZ/su prices, waning rate and initial efficacy of a dose of HZ/su, and the adherence rate. This analysis revealed that, compared with no vaccination, HZ/su would provide cost savings up to a price of $160, or $80 per dose.
Regardless of circumstance, HZ/su was always more effective than ZVL according to the two-way sensitivity analysis. This analysis took into account the joint effect of price, adherence to two doses of HZ/su, efficacy, and the waning rate of one dose and two doses of HZ/su and ZVL. Compared with ZVL, HZ/su would be less costly up to a price of $350 per series.
Adherence rates to vaccination schedules were important in determining the efficacy and waning rate which ultimately effected cost-effectiveness. The three-way sensitivity analysis found that, if HZ/su adherence to the second dose was greater than 56.8%, results were insensitive to the variation of single-dose efficacy and waning rate of HZ/su. But if adherence rates fell below 40%, combinations of waning rate and lower efficacy made HZ/su cost ineffective. Most importantly, ZVL was never cost effective for 60-year-old patients.
Despite a projected price of $280 per series, HZ/su is still more effective and less expensive than ZVL for adults 60 years or older. According to Dr. Le and Dr. Rothberg, the assumptions about the vaccine’s efficacy duration and price were reasonable. But, if the vaccine price were to rise in the future, or a single dose becomes much less effective than reported by GlaxoSmithKline, or if adherence to the second dose was remarkably low, the results of the study would be changed.
“An ACIP recommendation stating a preference for HZ/su over ZVL could lead to future price increases, which would render the vaccine no longer cost effective” wrote Dr. Le and Dr. Rothberg. “Therefore, a recommendation linked to periodic reassessment of cost-effectiveness based on the vaccine price might help to mitigate the effect of the recommendation on vaccine affordability.”
Dr. Le and Dr. Rothberg reported having no conflicts of interest.
The HZ/su vaccine is not yet approved by the U.S. Food and Drug Administration, but in 2017, the FDA Advisory Committee unanimously voted in favor of its use in adults age 50 years and older.
SOURCE: Phuc L et al. JAMA Intern Med. 2018 Jan 2. doi: 10.1001/jamainternmed.2017.7431. Najafzadeh M. JAMA Intern Med. 2018. doi: 10.1001/jamainternmed.2017.7442.
The herpes zoster (HZ) virus disproportionately affects elderly populations. As the U.S. population ages, tools and mechanisms to reduce the clinical and economic burden of HZ will be needed in the coming years.
The work of Dr. Le and Dr. Rothberg presents the results of an economic evaluation on randomized clinical trials of a yet-to-be-approved novel HZ subunit vaccine (HZ/su) to determine the economic and clinical benefit of the new vaccine, compared with the currently used vaccine. Although HZ/su is intended to be a two-dose vaccine, the study focused on a one-time vaccine strategy because booster vaccines are unpopular and not recommended by the Advisory Committee on Immunization Practices.
“If priced at $280 per two required doses, HZ/su appears to be a cost-saving option, compared with ZVL and a cost-effective option, compared with no-vaccine strategies,” wrote Dr. Najafzadeh. “However, the value of HZ/su vaccine would be even higher if it could be marketed at a price comparable to that of ZVL.” An added benefit of the HZ/su vaccine is that it can be used in immunocompromised patients.
Mehdi Najafzadeh, PhD , is an instructor in medicine at Harvard Medical School, Boston. He also serves as an associate statistician/epidemiologist in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.
The herpes zoster (HZ) virus disproportionately affects elderly populations. As the U.S. population ages, tools and mechanisms to reduce the clinical and economic burden of HZ will be needed in the coming years.
The work of Dr. Le and Dr. Rothberg presents the results of an economic evaluation on randomized clinical trials of a yet-to-be-approved novel HZ subunit vaccine (HZ/su) to determine the economic and clinical benefit of the new vaccine, compared with the currently used vaccine. Although HZ/su is intended to be a two-dose vaccine, the study focused on a one-time vaccine strategy because booster vaccines are unpopular and not recommended by the Advisory Committee on Immunization Practices.
“If priced at $280 per two required doses, HZ/su appears to be a cost-saving option, compared with ZVL and a cost-effective option, compared with no-vaccine strategies,” wrote Dr. Najafzadeh. “However, the value of HZ/su vaccine would be even higher if it could be marketed at a price comparable to that of ZVL.” An added benefit of the HZ/su vaccine is that it can be used in immunocompromised patients.
Mehdi Najafzadeh, PhD , is an instructor in medicine at Harvard Medical School, Boston. He also serves as an associate statistician/epidemiologist in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.
The herpes zoster (HZ) virus disproportionately affects elderly populations. As the U.S. population ages, tools and mechanisms to reduce the clinical and economic burden of HZ will be needed in the coming years.
The work of Dr. Le and Dr. Rothberg presents the results of an economic evaluation on randomized clinical trials of a yet-to-be-approved novel HZ subunit vaccine (HZ/su) to determine the economic and clinical benefit of the new vaccine, compared with the currently used vaccine. Although HZ/su is intended to be a two-dose vaccine, the study focused on a one-time vaccine strategy because booster vaccines are unpopular and not recommended by the Advisory Committee on Immunization Practices.
“If priced at $280 per two required doses, HZ/su appears to be a cost-saving option, compared with ZVL and a cost-effective option, compared with no-vaccine strategies,” wrote Dr. Najafzadeh. “However, the value of HZ/su vaccine would be even higher if it could be marketed at a price comparable to that of ZVL.” An added benefit of the HZ/su vaccine is that it can be used in immunocompromised patients.
Mehdi Najafzadeh, PhD , is an instructor in medicine at Harvard Medical School, Boston. He also serves as an associate statistician/epidemiologist in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.
The novel herpes zoster subunit vaccine (HZ/su) is more effective and less expensive than the currently used live attenuated virus (ZVL), according to a study from the Center for Value-Based Research.
Phuc Le, PhD, of the Cleveland Clinic and her colleague Michael Rothberg, MD, conducted an economic analysis of vaccine strategies from the societal perspective. This included the direct medical costs and productivity losses associated with HZ disease and complications.
The one-, two-, and three-way sensitivity analyses examined how different variables affected the cost-effectiveness of different vaccine strategies. The one-way analysis examined the association of input variables and cost-effectiveness. This included HZ/su prices, waning rate and initial efficacy of a dose of HZ/su, and the adherence rate. This analysis revealed that, compared with no vaccination, HZ/su would provide cost savings up to a price of $160, or $80 per dose.
Regardless of circumstance, HZ/su was always more effective than ZVL according to the two-way sensitivity analysis. This analysis took into account the joint effect of price, adherence to two doses of HZ/su, efficacy, and the waning rate of one dose and two doses of HZ/su and ZVL. Compared with ZVL, HZ/su would be less costly up to a price of $350 per series.
Adherence rates to vaccination schedules were important in determining the efficacy and waning rate which ultimately effected cost-effectiveness. The three-way sensitivity analysis found that, if HZ/su adherence to the second dose was greater than 56.8%, results were insensitive to the variation of single-dose efficacy and waning rate of HZ/su. But if adherence rates fell below 40%, combinations of waning rate and lower efficacy made HZ/su cost ineffective. Most importantly, ZVL was never cost effective for 60-year-old patients.
Despite a projected price of $280 per series, HZ/su is still more effective and less expensive than ZVL for adults 60 years or older. According to Dr. Le and Dr. Rothberg, the assumptions about the vaccine’s efficacy duration and price were reasonable. But, if the vaccine price were to rise in the future, or a single dose becomes much less effective than reported by GlaxoSmithKline, or if adherence to the second dose was remarkably low, the results of the study would be changed.
“An ACIP recommendation stating a preference for HZ/su over ZVL could lead to future price increases, which would render the vaccine no longer cost effective” wrote Dr. Le and Dr. Rothberg. “Therefore, a recommendation linked to periodic reassessment of cost-effectiveness based on the vaccine price might help to mitigate the effect of the recommendation on vaccine affordability.”
Dr. Le and Dr. Rothberg reported having no conflicts of interest.
The HZ/su vaccine is not yet approved by the U.S. Food and Drug Administration, but in 2017, the FDA Advisory Committee unanimously voted in favor of its use in adults age 50 years and older.
SOURCE: Phuc L et al. JAMA Intern Med. 2018 Jan 2. doi: 10.1001/jamainternmed.2017.7431. Najafzadeh M. JAMA Intern Med. 2018. doi: 10.1001/jamainternmed.2017.7442.
The novel herpes zoster subunit vaccine (HZ/su) is more effective and less expensive than the currently used live attenuated virus (ZVL), according to a study from the Center for Value-Based Research.
Phuc Le, PhD, of the Cleveland Clinic and her colleague Michael Rothberg, MD, conducted an economic analysis of vaccine strategies from the societal perspective. This included the direct medical costs and productivity losses associated with HZ disease and complications.
The one-, two-, and three-way sensitivity analyses examined how different variables affected the cost-effectiveness of different vaccine strategies. The one-way analysis examined the association of input variables and cost-effectiveness. This included HZ/su prices, waning rate and initial efficacy of a dose of HZ/su, and the adherence rate. This analysis revealed that, compared with no vaccination, HZ/su would provide cost savings up to a price of $160, or $80 per dose.
Regardless of circumstance, HZ/su was always more effective than ZVL according to the two-way sensitivity analysis. This analysis took into account the joint effect of price, adherence to two doses of HZ/su, efficacy, and the waning rate of one dose and two doses of HZ/su and ZVL. Compared with ZVL, HZ/su would be less costly up to a price of $350 per series.
Adherence rates to vaccination schedules were important in determining the efficacy and waning rate which ultimately effected cost-effectiveness. The three-way sensitivity analysis found that, if HZ/su adherence to the second dose was greater than 56.8%, results were insensitive to the variation of single-dose efficacy and waning rate of HZ/su. But if adherence rates fell below 40%, combinations of waning rate and lower efficacy made HZ/su cost ineffective. Most importantly, ZVL was never cost effective for 60-year-old patients.
Despite a projected price of $280 per series, HZ/su is still more effective and less expensive than ZVL for adults 60 years or older. According to Dr. Le and Dr. Rothberg, the assumptions about the vaccine’s efficacy duration and price were reasonable. But, if the vaccine price were to rise in the future, or a single dose becomes much less effective than reported by GlaxoSmithKline, or if adherence to the second dose was remarkably low, the results of the study would be changed.
“An ACIP recommendation stating a preference for HZ/su over ZVL could lead to future price increases, which would render the vaccine no longer cost effective” wrote Dr. Le and Dr. Rothberg. “Therefore, a recommendation linked to periodic reassessment of cost-effectiveness based on the vaccine price might help to mitigate the effect of the recommendation on vaccine affordability.”
Dr. Le and Dr. Rothberg reported having no conflicts of interest.
The HZ/su vaccine is not yet approved by the U.S. Food and Drug Administration, but in 2017, the FDA Advisory Committee unanimously voted in favor of its use in adults age 50 years and older.
SOURCE: Phuc L et al. JAMA Intern Med. 2018 Jan 2. doi: 10.1001/jamainternmed.2017.7431. Najafzadeh M. JAMA Intern Med. 2018. doi: 10.1001/jamainternmed.2017.7442.
FROM JAMA INTERNAL MEDICINE
Key clinical point: Cost-effectiveness can be an important factor in considering patient treatment for herpes zoster.
Major finding:
Study details: The study was based on U.S. medical literature. Data were derived from adults 60 years or older in patient groups of 100-30,000 from July 1 to July 31, 2017.
Disclosures: None of the researchers had conflicts of interest to report.
Source: L. Phuc et al. JAMA Intern Med. 2018 Jan 2. doi: 10.1001/jamainternmed.2017.7431; Najafzadeh M. JAMA Intern Med. 2018. doi: 10.1001/jamainternmed.2017.7442.
Phase 1 study: Human IL-10 plus checkpoint blockade looks promising in RCC, NSCLC
NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.
The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.
Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.
In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.
In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.
The responses were durable.
“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.
Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).
Progression-free survival was not reached in this cohort.
An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.
Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.
The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.
AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.
Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.
“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.
The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.
The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.
Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
SOURCE: Naing A et al. SITC Abstract 012.
NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.
The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.
Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.
In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.
In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.
The responses were durable.
“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.
Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).
Progression-free survival was not reached in this cohort.
An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.
Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.
The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.
AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.
Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.
“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.
The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.
The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.
Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
SOURCE: Naing A et al. SITC Abstract 012.
NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.
The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.
Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.
In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.
In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.
The responses were durable.
“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.
Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).
Progression-free survival was not reached in this cohort.
An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.
Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.
The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.
AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.
Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.
“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.
The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.
The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.
Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
SOURCE: Naing A et al. SITC Abstract 012.
REPORTING FROM SITC 2017
Key clinical point:
Major finding: 15 of 34 RCC patients had an objective response and two of those had a complete response.
Study details: Expansion cohorts including 64 patients from a phase 1 study.
Disclosures: Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
Source: A. Naing et al. SITC 2017 Abstract 012.