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Poor smell predicts 6-year risk of Parkinson’s
Poor olfaction is a predictor of Parkinson’s disease (PD) in both the short and immediate term, with accuracy out to at least 6 years, especially in white men, according to a retrospective case adjudication of the Health ABC study published in Neurology.
Of 2,462 study participants, 42 were found to have PD during an average of 9.8 years of follow-up, Honglei Chen, MD, PhD, of the department of epidemiology and biostatistics at Michigan State University, East Lansing, and his coauthors wrote. Of those cases, 26 (62%) were associated with a poor Brief Smell Identification Test (BSIT) score of 0-8 out of 12 (hazard ratio, 5.1; 95% confidence interval, 2.1-11.9), supporting other studies that indicate that olfactory impairment is one of the early symptoms of PD.
In contrast to previous studies, however, “the current study has longer follow-up and showed that poor olfaction was associated with PD beyond the first [4] years of follow-up, although the association was somewhat attenuated,” the researchers said. Both before and after the first 5 years of follow-up, 13 people in the lowest BSIT tertile were diagnosed with PD (HR, 4.2; 95% CI, 1.7-10.8 vs. HR, 4.1; 95% CI, 1.7-9.8, respectively),
In addition, poor sense of smell was more clearly associated with PD diagnosis in white patients, Dr. Chen and her coauthors said. Of 30 PD diagnoses in white participants, 19 were associated with poor smell (HR, 4.9; 95% CI, 2.3-10.5), compared with 7 out of 12 diagnoses in black participants (HR, 2.5; 95% CI, 0.8-8.1; P = .3). Similarly, 19 out of 26 diagnoses in men were associated with poor smell (HR, 5.4; 95% CI, 2.3-12.9), compared with 7 out of 16 diagnoses in women (HR, 2.9; 95% CI, 1.1-7.8; P = .4).
Future studies should confirm these stratified findings. Olfactory dysfunction’s “potential usefulness as a screening tool for prodromal or undiagnosed PD in other general population awaits further investigations,” the authors said.
Dr. Chen reported editorial roles for a number of medical journals. None of the authors reported any financial disclosures.
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Olfactory dysfunction is high in Parkinson’s disease, and the study by Chen et al. is the first to describe the natural history of olfactory dysfunction in the evolution of PD prior to diagnosis in diverse populations with extended periods of follow-up.
The length of follow-up is the longest to date, and includes important data on a large cohort of black participants. The results are a start for creating a much needed preventional paradigm, but more granularity will be needed to determine how poor smell, especially as stratified by race and sex, might help in prevention and treatment of PD.
Gene L. Bowman, ND, MPH, is a physician in the department of neurology at Oregon Health & Science University, Portland. His editorial comments accompanied the Chen et al. article in Neurology. He reported no financial disclosures.
Olfactory dysfunction is high in Parkinson’s disease, and the study by Chen et al. is the first to describe the natural history of olfactory dysfunction in the evolution of PD prior to diagnosis in diverse populations with extended periods of follow-up.
The length of follow-up is the longest to date, and includes important data on a large cohort of black participants. The results are a start for creating a much needed preventional paradigm, but more granularity will be needed to determine how poor smell, especially as stratified by race and sex, might help in prevention and treatment of PD.
Gene L. Bowman, ND, MPH, is a physician in the department of neurology at Oregon Health & Science University, Portland. His editorial comments accompanied the Chen et al. article in Neurology. He reported no financial disclosures.
Olfactory dysfunction is high in Parkinson’s disease, and the study by Chen et al. is the first to describe the natural history of olfactory dysfunction in the evolution of PD prior to diagnosis in diverse populations with extended periods of follow-up.
The length of follow-up is the longest to date, and includes important data on a large cohort of black participants. The results are a start for creating a much needed preventional paradigm, but more granularity will be needed to determine how poor smell, especially as stratified by race and sex, might help in prevention and treatment of PD.
Gene L. Bowman, ND, MPH, is a physician in the department of neurology at Oregon Health & Science University, Portland. His editorial comments accompanied the Chen et al. article in Neurology. He reported no financial disclosures.
Poor olfaction is a predictor of Parkinson’s disease (PD) in both the short and immediate term, with accuracy out to at least 6 years, especially in white men, according to a retrospective case adjudication of the Health ABC study published in Neurology.
Of 2,462 study participants, 42 were found to have PD during an average of 9.8 years of follow-up, Honglei Chen, MD, PhD, of the department of epidemiology and biostatistics at Michigan State University, East Lansing, and his coauthors wrote. Of those cases, 26 (62%) were associated with a poor Brief Smell Identification Test (BSIT) score of 0-8 out of 12 (hazard ratio, 5.1; 95% confidence interval, 2.1-11.9), supporting other studies that indicate that olfactory impairment is one of the early symptoms of PD.
In contrast to previous studies, however, “the current study has longer follow-up and showed that poor olfaction was associated with PD beyond the first [4] years of follow-up, although the association was somewhat attenuated,” the researchers said. Both before and after the first 5 years of follow-up, 13 people in the lowest BSIT tertile were diagnosed with PD (HR, 4.2; 95% CI, 1.7-10.8 vs. HR, 4.1; 95% CI, 1.7-9.8, respectively),
In addition, poor sense of smell was more clearly associated with PD diagnosis in white patients, Dr. Chen and her coauthors said. Of 30 PD diagnoses in white participants, 19 were associated with poor smell (HR, 4.9; 95% CI, 2.3-10.5), compared with 7 out of 12 diagnoses in black participants (HR, 2.5; 95% CI, 0.8-8.1; P = .3). Similarly, 19 out of 26 diagnoses in men were associated with poor smell (HR, 5.4; 95% CI, 2.3-12.9), compared with 7 out of 16 diagnoses in women (HR, 2.9; 95% CI, 1.1-7.8; P = .4).
Future studies should confirm these stratified findings. Olfactory dysfunction’s “potential usefulness as a screening tool for prodromal or undiagnosed PD in other general population awaits further investigations,” the authors said.
Dr. Chen reported editorial roles for a number of medical journals. None of the authors reported any financial disclosures.
email address
Poor olfaction is a predictor of Parkinson’s disease (PD) in both the short and immediate term, with accuracy out to at least 6 years, especially in white men, according to a retrospective case adjudication of the Health ABC study published in Neurology.
Of 2,462 study participants, 42 were found to have PD during an average of 9.8 years of follow-up, Honglei Chen, MD, PhD, of the department of epidemiology and biostatistics at Michigan State University, East Lansing, and his coauthors wrote. Of those cases, 26 (62%) were associated with a poor Brief Smell Identification Test (BSIT) score of 0-8 out of 12 (hazard ratio, 5.1; 95% confidence interval, 2.1-11.9), supporting other studies that indicate that olfactory impairment is one of the early symptoms of PD.
In contrast to previous studies, however, “the current study has longer follow-up and showed that poor olfaction was associated with PD beyond the first [4] years of follow-up, although the association was somewhat attenuated,” the researchers said. Both before and after the first 5 years of follow-up, 13 people in the lowest BSIT tertile were diagnosed with PD (HR, 4.2; 95% CI, 1.7-10.8 vs. HR, 4.1; 95% CI, 1.7-9.8, respectively),
In addition, poor sense of smell was more clearly associated with PD diagnosis in white patients, Dr. Chen and her coauthors said. Of 30 PD diagnoses in white participants, 19 were associated with poor smell (HR, 4.9; 95% CI, 2.3-10.5), compared with 7 out of 12 diagnoses in black participants (HR, 2.5; 95% CI, 0.8-8.1; P = .3). Similarly, 19 out of 26 diagnoses in men were associated with poor smell (HR, 5.4; 95% CI, 2.3-12.9), compared with 7 out of 16 diagnoses in women (HR, 2.9; 95% CI, 1.1-7.8; P = .4).
Future studies should confirm these stratified findings. Olfactory dysfunction’s “potential usefulness as a screening tool for prodromal or undiagnosed PD in other general population awaits further investigations,” the authors said.
Dr. Chen reported editorial roles for a number of medical journals. None of the authors reported any financial disclosures.
email address
FROM NEUROLOGY
Key clinical point:
Major finding: Both before and after the first 5 years of follow-up, 13 people in the lowest BSIT tertile were diagnosed with PD (HR, 4.2; 95% CI, 1.7-10.8 vs. HR, 4.1; 95% CI, 1.7-9.8, respectively).
Data source: A retrospective case adjudication of PD cases diagnosed in the Health ABC study.
Disclosures: Dr. Chen reported editorial roles for a number of medical journals. None of the authors reported any financial disclosures.
Study finds low risk for jaw osteonecrosis with denosumab for postmenopausal osteoporosis
AT ASBMR
DENVER – Osteonecrosis of the jaw (ONJ) was a rare adverse event in women taking denosumab for postmenopausal osteoporosis, with a 0.7% rate for women who reported an invasive oral procedure or event while taking the drug and a 0.05% rate for women who did not have such procedures, Nelson Watts, MD, reported at the annual meeting of the American Society of Bone and Mineral Research.
The finding comes from a new analysis of a 7-year extension study of denosumab use in 4,550 women who participated in the 3-year, double-blind, phase 3 FREEDOM trial (NCT00089791) that compared denosumab 60 mg and placebo every 6 months. Those who missed 1 dose or fewer and completed visits through year 3 of the initial study were eligible to continue in the 7-year, open-label extension study. Those who had received placebo in the initial trial were crossed over to denosumab for the extension study.
Extension study participants were instructed to chronicle invasive oral procedures and events that had occurred in the initial trial and completed an oral event questionnaire once every 6 months of the extension trial.
All surveys were completed by 3,591 (79%) of the extension study participants, and 45.1% reported at least one invasive oral procedure or event during that time. The frequency of events was similar for the crossover and long-term denosumab groups; these events included scaling or root planing (29.1% and 28.5%), tooth extraction (25.1% and 24.6%), dental implant (5.8% and 6.0%), natural tooth loss (4.2% and 4.0%), and jaw surgery (0.9% and 0.9%). ONJ occurred at a rate of 5.2 cases per 10,000 patient-years of denosumab use, said Nelson Watts, MD, director of osteoporosis and bone health services at Mercy Health Services in Cincinnati, Ohio.
Of the 12 ONJ cases identified in the study, 11 occurred in women who reported an invasive oral procedure or event. This translated to a 0.7% risk of ONJ in women who reported an invasive oral procedure or event (11 in 1,621) and a 0.05% risk in women who did not (1 in 1,970).
The most common inciting event for ONJ appeared to be dental extractions, often of two or three teeth. The next most common dental issue associated with ONJ seemed to be poorly-fitted dentures.
ONJ resolved with treatment in 10 of 12 cases; one case was ongoing at the end of the study and one had an unknown outcome because the subject had withdrawn from the study. “With effective dental therapy, healing is the most likely outcome,” said Dr. Watts.
In clinical trials, ONJ occurred at a rate between 1 and 10 per 10,000 patient-years. A report in 2003, however, described severe ONJ in 36 cancer patients who received bisphosphonates (https://www.ncbi.nlm.nih.gov/pubmed/12966493).
The denosumab doses that cancer patients receive can be 10 to 12 times higher than the typical dose given to a postmenopausal woman being treated for osteoporosis.
“I can’t tell you how many phone calls I get from patients who are worried somehow or worried in situations created by their dentists that whatever procedure they’re going to have is going to end horribly,” Dr. Watts said. “In some cases dentists are telling my patients to either stop the drug that I’m giving them or to wait to get the next dose, and there’s absolutely nothing to support that.”
The study was funded by Amgen, the maker of denosumab (Prolia). Dr. Watts has received research support from Shire and has consulted for Abbvie, Amgen, and Radius. He is on the speakers’ bureau for Amgen, Radius, and Shire.
AT ASBMR
DENVER – Osteonecrosis of the jaw (ONJ) was a rare adverse event in women taking denosumab for postmenopausal osteoporosis, with a 0.7% rate for women who reported an invasive oral procedure or event while taking the drug and a 0.05% rate for women who did not have such procedures, Nelson Watts, MD, reported at the annual meeting of the American Society of Bone and Mineral Research.
The finding comes from a new analysis of a 7-year extension study of denosumab use in 4,550 women who participated in the 3-year, double-blind, phase 3 FREEDOM trial (NCT00089791) that compared denosumab 60 mg and placebo every 6 months. Those who missed 1 dose or fewer and completed visits through year 3 of the initial study were eligible to continue in the 7-year, open-label extension study. Those who had received placebo in the initial trial were crossed over to denosumab for the extension study.
Extension study participants were instructed to chronicle invasive oral procedures and events that had occurred in the initial trial and completed an oral event questionnaire once every 6 months of the extension trial.
All surveys were completed by 3,591 (79%) of the extension study participants, and 45.1% reported at least one invasive oral procedure or event during that time. The frequency of events was similar for the crossover and long-term denosumab groups; these events included scaling or root planing (29.1% and 28.5%), tooth extraction (25.1% and 24.6%), dental implant (5.8% and 6.0%), natural tooth loss (4.2% and 4.0%), and jaw surgery (0.9% and 0.9%). ONJ occurred at a rate of 5.2 cases per 10,000 patient-years of denosumab use, said Nelson Watts, MD, director of osteoporosis and bone health services at Mercy Health Services in Cincinnati, Ohio.
Of the 12 ONJ cases identified in the study, 11 occurred in women who reported an invasive oral procedure or event. This translated to a 0.7% risk of ONJ in women who reported an invasive oral procedure or event (11 in 1,621) and a 0.05% risk in women who did not (1 in 1,970).
The most common inciting event for ONJ appeared to be dental extractions, often of two or three teeth. The next most common dental issue associated with ONJ seemed to be poorly-fitted dentures.
ONJ resolved with treatment in 10 of 12 cases; one case was ongoing at the end of the study and one had an unknown outcome because the subject had withdrawn from the study. “With effective dental therapy, healing is the most likely outcome,” said Dr. Watts.
In clinical trials, ONJ occurred at a rate between 1 and 10 per 10,000 patient-years. A report in 2003, however, described severe ONJ in 36 cancer patients who received bisphosphonates (https://www.ncbi.nlm.nih.gov/pubmed/12966493).
The denosumab doses that cancer patients receive can be 10 to 12 times higher than the typical dose given to a postmenopausal woman being treated for osteoporosis.
“I can’t tell you how many phone calls I get from patients who are worried somehow or worried in situations created by their dentists that whatever procedure they’re going to have is going to end horribly,” Dr. Watts said. “In some cases dentists are telling my patients to either stop the drug that I’m giving them or to wait to get the next dose, and there’s absolutely nothing to support that.”
The study was funded by Amgen, the maker of denosumab (Prolia). Dr. Watts has received research support from Shire and has consulted for Abbvie, Amgen, and Radius. He is on the speakers’ bureau for Amgen, Radius, and Shire.
AT ASBMR
DENVER – Osteonecrosis of the jaw (ONJ) was a rare adverse event in women taking denosumab for postmenopausal osteoporosis, with a 0.7% rate for women who reported an invasive oral procedure or event while taking the drug and a 0.05% rate for women who did not have such procedures, Nelson Watts, MD, reported at the annual meeting of the American Society of Bone and Mineral Research.
The finding comes from a new analysis of a 7-year extension study of denosumab use in 4,550 women who participated in the 3-year, double-blind, phase 3 FREEDOM trial (NCT00089791) that compared denosumab 60 mg and placebo every 6 months. Those who missed 1 dose or fewer and completed visits through year 3 of the initial study were eligible to continue in the 7-year, open-label extension study. Those who had received placebo in the initial trial were crossed over to denosumab for the extension study.
Extension study participants were instructed to chronicle invasive oral procedures and events that had occurred in the initial trial and completed an oral event questionnaire once every 6 months of the extension trial.
All surveys were completed by 3,591 (79%) of the extension study participants, and 45.1% reported at least one invasive oral procedure or event during that time. The frequency of events was similar for the crossover and long-term denosumab groups; these events included scaling or root planing (29.1% and 28.5%), tooth extraction (25.1% and 24.6%), dental implant (5.8% and 6.0%), natural tooth loss (4.2% and 4.0%), and jaw surgery (0.9% and 0.9%). ONJ occurred at a rate of 5.2 cases per 10,000 patient-years of denosumab use, said Nelson Watts, MD, director of osteoporosis and bone health services at Mercy Health Services in Cincinnati, Ohio.
Of the 12 ONJ cases identified in the study, 11 occurred in women who reported an invasive oral procedure or event. This translated to a 0.7% risk of ONJ in women who reported an invasive oral procedure or event (11 in 1,621) and a 0.05% risk in women who did not (1 in 1,970).
The most common inciting event for ONJ appeared to be dental extractions, often of two or three teeth. The next most common dental issue associated with ONJ seemed to be poorly-fitted dentures.
ONJ resolved with treatment in 10 of 12 cases; one case was ongoing at the end of the study and one had an unknown outcome because the subject had withdrawn from the study. “With effective dental therapy, healing is the most likely outcome,” said Dr. Watts.
In clinical trials, ONJ occurred at a rate between 1 and 10 per 10,000 patient-years. A report in 2003, however, described severe ONJ in 36 cancer patients who received bisphosphonates (https://www.ncbi.nlm.nih.gov/pubmed/12966493).
The denosumab doses that cancer patients receive can be 10 to 12 times higher than the typical dose given to a postmenopausal woman being treated for osteoporosis.
“I can’t tell you how many phone calls I get from patients who are worried somehow or worried in situations created by their dentists that whatever procedure they’re going to have is going to end horribly,” Dr. Watts said. “In some cases dentists are telling my patients to either stop the drug that I’m giving them or to wait to get the next dose, and there’s absolutely nothing to support that.”
The study was funded by Amgen, the maker of denosumab (Prolia). Dr. Watts has received research support from Shire and has consulted for Abbvie, Amgen, and Radius. He is on the speakers’ bureau for Amgen, Radius, and Shire.
Meningitis B vaccine’s high price tag poses a health care conundrum
Four years ago, when meningitis B, an extremely rare but potentially lethal form of the infection, sickened a small number of college students at Princeton and the University of California–Santa Barbara, there was no vaccine against the disease sold in the U.S. Despite its availability abroad, it had never been licensed in the country due to its limited marketability.
Scientific evidence supporting an absolute need to immunize against meningitis B still falls short. The risk of contracting it is smaller than that of being involved in a car crash.
But the headlines prompted by those 13 campus cases – which resulted in one death and one double amputation – helped reshape the financial prospects for a vaccine.
Today, two brand-name vaccines, both with price tags of more than $300, are widely advertised on television and touted as a smart investment for parents who love their college-bound kids.
“As moms, we send our kids out into the world, full of hope,” says a mother in the ad for Bexsero, sold by pharmaceutical giant GlaxoSmithKline, as her son loads up the car to go off to college.
Says another voice, “And we don’t want something like meningitis B getting in their way.”
Analysts expect the two vaccines to generate annually at least hundreds of millions of dollars in global sales.
As new crops of students head to college, some physicians and other industry experts, though, are growing uneasy about the role of marketing in leveraging parental fears to sell the MenB vaccine – as well as ever more expensive vaccines that prevent quite rare illnesses. A complete Bexsero series costs $320; a competing vaccine, Trumenba, costs $345.
“Parents believe their children are susceptible to this terrible condition, and [drugmakers] use that fear to get parents to take action,” said Adrienne Faerber, a lecturer at the Dartmouth Institute for Health Policy and Clinical Practice who researches drug marketing.
The advertising, especially when coupled with news coverage, puts parents in a quandary left unresolved by federal vaccination guidelines and university requirements.
The Centers for Disease Control and Prevention recommends doctors consider the meningitis B vaccine for people ages 16-23 years on an individual basis. This recommendation – ranked as a category B – is not as universal as the approach applied to illnesses such as measles or human papillomavirus vaccines or even the “quadrivalent” vaccine for meningitis A, C, W, and Y, which all students must get.
Meanwhile, insurers generally cover it as part of preventive care. Still, most universities don’t require the vaccine but simply list it as an option for families to consider.
The resulting messages can confuse parents.
“There is perhaps, with all the marketing and advertising, some bending of the truth, and perhaps a little bit of creating fear – again recognizing that meningitis disease is a very severe disease,” said William Moss, a professor at Johns Hopkins Bloomberg School of Public Health who specializes in vaccines and global children’s health. “[The risk] is not a large enough problem to warrant routine vaccination.”
In recent years, drugmakers’ interests have begun to expand beyond the relatively cheap, broadly used immunizations – such as a tetanus shot or the children’s hepatitis A vaccine – to new, much pricier ones for less common infections.
These newer treatments have the potential to transform what’s long been a less lucrative side of drug production, manufacturing vaccines, into a major cash cow. But since the newer vaccines are regarded as less crucial than, say, preventing measles – and are often not required – marketing has become a big part of the sales equation.
Bexsero and its competitor, Trumenba, offer clues into how this scenario plays out.
Both vaccines got accelerated approval by the Food and Drug Administration in 2015 and 2014 respectively, following the Princeton and UCSB outbreaks.
Meningitis B does not spread readily from person to person. It requires close physical contact, like kissing or sharing utensils. It can be fatal but is treatable with antibiotics if caught early. Caused by the B serogroup of the meningococcal infection, it tends to appear in rare-scatter, slowed, self-limited outbreaks on college campuses. The standard meningitis vaccine doesn’t prevent it.
After new cases at Princeton and UC Santa Barbara kept appearing over many months, the CDC arranged for an emergency import of Bexsero. All students on those campuses got the shots, and there were no more cases.
Now the drugmakers are urging all parents to be proactive. Last year, Pfizer put more than $21 million into paid advertisements for the vaccine, according to figures kept by Kantar Media, a firm that tracks multimedia advertising. GlaxoSmithKline put in just about $79,000.
Those figures don’t account for other efforts such as meningitis awareness and ongoing social media campaigns done by GlaxoSmithKline, a “substantial effort” that “wasn’t cheap,” said Sriram Jambunathan, who heads GlaxoSmithKline’s meningococcal franchise in the United States. They also don’t include Pfizer’s investments in similar activities.
Already, industry analysts forecast Bexsero could bring in global revenue north of $1 billion per year by 2022. Trumenba is expected to earn Pfizer $880 million by that time.
But the industry’s gain may come at the expense of efficient health care spending and inflated consumer concern.
First, there’s the relative rarity of meningitis B. The CDC has estimated fewer than 300 cases occur in the United States per year, and some medical experts interviewed suggested the number may be closer to 50 or 60.
“As a mom, I would say, if my kid got this disease, and I had had the opportunity to prevent it, and I didn’t, I would kill myself,” said Martha Arden, a practicing physician and the medical director of Mount Sinai Adolescent Health Center’s school-based health program in New York City. “But the odds are small. It’s much more dangerous to send a kid out skiing than it is to not give the vaccine.”
Jambunathan said the price tag is warranted given the resources needed to bring Bexsero to market. Similar vaccines, he added, are comparably priced, and firms won’t necessarily want to develop these pharmaceuticals if they aren’t sure they can recoup their investment.
For parents who opt for the vaccines, there are caveats. Researchers don’t know, for instance, how long its immunity lasts. Many noted it also doesn’t cover all strains of the infection, so its efficacy in the United States is uncertain (there are different strains in different parts of the world).
And the cost of vaccination, while substantial, isn’t immediately felt by consumers because the treatment usually is covered without having to pay out-of-pocket. But the price tag may contribute to increasing premium costs.
In a world where there already aren’t enough health care dollars to address every possible harm, many experts noted, other health concerns might be a smarter investment.
Still, the price tag might not cause parents to blink. “When it’s your child or one case you know about, suddenly the health economic arguments feel difficult to have,” Jambunathan said.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
In October 2014 and January 2015, the Food and Drug Administration licensed two meningococcal serogroup B vaccines for administration in adolescents and young adults aged 10-25 years based on each vaccine's ability to elicit bactericidal antibody against the majority of invasive serogroup B strains and demonstrated safety. Each vaccine represented novel technology that overcame the challenge of both the poor immunogenicity of serogroup B polysaccharide protein conjugates and the potential cross reactivity with fetal brain tissue. In the United States, the vaccine was recommended (category A) for individuals in this age grouping with complement deficiency, anatomic or functional asplenia, outbreaks (when indicated), and for microbiologists. The Centers for Disease Control and Prevention also recommends that physicians consider the MenB vaccine for individuals aged 16-23 years who wish to obtain short-term protection against diverse strains of serogroup B meningococcal disease (category B). The American Academy of Pediatrics encouraged pediatricians to discuss the availability of the MenB vaccines with families.
The annual incidence of meningococcal disease varied between approximately 0.5-1.5 cases per 100,000 population between 1950 and 1990 - approximately 3,000 cases annually. Between 1990 and 2010, disease caused by the three common serogroups in the United States (B, C, and Y) declined to approximately 0.35 cases per 100,000. Subsequent to the introduction of a tetravalent meningococcal conjugate vaccine (MCV4) further declines - sustained over a longer time period than previously observed - have occurred, reaching a nadir of approximately 400 annual cases. Despite the absence of serogroup B component in MCV4, declines in serogroup B disease were reported in addition to vaccine serogroups C and Y. The biological explanations for the substantial decline in the overall rate of meningococcal disease are unknown. This decline in meningococcal serogroup B disease has created a controversy about implementation of Advisory Committee of Immunization Practices and the AAP and American Academy of Family Physician recommendations reflected in Shefali Luthra's writings.
There is widespread agreement about the severity of invasive meningococcal disease, the peaks of incidence in infancy and late adolescence, a 10% case fatality rate, an additional 10%-15% morbidity, and the limited number of cases (in the United States) to be prevented by adolescent immunization despite serogroup B being the most common. The effectiveness (greater than 80%) of at least one of these vaccines (MenB-4C) has been established in the United Kingdom, where it is recommended for all infants as part of a three-dose series at 2, 4, and 12 months. The value proposition (number of people immunized to prevent one death), however, is estimated at 1 million vaccinees for each death prevented.
Some experts believe the small burden of disease that might be prevented by these expensive vaccines requires thoughtful consideration in this era of increasingly limited resources. Others (as cited in the accompanying article) believe the marketing and advertising bend the truth and create fear in the public and conclude the risk is not great enough to warrant universal immunization (called category A by ACIP designation). In contrast, parent groups (especially those including parents of children who had meningococcal serogroup B disease) advocate strongly for a universal approach. For example, Alicia Stillman, director of the Emily Stillman Foundation, feels the current recommendation is "irresponsible" because it leaves so many teens and young adults vulnerable to the disease. The group believes that ACIP has made the menB vaccine to be an "optional item," but there is no requirement to provide the education to the parent and/or patient so they are aware of this option.
For me, the question is this: Who should decide how we use limited resources? I am reminded of an editorial in the New England Journal of Medicine titled, "The Meningococcal Vaccine - Public Policy and Individual Choices" by Paul Offit, MD, and Georges Peter, MD, that examined this question (N Engl J Med. 2003;349[24]:2353-6). They advocated that parents, if aware, may choose vaccination to protect adolescents and young adults from devastating infection, even if they were required to pay. I believe the CDC foresaw this as likely and moved to recommend individual choice. The wisdom of this was that category B status required MenB vaccine to be covered by insurers, thus preventing a potential divergent uptake, where families that could afford the price would recognize its value and those unable to pay for the vaccine would have no choice but to decline. This is especially relevant as there are not specific risk factors among healthy adolescents to warrant prioritizing one group over another.
MenB vaccines are valuable but costly tools for the prevention of life-threatening infectious disease. The use of increasingly limited resources, as raised by Dr. Moss and others, is a relevant and important question, and a call for a national dialogue.
As new medical breakthroughs increase, seemingly exponentially, how do we resolve the individual versus societal benefit of costly new treatments or preventions? How do we value prevention of life-threatening illness and death in mostly healthy adolescents, compared with treatment of end-stage diseases? These are important conversations that are only in their infancy.
Abraham Verghese wrote, in his book "Cutting for Stone," that American ambulance crews "salvaged people we'd never see in Missing [fictional hospital in Addis Ababa], because no one would have tried to bring them to a hospital [in Addis Ababa]. Judging someone to be beyond help never crossed the minds of police, firemen, or doctors here" in the United States. We need transparency and a national dialogue to develop consensus about priorities. We need to make sure the discussions are comprehensive and civil - not about pushing grandmothers over cliffs or death panels. Currently, ACIP and AAP have advocated for individual choice and to empower the parent and adolescent to choose after we (clinicians) communicate disease severity, the risk to the adolescent, and adverse events associated with MenB vaccine.
Stephen I. Pelton, MD, is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. Dr. Pelton disclosed that he has participated in advisory boards on meningitis B vaccines for GlaxoSmithKline and Pfizer, has research grants from Pfizer and Merck, and has spoken at CME events on meningitis B vaccines.
In October 2014 and January 2015, the Food and Drug Administration licensed two meningococcal serogroup B vaccines for administration in adolescents and young adults aged 10-25 years based on each vaccine's ability to elicit bactericidal antibody against the majority of invasive serogroup B strains and demonstrated safety. Each vaccine represented novel technology that overcame the challenge of both the poor immunogenicity of serogroup B polysaccharide protein conjugates and the potential cross reactivity with fetal brain tissue. In the United States, the vaccine was recommended (category A) for individuals in this age grouping with complement deficiency, anatomic or functional asplenia, outbreaks (when indicated), and for microbiologists. The Centers for Disease Control and Prevention also recommends that physicians consider the MenB vaccine for individuals aged 16-23 years who wish to obtain short-term protection against diverse strains of serogroup B meningococcal disease (category B). The American Academy of Pediatrics encouraged pediatricians to discuss the availability of the MenB vaccines with families.
The annual incidence of meningococcal disease varied between approximately 0.5-1.5 cases per 100,000 population between 1950 and 1990 - approximately 3,000 cases annually. Between 1990 and 2010, disease caused by the three common serogroups in the United States (B, C, and Y) declined to approximately 0.35 cases per 100,000. Subsequent to the introduction of a tetravalent meningococcal conjugate vaccine (MCV4) further declines - sustained over a longer time period than previously observed - have occurred, reaching a nadir of approximately 400 annual cases. Despite the absence of serogroup B component in MCV4, declines in serogroup B disease were reported in addition to vaccine serogroups C and Y. The biological explanations for the substantial decline in the overall rate of meningococcal disease are unknown. This decline in meningococcal serogroup B disease has created a controversy about implementation of Advisory Committee of Immunization Practices and the AAP and American Academy of Family Physician recommendations reflected in Shefali Luthra's writings.
There is widespread agreement about the severity of invasive meningococcal disease, the peaks of incidence in infancy and late adolescence, a 10% case fatality rate, an additional 10%-15% morbidity, and the limited number of cases (in the United States) to be prevented by adolescent immunization despite serogroup B being the most common. The effectiveness (greater than 80%) of at least one of these vaccines (MenB-4C) has been established in the United Kingdom, where it is recommended for all infants as part of a three-dose series at 2, 4, and 12 months. The value proposition (number of people immunized to prevent one death), however, is estimated at 1 million vaccinees for each death prevented.
Some experts believe the small burden of disease that might be prevented by these expensive vaccines requires thoughtful consideration in this era of increasingly limited resources. Others (as cited in the accompanying article) believe the marketing and advertising bend the truth and create fear in the public and conclude the risk is not great enough to warrant universal immunization (called category A by ACIP designation). In contrast, parent groups (especially those including parents of children who had meningococcal serogroup B disease) advocate strongly for a universal approach. For example, Alicia Stillman, director of the Emily Stillman Foundation, feels the current recommendation is "irresponsible" because it leaves so many teens and young adults vulnerable to the disease. The group believes that ACIP has made the menB vaccine to be an "optional item," but there is no requirement to provide the education to the parent and/or patient so they are aware of this option.
For me, the question is this: Who should decide how we use limited resources? I am reminded of an editorial in the New England Journal of Medicine titled, "The Meningococcal Vaccine - Public Policy and Individual Choices" by Paul Offit, MD, and Georges Peter, MD, that examined this question (N Engl J Med. 2003;349[24]:2353-6). They advocated that parents, if aware, may choose vaccination to protect adolescents and young adults from devastating infection, even if they were required to pay. I believe the CDC foresaw this as likely and moved to recommend individual choice. The wisdom of this was that category B status required MenB vaccine to be covered by insurers, thus preventing a potential divergent uptake, where families that could afford the price would recognize its value and those unable to pay for the vaccine would have no choice but to decline. This is especially relevant as there are not specific risk factors among healthy adolescents to warrant prioritizing one group over another.
MenB vaccines are valuable but costly tools for the prevention of life-threatening infectious disease. The use of increasingly limited resources, as raised by Dr. Moss and others, is a relevant and important question, and a call for a national dialogue.
As new medical breakthroughs increase, seemingly exponentially, how do we resolve the individual versus societal benefit of costly new treatments or preventions? How do we value prevention of life-threatening illness and death in mostly healthy adolescents, compared with treatment of end-stage diseases? These are important conversations that are only in their infancy.
Abraham Verghese wrote, in his book "Cutting for Stone," that American ambulance crews "salvaged people we'd never see in Missing [fictional hospital in Addis Ababa], because no one would have tried to bring them to a hospital [in Addis Ababa]. Judging someone to be beyond help never crossed the minds of police, firemen, or doctors here" in the United States. We need transparency and a national dialogue to develop consensus about priorities. We need to make sure the discussions are comprehensive and civil - not about pushing grandmothers over cliffs or death panels. Currently, ACIP and AAP have advocated for individual choice and to empower the parent and adolescent to choose after we (clinicians) communicate disease severity, the risk to the adolescent, and adverse events associated with MenB vaccine.
Stephen I. Pelton, MD, is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. Dr. Pelton disclosed that he has participated in advisory boards on meningitis B vaccines for GlaxoSmithKline and Pfizer, has research grants from Pfizer and Merck, and has spoken at CME events on meningitis B vaccines.
In October 2014 and January 2015, the Food and Drug Administration licensed two meningococcal serogroup B vaccines for administration in adolescents and young adults aged 10-25 years based on each vaccine's ability to elicit bactericidal antibody against the majority of invasive serogroup B strains and demonstrated safety. Each vaccine represented novel technology that overcame the challenge of both the poor immunogenicity of serogroup B polysaccharide protein conjugates and the potential cross reactivity with fetal brain tissue. In the United States, the vaccine was recommended (category A) for individuals in this age grouping with complement deficiency, anatomic or functional asplenia, outbreaks (when indicated), and for microbiologists. The Centers for Disease Control and Prevention also recommends that physicians consider the MenB vaccine for individuals aged 16-23 years who wish to obtain short-term protection against diverse strains of serogroup B meningococcal disease (category B). The American Academy of Pediatrics encouraged pediatricians to discuss the availability of the MenB vaccines with families.
The annual incidence of meningococcal disease varied between approximately 0.5-1.5 cases per 100,000 population between 1950 and 1990 - approximately 3,000 cases annually. Between 1990 and 2010, disease caused by the three common serogroups in the United States (B, C, and Y) declined to approximately 0.35 cases per 100,000. Subsequent to the introduction of a tetravalent meningococcal conjugate vaccine (MCV4) further declines - sustained over a longer time period than previously observed - have occurred, reaching a nadir of approximately 400 annual cases. Despite the absence of serogroup B component in MCV4, declines in serogroup B disease were reported in addition to vaccine serogroups C and Y. The biological explanations for the substantial decline in the overall rate of meningococcal disease are unknown. This decline in meningococcal serogroup B disease has created a controversy about implementation of Advisory Committee of Immunization Practices and the AAP and American Academy of Family Physician recommendations reflected in Shefali Luthra's writings.
There is widespread agreement about the severity of invasive meningococcal disease, the peaks of incidence in infancy and late adolescence, a 10% case fatality rate, an additional 10%-15% morbidity, and the limited number of cases (in the United States) to be prevented by adolescent immunization despite serogroup B being the most common. The effectiveness (greater than 80%) of at least one of these vaccines (MenB-4C) has been established in the United Kingdom, where it is recommended for all infants as part of a three-dose series at 2, 4, and 12 months. The value proposition (number of people immunized to prevent one death), however, is estimated at 1 million vaccinees for each death prevented.
Some experts believe the small burden of disease that might be prevented by these expensive vaccines requires thoughtful consideration in this era of increasingly limited resources. Others (as cited in the accompanying article) believe the marketing and advertising bend the truth and create fear in the public and conclude the risk is not great enough to warrant universal immunization (called category A by ACIP designation). In contrast, parent groups (especially those including parents of children who had meningococcal serogroup B disease) advocate strongly for a universal approach. For example, Alicia Stillman, director of the Emily Stillman Foundation, feels the current recommendation is "irresponsible" because it leaves so many teens and young adults vulnerable to the disease. The group believes that ACIP has made the menB vaccine to be an "optional item," but there is no requirement to provide the education to the parent and/or patient so they are aware of this option.
For me, the question is this: Who should decide how we use limited resources? I am reminded of an editorial in the New England Journal of Medicine titled, "The Meningococcal Vaccine - Public Policy and Individual Choices" by Paul Offit, MD, and Georges Peter, MD, that examined this question (N Engl J Med. 2003;349[24]:2353-6). They advocated that parents, if aware, may choose vaccination to protect adolescents and young adults from devastating infection, even if they were required to pay. I believe the CDC foresaw this as likely and moved to recommend individual choice. The wisdom of this was that category B status required MenB vaccine to be covered by insurers, thus preventing a potential divergent uptake, where families that could afford the price would recognize its value and those unable to pay for the vaccine would have no choice but to decline. This is especially relevant as there are not specific risk factors among healthy adolescents to warrant prioritizing one group over another.
MenB vaccines are valuable but costly tools for the prevention of life-threatening infectious disease. The use of increasingly limited resources, as raised by Dr. Moss and others, is a relevant and important question, and a call for a national dialogue.
As new medical breakthroughs increase, seemingly exponentially, how do we resolve the individual versus societal benefit of costly new treatments or preventions? How do we value prevention of life-threatening illness and death in mostly healthy adolescents, compared with treatment of end-stage diseases? These are important conversations that are only in their infancy.
Abraham Verghese wrote, in his book "Cutting for Stone," that American ambulance crews "salvaged people we'd never see in Missing [fictional hospital in Addis Ababa], because no one would have tried to bring them to a hospital [in Addis Ababa]. Judging someone to be beyond help never crossed the minds of police, firemen, or doctors here" in the United States. We need transparency and a national dialogue to develop consensus about priorities. We need to make sure the discussions are comprehensive and civil - not about pushing grandmothers over cliffs or death panels. Currently, ACIP and AAP have advocated for individual choice and to empower the parent and adolescent to choose after we (clinicians) communicate disease severity, the risk to the adolescent, and adverse events associated with MenB vaccine.
Stephen I. Pelton, MD, is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. Dr. Pelton disclosed that he has participated in advisory boards on meningitis B vaccines for GlaxoSmithKline and Pfizer, has research grants from Pfizer and Merck, and has spoken at CME events on meningitis B vaccines.
Four years ago, when meningitis B, an extremely rare but potentially lethal form of the infection, sickened a small number of college students at Princeton and the University of California–Santa Barbara, there was no vaccine against the disease sold in the U.S. Despite its availability abroad, it had never been licensed in the country due to its limited marketability.
Scientific evidence supporting an absolute need to immunize against meningitis B still falls short. The risk of contracting it is smaller than that of being involved in a car crash.
But the headlines prompted by those 13 campus cases – which resulted in one death and one double amputation – helped reshape the financial prospects for a vaccine.
Today, two brand-name vaccines, both with price tags of more than $300, are widely advertised on television and touted as a smart investment for parents who love their college-bound kids.
“As moms, we send our kids out into the world, full of hope,” says a mother in the ad for Bexsero, sold by pharmaceutical giant GlaxoSmithKline, as her son loads up the car to go off to college.
Says another voice, “And we don’t want something like meningitis B getting in their way.”
Analysts expect the two vaccines to generate annually at least hundreds of millions of dollars in global sales.
As new crops of students head to college, some physicians and other industry experts, though, are growing uneasy about the role of marketing in leveraging parental fears to sell the MenB vaccine – as well as ever more expensive vaccines that prevent quite rare illnesses. A complete Bexsero series costs $320; a competing vaccine, Trumenba, costs $345.
“Parents believe their children are susceptible to this terrible condition, and [drugmakers] use that fear to get parents to take action,” said Adrienne Faerber, a lecturer at the Dartmouth Institute for Health Policy and Clinical Practice who researches drug marketing.
The advertising, especially when coupled with news coverage, puts parents in a quandary left unresolved by federal vaccination guidelines and university requirements.
The Centers for Disease Control and Prevention recommends doctors consider the meningitis B vaccine for people ages 16-23 years on an individual basis. This recommendation – ranked as a category B – is not as universal as the approach applied to illnesses such as measles or human papillomavirus vaccines or even the “quadrivalent” vaccine for meningitis A, C, W, and Y, which all students must get.
Meanwhile, insurers generally cover it as part of preventive care. Still, most universities don’t require the vaccine but simply list it as an option for families to consider.
The resulting messages can confuse parents.
“There is perhaps, with all the marketing and advertising, some bending of the truth, and perhaps a little bit of creating fear – again recognizing that meningitis disease is a very severe disease,” said William Moss, a professor at Johns Hopkins Bloomberg School of Public Health who specializes in vaccines and global children’s health. “[The risk] is not a large enough problem to warrant routine vaccination.”
In recent years, drugmakers’ interests have begun to expand beyond the relatively cheap, broadly used immunizations – such as a tetanus shot or the children’s hepatitis A vaccine – to new, much pricier ones for less common infections.
These newer treatments have the potential to transform what’s long been a less lucrative side of drug production, manufacturing vaccines, into a major cash cow. But since the newer vaccines are regarded as less crucial than, say, preventing measles – and are often not required – marketing has become a big part of the sales equation.
Bexsero and its competitor, Trumenba, offer clues into how this scenario plays out.
Both vaccines got accelerated approval by the Food and Drug Administration in 2015 and 2014 respectively, following the Princeton and UCSB outbreaks.
Meningitis B does not spread readily from person to person. It requires close physical contact, like kissing or sharing utensils. It can be fatal but is treatable with antibiotics if caught early. Caused by the B serogroup of the meningococcal infection, it tends to appear in rare-scatter, slowed, self-limited outbreaks on college campuses. The standard meningitis vaccine doesn’t prevent it.
After new cases at Princeton and UC Santa Barbara kept appearing over many months, the CDC arranged for an emergency import of Bexsero. All students on those campuses got the shots, and there were no more cases.
Now the drugmakers are urging all parents to be proactive. Last year, Pfizer put more than $21 million into paid advertisements for the vaccine, according to figures kept by Kantar Media, a firm that tracks multimedia advertising. GlaxoSmithKline put in just about $79,000.
Those figures don’t account for other efforts such as meningitis awareness and ongoing social media campaigns done by GlaxoSmithKline, a “substantial effort” that “wasn’t cheap,” said Sriram Jambunathan, who heads GlaxoSmithKline’s meningococcal franchise in the United States. They also don’t include Pfizer’s investments in similar activities.
Already, industry analysts forecast Bexsero could bring in global revenue north of $1 billion per year by 2022. Trumenba is expected to earn Pfizer $880 million by that time.
But the industry’s gain may come at the expense of efficient health care spending and inflated consumer concern.
First, there’s the relative rarity of meningitis B. The CDC has estimated fewer than 300 cases occur in the United States per year, and some medical experts interviewed suggested the number may be closer to 50 or 60.
“As a mom, I would say, if my kid got this disease, and I had had the opportunity to prevent it, and I didn’t, I would kill myself,” said Martha Arden, a practicing physician and the medical director of Mount Sinai Adolescent Health Center’s school-based health program in New York City. “But the odds are small. It’s much more dangerous to send a kid out skiing than it is to not give the vaccine.”
Jambunathan said the price tag is warranted given the resources needed to bring Bexsero to market. Similar vaccines, he added, are comparably priced, and firms won’t necessarily want to develop these pharmaceuticals if they aren’t sure they can recoup their investment.
For parents who opt for the vaccines, there are caveats. Researchers don’t know, for instance, how long its immunity lasts. Many noted it also doesn’t cover all strains of the infection, so its efficacy in the United States is uncertain (there are different strains in different parts of the world).
And the cost of vaccination, while substantial, isn’t immediately felt by consumers because the treatment usually is covered without having to pay out-of-pocket. But the price tag may contribute to increasing premium costs.
In a world where there already aren’t enough health care dollars to address every possible harm, many experts noted, other health concerns might be a smarter investment.
Still, the price tag might not cause parents to blink. “When it’s your child or one case you know about, suddenly the health economic arguments feel difficult to have,” Jambunathan said.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
Four years ago, when meningitis B, an extremely rare but potentially lethal form of the infection, sickened a small number of college students at Princeton and the University of California–Santa Barbara, there was no vaccine against the disease sold in the U.S. Despite its availability abroad, it had never been licensed in the country due to its limited marketability.
Scientific evidence supporting an absolute need to immunize against meningitis B still falls short. The risk of contracting it is smaller than that of being involved in a car crash.
But the headlines prompted by those 13 campus cases – which resulted in one death and one double amputation – helped reshape the financial prospects for a vaccine.
Today, two brand-name vaccines, both with price tags of more than $300, are widely advertised on television and touted as a smart investment for parents who love their college-bound kids.
“As moms, we send our kids out into the world, full of hope,” says a mother in the ad for Bexsero, sold by pharmaceutical giant GlaxoSmithKline, as her son loads up the car to go off to college.
Says another voice, “And we don’t want something like meningitis B getting in their way.”
Analysts expect the two vaccines to generate annually at least hundreds of millions of dollars in global sales.
As new crops of students head to college, some physicians and other industry experts, though, are growing uneasy about the role of marketing in leveraging parental fears to sell the MenB vaccine – as well as ever more expensive vaccines that prevent quite rare illnesses. A complete Bexsero series costs $320; a competing vaccine, Trumenba, costs $345.
“Parents believe their children are susceptible to this terrible condition, and [drugmakers] use that fear to get parents to take action,” said Adrienne Faerber, a lecturer at the Dartmouth Institute for Health Policy and Clinical Practice who researches drug marketing.
The advertising, especially when coupled with news coverage, puts parents in a quandary left unresolved by federal vaccination guidelines and university requirements.
The Centers for Disease Control and Prevention recommends doctors consider the meningitis B vaccine for people ages 16-23 years on an individual basis. This recommendation – ranked as a category B – is not as universal as the approach applied to illnesses such as measles or human papillomavirus vaccines or even the “quadrivalent” vaccine for meningitis A, C, W, and Y, which all students must get.
Meanwhile, insurers generally cover it as part of preventive care. Still, most universities don’t require the vaccine but simply list it as an option for families to consider.
The resulting messages can confuse parents.
“There is perhaps, with all the marketing and advertising, some bending of the truth, and perhaps a little bit of creating fear – again recognizing that meningitis disease is a very severe disease,” said William Moss, a professor at Johns Hopkins Bloomberg School of Public Health who specializes in vaccines and global children’s health. “[The risk] is not a large enough problem to warrant routine vaccination.”
In recent years, drugmakers’ interests have begun to expand beyond the relatively cheap, broadly used immunizations – such as a tetanus shot or the children’s hepatitis A vaccine – to new, much pricier ones for less common infections.
These newer treatments have the potential to transform what’s long been a less lucrative side of drug production, manufacturing vaccines, into a major cash cow. But since the newer vaccines are regarded as less crucial than, say, preventing measles – and are often not required – marketing has become a big part of the sales equation.
Bexsero and its competitor, Trumenba, offer clues into how this scenario plays out.
Both vaccines got accelerated approval by the Food and Drug Administration in 2015 and 2014 respectively, following the Princeton and UCSB outbreaks.
Meningitis B does not spread readily from person to person. It requires close physical contact, like kissing or sharing utensils. It can be fatal but is treatable with antibiotics if caught early. Caused by the B serogroup of the meningococcal infection, it tends to appear in rare-scatter, slowed, self-limited outbreaks on college campuses. The standard meningitis vaccine doesn’t prevent it.
After new cases at Princeton and UC Santa Barbara kept appearing over many months, the CDC arranged for an emergency import of Bexsero. All students on those campuses got the shots, and there were no more cases.
Now the drugmakers are urging all parents to be proactive. Last year, Pfizer put more than $21 million into paid advertisements for the vaccine, according to figures kept by Kantar Media, a firm that tracks multimedia advertising. GlaxoSmithKline put in just about $79,000.
Those figures don’t account for other efforts such as meningitis awareness and ongoing social media campaigns done by GlaxoSmithKline, a “substantial effort” that “wasn’t cheap,” said Sriram Jambunathan, who heads GlaxoSmithKline’s meningococcal franchise in the United States. They also don’t include Pfizer’s investments in similar activities.
Already, industry analysts forecast Bexsero could bring in global revenue north of $1 billion per year by 2022. Trumenba is expected to earn Pfizer $880 million by that time.
But the industry’s gain may come at the expense of efficient health care spending and inflated consumer concern.
First, there’s the relative rarity of meningitis B. The CDC has estimated fewer than 300 cases occur in the United States per year, and some medical experts interviewed suggested the number may be closer to 50 or 60.
“As a mom, I would say, if my kid got this disease, and I had had the opportunity to prevent it, and I didn’t, I would kill myself,” said Martha Arden, a practicing physician and the medical director of Mount Sinai Adolescent Health Center’s school-based health program in New York City. “But the odds are small. It’s much more dangerous to send a kid out skiing than it is to not give the vaccine.”
Jambunathan said the price tag is warranted given the resources needed to bring Bexsero to market. Similar vaccines, he added, are comparably priced, and firms won’t necessarily want to develop these pharmaceuticals if they aren’t sure they can recoup their investment.
For parents who opt for the vaccines, there are caveats. Researchers don’t know, for instance, how long its immunity lasts. Many noted it also doesn’t cover all strains of the infection, so its efficacy in the United States is uncertain (there are different strains in different parts of the world).
And the cost of vaccination, while substantial, isn’t immediately felt by consumers because the treatment usually is covered without having to pay out-of-pocket. But the price tag may contribute to increasing premium costs.
In a world where there already aren’t enough health care dollars to address every possible harm, many experts noted, other health concerns might be a smarter investment.
Still, the price tag might not cause parents to blink. “When it’s your child or one case you know about, suddenly the health economic arguments feel difficult to have,” Jambunathan said.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
CB-5083 showed significant activity against B-ALL
A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.
The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.
CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext
The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”
The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.
A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.
The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.
CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext
The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”
The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.
A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.
The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.
CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext
The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”
The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.
FROM NEOPLASIA
Key clinical point: A novel oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells.
Major finding: After exposure, BALL1 and OP1 cell lines showed early and strong indicators of apoptosis and robust cleavage of PARP.
Data source: In vitro studies of human B-ALL cells and in vivo studies in mice.
Disclosures: The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.
CCSs have higher burden of chronic conditions
Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.
The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.
“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.
The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.
At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).
The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).
The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.
For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.
And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.
“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.
“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.” 
Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.
The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.
“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.
The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.
At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).
The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).
The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.
For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.
And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.
“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.
“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”
Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.
The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.
“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.
The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.
At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).
The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).
The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.
For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.
And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.
“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.
“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”
How to tackle telangiectasias with light
AT MOAS 2017
SAN DIEGO – Multiple light-based devices can be used to treat telangiectasias, often with little or no down time.
During a presentation at the annual Masters of Aesthetics Symposium, Kristen M. Kelly, MD, listed her preferred light-based treatment options for telangiectasias as the pulsed dye laser (PDL), the 532 nm Nd:YAG laser, and the diode laser. The PDL has been around the longest and “is one of the greatest devices for treating vasculature, because it’s very specific,” she said. Purpura can result, but for cosmetic indications, pulse durations of 6 milliseconds or more work well. “Keep in mind, though, that when you’re using longer pulse durations, patients will often require more than one treatment,” she said. “Most people are okay with that, knowing that they’re going to have minimal to no down time with these procedures.”
Dr. Kelly, professor of dermatology and surgery at the University of California, Irvine, noted that erythematotelangiectatic rosacea generally responds well to light-based devices, while papulopustular/inflammatory forms of the condition are best treated with anti-inflammatory agents or antibiotics. Multiple passes or judicious pulse stacking can be used with PDL for treating telangiectases, “but always know what your endpoint is,” Dr. Kelly advised. “You generally don’t want to pulse over purpura when treating telangiectasias; that just increases the risk of adverse effects.”
Settings to consider vary, depending on the patient and the area to be treated. The desired endpoints for telangiectasia are vessel blanching or diminution, or a darker red/purple change to the vessel. “You should not see graying or whitening of the skin; that’s when you’re getting epidermal damage, so you want to watch for that,” she said. For a first pass, Dr. Kelly will often treat with a spot size of 10 mm or 12 mm with a 6-millisecond pulse duration with cryogen spray cooling set at 30 milliseconds with a 30-millisecond delay. If a second pass is required, she will often treat with a spot size of 7 mm and a 6-millisecond pulse duration and slightly higher fluence, again using cryogen spray cooling. “It is important to know your specific device to determine settings,” she said.
The frequency-doubled Nd:YAG laser features a wavelength of 532 nm but requires cautious use in patients with darker skin types or photodamaged skin. The desired endpoint is a darkening of the vessel or vessel disappearance. “Many of these devices have contact cooling, which is an excellent method of cooling, but you have to make sure you keep the contact,” she said. Other cooling options include cryogen spray and the application of cold air. “When you’re doing cold-air cooling, you want to be careful not to point it toward someone’s nose,” she said. “It sounds funny, but this is uncomfortable for the patient.”
Diode lasers with wavelengths of 800-980 nm allow the user to treat larger blood vessels, such as nasal telangiectasias. “Some devices with small spot sizes allow you to trace along the vessel, and you can see it disappear before your eyes, and when the patient leaves, they’re generally very happy,” she said.
Intense pulsed light works well in patients with both pigmentary and vascular changes, especially for poikiloderma with brown and red pigment. “Multiple treatments are required, and there is significant melanin absorption, so you don’t want to treat people with tanned skin,” she said.
Dr. Kelly emphasized the importance of being familiar with the device you use and knowing the desired tissue endpoint. Decisions depend on the patient’s skin type, their tolerance for down time and multiple treatments, and the devices at your disposal. “Patients should be aware of all options, even if you may not have a certain device in your office,” she said. “You can refer them.”
She disclosed having drugs or devices donated by Light Sciences Oncology, Solta Medical, Syneron Candela, ThermiRF, and Novartis. She is also a consultant for MundiPharma, Allergan, and Syneron Candela.
[email protected]
AT MOAS 2017
SAN DIEGO – Multiple light-based devices can be used to treat telangiectasias, often with little or no down time.
During a presentation at the annual Masters of Aesthetics Symposium, Kristen M. Kelly, MD, listed her preferred light-based treatment options for telangiectasias as the pulsed dye laser (PDL), the 532 nm Nd:YAG laser, and the diode laser. The PDL has been around the longest and “is one of the greatest devices for treating vasculature, because it’s very specific,” she said. Purpura can result, but for cosmetic indications, pulse durations of 6 milliseconds or more work well. “Keep in mind, though, that when you’re using longer pulse durations, patients will often require more than one treatment,” she said. “Most people are okay with that, knowing that they’re going to have minimal to no down time with these procedures.”
Dr. Kelly, professor of dermatology and surgery at the University of California, Irvine, noted that erythematotelangiectatic rosacea generally responds well to light-based devices, while papulopustular/inflammatory forms of the condition are best treated with anti-inflammatory agents or antibiotics. Multiple passes or judicious pulse stacking can be used with PDL for treating telangiectases, “but always know what your endpoint is,” Dr. Kelly advised. “You generally don’t want to pulse over purpura when treating telangiectasias; that just increases the risk of adverse effects.”
Settings to consider vary, depending on the patient and the area to be treated. The desired endpoints for telangiectasia are vessel blanching or diminution, or a darker red/purple change to the vessel. “You should not see graying or whitening of the skin; that’s when you’re getting epidermal damage, so you want to watch for that,” she said. For a first pass, Dr. Kelly will often treat with a spot size of 10 mm or 12 mm with a 6-millisecond pulse duration with cryogen spray cooling set at 30 milliseconds with a 30-millisecond delay. If a second pass is required, she will often treat with a spot size of 7 mm and a 6-millisecond pulse duration and slightly higher fluence, again using cryogen spray cooling. “It is important to know your specific device to determine settings,” she said.
The frequency-doubled Nd:YAG laser features a wavelength of 532 nm but requires cautious use in patients with darker skin types or photodamaged skin. The desired endpoint is a darkening of the vessel or vessel disappearance. “Many of these devices have contact cooling, which is an excellent method of cooling, but you have to make sure you keep the contact,” she said. Other cooling options include cryogen spray and the application of cold air. “When you’re doing cold-air cooling, you want to be careful not to point it toward someone’s nose,” she said. “It sounds funny, but this is uncomfortable for the patient.”
Diode lasers with wavelengths of 800-980 nm allow the user to treat larger blood vessels, such as nasal telangiectasias. “Some devices with small spot sizes allow you to trace along the vessel, and you can see it disappear before your eyes, and when the patient leaves, they’re generally very happy,” she said.
Intense pulsed light works well in patients with both pigmentary and vascular changes, especially for poikiloderma with brown and red pigment. “Multiple treatments are required, and there is significant melanin absorption, so you don’t want to treat people with tanned skin,” she said.
Dr. Kelly emphasized the importance of being familiar with the device you use and knowing the desired tissue endpoint. Decisions depend on the patient’s skin type, their tolerance for down time and multiple treatments, and the devices at your disposal. “Patients should be aware of all options, even if you may not have a certain device in your office,” she said. “You can refer them.”
She disclosed having drugs or devices donated by Light Sciences Oncology, Solta Medical, Syneron Candela, ThermiRF, and Novartis. She is also a consultant for MundiPharma, Allergan, and Syneron Candela.
[email protected]
AT MOAS 2017
SAN DIEGO – Multiple light-based devices can be used to treat telangiectasias, often with little or no down time.
During a presentation at the annual Masters of Aesthetics Symposium, Kristen M. Kelly, MD, listed her preferred light-based treatment options for telangiectasias as the pulsed dye laser (PDL), the 532 nm Nd:YAG laser, and the diode laser. The PDL has been around the longest and “is one of the greatest devices for treating vasculature, because it’s very specific,” she said. Purpura can result, but for cosmetic indications, pulse durations of 6 milliseconds or more work well. “Keep in mind, though, that when you’re using longer pulse durations, patients will often require more than one treatment,” she said. “Most people are okay with that, knowing that they’re going to have minimal to no down time with these procedures.”
Dr. Kelly, professor of dermatology and surgery at the University of California, Irvine, noted that erythematotelangiectatic rosacea generally responds well to light-based devices, while papulopustular/inflammatory forms of the condition are best treated with anti-inflammatory agents or antibiotics. Multiple passes or judicious pulse stacking can be used with PDL for treating telangiectases, “but always know what your endpoint is,” Dr. Kelly advised. “You generally don’t want to pulse over purpura when treating telangiectasias; that just increases the risk of adverse effects.”
Settings to consider vary, depending on the patient and the area to be treated. The desired endpoints for telangiectasia are vessel blanching or diminution, or a darker red/purple change to the vessel. “You should not see graying or whitening of the skin; that’s when you’re getting epidermal damage, so you want to watch for that,” she said. For a first pass, Dr. Kelly will often treat with a spot size of 10 mm or 12 mm with a 6-millisecond pulse duration with cryogen spray cooling set at 30 milliseconds with a 30-millisecond delay. If a second pass is required, she will often treat with a spot size of 7 mm and a 6-millisecond pulse duration and slightly higher fluence, again using cryogen spray cooling. “It is important to know your specific device to determine settings,” she said.
The frequency-doubled Nd:YAG laser features a wavelength of 532 nm but requires cautious use in patients with darker skin types or photodamaged skin. The desired endpoint is a darkening of the vessel or vessel disappearance. “Many of these devices have contact cooling, which is an excellent method of cooling, but you have to make sure you keep the contact,” she said. Other cooling options include cryogen spray and the application of cold air. “When you’re doing cold-air cooling, you want to be careful not to point it toward someone’s nose,” she said. “It sounds funny, but this is uncomfortable for the patient.”
Diode lasers with wavelengths of 800-980 nm allow the user to treat larger blood vessels, such as nasal telangiectasias. “Some devices with small spot sizes allow you to trace along the vessel, and you can see it disappear before your eyes, and when the patient leaves, they’re generally very happy,” she said.
Intense pulsed light works well in patients with both pigmentary and vascular changes, especially for poikiloderma with brown and red pigment. “Multiple treatments are required, and there is significant melanin absorption, so you don’t want to treat people with tanned skin,” she said.
Dr. Kelly emphasized the importance of being familiar with the device you use and knowing the desired tissue endpoint. Decisions depend on the patient’s skin type, their tolerance for down time and multiple treatments, and the devices at your disposal. “Patients should be aware of all options, even if you may not have a certain device in your office,” she said. “You can refer them.”
She disclosed having drugs or devices donated by Light Sciences Oncology, Solta Medical, Syneron Candela, ThermiRF, and Novartis. She is also a consultant for MundiPharma, Allergan, and Syneron Candela.
[email protected]
Absorb bioresorbable scaffold folds
The first bioresorbable vascular scaffold to reach clinical practice is no longer available because of poor sales, following nearly a year of bad news for the innovative device.
"We took this decision for commercial reasons, not for safety," Kristina Becker, director of communications at Abbott's Vascular business. Abbott announced that sales of the Absorb scaffold would cease worldwide as of Sept. 14, 2017, adding that the company would continue to follow patients in existing clinical trials according to their protocols.
The device was approved by the Food and Drug Administration in July 2016, but soon after, long-term trial results took an ominous turn. In March 2017, the agency issued a safety alert regarding the Absorb scaffold after release of the 2-year data from the 2,008-patient ABSORB III trial showing a significantly higher rate of target-lesion failure than with the everolimus-eluting metallic Xience stent, also marketed by Abbott.
Meanwhile, 3-year results of the ABSORB II trial, reported last October, revealed a 1% per year rate of late stent thrombosis during both the second and third years following Absorb placement in coronary arteries, the period when the Absorb scaffold was in the process of disappearing. More bad news came in July, when device thrombosis occurred nearly four times more frequently in recipients of the Absorb scaffold than with the Xience stent during 2 years of prospective follow-up in the randomized, investigator-initiated AIDA trial.
Abbott is not giving up on the idea of nonpermanent stents. “We recognize that [bioresorbable scaffold] technologies offer patients the possibility of life without permanent metallic implants, and we will continue to work on a next generation device while monitoring long-term outcomes after stent resorption in current Absorb trials,” the announcement said.
This article was updated 9/8/17.
The first bioresorbable vascular scaffold to reach clinical practice is no longer available because of poor sales, following nearly a year of bad news for the innovative device.
"We took this decision for commercial reasons, not for safety," Kristina Becker, director of communications at Abbott's Vascular business. Abbott announced that sales of the Absorb scaffold would cease worldwide as of Sept. 14, 2017, adding that the company would continue to follow patients in existing clinical trials according to their protocols.
The device was approved by the Food and Drug Administration in July 2016, but soon after, long-term trial results took an ominous turn. In March 2017, the agency issued a safety alert regarding the Absorb scaffold after release of the 2-year data from the 2,008-patient ABSORB III trial showing a significantly higher rate of target-lesion failure than with the everolimus-eluting metallic Xience stent, also marketed by Abbott.
Meanwhile, 3-year results of the ABSORB II trial, reported last October, revealed a 1% per year rate of late stent thrombosis during both the second and third years following Absorb placement in coronary arteries, the period when the Absorb scaffold was in the process of disappearing. More bad news came in July, when device thrombosis occurred nearly four times more frequently in recipients of the Absorb scaffold than with the Xience stent during 2 years of prospective follow-up in the randomized, investigator-initiated AIDA trial.
Abbott is not giving up on the idea of nonpermanent stents. “We recognize that [bioresorbable scaffold] technologies offer patients the possibility of life without permanent metallic implants, and we will continue to work on a next generation device while monitoring long-term outcomes after stent resorption in current Absorb trials,” the announcement said.
This article was updated 9/8/17.
The first bioresorbable vascular scaffold to reach clinical practice is no longer available because of poor sales, following nearly a year of bad news for the innovative device.
"We took this decision for commercial reasons, not for safety," Kristina Becker, director of communications at Abbott's Vascular business. Abbott announced that sales of the Absorb scaffold would cease worldwide as of Sept. 14, 2017, adding that the company would continue to follow patients in existing clinical trials according to their protocols.
The device was approved by the Food and Drug Administration in July 2016, but soon after, long-term trial results took an ominous turn. In March 2017, the agency issued a safety alert regarding the Absorb scaffold after release of the 2-year data from the 2,008-patient ABSORB III trial showing a significantly higher rate of target-lesion failure than with the everolimus-eluting metallic Xience stent, also marketed by Abbott.
Meanwhile, 3-year results of the ABSORB II trial, reported last October, revealed a 1% per year rate of late stent thrombosis during both the second and third years following Absorb placement in coronary arteries, the period when the Absorb scaffold was in the process of disappearing. More bad news came in July, when device thrombosis occurred nearly four times more frequently in recipients of the Absorb scaffold than with the Xience stent during 2 years of prospective follow-up in the randomized, investigator-initiated AIDA trial.
Abbott is not giving up on the idea of nonpermanent stents. “We recognize that [bioresorbable scaffold] technologies offer patients the possibility of life without permanent metallic implants, and we will continue to work on a next generation device while monitoring long-term outcomes after stent resorption in current Absorb trials,” the announcement said.
This article was updated 9/8/17.
Honoring a physician who led by example
In July, mostly unnoticed by Americans, a remarkable physician died in Japan.
Dr. Shigeaki Hinohara was a young 105 years old at the end, still practicing medicine.
When he was born in 1911, the average Japanese lifespan was 40. Due in part to him, it’s now one of the longest on Earth.
No stranger to medical disasters, he cared for those injured in the 1945 firebombing of Tokyo. Fifty years later, still working, he treated 640 victims of the 1995 nerve gas terror attack on the city’s subway. Between them, he survived being taken hostage in a 4-day plane hijacking in 1970.
He didn’t believe in retirement, since keeping busy is good. At the same time he advocated for finding fun in what you were doing.
A staunch opponent of obesity, he advocated a spartan lifestyle. For breakfast he had coffee, milk, and orange juice (the last with a spoonful of olive oil mixed in). For lunch (if he didn’t skip it) hard biscuits and milk. Dinner was vegetables, rice, and a small amount of either beef or fish.
He believed in exercise, even if it was limited to your daily routine. Always take stairs. Carry your own bags and packages. Even in his last months, using a cane, he walked 2,000 steps per day.
At the end, unable to eat, he still led by example. He refused a feeding tube and opted to leave quietly, passing on at home.
Medicine today, including my own field, is full of gadgets. Amazing tests and treatments. I believe in them 100%, and use them, as we all do, to help alleviate suffering and help people live longer and better lives.
But at the same time, we need to keep in mind that prevention is the best treatment. Keeping your mind active is good. Palliative care doesn’t mean you gave up.
In a world of increasing obesity, diabetes, and vascular disease, his simple advice on exercise and eating modestly is a lesson for many, including myself.
Never underestimate the benefits of music and pets.
And always have fun.
Good night, good doctor.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
In July, mostly unnoticed by Americans, a remarkable physician died in Japan.
Dr. Shigeaki Hinohara was a young 105 years old at the end, still practicing medicine.
When he was born in 1911, the average Japanese lifespan was 40. Due in part to him, it’s now one of the longest on Earth.
No stranger to medical disasters, he cared for those injured in the 1945 firebombing of Tokyo. Fifty years later, still working, he treated 640 victims of the 1995 nerve gas terror attack on the city’s subway. Between them, he survived being taken hostage in a 4-day plane hijacking in 1970.
He didn’t believe in retirement, since keeping busy is good. At the same time he advocated for finding fun in what you were doing.
A staunch opponent of obesity, he advocated a spartan lifestyle. For breakfast he had coffee, milk, and orange juice (the last with a spoonful of olive oil mixed in). For lunch (if he didn’t skip it) hard biscuits and milk. Dinner was vegetables, rice, and a small amount of either beef or fish.
He believed in exercise, even if it was limited to your daily routine. Always take stairs. Carry your own bags and packages. Even in his last months, using a cane, he walked 2,000 steps per day.
At the end, unable to eat, he still led by example. He refused a feeding tube and opted to leave quietly, passing on at home.
Medicine today, including my own field, is full of gadgets. Amazing tests and treatments. I believe in them 100%, and use them, as we all do, to help alleviate suffering and help people live longer and better lives.
But at the same time, we need to keep in mind that prevention is the best treatment. Keeping your mind active is good. Palliative care doesn’t mean you gave up.
In a world of increasing obesity, diabetes, and vascular disease, his simple advice on exercise and eating modestly is a lesson for many, including myself.
Never underestimate the benefits of music and pets.
And always have fun.
Good night, good doctor.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
In July, mostly unnoticed by Americans, a remarkable physician died in Japan.
Dr. Shigeaki Hinohara was a young 105 years old at the end, still practicing medicine.
When he was born in 1911, the average Japanese lifespan was 40. Due in part to him, it’s now one of the longest on Earth.
No stranger to medical disasters, he cared for those injured in the 1945 firebombing of Tokyo. Fifty years later, still working, he treated 640 victims of the 1995 nerve gas terror attack on the city’s subway. Between them, he survived being taken hostage in a 4-day plane hijacking in 1970.
He didn’t believe in retirement, since keeping busy is good. At the same time he advocated for finding fun in what you were doing.
A staunch opponent of obesity, he advocated a spartan lifestyle. For breakfast he had coffee, milk, and orange juice (the last with a spoonful of olive oil mixed in). For lunch (if he didn’t skip it) hard biscuits and milk. Dinner was vegetables, rice, and a small amount of either beef or fish.
He believed in exercise, even if it was limited to your daily routine. Always take stairs. Carry your own bags and packages. Even in his last months, using a cane, he walked 2,000 steps per day.
At the end, unable to eat, he still led by example. He refused a feeding tube and opted to leave quietly, passing on at home.
Medicine today, including my own field, is full of gadgets. Amazing tests and treatments. I believe in them 100%, and use them, as we all do, to help alleviate suffering and help people live longer and better lives.
But at the same time, we need to keep in mind that prevention is the best treatment. Keeping your mind active is good. Palliative care doesn’t mean you gave up.
In a world of increasing obesity, diabetes, and vascular disease, his simple advice on exercise and eating modestly is a lesson for many, including myself.
Never underestimate the benefits of music and pets.
And always have fun.
Good night, good doctor.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
New AML approvals changing the treatment landscape
With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.
Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.
“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.
In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.
Vyxeos
The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.
In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).
“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.
Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.
The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”
“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”
The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.
Vyxeos is a fixed-dose combination that comes in vials containing 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes. Patient dosing is based on the daunorubicin component and calculated based on body surface area (mg/m2), meaning the cytarabine dose does not need to be calculated. There are both pros and cons to this approach, she explained.
Benefits include a longer half-life with Vyxeos vs. standard 7+3, and the fact that during induction the drug is delivered on days 1, 3, and 5 for 90 minutes rather than continuously for 7 days as with 7+3, Dr. Capozzi said.
The main concern relates to ensuring that the dosing is calculated based on the proper component, she said.
“We had our first patient last week. It was very time consuming, with double and triple checking to make sure everything was correct,” she said. Preparing the drug is also time-consuming, as it involves multiple steps, such as warming, which is not required with standard 7+3; the additional labor factors will have to be built into workflow, she noted.
“The other piece not fully in place right now is building [the use of Vyxeos] into electronic health records,” she said, adding that safeguards put into place through EHRs will also help to streamline the administration process.
For example, cardiac toxicity is a known effect of daunorubicin; the EHR will help track lifetime cumulative dosing of that component, which is otherwise challenging, especially when using a combination product, she said.
The process will get easier over time, as use of Vyxeos becomes more prevalent in practice, she added. “None of these are insurmountable issues.”
Cost is another matter. Based on average wholesale prices, the cost per cycle is approximately $40,000 with Vyxeos vs. about $4,300 for conventional 7+3 therapy, Dr. Capozzi said. Given the differential, there will be a great deal of debate as to which patients will derive the most benefit from Vyxeos, she said.
Also, it will take time to figure out the extent of adverse events. “For liposomal products in general, rash-type side effects can be really significant. Hand-foot syndrome was not reported in the initial trials, but we’ll keep our eyes open to see how that plays out,” she said noting that the one patient treated so far at the University of Pennsylvania is doing very well. “We will learn more with real world experience.”
Oral targeted therapies
Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.
In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.
Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.
“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.
This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”
Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.
The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.
“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.
Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).
The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.
Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.
Targeted therapies in development
Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.
Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.
For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.
“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”
An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.
Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.
“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.
Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.
“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.
“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”
Future direction and outcomes
So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?
Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.
“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”
Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.
With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.
Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.
“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.
In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.
Vyxeos
The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.
In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).
“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.
Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.
The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”
“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”
The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.
Vyxeos is a fixed-dose combination that comes in vials containing 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes. Patient dosing is based on the daunorubicin component and calculated based on body surface area (mg/m2), meaning the cytarabine dose does not need to be calculated. There are both pros and cons to this approach, she explained.
Benefits include a longer half-life with Vyxeos vs. standard 7+3, and the fact that during induction the drug is delivered on days 1, 3, and 5 for 90 minutes rather than continuously for 7 days as with 7+3, Dr. Capozzi said.
The main concern relates to ensuring that the dosing is calculated based on the proper component, she said.
“We had our first patient last week. It was very time consuming, with double and triple checking to make sure everything was correct,” she said. Preparing the drug is also time-consuming, as it involves multiple steps, such as warming, which is not required with standard 7+3; the additional labor factors will have to be built into workflow, she noted.
“The other piece not fully in place right now is building [the use of Vyxeos] into electronic health records,” she said, adding that safeguards put into place through EHRs will also help to streamline the administration process.
For example, cardiac toxicity is a known effect of daunorubicin; the EHR will help track lifetime cumulative dosing of that component, which is otherwise challenging, especially when using a combination product, she said.
The process will get easier over time, as use of Vyxeos becomes more prevalent in practice, she added. “None of these are insurmountable issues.”
Cost is another matter. Based on average wholesale prices, the cost per cycle is approximately $40,000 with Vyxeos vs. about $4,300 for conventional 7+3 therapy, Dr. Capozzi said. Given the differential, there will be a great deal of debate as to which patients will derive the most benefit from Vyxeos, she said.
Also, it will take time to figure out the extent of adverse events. “For liposomal products in general, rash-type side effects can be really significant. Hand-foot syndrome was not reported in the initial trials, but we’ll keep our eyes open to see how that plays out,” she said noting that the one patient treated so far at the University of Pennsylvania is doing very well. “We will learn more with real world experience.”
Oral targeted therapies
Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.
In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.
Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.
“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.
This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”
Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.
The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.
“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.
Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).
The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.
Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.
Targeted therapies in development
Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.
Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.
For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.
“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”
An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.
Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.
“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.
Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.
“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.
“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”
Future direction and outcomes
So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?
Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.
“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”
Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.
With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.
Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.
“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.
In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.
Vyxeos
The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.
In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).
“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.
Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.
The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”
“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”
The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.
Vyxeos is a fixed-dose combination that comes in vials containing 44 mg daunorubicin and 100 mg cytarabine encapsulated in liposomes. Patient dosing is based on the daunorubicin component and calculated based on body surface area (mg/m2), meaning the cytarabine dose does not need to be calculated. There are both pros and cons to this approach, she explained.
Benefits include a longer half-life with Vyxeos vs. standard 7+3, and the fact that during induction the drug is delivered on days 1, 3, and 5 for 90 minutes rather than continuously for 7 days as with 7+3, Dr. Capozzi said.
The main concern relates to ensuring that the dosing is calculated based on the proper component, she said.
“We had our first patient last week. It was very time consuming, with double and triple checking to make sure everything was correct,” she said. Preparing the drug is also time-consuming, as it involves multiple steps, such as warming, which is not required with standard 7+3; the additional labor factors will have to be built into workflow, she noted.
“The other piece not fully in place right now is building [the use of Vyxeos] into electronic health records,” she said, adding that safeguards put into place through EHRs will also help to streamline the administration process.
For example, cardiac toxicity is a known effect of daunorubicin; the EHR will help track lifetime cumulative dosing of that component, which is otherwise challenging, especially when using a combination product, she said.
The process will get easier over time, as use of Vyxeos becomes more prevalent in practice, she added. “None of these are insurmountable issues.”
Cost is another matter. Based on average wholesale prices, the cost per cycle is approximately $40,000 with Vyxeos vs. about $4,300 for conventional 7+3 therapy, Dr. Capozzi said. Given the differential, there will be a great deal of debate as to which patients will derive the most benefit from Vyxeos, she said.
Also, it will take time to figure out the extent of adverse events. “For liposomal products in general, rash-type side effects can be really significant. Hand-foot syndrome was not reported in the initial trials, but we’ll keep our eyes open to see how that plays out,” she said noting that the one patient treated so far at the University of Pennsylvania is doing very well. “We will learn more with real world experience.”
Oral targeted therapies
Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.
In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.
Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.
“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.
This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”
Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.
The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.
“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.
Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).
The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.
Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.
Targeted therapies in development
Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.
Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.
For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.
“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”
An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.
Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.
“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.
Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.
“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.
“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”
Future direction and outcomes
So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?
Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.
“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”
Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.
Tender Edematous Nodules on the Hand
The Diagnosis: Ecthyma Contagiosum (Orf)
Orf, or ecthyma contagiosum, is a zoonotic cutaneous infection caused by the orf DNA virus of the genus Parapoxvirus of the family Poxviridae. It is transmitted to humans through direct contact with infected animals, namely sheep and goats, and as such is most commonly seen in patients with occupational exposure to these animals such as butchers, farmers, veterinarians, and shepherds.1,2 Human-to-human transmission is exceedingly rare in immunocompetent patients.2,3 In affected animals, lesions usually are found around the mouth, muzzle, and eyes. In humans, hands are the most commonly affected site, and lesions occur 3 to 10 days after contact. Clinically, the lesions are nonspecific, and our patient presented with tender, erythematous, edematous nodules on the left hand. The differential diagnosis is broad and includes a milker's nodule, pyogenic granuloma, tularemia, anthrax, atypical mycobacterial infection, and sporotrichosis.1,4,5
The diagnosis usually is made with a thorough history and examination, but in cases of uncertainty, routine pathology with hematoxylin and eosin staining, electron microscopy, or real-time polymerase chain reaction may be used.2-4 Histopathologically, lesions demonstrate intraepidermal vesicles, vacuolization of keratinocytes of the upper epidermis with characteristic cytoplasmic inclusion bodies, rete ridge elongation, and dilated vessels in the intervening dermal papillae. Central necrosis may occur in well-developed lesions.2,6 Interestingly, our patient's biopsy exhibited all of these findings (Figure). Immunostains for cytomegalovirus and herpes simplex virus were negative, and Grocott-Gomori methenamine-silver and acid-fast bacillus stains also were negative.
Our patient also developed lymphangitic streaking suggestive of a bacterial superinfection and was treated with a course of intravenous antibiotics. She eventually was discharged with reassurance, wound care instructions, and outpatient antibiotics. She returned to an outside institution's emergency department for further evaluation, and she was admitted for workup. A lesional swab was sent for real-time polymerase chain reaction, which confirmed the diagnosis as orf. When the patient was contacted for follow-up 1 week after biopsy, the hand lesions had notably improved.
Orf is self-limited and typically resolves within 4 to 8 weeks after undergoing evolution through 5 described stages. The maculopapular stage is denoted by enlarging erythematous macule. The targetoid stage is described by a red center within a white halo surrounded by a broader red halo. The nodular stage is self-descriptive. The regenerative and regression stages describe the progressively improving, drier, and crusted nodules.3
Because orf is self-limited, no treatment is required, and patients should be counseled that their lesions should resolve within weeks. Complications include lymphangitis, secondary bacterial infection, and erythema multiforme.1,2,4,5 Immunocompromised patients may develop recalcitrant, giant, or multiple lesions that may be treated with topical imiquimod, topical cidofovir, intralesional interferon alfa, or surgical excision.1,2,4,7
We present a case of orf to remind practitioners of this rare entity. Although the disease is endemic worldwide, it likely is underreported due to its self-limited nature.2,4 A careful history may reveal the diagnosis, and overtreatment with antibiotics, many of which have their own significant side-effect profile, can then be avoided.
Acknowledgment
We thank Eric Behling, MD (Camden, New Jersey), for his contributions in obtaining the histologic images.
- Veraldi S, Nazzaro G, Vaira F, et al. Presentation of orf (ecthyma contagiosum) after sheep slaughtering for religious feasts. Infection. 2014;42:767-769.
- Al-Salam S, Nowotny N, Sohail MR, et al. Ecthyma contagiosum (orf)--report of a human case from the United Arab Emirates and review of the literature. J Cutan Pathol. 2008;35:603-607.
- Thurman RJ, Fitch RW. Images in clinical medicine. contagious ecthyma. N Engl J Med. 2015;372:E12.
- Meier R, Sommacal A, Stahel A, et al. Orf--an orphan disease? JRSM Open. 2015;6:2054270415593718.
- Joseph RH, Haddad FA, Matthews AL, et al. Erythema multiforme after orf virus infection: a report of two cases and literature review. Epidemiol Infect. 2015;143:385-390.
- Xu X, Yun SJ, Erikson L, et al. Diseases caused by viruses. In: Elder DE, Elenitsas R, Rosenbach M, eds. Lever's Histopathology of the Skin. 11th ed. Philadelphia, PA: Wolters Kluwer; 2015:781-815.
- Koufakis T, Katsaitis P, Gabranis I. Orf disease: a report of a case. Braz J Infect Dis. 2014;18:568-569.
The Diagnosis: Ecthyma Contagiosum (Orf)
Orf, or ecthyma contagiosum, is a zoonotic cutaneous infection caused by the orf DNA virus of the genus Parapoxvirus of the family Poxviridae. It is transmitted to humans through direct contact with infected animals, namely sheep and goats, and as such is most commonly seen in patients with occupational exposure to these animals such as butchers, farmers, veterinarians, and shepherds.1,2 Human-to-human transmission is exceedingly rare in immunocompetent patients.2,3 In affected animals, lesions usually are found around the mouth, muzzle, and eyes. In humans, hands are the most commonly affected site, and lesions occur 3 to 10 days after contact. Clinically, the lesions are nonspecific, and our patient presented with tender, erythematous, edematous nodules on the left hand. The differential diagnosis is broad and includes a milker's nodule, pyogenic granuloma, tularemia, anthrax, atypical mycobacterial infection, and sporotrichosis.1,4,5
The diagnosis usually is made with a thorough history and examination, but in cases of uncertainty, routine pathology with hematoxylin and eosin staining, electron microscopy, or real-time polymerase chain reaction may be used.2-4 Histopathologically, lesions demonstrate intraepidermal vesicles, vacuolization of keratinocytes of the upper epidermis with characteristic cytoplasmic inclusion bodies, rete ridge elongation, and dilated vessels in the intervening dermal papillae. Central necrosis may occur in well-developed lesions.2,6 Interestingly, our patient's biopsy exhibited all of these findings (Figure). Immunostains for cytomegalovirus and herpes simplex virus were negative, and Grocott-Gomori methenamine-silver and acid-fast bacillus stains also were negative.
Our patient also developed lymphangitic streaking suggestive of a bacterial superinfection and was treated with a course of intravenous antibiotics. She eventually was discharged with reassurance, wound care instructions, and outpatient antibiotics. She returned to an outside institution's emergency department for further evaluation, and she was admitted for workup. A lesional swab was sent for real-time polymerase chain reaction, which confirmed the diagnosis as orf. When the patient was contacted for follow-up 1 week after biopsy, the hand lesions had notably improved.
Orf is self-limited and typically resolves within 4 to 8 weeks after undergoing evolution through 5 described stages. The maculopapular stage is denoted by enlarging erythematous macule. The targetoid stage is described by a red center within a white halo surrounded by a broader red halo. The nodular stage is self-descriptive. The regenerative and regression stages describe the progressively improving, drier, and crusted nodules.3
Because orf is self-limited, no treatment is required, and patients should be counseled that their lesions should resolve within weeks. Complications include lymphangitis, secondary bacterial infection, and erythema multiforme.1,2,4,5 Immunocompromised patients may develop recalcitrant, giant, or multiple lesions that may be treated with topical imiquimod, topical cidofovir, intralesional interferon alfa, or surgical excision.1,2,4,7
We present a case of orf to remind practitioners of this rare entity. Although the disease is endemic worldwide, it likely is underreported due to its self-limited nature.2,4 A careful history may reveal the diagnosis, and overtreatment with antibiotics, many of which have their own significant side-effect profile, can then be avoided.
Acknowledgment
We thank Eric Behling, MD (Camden, New Jersey), for his contributions in obtaining the histologic images.
The Diagnosis: Ecthyma Contagiosum (Orf)
Orf, or ecthyma contagiosum, is a zoonotic cutaneous infection caused by the orf DNA virus of the genus Parapoxvirus of the family Poxviridae. It is transmitted to humans through direct contact with infected animals, namely sheep and goats, and as such is most commonly seen in patients with occupational exposure to these animals such as butchers, farmers, veterinarians, and shepherds.1,2 Human-to-human transmission is exceedingly rare in immunocompetent patients.2,3 In affected animals, lesions usually are found around the mouth, muzzle, and eyes. In humans, hands are the most commonly affected site, and lesions occur 3 to 10 days after contact. Clinically, the lesions are nonspecific, and our patient presented with tender, erythematous, edematous nodules on the left hand. The differential diagnosis is broad and includes a milker's nodule, pyogenic granuloma, tularemia, anthrax, atypical mycobacterial infection, and sporotrichosis.1,4,5
The diagnosis usually is made with a thorough history and examination, but in cases of uncertainty, routine pathology with hematoxylin and eosin staining, electron microscopy, or real-time polymerase chain reaction may be used.2-4 Histopathologically, lesions demonstrate intraepidermal vesicles, vacuolization of keratinocytes of the upper epidermis with characteristic cytoplasmic inclusion bodies, rete ridge elongation, and dilated vessels in the intervening dermal papillae. Central necrosis may occur in well-developed lesions.2,6 Interestingly, our patient's biopsy exhibited all of these findings (Figure). Immunostains for cytomegalovirus and herpes simplex virus were negative, and Grocott-Gomori methenamine-silver and acid-fast bacillus stains also were negative.
Our patient also developed lymphangitic streaking suggestive of a bacterial superinfection and was treated with a course of intravenous antibiotics. She eventually was discharged with reassurance, wound care instructions, and outpatient antibiotics. She returned to an outside institution's emergency department for further evaluation, and she was admitted for workup. A lesional swab was sent for real-time polymerase chain reaction, which confirmed the diagnosis as orf. When the patient was contacted for follow-up 1 week after biopsy, the hand lesions had notably improved.
Orf is self-limited and typically resolves within 4 to 8 weeks after undergoing evolution through 5 described stages. The maculopapular stage is denoted by enlarging erythematous macule. The targetoid stage is described by a red center within a white halo surrounded by a broader red halo. The nodular stage is self-descriptive. The regenerative and regression stages describe the progressively improving, drier, and crusted nodules.3
Because orf is self-limited, no treatment is required, and patients should be counseled that their lesions should resolve within weeks. Complications include lymphangitis, secondary bacterial infection, and erythema multiforme.1,2,4,5 Immunocompromised patients may develop recalcitrant, giant, or multiple lesions that may be treated with topical imiquimod, topical cidofovir, intralesional interferon alfa, or surgical excision.1,2,4,7
We present a case of orf to remind practitioners of this rare entity. Although the disease is endemic worldwide, it likely is underreported due to its self-limited nature.2,4 A careful history may reveal the diagnosis, and overtreatment with antibiotics, many of which have their own significant side-effect profile, can then be avoided.
Acknowledgment
We thank Eric Behling, MD (Camden, New Jersey), for his contributions in obtaining the histologic images.
- Veraldi S, Nazzaro G, Vaira F, et al. Presentation of orf (ecthyma contagiosum) after sheep slaughtering for religious feasts. Infection. 2014;42:767-769.
- Al-Salam S, Nowotny N, Sohail MR, et al. Ecthyma contagiosum (orf)--report of a human case from the United Arab Emirates and review of the literature. J Cutan Pathol. 2008;35:603-607.
- Thurman RJ, Fitch RW. Images in clinical medicine. contagious ecthyma. N Engl J Med. 2015;372:E12.
- Meier R, Sommacal A, Stahel A, et al. Orf--an orphan disease? JRSM Open. 2015;6:2054270415593718.
- Joseph RH, Haddad FA, Matthews AL, et al. Erythema multiforme after orf virus infection: a report of two cases and literature review. Epidemiol Infect. 2015;143:385-390.
- Xu X, Yun SJ, Erikson L, et al. Diseases caused by viruses. In: Elder DE, Elenitsas R, Rosenbach M, eds. Lever's Histopathology of the Skin. 11th ed. Philadelphia, PA: Wolters Kluwer; 2015:781-815.
- Koufakis T, Katsaitis P, Gabranis I. Orf disease: a report of a case. Braz J Infect Dis. 2014;18:568-569.
- Veraldi S, Nazzaro G, Vaira F, et al. Presentation of orf (ecthyma contagiosum) after sheep slaughtering for religious feasts. Infection. 2014;42:767-769.
- Al-Salam S, Nowotny N, Sohail MR, et al. Ecthyma contagiosum (orf)--report of a human case from the United Arab Emirates and review of the literature. J Cutan Pathol. 2008;35:603-607.
- Thurman RJ, Fitch RW. Images in clinical medicine. contagious ecthyma. N Engl J Med. 2015;372:E12.
- Meier R, Sommacal A, Stahel A, et al. Orf--an orphan disease? JRSM Open. 2015;6:2054270415593718.
- Joseph RH, Haddad FA, Matthews AL, et al. Erythema multiforme after orf virus infection: a report of two cases and literature review. Epidemiol Infect. 2015;143:385-390.
- Xu X, Yun SJ, Erikson L, et al. Diseases caused by viruses. In: Elder DE, Elenitsas R, Rosenbach M, eds. Lever's Histopathology of the Skin. 11th ed. Philadelphia, PA: Wolters Kluwer; 2015:781-815.
- Koufakis T, Katsaitis P, Gabranis I. Orf disease: a report of a case. Braz J Infect Dis. 2014;18:568-569.
A 57-year-old woman presented to the emergency department (ED) for evaluation of a rash on the left hand of 2 weeks' duration. She described pinpoint red lesions on the left palm, as well as the third, fourth, and fifth fingers, which gradually enlarged and became painful. She denied any specific trauma but recalled cutting her hand on a piece of metal in the ground prior to the onset of the rash. She worked on a farm and bottle-fed sheep and chickens. Physical examination revealed tender edematous nodules with central gray pustules, and the left axillary lymph node was enlarged and tender. Ulceration was not appreciated. Various antibiotics including cephalexin, trimethoprim-sulfamethoxazole, and clindamycin were prescribed during prior ED visits, but she reported no improvement with these medications. She remained afebrile throughout the course of the hand rash, and laboratory workup was consistently unremarkable. Two sets of herpes simplex virus cultures from the ED visits showed no growth, and a hand radiograph also was normal. Medical history included coronary artery disease, myocardial infarction, mitral regurgitation, and hyperlipidemia.
