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Novel acne drug now under review at the FDA
LAHAINA, HAWAII – by the Food and Drug Administration, is already generating considerable buzz in the patient-advocacy community even though the agency won’t issue its decision until August.
“I’ve actually had a lot of interest in this already from parents, especially regarding girls who have very hormonal acne but the parents are really not interested in starting them on a systemic hormonal therapy at their age,” Jessica Sprague, MD, said at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Clascoterone targets androgen receptors in the skin in order to reduce cutaneous 5-alpha dihydrotestosterone.
“It’s being developed for use in both males and females, which is great because at this point there’s no hormonal treatment for males,” noted Dr. Sprague, a pediatric dermatologist at Rady Children’s Hospital and the University of California, both in San Diego.
The manufacturer’s application for marketing approval of clascoterone cream 1% under FDA review includes evidence from two identical phase-3, double-blind, vehicle-controlled, 12-week, randomized trials. The two studies included a total of 1,440 patients aged 9 years through adulthood with moderate to severe facial acne vulgaris who were randomized to twice-daily application of clascoterone or its vehicle.
The primary outcome was the reduction in inflammatory lesions at week 12: a 46.2% decline from baseline with clascoterone 1% cream, which was a significantly greater improvement than the 32.7% reduction for vehicle. The secondary outcome – change in noninflammatory lesion counts at week 12 – was also positive for the topical androgen receptor inhibitor, which achieved a 29.8% reduction, compared with 18.9% for vehicle. Clascoterone exhibited a favorable safety and tolerability profile, with numerically fewer treatment-emergent adverse events than in the vehicle control group. A stronger formulation of the topical agent is in advanced clinical trials for the treatment of androgenetic alopecia in both males and females.
Dr. Sprague reported having no financial conflicts regarding her presentation.
The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – by the Food and Drug Administration, is already generating considerable buzz in the patient-advocacy community even though the agency won’t issue its decision until August.
“I’ve actually had a lot of interest in this already from parents, especially regarding girls who have very hormonal acne but the parents are really not interested in starting them on a systemic hormonal therapy at their age,” Jessica Sprague, MD, said at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Clascoterone targets androgen receptors in the skin in order to reduce cutaneous 5-alpha dihydrotestosterone.
“It’s being developed for use in both males and females, which is great because at this point there’s no hormonal treatment for males,” noted Dr. Sprague, a pediatric dermatologist at Rady Children’s Hospital and the University of California, both in San Diego.
The manufacturer’s application for marketing approval of clascoterone cream 1% under FDA review includes evidence from two identical phase-3, double-blind, vehicle-controlled, 12-week, randomized trials. The two studies included a total of 1,440 patients aged 9 years through adulthood with moderate to severe facial acne vulgaris who were randomized to twice-daily application of clascoterone or its vehicle.
The primary outcome was the reduction in inflammatory lesions at week 12: a 46.2% decline from baseline with clascoterone 1% cream, which was a significantly greater improvement than the 32.7% reduction for vehicle. The secondary outcome – change in noninflammatory lesion counts at week 12 – was also positive for the topical androgen receptor inhibitor, which achieved a 29.8% reduction, compared with 18.9% for vehicle. Clascoterone exhibited a favorable safety and tolerability profile, with numerically fewer treatment-emergent adverse events than in the vehicle control group. A stronger formulation of the topical agent is in advanced clinical trials for the treatment of androgenetic alopecia in both males and females.
Dr. Sprague reported having no financial conflicts regarding her presentation.
The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – by the Food and Drug Administration, is already generating considerable buzz in the patient-advocacy community even though the agency won’t issue its decision until August.
“I’ve actually had a lot of interest in this already from parents, especially regarding girls who have very hormonal acne but the parents are really not interested in starting them on a systemic hormonal therapy at their age,” Jessica Sprague, MD, said at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Clascoterone targets androgen receptors in the skin in order to reduce cutaneous 5-alpha dihydrotestosterone.
“It’s being developed for use in both males and females, which is great because at this point there’s no hormonal treatment for males,” noted Dr. Sprague, a pediatric dermatologist at Rady Children’s Hospital and the University of California, both in San Diego.
The manufacturer’s application for marketing approval of clascoterone cream 1% under FDA review includes evidence from two identical phase-3, double-blind, vehicle-controlled, 12-week, randomized trials. The two studies included a total of 1,440 patients aged 9 years through adulthood with moderate to severe facial acne vulgaris who were randomized to twice-daily application of clascoterone or its vehicle.
The primary outcome was the reduction in inflammatory lesions at week 12: a 46.2% decline from baseline with clascoterone 1% cream, which was a significantly greater improvement than the 32.7% reduction for vehicle. The secondary outcome – change in noninflammatory lesion counts at week 12 – was also positive for the topical androgen receptor inhibitor, which achieved a 29.8% reduction, compared with 18.9% for vehicle. Clascoterone exhibited a favorable safety and tolerability profile, with numerically fewer treatment-emergent adverse events than in the vehicle control group. A stronger formulation of the topical agent is in advanced clinical trials for the treatment of androgenetic alopecia in both males and females.
Dr. Sprague reported having no financial conflicts regarding her presentation.
The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM THE SDEF HAWAII DERMATOLOGY SEMINAR
Stage I mycosis fungoides is the general dermatologist’s bailiwick
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
Oral propranolol shown safe in PHACE
LAHAINA, HAWAII – Reassuring evidence of the safety of oral propranolol for treatment of complicated infantile hemangiomas in patients with PHACE syndrome comes from a recent multicenter study.
Oral propranolol is now well-ensconced as first-line therapy for complicated infantile hemangiomas in otherwise healthy children. However, the beta-blocker’s use in PHACE (Posterior fossa malformations, Hemangiomas, Arterial anomalies, Cardiac defects, and Eye abnormalities) syndrome has been controversial, with concerns raised by some that it might raise the risk for arterial ischemic stroke. Not so, Moise L. Levy, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
“I’m not suggesting you use propranolol with reckless abandon in this population, but this stroke concern is something that should be put to bed based on this study,” advised Dr. Levy, professor of dermatology and pediatrics at Dell Medical School in Austin, Tex., and physician-in-chief at Dell Children’s Medical Center.
PHACE syndrome is characterized by large, thick, plaque-like hemangiomas greater than 5 cm in size, most commonly on the face, although they can be located elsewhere.
“There was concern that if you found severely altered cerebrovascular arterial flow and you put a kid on a beta-blocker you might be causing some harm. But what I will tell you is that in this recently published paper this was not in fact an issue,” he said.
Dr. Levy was not an investigator in the multicenter retrospective study, which included 76 patients with PHACE syndrome treated for infantile hemangioma with oral propranolol at 0.3 mg/kg per dose or more at 11 academic tertiary care pediatric dermatology clinics. Treatment started at a median age of 56 days.
There were no strokes, TIAs, cardiovascular events, or other significant problems associated with treatment. Twenty-nine children experienced mild adverse events: minor gastrointestinal or respiratory symptoms, and sleep disturbances were threefold more frequent than reported with placebo in another study. The investigators noted that the safety experience in their PHACE syndrome population compared favorably with that in 726 infants without PHACE syndrome who received oral propranolol for hemangiomas, where the incidence of serious adverse events on treatment was 0.4% (JAMA Dermatol. 2019 Dec 11. doi: 10.1001/jamadermatol.2019.3839).
‘Hemangiomas – but we were taught that they go away’
Dr. Levy gave a shout-out to the American Academy of Pediatrics for publishing interdisciplinary expert consensus-based practice guidelines for the management of infantile hemangiomas, which he praised as “quite well done” (Pediatrics. 2019 Jan;143[1]. pii: e20183475. doi: 10.1542/peds.2018-3475).
Following release of the guidelines last year, he and other pediatric vascular anomalies experts saw an uptick in referrals from general pediatricians, which has since tapered off.
“It’s probably like for all of us: We read an article, it’s fresh on the mind, then you forget about the article and what you’ve read. So we need a little reinforcement from a learning perspective. This is a great article,” he said.
The guidelines debunk as myth the classic teaching that infantile hemangiomas go away. Explicit information is provided about the high-risk anatomic sites warranting consideration for early referral, including the periocular, lumbosacral, and perineal areas, the lip, and lower face.
“The major point is early identification of those lesions requiring evaluation and intervention. Hemangiomas generally speaking are at their ultimate size by 3-5 months of age. The bottom line is if you think something needs to be done, please send that patient, or act upon that patient, sooner rather than later. I can’t tell you how many cases of hemangiomas I’ve seen when the kid is 18 months of age, 3 years of age, 5 years, with a large area of redundant skin, scarring, or something of that sort, and it would have been really nice to have seen them earlier and acted upon them then,” the pediatric dermatologist said.
The guidelines recommend intervention or referral by 1 month of age, ideally. Guidance is provided about the use of oral propranolol as first-line therapy.
“Propranolol is something that has been a real game changer for us,” he noted. “Many people continue to be worried about side effects in using this, particularly in the young childhood population, but this paper shows pretty clearly that hypotension or bradycardia is not a real concern. I never hospitalize these patients for propranolol therapy except in high-risk populations: very preemie, any history of breathing problems. We check the blood pressure and heart rate at baseline, again at 7-10 days, and at every visit. We’ve never found any significant drop in blood pressure.”
Dr. Levy reported financial relationships with half a dozen pharmaceutical companies, none relevant to his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – Reassuring evidence of the safety of oral propranolol for treatment of complicated infantile hemangiomas in patients with PHACE syndrome comes from a recent multicenter study.
Oral propranolol is now well-ensconced as first-line therapy for complicated infantile hemangiomas in otherwise healthy children. However, the beta-blocker’s use in PHACE (Posterior fossa malformations, Hemangiomas, Arterial anomalies, Cardiac defects, and Eye abnormalities) syndrome has been controversial, with concerns raised by some that it might raise the risk for arterial ischemic stroke. Not so, Moise L. Levy, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
“I’m not suggesting you use propranolol with reckless abandon in this population, but this stroke concern is something that should be put to bed based on this study,” advised Dr. Levy, professor of dermatology and pediatrics at Dell Medical School in Austin, Tex., and physician-in-chief at Dell Children’s Medical Center.
PHACE syndrome is characterized by large, thick, plaque-like hemangiomas greater than 5 cm in size, most commonly on the face, although they can be located elsewhere.
“There was concern that if you found severely altered cerebrovascular arterial flow and you put a kid on a beta-blocker you might be causing some harm. But what I will tell you is that in this recently published paper this was not in fact an issue,” he said.
Dr. Levy was not an investigator in the multicenter retrospective study, which included 76 patients with PHACE syndrome treated for infantile hemangioma with oral propranolol at 0.3 mg/kg per dose or more at 11 academic tertiary care pediatric dermatology clinics. Treatment started at a median age of 56 days.
There were no strokes, TIAs, cardiovascular events, or other significant problems associated with treatment. Twenty-nine children experienced mild adverse events: minor gastrointestinal or respiratory symptoms, and sleep disturbances were threefold more frequent than reported with placebo in another study. The investigators noted that the safety experience in their PHACE syndrome population compared favorably with that in 726 infants without PHACE syndrome who received oral propranolol for hemangiomas, where the incidence of serious adverse events on treatment was 0.4% (JAMA Dermatol. 2019 Dec 11. doi: 10.1001/jamadermatol.2019.3839).
‘Hemangiomas – but we were taught that they go away’
Dr. Levy gave a shout-out to the American Academy of Pediatrics for publishing interdisciplinary expert consensus-based practice guidelines for the management of infantile hemangiomas, which he praised as “quite well done” (Pediatrics. 2019 Jan;143[1]. pii: e20183475. doi: 10.1542/peds.2018-3475).
Following release of the guidelines last year, he and other pediatric vascular anomalies experts saw an uptick in referrals from general pediatricians, which has since tapered off.
“It’s probably like for all of us: We read an article, it’s fresh on the mind, then you forget about the article and what you’ve read. So we need a little reinforcement from a learning perspective. This is a great article,” he said.
The guidelines debunk as myth the classic teaching that infantile hemangiomas go away. Explicit information is provided about the high-risk anatomic sites warranting consideration for early referral, including the periocular, lumbosacral, and perineal areas, the lip, and lower face.
“The major point is early identification of those lesions requiring evaluation and intervention. Hemangiomas generally speaking are at their ultimate size by 3-5 months of age. The bottom line is if you think something needs to be done, please send that patient, or act upon that patient, sooner rather than later. I can’t tell you how many cases of hemangiomas I’ve seen when the kid is 18 months of age, 3 years of age, 5 years, with a large area of redundant skin, scarring, or something of that sort, and it would have been really nice to have seen them earlier and acted upon them then,” the pediatric dermatologist said.
The guidelines recommend intervention or referral by 1 month of age, ideally. Guidance is provided about the use of oral propranolol as first-line therapy.
“Propranolol is something that has been a real game changer for us,” he noted. “Many people continue to be worried about side effects in using this, particularly in the young childhood population, but this paper shows pretty clearly that hypotension or bradycardia is not a real concern. I never hospitalize these patients for propranolol therapy except in high-risk populations: very preemie, any history of breathing problems. We check the blood pressure and heart rate at baseline, again at 7-10 days, and at every visit. We’ve never found any significant drop in blood pressure.”
Dr. Levy reported financial relationships with half a dozen pharmaceutical companies, none relevant to his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – Reassuring evidence of the safety of oral propranolol for treatment of complicated infantile hemangiomas in patients with PHACE syndrome comes from a recent multicenter study.
Oral propranolol is now well-ensconced as first-line therapy for complicated infantile hemangiomas in otherwise healthy children. However, the beta-blocker’s use in PHACE (Posterior fossa malformations, Hemangiomas, Arterial anomalies, Cardiac defects, and Eye abnormalities) syndrome has been controversial, with concerns raised by some that it might raise the risk for arterial ischemic stroke. Not so, Moise L. Levy, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
“I’m not suggesting you use propranolol with reckless abandon in this population, but this stroke concern is something that should be put to bed based on this study,” advised Dr. Levy, professor of dermatology and pediatrics at Dell Medical School in Austin, Tex., and physician-in-chief at Dell Children’s Medical Center.
PHACE syndrome is characterized by large, thick, plaque-like hemangiomas greater than 5 cm in size, most commonly on the face, although they can be located elsewhere.
“There was concern that if you found severely altered cerebrovascular arterial flow and you put a kid on a beta-blocker you might be causing some harm. But what I will tell you is that in this recently published paper this was not in fact an issue,” he said.
Dr. Levy was not an investigator in the multicenter retrospective study, which included 76 patients with PHACE syndrome treated for infantile hemangioma with oral propranolol at 0.3 mg/kg per dose or more at 11 academic tertiary care pediatric dermatology clinics. Treatment started at a median age of 56 days.
There were no strokes, TIAs, cardiovascular events, or other significant problems associated with treatment. Twenty-nine children experienced mild adverse events: minor gastrointestinal or respiratory symptoms, and sleep disturbances were threefold more frequent than reported with placebo in another study. The investigators noted that the safety experience in their PHACE syndrome population compared favorably with that in 726 infants without PHACE syndrome who received oral propranolol for hemangiomas, where the incidence of serious adverse events on treatment was 0.4% (JAMA Dermatol. 2019 Dec 11. doi: 10.1001/jamadermatol.2019.3839).
‘Hemangiomas – but we were taught that they go away’
Dr. Levy gave a shout-out to the American Academy of Pediatrics for publishing interdisciplinary expert consensus-based practice guidelines for the management of infantile hemangiomas, which he praised as “quite well done” (Pediatrics. 2019 Jan;143[1]. pii: e20183475. doi: 10.1542/peds.2018-3475).
Following release of the guidelines last year, he and other pediatric vascular anomalies experts saw an uptick in referrals from general pediatricians, which has since tapered off.
“It’s probably like for all of us: We read an article, it’s fresh on the mind, then you forget about the article and what you’ve read. So we need a little reinforcement from a learning perspective. This is a great article,” he said.
The guidelines debunk as myth the classic teaching that infantile hemangiomas go away. Explicit information is provided about the high-risk anatomic sites warranting consideration for early referral, including the periocular, lumbosacral, and perineal areas, the lip, and lower face.
“The major point is early identification of those lesions requiring evaluation and intervention. Hemangiomas generally speaking are at their ultimate size by 3-5 months of age. The bottom line is if you think something needs to be done, please send that patient, or act upon that patient, sooner rather than later. I can’t tell you how many cases of hemangiomas I’ve seen when the kid is 18 months of age, 3 years of age, 5 years, with a large area of redundant skin, scarring, or something of that sort, and it would have been really nice to have seen them earlier and acted upon them then,” the pediatric dermatologist said.
The guidelines recommend intervention or referral by 1 month of age, ideally. Guidance is provided about the use of oral propranolol as first-line therapy.
“Propranolol is something that has been a real game changer for us,” he noted. “Many people continue to be worried about side effects in using this, particularly in the young childhood population, but this paper shows pretty clearly that hypotension or bradycardia is not a real concern. I never hospitalize these patients for propranolol therapy except in high-risk populations: very preemie, any history of breathing problems. We check the blood pressure and heart rate at baseline, again at 7-10 days, and at every visit. We’ve never found any significant drop in blood pressure.”
Dr. Levy reported financial relationships with half a dozen pharmaceutical companies, none relevant to his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
Don’t call it perioral dermatitis
LAHAINA, HAWAII – , according to Jessica Sprague, MD, a pediatric dermatologist at the University of California, San Diego, and Rady Children’s Hospital.
Years ago, some of her senior colleagues at the children’s hospital carried out a retrospective study of 79 patients, aged 6 months to 18 years, who were treated for what’s typically called perioral dermatitis. Of note, only 40% of patients had isolated perioral involvement, while 30% of the patients had no perioral lesions at all. Perinasal lesions were present in 43%, and 25% had periocular involvement, she noted at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
The peak incidence of periorificial dermatitis in this series was under age 5 years. At presentation, the rash had been present for an average of 8 months. Seventy-two percent of patients had a history of exposure to corticosteroids, most often in the form of topical steroids, but in some cases inhaled or systemic steroids.
“Obviously you want to discontinue the topical steroid. Sometimes you need to taper them off, or you can switch to a topical calcineurin inhibitor [TCI] because they tend to flare a lot when you stop their topical steroid, although there are cases of TCIs precipitating periorificial dermatitis, so keep that in mind,” Dr. Sprague said.
If a patient is on inhaled steroids by mask for asthma, switching to a tube can sometimes limit the exposure, she continued.
Her first-line therapy for mild to moderate periorificial dermatitis, and the one supported by the strongest evidence base, is metronidazole cream. Other topical agents shown to be effective include azelaic acid, sulfacetamide, clindamycin, and topical calcineurin inhibitors.
Oral therapy is a good option for more extensive or recalcitrant cases.
“If parents are very anxious, like before school photos or holiday photos, sometimes I’ll use oral therapy as well. In younger kids, I prefer erythromycin at 30 mg/kg per day t.i.d. for 3-6 weeks. In kids 8 years old and up you can use doxycycline at 50-100 mg b.i.d., again for 3-6 weeks. And you have to tell them it’s going to take a while for this to go away,” Dr. Sprague said.
She reported having no financial conflicts regarding her presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – , according to Jessica Sprague, MD, a pediatric dermatologist at the University of California, San Diego, and Rady Children’s Hospital.
Years ago, some of her senior colleagues at the children’s hospital carried out a retrospective study of 79 patients, aged 6 months to 18 years, who were treated for what’s typically called perioral dermatitis. Of note, only 40% of patients had isolated perioral involvement, while 30% of the patients had no perioral lesions at all. Perinasal lesions were present in 43%, and 25% had periocular involvement, she noted at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
The peak incidence of periorificial dermatitis in this series was under age 5 years. At presentation, the rash had been present for an average of 8 months. Seventy-two percent of patients had a history of exposure to corticosteroids, most often in the form of topical steroids, but in some cases inhaled or systemic steroids.
“Obviously you want to discontinue the topical steroid. Sometimes you need to taper them off, or you can switch to a topical calcineurin inhibitor [TCI] because they tend to flare a lot when you stop their topical steroid, although there are cases of TCIs precipitating periorificial dermatitis, so keep that in mind,” Dr. Sprague said.
If a patient is on inhaled steroids by mask for asthma, switching to a tube can sometimes limit the exposure, she continued.
Her first-line therapy for mild to moderate periorificial dermatitis, and the one supported by the strongest evidence base, is metronidazole cream. Other topical agents shown to be effective include azelaic acid, sulfacetamide, clindamycin, and topical calcineurin inhibitors.
Oral therapy is a good option for more extensive or recalcitrant cases.
“If parents are very anxious, like before school photos or holiday photos, sometimes I’ll use oral therapy as well. In younger kids, I prefer erythromycin at 30 mg/kg per day t.i.d. for 3-6 weeks. In kids 8 years old and up you can use doxycycline at 50-100 mg b.i.d., again for 3-6 weeks. And you have to tell them it’s going to take a while for this to go away,” Dr. Sprague said.
She reported having no financial conflicts regarding her presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – , according to Jessica Sprague, MD, a pediatric dermatologist at the University of California, San Diego, and Rady Children’s Hospital.
Years ago, some of her senior colleagues at the children’s hospital carried out a retrospective study of 79 patients, aged 6 months to 18 years, who were treated for what’s typically called perioral dermatitis. Of note, only 40% of patients had isolated perioral involvement, while 30% of the patients had no perioral lesions at all. Perinasal lesions were present in 43%, and 25% had periocular involvement, she noted at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
The peak incidence of periorificial dermatitis in this series was under age 5 years. At presentation, the rash had been present for an average of 8 months. Seventy-two percent of patients had a history of exposure to corticosteroids, most often in the form of topical steroids, but in some cases inhaled or systemic steroids.
“Obviously you want to discontinue the topical steroid. Sometimes you need to taper them off, or you can switch to a topical calcineurin inhibitor [TCI] because they tend to flare a lot when you stop their topical steroid, although there are cases of TCIs precipitating periorificial dermatitis, so keep that in mind,” Dr. Sprague said.
If a patient is on inhaled steroids by mask for asthma, switching to a tube can sometimes limit the exposure, she continued.
Her first-line therapy for mild to moderate periorificial dermatitis, and the one supported by the strongest evidence base, is metronidazole cream. Other topical agents shown to be effective include azelaic acid, sulfacetamide, clindamycin, and topical calcineurin inhibitors.
Oral therapy is a good option for more extensive or recalcitrant cases.
“If parents are very anxious, like before school photos or holiday photos, sometimes I’ll use oral therapy as well. In younger kids, I prefer erythromycin at 30 mg/kg per day t.i.d. for 3-6 weeks. In kids 8 years old and up you can use doxycycline at 50-100 mg b.i.d., again for 3-6 weeks. And you have to tell them it’s going to take a while for this to go away,” Dr. Sprague said.
She reported having no financial conflicts regarding her presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
New topicals coming for pediatric atopic dermatitis
LAHAINA, HAWAII – Novel topical medications are in the works that will address the longstanding unmet need for a Food and Drug Administration–approved noncorticosteroid topical for use in pediatric atopic dermatitis, Lawrence F. Eichenfield, MD, reported at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
These new agents will be embraced by clinicians for use in delicate skin areas, as well as in the common clinical scenario involving steroid-averse parents, predicted Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.
First up is crisaborole (Eucrisa), which is approved for atopic dermatitis (AD) in children aged two years and older and has been under review at the Food and Drug Administration for use in infantile AD. (On March 24, several weeks after the meeting, the FDA approved crisaborole down to aged three months for treatment of mild to moderate AD). Agents earlier in the developmental pipeline include two topical Janus kinase (JAK) inhibitors, ruxolitinib and delgocitinib, as well as tapinarof.
Crisaborole: This phosphodiesterase 4 inhibitor is FDA approved down to 2 years of age. In the phase 4, open-label CrisADe CARE 1 study, crisaborole was studied in 137 children ages 3 months to under 24 months. CrisADe CARE 1, presented at the 2019 annual conference of the Pediatric Dermatology Research Alliance (PeDRA), showed close to a 60% reduction from baseline in Eczema Area and Severity Index (EASI) scores after 28 days of twice-daily therapy in the youngsters, 61% of who had moderate AD, the rest mild disease.
Tolerability and safety were reassuring in the phase 4 study. Although about 3% of subjects each experienced application site pain, discomfort, or erythema, the rate of study discontinuation was impressively low at 2.9%, Dr. Eichenfield observed.
Delgocitinib: Japanese investigators have reported positive results in a phase 2 study of delgocitinib ointment in 98 children and adolescents aged 2-15 years, with AD. After 4 weeks of twice-daily treatment, modified EASI scores improved by a mean of 54% with delgocitinib 0.25% and by 62% with 0.5%, compared with less than a 5% improvement with the vehicle control (J Allergy Clin Immunol. 2019 Dec;144[6]:1575-83). The ointment formulation is being developed specifically for the Japanese market.
Studies of an alternative formulation of the JAK inhibitor as a cream rather than ointment, intended for the U.S. and European markets, are in the early stages, conducted by Leo Pharma. Delgocitinib cream, under study in adults and children down to age 2 years with AD, is also under study for chronic hand dermatitis, a program Dr. Eichenfield is enthusiastic about.
“Hand eczema is something you’re going to hear a lot about in the next 2 years. In the U.S., we have no drug approved specifically for hand eczema. And we actually see a lot of hand eczema in pediatric and adolescent patients. I’d say 75%-80% of the ones I see also have atopic dermatitis,” he said.
Ruxolitinib: Incyte, which is developing the topical JAK inhibitor, recently announced positive results in the first of four phase 3 randomized trials, this one conducted in AD patients aged 12 years and older. The efficacy appears to be comparable to that of topical steroids. Studies in younger children are also planned. Ruxolitinib cream is in advanced clinical trials for treatment of vitiligo.
Tapinarof: This topical aryl hydrocarbon receptor agonist downregulates Th17 cytokines, an attribute desirable for treatment of psoriasis. But it also downregulates Th2 cytokines and improves the damaged skin barrier characteristic of AD via upregulation of the filaggrin and involucrin genes in keratinocytes. In a phase 2b, double-blind clinical trial conducted in 247 adults and adolescents with moderate to severe AD, 12 weeks of once-daily tapinarof 1% enabled 51% of patients to achieve a 75% or greater improvement in EASI scores, compared with 18% in controls on vehicle (J Am Acad Dermatol. 2019 Jan;80[1]:89-98.e3).
Dermavant, which is developing the drug, plans to seek an initial indication for treatment of psoriasis, where a phase 3 study is underway, before pursuing regulatory approval in AD.
Dr. Eichenfield disclosed serving as a consultant or investigator for various pharmaceutical companies, including Pfizer, and Dermavant.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
This article was updated 3/27/20.
LAHAINA, HAWAII – Novel topical medications are in the works that will address the longstanding unmet need for a Food and Drug Administration–approved noncorticosteroid topical for use in pediatric atopic dermatitis, Lawrence F. Eichenfield, MD, reported at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
These new agents will be embraced by clinicians for use in delicate skin areas, as well as in the common clinical scenario involving steroid-averse parents, predicted Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.
First up is crisaborole (Eucrisa), which is approved for atopic dermatitis (AD) in children aged two years and older and has been under review at the Food and Drug Administration for use in infantile AD. (On March 24, several weeks after the meeting, the FDA approved crisaborole down to aged three months for treatment of mild to moderate AD). Agents earlier in the developmental pipeline include two topical Janus kinase (JAK) inhibitors, ruxolitinib and delgocitinib, as well as tapinarof.
Crisaborole: This phosphodiesterase 4 inhibitor is FDA approved down to 2 years of age. In the phase 4, open-label CrisADe CARE 1 study, crisaborole was studied in 137 children ages 3 months to under 24 months. CrisADe CARE 1, presented at the 2019 annual conference of the Pediatric Dermatology Research Alliance (PeDRA), showed close to a 60% reduction from baseline in Eczema Area and Severity Index (EASI) scores after 28 days of twice-daily therapy in the youngsters, 61% of who had moderate AD, the rest mild disease.
Tolerability and safety were reassuring in the phase 4 study. Although about 3% of subjects each experienced application site pain, discomfort, or erythema, the rate of study discontinuation was impressively low at 2.9%, Dr. Eichenfield observed.
Delgocitinib: Japanese investigators have reported positive results in a phase 2 study of delgocitinib ointment in 98 children and adolescents aged 2-15 years, with AD. After 4 weeks of twice-daily treatment, modified EASI scores improved by a mean of 54% with delgocitinib 0.25% and by 62% with 0.5%, compared with less than a 5% improvement with the vehicle control (J Allergy Clin Immunol. 2019 Dec;144[6]:1575-83). The ointment formulation is being developed specifically for the Japanese market.
Studies of an alternative formulation of the JAK inhibitor as a cream rather than ointment, intended for the U.S. and European markets, are in the early stages, conducted by Leo Pharma. Delgocitinib cream, under study in adults and children down to age 2 years with AD, is also under study for chronic hand dermatitis, a program Dr. Eichenfield is enthusiastic about.
“Hand eczema is something you’re going to hear a lot about in the next 2 years. In the U.S., we have no drug approved specifically for hand eczema. And we actually see a lot of hand eczema in pediatric and adolescent patients. I’d say 75%-80% of the ones I see also have atopic dermatitis,” he said.
Ruxolitinib: Incyte, which is developing the topical JAK inhibitor, recently announced positive results in the first of four phase 3 randomized trials, this one conducted in AD patients aged 12 years and older. The efficacy appears to be comparable to that of topical steroids. Studies in younger children are also planned. Ruxolitinib cream is in advanced clinical trials for treatment of vitiligo.
Tapinarof: This topical aryl hydrocarbon receptor agonist downregulates Th17 cytokines, an attribute desirable for treatment of psoriasis. But it also downregulates Th2 cytokines and improves the damaged skin barrier characteristic of AD via upregulation of the filaggrin and involucrin genes in keratinocytes. In a phase 2b, double-blind clinical trial conducted in 247 adults and adolescents with moderate to severe AD, 12 weeks of once-daily tapinarof 1% enabled 51% of patients to achieve a 75% or greater improvement in EASI scores, compared with 18% in controls on vehicle (J Am Acad Dermatol. 2019 Jan;80[1]:89-98.e3).
Dermavant, which is developing the drug, plans to seek an initial indication for treatment of psoriasis, where a phase 3 study is underway, before pursuing regulatory approval in AD.
Dr. Eichenfield disclosed serving as a consultant or investigator for various pharmaceutical companies, including Pfizer, and Dermavant.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
This article was updated 3/27/20.
LAHAINA, HAWAII – Novel topical medications are in the works that will address the longstanding unmet need for a Food and Drug Administration–approved noncorticosteroid topical for use in pediatric atopic dermatitis, Lawrence F. Eichenfield, MD, reported at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
These new agents will be embraced by clinicians for use in delicate skin areas, as well as in the common clinical scenario involving steroid-averse parents, predicted Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.
First up is crisaborole (Eucrisa), which is approved for atopic dermatitis (AD) in children aged two years and older and has been under review at the Food and Drug Administration for use in infantile AD. (On March 24, several weeks after the meeting, the FDA approved crisaborole down to aged three months for treatment of mild to moderate AD). Agents earlier in the developmental pipeline include two topical Janus kinase (JAK) inhibitors, ruxolitinib and delgocitinib, as well as tapinarof.
Crisaborole: This phosphodiesterase 4 inhibitor is FDA approved down to 2 years of age. In the phase 4, open-label CrisADe CARE 1 study, crisaborole was studied in 137 children ages 3 months to under 24 months. CrisADe CARE 1, presented at the 2019 annual conference of the Pediatric Dermatology Research Alliance (PeDRA), showed close to a 60% reduction from baseline in Eczema Area and Severity Index (EASI) scores after 28 days of twice-daily therapy in the youngsters, 61% of who had moderate AD, the rest mild disease.
Tolerability and safety were reassuring in the phase 4 study. Although about 3% of subjects each experienced application site pain, discomfort, or erythema, the rate of study discontinuation was impressively low at 2.9%, Dr. Eichenfield observed.
Delgocitinib: Japanese investigators have reported positive results in a phase 2 study of delgocitinib ointment in 98 children and adolescents aged 2-15 years, with AD. After 4 weeks of twice-daily treatment, modified EASI scores improved by a mean of 54% with delgocitinib 0.25% and by 62% with 0.5%, compared with less than a 5% improvement with the vehicle control (J Allergy Clin Immunol. 2019 Dec;144[6]:1575-83). The ointment formulation is being developed specifically for the Japanese market.
Studies of an alternative formulation of the JAK inhibitor as a cream rather than ointment, intended for the U.S. and European markets, are in the early stages, conducted by Leo Pharma. Delgocitinib cream, under study in adults and children down to age 2 years with AD, is also under study for chronic hand dermatitis, a program Dr. Eichenfield is enthusiastic about.
“Hand eczema is something you’re going to hear a lot about in the next 2 years. In the U.S., we have no drug approved specifically for hand eczema. And we actually see a lot of hand eczema in pediatric and adolescent patients. I’d say 75%-80% of the ones I see also have atopic dermatitis,” he said.
Ruxolitinib: Incyte, which is developing the topical JAK inhibitor, recently announced positive results in the first of four phase 3 randomized trials, this one conducted in AD patients aged 12 years and older. The efficacy appears to be comparable to that of topical steroids. Studies in younger children are also planned. Ruxolitinib cream is in advanced clinical trials for treatment of vitiligo.
Tapinarof: This topical aryl hydrocarbon receptor agonist downregulates Th17 cytokines, an attribute desirable for treatment of psoriasis. But it also downregulates Th2 cytokines and improves the damaged skin barrier characteristic of AD via upregulation of the filaggrin and involucrin genes in keratinocytes. In a phase 2b, double-blind clinical trial conducted in 247 adults and adolescents with moderate to severe AD, 12 weeks of once-daily tapinarof 1% enabled 51% of patients to achieve a 75% or greater improvement in EASI scores, compared with 18% in controls on vehicle (J Am Acad Dermatol. 2019 Jan;80[1]:89-98.e3).
Dermavant, which is developing the drug, plans to seek an initial indication for treatment of psoriasis, where a phase 3 study is underway, before pursuing regulatory approval in AD.
Dr. Eichenfield disclosed serving as a consultant or investigator for various pharmaceutical companies, including Pfizer, and Dermavant.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
This article was updated 3/27/20.
REPORTING FROM THE SDEF HAWAII DERMATOLOGY SEMINAR
Dupilumab approval sought for AD under age 12
LAHAINA, HAWAII – Reassuring evidence of the long-term effectiveness and safety of dupilumab in adolescents with moderate to severe atopic dermatitis comes from a phase 3 open-label extension study of the first teenagers in the world to have received the monoclonal antibody, Lawrence F. Eichenfield, MD, reported at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Dupilumab (Dupixent), a monoclonal antibody directed against interleukins-4 and -13 initially approved in adults, received an expanded indication from the Food and Drug Administration in March 2019 for treatment of 12- to 17-year-olds with moderate to severe atopic dermatitis (AD) on the strength of a pivotal 251-patient, phase 3 randomized trial of 16 weeks’ duration (JAMA Dermatol. 2019 Nov 6. doi: 10.1001/jamadermatol.2019.3336). But since AD is a chronic disease, it was important to learn how dupilumab performs well beyond the 16-week mark in adolescents, observed Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.
In addition to highlighting some of the emerging fine points of dupilumab therapy in adolescents, Dr. Eichenfield discussed the clinical implications of a potential further expanded indication for treatment of 6- to 12-year-olds, an event he considers likely in the coming months. He also described early data from an ongoing dupilumab clinical trials program in the 2- to 5-year-olds.
Long-term dupilumab in teens
Dr. Eichenfield was a coauthor of the recently published phase 3 international long-term extension study. The 40 participants experienced a mean 85% decrease from baseline at 52 weeks in EASI (Eczema Area and Severity Index) scores on 2 mg/kg per week dosing and an 84% reduction on 4 mg/kg per week dosing. This represented a substantial further improvement from week 2, when the EASI reductions were 34% and 51%, respectively.
The mean trough serum dupilumab concentrations over the course of the year were markedly lower in the 2 mg/kg group: 74 mg/L, as compared to 161 mg/L with dosing at 4 mg/kg per week (Br J Dermatol. 2020 Jan;182[1]:85-96).
“It’ll be interesting to see how this works out over time,” the dermatologist commented. “The issue of dose by weight becomes important as we start to treat younger patients because the pharmacokinetics are very different at 4 and 2 mg/kg, and it may have an impact on efficacy.”
The extension study also established the safety and effectiveness of utilizing dupilumab in combination with standard topical corticosteroid therapy, which wasn’t allowed in the pivotal 16-week trial.
Some have commented that dupilumab may be less effective in adolescents than in adults. They point to the 24% rate of an Investigator Global Assessment (IGA) of 0 or 1 – that is, clear or almost clear – at week 16 in the pivotal adolescent trial, a substantially lower rate than in the adult trials. However, Dr. Eichenfield noted that the adolescent study population was heavily skewed to the severe end of the disease spectrum, the placebo response rate was very low, and the absolute placebo-subtracted benefit turned out to be quite similar to what was seen in the adult trials. Moreover, he added, in a post hoc analysis of the pivotal trial data which utilized a different measure of clinically meaningful response – a composite of either a 50% reduction in EASI score, a 3-point or greater improvement on a 10-point pruritus scale, or at least a 6-point improvement from baseline on the Children’s Dermatology Quality Life Index – that outcome was achieved by 74% of adolescents who didn’t achieve clear or almost clear.
What’s next for dupilumab in pediatric AD
Approval of dupilumab in children under aged 12 years is eagerly awaited, Dr. Eichenfield said. The Food and Drug Administration is now analyzing as-yet unreleased data from completed clinical trials of dupilumab in 6- to 12-year-olds with moderate to severe AD with an eye toward a possible further expanded indication. The side effect profile appears to be the same as in 12- to 18-year-olds.
“I assume it will be approved,” Dr. Eichenfield said. “We don’t know what’s going to happen in 6- to 12-year-olds in terms of the ultimate dosing recommendations that will be put out, but be aware that the pharmacokinetics vary by weight over time.”
Early data in children aged 2-5 years with severe AD from the phase 2, open-label, single ascending dose Liberty AD PRESCHOOL study showed that weight-based dosing in that age group made a big difference in terms of pharmacokinetics. In terms of efficacy, the mean reduction in EASI scores 4 weeks after a single dose of dupilumab was 27% with 3 mg/kg and 49% with 6 mg/kg.
Avoidance of live vaccines while on dupilumab becomes more of a consideration in the under-12 population. The second dose of varicella is supposed to be administered at 4 to 6 years of age, as is the second dose of MMR. The nasal influenza vaccine is a live virus vaccine, as is the yellow fever vaccine.
“We don’t know if live vaccines are dangerous for someone on dupilumab, it’s just that it’s listed that you shouldn’t use them and they haven’t been studied,” Dr. Eichenfield observed.
He reported receiving research grants from or serving as a consultant to several dozen pharmaceutical companies.
The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – Reassuring evidence of the long-term effectiveness and safety of dupilumab in adolescents with moderate to severe atopic dermatitis comes from a phase 3 open-label extension study of the first teenagers in the world to have received the monoclonal antibody, Lawrence F. Eichenfield, MD, reported at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Dupilumab (Dupixent), a monoclonal antibody directed against interleukins-4 and -13 initially approved in adults, received an expanded indication from the Food and Drug Administration in March 2019 for treatment of 12- to 17-year-olds with moderate to severe atopic dermatitis (AD) on the strength of a pivotal 251-patient, phase 3 randomized trial of 16 weeks’ duration (JAMA Dermatol. 2019 Nov 6. doi: 10.1001/jamadermatol.2019.3336). But since AD is a chronic disease, it was important to learn how dupilumab performs well beyond the 16-week mark in adolescents, observed Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.
In addition to highlighting some of the emerging fine points of dupilumab therapy in adolescents, Dr. Eichenfield discussed the clinical implications of a potential further expanded indication for treatment of 6- to 12-year-olds, an event he considers likely in the coming months. He also described early data from an ongoing dupilumab clinical trials program in the 2- to 5-year-olds.
Long-term dupilumab in teens
Dr. Eichenfield was a coauthor of the recently published phase 3 international long-term extension study. The 40 participants experienced a mean 85% decrease from baseline at 52 weeks in EASI (Eczema Area and Severity Index) scores on 2 mg/kg per week dosing and an 84% reduction on 4 mg/kg per week dosing. This represented a substantial further improvement from week 2, when the EASI reductions were 34% and 51%, respectively.
The mean trough serum dupilumab concentrations over the course of the year were markedly lower in the 2 mg/kg group: 74 mg/L, as compared to 161 mg/L with dosing at 4 mg/kg per week (Br J Dermatol. 2020 Jan;182[1]:85-96).
“It’ll be interesting to see how this works out over time,” the dermatologist commented. “The issue of dose by weight becomes important as we start to treat younger patients because the pharmacokinetics are very different at 4 and 2 mg/kg, and it may have an impact on efficacy.”
The extension study also established the safety and effectiveness of utilizing dupilumab in combination with standard topical corticosteroid therapy, which wasn’t allowed in the pivotal 16-week trial.
Some have commented that dupilumab may be less effective in adolescents than in adults. They point to the 24% rate of an Investigator Global Assessment (IGA) of 0 or 1 – that is, clear or almost clear – at week 16 in the pivotal adolescent trial, a substantially lower rate than in the adult trials. However, Dr. Eichenfield noted that the adolescent study population was heavily skewed to the severe end of the disease spectrum, the placebo response rate was very low, and the absolute placebo-subtracted benefit turned out to be quite similar to what was seen in the adult trials. Moreover, he added, in a post hoc analysis of the pivotal trial data which utilized a different measure of clinically meaningful response – a composite of either a 50% reduction in EASI score, a 3-point or greater improvement on a 10-point pruritus scale, or at least a 6-point improvement from baseline on the Children’s Dermatology Quality Life Index – that outcome was achieved by 74% of adolescents who didn’t achieve clear or almost clear.
What’s next for dupilumab in pediatric AD
Approval of dupilumab in children under aged 12 years is eagerly awaited, Dr. Eichenfield said. The Food and Drug Administration is now analyzing as-yet unreleased data from completed clinical trials of dupilumab in 6- to 12-year-olds with moderate to severe AD with an eye toward a possible further expanded indication. The side effect profile appears to be the same as in 12- to 18-year-olds.
“I assume it will be approved,” Dr. Eichenfield said. “We don’t know what’s going to happen in 6- to 12-year-olds in terms of the ultimate dosing recommendations that will be put out, but be aware that the pharmacokinetics vary by weight over time.”
Early data in children aged 2-5 years with severe AD from the phase 2, open-label, single ascending dose Liberty AD PRESCHOOL study showed that weight-based dosing in that age group made a big difference in terms of pharmacokinetics. In terms of efficacy, the mean reduction in EASI scores 4 weeks after a single dose of dupilumab was 27% with 3 mg/kg and 49% with 6 mg/kg.
Avoidance of live vaccines while on dupilumab becomes more of a consideration in the under-12 population. The second dose of varicella is supposed to be administered at 4 to 6 years of age, as is the second dose of MMR. The nasal influenza vaccine is a live virus vaccine, as is the yellow fever vaccine.
“We don’t know if live vaccines are dangerous for someone on dupilumab, it’s just that it’s listed that you shouldn’t use them and they haven’t been studied,” Dr. Eichenfield observed.
He reported receiving research grants from or serving as a consultant to several dozen pharmaceutical companies.
The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – Reassuring evidence of the long-term effectiveness and safety of dupilumab in adolescents with moderate to severe atopic dermatitis comes from a phase 3 open-label extension study of the first teenagers in the world to have received the monoclonal antibody, Lawrence F. Eichenfield, MD, reported at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Dupilumab (Dupixent), a monoclonal antibody directed against interleukins-4 and -13 initially approved in adults, received an expanded indication from the Food and Drug Administration in March 2019 for treatment of 12- to 17-year-olds with moderate to severe atopic dermatitis (AD) on the strength of a pivotal 251-patient, phase 3 randomized trial of 16 weeks’ duration (JAMA Dermatol. 2019 Nov 6. doi: 10.1001/jamadermatol.2019.3336). But since AD is a chronic disease, it was important to learn how dupilumab performs well beyond the 16-week mark in adolescents, observed Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.
In addition to highlighting some of the emerging fine points of dupilumab therapy in adolescents, Dr. Eichenfield discussed the clinical implications of a potential further expanded indication for treatment of 6- to 12-year-olds, an event he considers likely in the coming months. He also described early data from an ongoing dupilumab clinical trials program in the 2- to 5-year-olds.
Long-term dupilumab in teens
Dr. Eichenfield was a coauthor of the recently published phase 3 international long-term extension study. The 40 participants experienced a mean 85% decrease from baseline at 52 weeks in EASI (Eczema Area and Severity Index) scores on 2 mg/kg per week dosing and an 84% reduction on 4 mg/kg per week dosing. This represented a substantial further improvement from week 2, when the EASI reductions were 34% and 51%, respectively.
The mean trough serum dupilumab concentrations over the course of the year were markedly lower in the 2 mg/kg group: 74 mg/L, as compared to 161 mg/L with dosing at 4 mg/kg per week (Br J Dermatol. 2020 Jan;182[1]:85-96).
“It’ll be interesting to see how this works out over time,” the dermatologist commented. “The issue of dose by weight becomes important as we start to treat younger patients because the pharmacokinetics are very different at 4 and 2 mg/kg, and it may have an impact on efficacy.”
The extension study also established the safety and effectiveness of utilizing dupilumab in combination with standard topical corticosteroid therapy, which wasn’t allowed in the pivotal 16-week trial.
Some have commented that dupilumab may be less effective in adolescents than in adults. They point to the 24% rate of an Investigator Global Assessment (IGA) of 0 or 1 – that is, clear or almost clear – at week 16 in the pivotal adolescent trial, a substantially lower rate than in the adult trials. However, Dr. Eichenfield noted that the adolescent study population was heavily skewed to the severe end of the disease spectrum, the placebo response rate was very low, and the absolute placebo-subtracted benefit turned out to be quite similar to what was seen in the adult trials. Moreover, he added, in a post hoc analysis of the pivotal trial data which utilized a different measure of clinically meaningful response – a composite of either a 50% reduction in EASI score, a 3-point or greater improvement on a 10-point pruritus scale, or at least a 6-point improvement from baseline on the Children’s Dermatology Quality Life Index – that outcome was achieved by 74% of adolescents who didn’t achieve clear or almost clear.
What’s next for dupilumab in pediatric AD
Approval of dupilumab in children under aged 12 years is eagerly awaited, Dr. Eichenfield said. The Food and Drug Administration is now analyzing as-yet unreleased data from completed clinical trials of dupilumab in 6- to 12-year-olds with moderate to severe AD with an eye toward a possible further expanded indication. The side effect profile appears to be the same as in 12- to 18-year-olds.
“I assume it will be approved,” Dr. Eichenfield said. “We don’t know what’s going to happen in 6- to 12-year-olds in terms of the ultimate dosing recommendations that will be put out, but be aware that the pharmacokinetics vary by weight over time.”
Early data in children aged 2-5 years with severe AD from the phase 2, open-label, single ascending dose Liberty AD PRESCHOOL study showed that weight-based dosing in that age group made a big difference in terms of pharmacokinetics. In terms of efficacy, the mean reduction in EASI scores 4 weeks after a single dose of dupilumab was 27% with 3 mg/kg and 49% with 6 mg/kg.
Avoidance of live vaccines while on dupilumab becomes more of a consideration in the under-12 population. The second dose of varicella is supposed to be administered at 4 to 6 years of age, as is the second dose of MMR. The nasal influenza vaccine is a live virus vaccine, as is the yellow fever vaccine.
“We don’t know if live vaccines are dangerous for someone on dupilumab, it’s just that it’s listed that you shouldn’t use them and they haven’t been studied,” Dr. Eichenfield observed.
He reported receiving research grants from or serving as a consultant to several dozen pharmaceutical companies.
The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
Merkel cell carcinoma management undergoes revolution
LAHAINA, HAWAII – The , Paul Nghiem, MD, PhD, declared at the SDEF Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
That’s because dermatologists are typically the physicians who make the diagnosis of Merkel cell carcinoma (MCC), so they’re on the scene from the outset and well positioned to help direct early management of this particularly aggressive malignancy, explained Dr. Nghiem, professor and head of dermatology at the University of Washington, Seattle.
“The management of Merkel is pretty high stakes, and if you get it right at the beginning it makes a huge difference in the side effects, as well as the chances that the patient will have the disease under control,” said Dr. Nghiem, who is sometimes called “the Merkel man” because of his many pioneering contributions to the field.
Better early management
Getting early management right, he added, hinges upon ordering a baseline PET-CT scan to search for metastases before performing definitive surgical excision of the primary tumor.
“There are really important prognostic and therapeutic implications for a baseline scan in almost any patient with early Merkel – and that’s a very different situation than with melanoma,” the dermatologist said. “There’s at least a threefold higher likelihood that the cancer has spread asymptomatically at baseline with Merkel cell carcinoma than with melanoma.”
In a soon-to-be-published study by Dr. Nghiem and coworkers, baseline imaging resulted in prognostically important upstaging that led to an altered management strategy in 12% of 584 patients with MCC, or 1 in 8.
“You don’t want to overtreat locally a lesion that has already spread distantly; you want to start focusing on the distant disease. The local disease is secondary,” he said.
The surgical excision of the primary lesion should be thoughtfully wide without being aggressive or mutilating, and it should involve primary closure. “Definitely avoid flaps and grafts, which delay your further management with radiotherapy by months and months,” Dr. Nghiem advised.
Adjuvant radiotherapy of the primary tumor site is extremely effective at preventing recurrent MCC. In Dr. Nghiem’s view, almost everyone is a candidate: In a series of 803 patients in the Seattle MCC cohort, 92% received local adjuvant radiotherapy. The national rate, in contrast, is only about 50%, highlighting the need for additional physician education.
“A little bit of radiation – one dose – appears to be just as effective as 6 weeks in controlling microscopic disease. That’s probably something we’re going to be moving towards as a field,” he predicted.
Indeed, local adjuvant radiotherapy is so effective in MCC that the surgical margins make no difference. This was demonstrated in a study by Dr. Nghiem and his coinvestigators involving 70 patients with margins greater than 1 cm who received radiotherapy, 70 others with smaller or even positive margins who received radiotherapy, and 35 patients with margins of 1 cm or less who did not receive radiotherapy. There were no MCC recurrences in any of the radiotherapy recipients, regardless of their margin status. In contrast, 7 of the 35 patients who didn’t receive radiation therapy developed a cancer recurrence. Of note, the recurrence rate of MCC is historically about 40% – far greater than for any other skin cancer. Most recurrences happen within the first 2-3 years, Dr. Nghiem observed.
Immune therapy takes center stage
Another major transformation in MCC management has been the emergence of immune therapy as first-line systemic therapy. It has replaced chemotherapy, which is more toxic and has a much shorter average duration of response. Avelumab (Bavencio) and pembrolizumab (Keytruda), the two monoclonal antibodies directed against the protein programmed death–ligand 1 (PD-L1) receptor which are approved for MCC and have been incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, provide a sixfold improvement in survival, compared with chemotherapy. For example, Dr. Nghiem was first author of a multicenter phase 2 study of pembrolizumab in which the 12- and 24-month overall survival rates in pembrolizumab responders were 85% and 79%, compared with just 12% and 6%, respectively, in historical controls on first-line chemotherapy (J Clin Oncol. 2019 Mar 20;37[9]:693-702).
“Merkel cell carcinoma is the most responsive solid tumor to immune therapy,” Dr. Nghiem commented.
Why MCC matters
Although rare, MCC is important because it’s five times more lethal than melanoma. Moreover, its incidence has been rising at a rate roughly twice that of the increase in melanoma since the turn of the century. There are now more than 3,000 new cases of MCC annually, about the same as for cutaneous T-cell lymphoma (CTCL).
“It’s just that you live a long time with CTCL and you don’t with Merkel cell carcinoma. You either get rid of Merkel fast or it gets rid of you,” the dermatologist observed.
It’s a fascinating malignancy, he continued. Eight of 10 cases are caused by Merkel cell polyomavirus, discovered in 2008. The virus is ubiquitously acquired in childhood and then lies dormant on the skin for the next 6 or 7 decades, at which point MCC rates shoot up dramatically, probably due to immunosenescence. Immunosuppressed patients are at 10-fold increased risk for MCC.
Given the rarity of MCC, it doesn’t make sense to actively hunt for it. But Dr. Nghiem and coworkers have developed a handy vowel-based mnemonic that serves to raise the index of suspicion: the “AEIOU” features.
- A = asymptomatic.
- E = expanding rapidly within past 3 months.
- I = immune-mediated.
- O = older than age 50.
- U = UV-exposed skin.
The investigators found in a series of 195 MCC patients that 89% of them possessed three or more of these features (J Am Acad Dermatol. 2008 Mar;58[3]:375-81). But while the AEIOU guide is quite sensitive, it’s not specific.
“If you have any three or more of these features, that lesion probably deserves a biopsy if it’s not readily explained. Even if it’s not a Merkel, it may turn out to be a different nonmelanoma skin cancer, something you want to know about,” Dr. Nghiem said.
A shift in surveillance strategy
Dr. Nghiem was senior author of a major study that validated the clinical utility of a Merkel polyomavirus serology test for monitoring the disease status of patients treated for MCC (Cancer. 2017 Apr 15;123[8]:1464-74). The test, which measures antibodies to Merkel cell polyomavirus oncoproteins, has been incorporated in NCCN guidelines. The blood test is used initially in newly diagnosed MCC to stratify patients into two subgroups: the half who are seropositive at baseline, and the other half who are seronegative. The seropositive group undergoes surveillance via repeat blood testing every 3 months. If antibody levels are low, there is a high degree of certainty that immune therapy is working and remission is present. Thus, the blood test spares patients in this group the expense and radiation exposure entailed in repeated surveillance scans. However, rising antibody levels indicate the cancer has already recurred or will do so within the next several months.
Unfortunately, the blood test cannot be used serially to track disease status in patients who are seronegative at baseline. That group is at 42% increased risk of MCC recurrence.
Immune therapy works in only about two-thirds of MCC patients with distant disease. Leaving the visible primary tumor in place to serve as a real-time window into immune treatment effectiveness is a useful contemporary surveillance strategy.
“By leaving the visible primary there, you will rapidly know if that patient is in the favorable two-thirds group or not,” he explained.
Historically, surgery and surveillance of MCC were based upon the melanoma model, and medical oncologists were trained to treat the malignancy as they would small cell lung cancer. These are now outmoded approaches, Dr. Nghiem said. That’s why a multidisciplinary approach is highly desirable for management of MCC, including dermatologists, pathologists, surgeons, radiation oncologists, medical oncologists, and imaging experts.
Dr. Nghiem and his colleagues have created a comprehensive source of information about Merkel cell carcinoma for physicians and patients at merkelcell.org.
He reported receiving research grants from Bristol-Myers Squibb and serving as a consultant to EMD Serono, Merck, Sanofi/Regeneron, and 4SC.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – The , Paul Nghiem, MD, PhD, declared at the SDEF Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
That’s because dermatologists are typically the physicians who make the diagnosis of Merkel cell carcinoma (MCC), so they’re on the scene from the outset and well positioned to help direct early management of this particularly aggressive malignancy, explained Dr. Nghiem, professor and head of dermatology at the University of Washington, Seattle.
“The management of Merkel is pretty high stakes, and if you get it right at the beginning it makes a huge difference in the side effects, as well as the chances that the patient will have the disease under control,” said Dr. Nghiem, who is sometimes called “the Merkel man” because of his many pioneering contributions to the field.
Better early management
Getting early management right, he added, hinges upon ordering a baseline PET-CT scan to search for metastases before performing definitive surgical excision of the primary tumor.
“There are really important prognostic and therapeutic implications for a baseline scan in almost any patient with early Merkel – and that’s a very different situation than with melanoma,” the dermatologist said. “There’s at least a threefold higher likelihood that the cancer has spread asymptomatically at baseline with Merkel cell carcinoma than with melanoma.”
In a soon-to-be-published study by Dr. Nghiem and coworkers, baseline imaging resulted in prognostically important upstaging that led to an altered management strategy in 12% of 584 patients with MCC, or 1 in 8.
“You don’t want to overtreat locally a lesion that has already spread distantly; you want to start focusing on the distant disease. The local disease is secondary,” he said.
The surgical excision of the primary lesion should be thoughtfully wide without being aggressive or mutilating, and it should involve primary closure. “Definitely avoid flaps and grafts, which delay your further management with radiotherapy by months and months,” Dr. Nghiem advised.
Adjuvant radiotherapy of the primary tumor site is extremely effective at preventing recurrent MCC. In Dr. Nghiem’s view, almost everyone is a candidate: In a series of 803 patients in the Seattle MCC cohort, 92% received local adjuvant radiotherapy. The national rate, in contrast, is only about 50%, highlighting the need for additional physician education.
“A little bit of radiation – one dose – appears to be just as effective as 6 weeks in controlling microscopic disease. That’s probably something we’re going to be moving towards as a field,” he predicted.
Indeed, local adjuvant radiotherapy is so effective in MCC that the surgical margins make no difference. This was demonstrated in a study by Dr. Nghiem and his coinvestigators involving 70 patients with margins greater than 1 cm who received radiotherapy, 70 others with smaller or even positive margins who received radiotherapy, and 35 patients with margins of 1 cm or less who did not receive radiotherapy. There were no MCC recurrences in any of the radiotherapy recipients, regardless of their margin status. In contrast, 7 of the 35 patients who didn’t receive radiation therapy developed a cancer recurrence. Of note, the recurrence rate of MCC is historically about 40% – far greater than for any other skin cancer. Most recurrences happen within the first 2-3 years, Dr. Nghiem observed.
Immune therapy takes center stage
Another major transformation in MCC management has been the emergence of immune therapy as first-line systemic therapy. It has replaced chemotherapy, which is more toxic and has a much shorter average duration of response. Avelumab (Bavencio) and pembrolizumab (Keytruda), the two monoclonal antibodies directed against the protein programmed death–ligand 1 (PD-L1) receptor which are approved for MCC and have been incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, provide a sixfold improvement in survival, compared with chemotherapy. For example, Dr. Nghiem was first author of a multicenter phase 2 study of pembrolizumab in which the 12- and 24-month overall survival rates in pembrolizumab responders were 85% and 79%, compared with just 12% and 6%, respectively, in historical controls on first-line chemotherapy (J Clin Oncol. 2019 Mar 20;37[9]:693-702).
“Merkel cell carcinoma is the most responsive solid tumor to immune therapy,” Dr. Nghiem commented.
Why MCC matters
Although rare, MCC is important because it’s five times more lethal than melanoma. Moreover, its incidence has been rising at a rate roughly twice that of the increase in melanoma since the turn of the century. There are now more than 3,000 new cases of MCC annually, about the same as for cutaneous T-cell lymphoma (CTCL).
“It’s just that you live a long time with CTCL and you don’t with Merkel cell carcinoma. You either get rid of Merkel fast or it gets rid of you,” the dermatologist observed.
It’s a fascinating malignancy, he continued. Eight of 10 cases are caused by Merkel cell polyomavirus, discovered in 2008. The virus is ubiquitously acquired in childhood and then lies dormant on the skin for the next 6 or 7 decades, at which point MCC rates shoot up dramatically, probably due to immunosenescence. Immunosuppressed patients are at 10-fold increased risk for MCC.
Given the rarity of MCC, it doesn’t make sense to actively hunt for it. But Dr. Nghiem and coworkers have developed a handy vowel-based mnemonic that serves to raise the index of suspicion: the “AEIOU” features.
- A = asymptomatic.
- E = expanding rapidly within past 3 months.
- I = immune-mediated.
- O = older than age 50.
- U = UV-exposed skin.
The investigators found in a series of 195 MCC patients that 89% of them possessed three or more of these features (J Am Acad Dermatol. 2008 Mar;58[3]:375-81). But while the AEIOU guide is quite sensitive, it’s not specific.
“If you have any three or more of these features, that lesion probably deserves a biopsy if it’s not readily explained. Even if it’s not a Merkel, it may turn out to be a different nonmelanoma skin cancer, something you want to know about,” Dr. Nghiem said.
A shift in surveillance strategy
Dr. Nghiem was senior author of a major study that validated the clinical utility of a Merkel polyomavirus serology test for monitoring the disease status of patients treated for MCC (Cancer. 2017 Apr 15;123[8]:1464-74). The test, which measures antibodies to Merkel cell polyomavirus oncoproteins, has been incorporated in NCCN guidelines. The blood test is used initially in newly diagnosed MCC to stratify patients into two subgroups: the half who are seropositive at baseline, and the other half who are seronegative. The seropositive group undergoes surveillance via repeat blood testing every 3 months. If antibody levels are low, there is a high degree of certainty that immune therapy is working and remission is present. Thus, the blood test spares patients in this group the expense and radiation exposure entailed in repeated surveillance scans. However, rising antibody levels indicate the cancer has already recurred or will do so within the next several months.
Unfortunately, the blood test cannot be used serially to track disease status in patients who are seronegative at baseline. That group is at 42% increased risk of MCC recurrence.
Immune therapy works in only about two-thirds of MCC patients with distant disease. Leaving the visible primary tumor in place to serve as a real-time window into immune treatment effectiveness is a useful contemporary surveillance strategy.
“By leaving the visible primary there, you will rapidly know if that patient is in the favorable two-thirds group or not,” he explained.
Historically, surgery and surveillance of MCC were based upon the melanoma model, and medical oncologists were trained to treat the malignancy as they would small cell lung cancer. These are now outmoded approaches, Dr. Nghiem said. That’s why a multidisciplinary approach is highly desirable for management of MCC, including dermatologists, pathologists, surgeons, radiation oncologists, medical oncologists, and imaging experts.
Dr. Nghiem and his colleagues have created a comprehensive source of information about Merkel cell carcinoma for physicians and patients at merkelcell.org.
He reported receiving research grants from Bristol-Myers Squibb and serving as a consultant to EMD Serono, Merck, Sanofi/Regeneron, and 4SC.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – The , Paul Nghiem, MD, PhD, declared at the SDEF Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
That’s because dermatologists are typically the physicians who make the diagnosis of Merkel cell carcinoma (MCC), so they’re on the scene from the outset and well positioned to help direct early management of this particularly aggressive malignancy, explained Dr. Nghiem, professor and head of dermatology at the University of Washington, Seattle.
“The management of Merkel is pretty high stakes, and if you get it right at the beginning it makes a huge difference in the side effects, as well as the chances that the patient will have the disease under control,” said Dr. Nghiem, who is sometimes called “the Merkel man” because of his many pioneering contributions to the field.
Better early management
Getting early management right, he added, hinges upon ordering a baseline PET-CT scan to search for metastases before performing definitive surgical excision of the primary tumor.
“There are really important prognostic and therapeutic implications for a baseline scan in almost any patient with early Merkel – and that’s a very different situation than with melanoma,” the dermatologist said. “There’s at least a threefold higher likelihood that the cancer has spread asymptomatically at baseline with Merkel cell carcinoma than with melanoma.”
In a soon-to-be-published study by Dr. Nghiem and coworkers, baseline imaging resulted in prognostically important upstaging that led to an altered management strategy in 12% of 584 patients with MCC, or 1 in 8.
“You don’t want to overtreat locally a lesion that has already spread distantly; you want to start focusing on the distant disease. The local disease is secondary,” he said.
The surgical excision of the primary lesion should be thoughtfully wide without being aggressive or mutilating, and it should involve primary closure. “Definitely avoid flaps and grafts, which delay your further management with radiotherapy by months and months,” Dr. Nghiem advised.
Adjuvant radiotherapy of the primary tumor site is extremely effective at preventing recurrent MCC. In Dr. Nghiem’s view, almost everyone is a candidate: In a series of 803 patients in the Seattle MCC cohort, 92% received local adjuvant radiotherapy. The national rate, in contrast, is only about 50%, highlighting the need for additional physician education.
“A little bit of radiation – one dose – appears to be just as effective as 6 weeks in controlling microscopic disease. That’s probably something we’re going to be moving towards as a field,” he predicted.
Indeed, local adjuvant radiotherapy is so effective in MCC that the surgical margins make no difference. This was demonstrated in a study by Dr. Nghiem and his coinvestigators involving 70 patients with margins greater than 1 cm who received radiotherapy, 70 others with smaller or even positive margins who received radiotherapy, and 35 patients with margins of 1 cm or less who did not receive radiotherapy. There were no MCC recurrences in any of the radiotherapy recipients, regardless of their margin status. In contrast, 7 of the 35 patients who didn’t receive radiation therapy developed a cancer recurrence. Of note, the recurrence rate of MCC is historically about 40% – far greater than for any other skin cancer. Most recurrences happen within the first 2-3 years, Dr. Nghiem observed.
Immune therapy takes center stage
Another major transformation in MCC management has been the emergence of immune therapy as first-line systemic therapy. It has replaced chemotherapy, which is more toxic and has a much shorter average duration of response. Avelumab (Bavencio) and pembrolizumab (Keytruda), the two monoclonal antibodies directed against the protein programmed death–ligand 1 (PD-L1) receptor which are approved for MCC and have been incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, provide a sixfold improvement in survival, compared with chemotherapy. For example, Dr. Nghiem was first author of a multicenter phase 2 study of pembrolizumab in which the 12- and 24-month overall survival rates in pembrolizumab responders were 85% and 79%, compared with just 12% and 6%, respectively, in historical controls on first-line chemotherapy (J Clin Oncol. 2019 Mar 20;37[9]:693-702).
“Merkel cell carcinoma is the most responsive solid tumor to immune therapy,” Dr. Nghiem commented.
Why MCC matters
Although rare, MCC is important because it’s five times more lethal than melanoma. Moreover, its incidence has been rising at a rate roughly twice that of the increase in melanoma since the turn of the century. There are now more than 3,000 new cases of MCC annually, about the same as for cutaneous T-cell lymphoma (CTCL).
“It’s just that you live a long time with CTCL and you don’t with Merkel cell carcinoma. You either get rid of Merkel fast or it gets rid of you,” the dermatologist observed.
It’s a fascinating malignancy, he continued. Eight of 10 cases are caused by Merkel cell polyomavirus, discovered in 2008. The virus is ubiquitously acquired in childhood and then lies dormant on the skin for the next 6 or 7 decades, at which point MCC rates shoot up dramatically, probably due to immunosenescence. Immunosuppressed patients are at 10-fold increased risk for MCC.
Given the rarity of MCC, it doesn’t make sense to actively hunt for it. But Dr. Nghiem and coworkers have developed a handy vowel-based mnemonic that serves to raise the index of suspicion: the “AEIOU” features.
- A = asymptomatic.
- E = expanding rapidly within past 3 months.
- I = immune-mediated.
- O = older than age 50.
- U = UV-exposed skin.
The investigators found in a series of 195 MCC patients that 89% of them possessed three or more of these features (J Am Acad Dermatol. 2008 Mar;58[3]:375-81). But while the AEIOU guide is quite sensitive, it’s not specific.
“If you have any three or more of these features, that lesion probably deserves a biopsy if it’s not readily explained. Even if it’s not a Merkel, it may turn out to be a different nonmelanoma skin cancer, something you want to know about,” Dr. Nghiem said.
A shift in surveillance strategy
Dr. Nghiem was senior author of a major study that validated the clinical utility of a Merkel polyomavirus serology test for monitoring the disease status of patients treated for MCC (Cancer. 2017 Apr 15;123[8]:1464-74). The test, which measures antibodies to Merkel cell polyomavirus oncoproteins, has been incorporated in NCCN guidelines. The blood test is used initially in newly diagnosed MCC to stratify patients into two subgroups: the half who are seropositive at baseline, and the other half who are seronegative. The seropositive group undergoes surveillance via repeat blood testing every 3 months. If antibody levels are low, there is a high degree of certainty that immune therapy is working and remission is present. Thus, the blood test spares patients in this group the expense and radiation exposure entailed in repeated surveillance scans. However, rising antibody levels indicate the cancer has already recurred or will do so within the next several months.
Unfortunately, the blood test cannot be used serially to track disease status in patients who are seronegative at baseline. That group is at 42% increased risk of MCC recurrence.
Immune therapy works in only about two-thirds of MCC patients with distant disease. Leaving the visible primary tumor in place to serve as a real-time window into immune treatment effectiveness is a useful contemporary surveillance strategy.
“By leaving the visible primary there, you will rapidly know if that patient is in the favorable two-thirds group or not,” he explained.
Historically, surgery and surveillance of MCC were based upon the melanoma model, and medical oncologists were trained to treat the malignancy as they would small cell lung cancer. These are now outmoded approaches, Dr. Nghiem said. That’s why a multidisciplinary approach is highly desirable for management of MCC, including dermatologists, pathologists, surgeons, radiation oncologists, medical oncologists, and imaging experts.
Dr. Nghiem and his colleagues have created a comprehensive source of information about Merkel cell carcinoma for physicians and patients at merkelcell.org.
He reported receiving research grants from Bristol-Myers Squibb and serving as a consultant to EMD Serono, Merck, Sanofi/Regeneron, and 4SC.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
Short-course calcipotriol plus 5-FU for AKs: potential major public health impact
LAHAINA, HAWAII – The most intriguing recent development in the treatment of actinic keratosis is a study in which a short-course of topical field therapy with , with a resultant markedly reduced risk of developing squamous cell carcinoma within the next 3 years, Kishwer S. Nehal, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
The annual cost of treating actinic keratoses (AKs) exceeds $1 billion in the United States, so the billion-dollar question in dermatology is, does AK reduction lead to long-term protection against cancer? And this 3-year study by investigators at Washington University in St. Louis and Massachusetts General Hospital in Boston suggests the answer may be yes – when topical immunotherapy is utilized to induce robust T cell immunity, said Dr. Nehal, director of Mohs micrographic and dermatologic surgery, and codirector of the multidisciplinary skin cancer management program at Memorial Sloan Kettering Cancer Center in New York.
The investigators previously conducted a randomized, double-blind clinical trial in which 130 participants with a substantial AK burden received a 4-day course of 0.005% calcipotriol ointment plus 5% 5-FU cream or Vaseline plus 5-FU. The combination therapy proved more effective than the comparator in eliminating AKs at 8 weeks of follow-up. Moreover, tissue analysis pointed to the mechanism of benefit: The combination treatment induced keratinocyte expression of thymic stromal lymphopoietin (TSLP) cytokine, which led to a powerful CD4+ T cell response against AKs.
The researchers’ follow-up study addressed two key questions: Whether this epidermal T cell immunity persists long term, and if it actually achieves a reduced risk of squamous cell carcinoma (SCC) over time. The answers were yes and yes.
Seventy of the original 130 patients were prospectively followed for 3 years. Only 2 of 30 (7%) in the short-course combination therapy group developed SCC in treated areas of the face and scalp, compared with 11 of 40 controls (28%), a statistically significant difference, which constitutes a 79% relative risk reduction. This chemopreventive effect was long lasting at the cellular level, as the combination therapy group still retained measurable T cell immunity in the skin at the 3-year mark. As expected, the topical therapy had no impact on the development of basal cell carcinoma. The question now becomes how long the chemopreventive effect extends beyond 3 years.
“These remarkable findings substantiate the use of immunotherapeutic agents with minimal side effects and high efficacy against precancerous lesions in order to reduce the risk of cancer development and recurrence, which may be broadly applicable to skin and internal malignancies,” the investigators wrote in the study (JCI Insight. 2019 Mar 21;4(6). pii: 125476. doi: 10.1172/jci.insight.125476). Dr. Nehal said that this study requires confirmation in light of its post hoc design and the relatively small numbers of patients and SCCs. But the potential public health implications are profound, since roughly 40 million Americans have AKs, subclinical AKs are 10 times more common than visible ones, AKs are known precursors for SCC, and high-risk SCC is the cause of roughly 10,000 deaths per year, an underappreciated mortality burden that’s actually comparable to that of melanoma.
While awaiting further studies, this short-course combination therapy also offers the ready appeal of a field therapy without much downtime due to treatment-induced inflammation. In the study, 4 days of combo therapy resulted in moderate inflammation which quickly resolved.
“Does treatment duration and severity affect patient compliance? I would argue that in 2020 it does. People have very active, busy lives and they don’t want a lot of downtime. I can tell you that in Manhattan they want no downtime,” said Dr. Nehal, professor of dermatology at Weill Cornell Medicine, New York.
Even though a traditional 4-week, twice-daily course of 5% 5-FU cream has been convincingly shown in a recent large randomized Dutch trial (N Engl J Med. 2019 Mar 7;380[10]:935-46) to be the most effective field therapy for eradicating AKs – outperforming in descending order of efficacy at 12 months of follow-up imiquimod (Zyclara), photodynamic therapy, and ingenol mebutate (Picato) – Dr. Nehal finds few takers for 5-FU. People balk at the downtime. Her female patients with a significant AK burden typically opt for photodynamic therapy because of the aesthetic side benefit and shorter downtime, while the men – even those who’ve already had a large SCC – are more likely to prefer a watch-and-wait approach, dealing with an SCC if and when it arises.
“I love the science behind using calcipotriol with 5-FU, but I wish it was more friendly to dermatologists,” said fellow panelist Paul Nghiem, MD, PhD. “Of all the things we should have a combination product for, the pharmaceutical industry should really prepare a [calcipotriol/5-FU] cream and market it with the improved efficacy data.”
He added that he has no use for the conventional 2- to 4-week, twice-daily 5-FU regimens employed by many dermatologists.
“I don’t understand this need to feel like you’ve got to treat patients until they look like they’ve fallen off a motorcycle at 50 mph. I just can’t see that,” said Dr. Nghiem, professor and chair of dermatology at the University of Washington, Seattle.
Instead, he routinely utilizes the nearly 3-decade-old Pearlman technique of weekly pulsed dosing of topical 5-FU (J Am Acad Dermatol. 1991 Oct;25[4]:665-7).
“I almost never even ask my patients, ‘Are you OK with having a bunch of downtime?’ I just say, ‘Treat with the 5-FU until you get some erythema, until you’re bothered by it, and then stop for a while,’ ” he explained. “I’ve treated many patients with that technique over the years. It might not be quite as effective, but I hardly have to do any treatment with liquid nitrogen.”
Session chair Ashfaq A. Marghoob, MD, is of a similar mind.
“I also don’t go to the point that you’re fire engine red. Once the irritation sets in, we stop,” said Dr. Marghoob, director of clinical dermatology, Memorial Sloan Kettering Skin Cancer Center Hauppauge (New York).
Neither Dr. Nehal nor Dr. Nghiem has used short-course calcipotriol plus 5-FU therapy. When they polled the large audience as to who has, only a few hands went up.
“I feel like residents who are keeping up with the literature are using it,” Dr. Nehal observed. “My fellows say, ‘Yup, that’s what we’re doing,’ but I’m not using it.”
“I use it,” volunteered fellow panelist Trilokraj Tejasvi, MBBS. “I was educated by one of my residents, and now I use it all the time, especially in my VA population. I’ve been using it for a year. Things get red, but it clears fast,” said Dr. Tejasvi, director of the cutaneous lymphoma program and director of teledermatology services at the University of Michigan, Ann Arbor, and chief of the dermatology service at Ann Arbor Veteran Affairs Hospital.
Dr. Nehal reported having no conflicts of interest regarding her presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – The most intriguing recent development in the treatment of actinic keratosis is a study in which a short-course of topical field therapy with , with a resultant markedly reduced risk of developing squamous cell carcinoma within the next 3 years, Kishwer S. Nehal, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
The annual cost of treating actinic keratoses (AKs) exceeds $1 billion in the United States, so the billion-dollar question in dermatology is, does AK reduction lead to long-term protection against cancer? And this 3-year study by investigators at Washington University in St. Louis and Massachusetts General Hospital in Boston suggests the answer may be yes – when topical immunotherapy is utilized to induce robust T cell immunity, said Dr. Nehal, director of Mohs micrographic and dermatologic surgery, and codirector of the multidisciplinary skin cancer management program at Memorial Sloan Kettering Cancer Center in New York.
The investigators previously conducted a randomized, double-blind clinical trial in which 130 participants with a substantial AK burden received a 4-day course of 0.005% calcipotriol ointment plus 5% 5-FU cream or Vaseline plus 5-FU. The combination therapy proved more effective than the comparator in eliminating AKs at 8 weeks of follow-up. Moreover, tissue analysis pointed to the mechanism of benefit: The combination treatment induced keratinocyte expression of thymic stromal lymphopoietin (TSLP) cytokine, which led to a powerful CD4+ T cell response against AKs.
The researchers’ follow-up study addressed two key questions: Whether this epidermal T cell immunity persists long term, and if it actually achieves a reduced risk of squamous cell carcinoma (SCC) over time. The answers were yes and yes.
Seventy of the original 130 patients were prospectively followed for 3 years. Only 2 of 30 (7%) in the short-course combination therapy group developed SCC in treated areas of the face and scalp, compared with 11 of 40 controls (28%), a statistically significant difference, which constitutes a 79% relative risk reduction. This chemopreventive effect was long lasting at the cellular level, as the combination therapy group still retained measurable T cell immunity in the skin at the 3-year mark. As expected, the topical therapy had no impact on the development of basal cell carcinoma. The question now becomes how long the chemopreventive effect extends beyond 3 years.
“These remarkable findings substantiate the use of immunotherapeutic agents with minimal side effects and high efficacy against precancerous lesions in order to reduce the risk of cancer development and recurrence, which may be broadly applicable to skin and internal malignancies,” the investigators wrote in the study (JCI Insight. 2019 Mar 21;4(6). pii: 125476. doi: 10.1172/jci.insight.125476). Dr. Nehal said that this study requires confirmation in light of its post hoc design and the relatively small numbers of patients and SCCs. But the potential public health implications are profound, since roughly 40 million Americans have AKs, subclinical AKs are 10 times more common than visible ones, AKs are known precursors for SCC, and high-risk SCC is the cause of roughly 10,000 deaths per year, an underappreciated mortality burden that’s actually comparable to that of melanoma.
While awaiting further studies, this short-course combination therapy also offers the ready appeal of a field therapy without much downtime due to treatment-induced inflammation. In the study, 4 days of combo therapy resulted in moderate inflammation which quickly resolved.
“Does treatment duration and severity affect patient compliance? I would argue that in 2020 it does. People have very active, busy lives and they don’t want a lot of downtime. I can tell you that in Manhattan they want no downtime,” said Dr. Nehal, professor of dermatology at Weill Cornell Medicine, New York.
Even though a traditional 4-week, twice-daily course of 5% 5-FU cream has been convincingly shown in a recent large randomized Dutch trial (N Engl J Med. 2019 Mar 7;380[10]:935-46) to be the most effective field therapy for eradicating AKs – outperforming in descending order of efficacy at 12 months of follow-up imiquimod (Zyclara), photodynamic therapy, and ingenol mebutate (Picato) – Dr. Nehal finds few takers for 5-FU. People balk at the downtime. Her female patients with a significant AK burden typically opt for photodynamic therapy because of the aesthetic side benefit and shorter downtime, while the men – even those who’ve already had a large SCC – are more likely to prefer a watch-and-wait approach, dealing with an SCC if and when it arises.
“I love the science behind using calcipotriol with 5-FU, but I wish it was more friendly to dermatologists,” said fellow panelist Paul Nghiem, MD, PhD. “Of all the things we should have a combination product for, the pharmaceutical industry should really prepare a [calcipotriol/5-FU] cream and market it with the improved efficacy data.”
He added that he has no use for the conventional 2- to 4-week, twice-daily 5-FU regimens employed by many dermatologists.
“I don’t understand this need to feel like you’ve got to treat patients until they look like they’ve fallen off a motorcycle at 50 mph. I just can’t see that,” said Dr. Nghiem, professor and chair of dermatology at the University of Washington, Seattle.
Instead, he routinely utilizes the nearly 3-decade-old Pearlman technique of weekly pulsed dosing of topical 5-FU (J Am Acad Dermatol. 1991 Oct;25[4]:665-7).
“I almost never even ask my patients, ‘Are you OK with having a bunch of downtime?’ I just say, ‘Treat with the 5-FU until you get some erythema, until you’re bothered by it, and then stop for a while,’ ” he explained. “I’ve treated many patients with that technique over the years. It might not be quite as effective, but I hardly have to do any treatment with liquid nitrogen.”
Session chair Ashfaq A. Marghoob, MD, is of a similar mind.
“I also don’t go to the point that you’re fire engine red. Once the irritation sets in, we stop,” said Dr. Marghoob, director of clinical dermatology, Memorial Sloan Kettering Skin Cancer Center Hauppauge (New York).
Neither Dr. Nehal nor Dr. Nghiem has used short-course calcipotriol plus 5-FU therapy. When they polled the large audience as to who has, only a few hands went up.
“I feel like residents who are keeping up with the literature are using it,” Dr. Nehal observed. “My fellows say, ‘Yup, that’s what we’re doing,’ but I’m not using it.”
“I use it,” volunteered fellow panelist Trilokraj Tejasvi, MBBS. “I was educated by one of my residents, and now I use it all the time, especially in my VA population. I’ve been using it for a year. Things get red, but it clears fast,” said Dr. Tejasvi, director of the cutaneous lymphoma program and director of teledermatology services at the University of Michigan, Ann Arbor, and chief of the dermatology service at Ann Arbor Veteran Affairs Hospital.
Dr. Nehal reported having no conflicts of interest regarding her presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – The most intriguing recent development in the treatment of actinic keratosis is a study in which a short-course of topical field therapy with , with a resultant markedly reduced risk of developing squamous cell carcinoma within the next 3 years, Kishwer S. Nehal, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
The annual cost of treating actinic keratoses (AKs) exceeds $1 billion in the United States, so the billion-dollar question in dermatology is, does AK reduction lead to long-term protection against cancer? And this 3-year study by investigators at Washington University in St. Louis and Massachusetts General Hospital in Boston suggests the answer may be yes – when topical immunotherapy is utilized to induce robust T cell immunity, said Dr. Nehal, director of Mohs micrographic and dermatologic surgery, and codirector of the multidisciplinary skin cancer management program at Memorial Sloan Kettering Cancer Center in New York.
The investigators previously conducted a randomized, double-blind clinical trial in which 130 participants with a substantial AK burden received a 4-day course of 0.005% calcipotriol ointment plus 5% 5-FU cream or Vaseline plus 5-FU. The combination therapy proved more effective than the comparator in eliminating AKs at 8 weeks of follow-up. Moreover, tissue analysis pointed to the mechanism of benefit: The combination treatment induced keratinocyte expression of thymic stromal lymphopoietin (TSLP) cytokine, which led to a powerful CD4+ T cell response against AKs.
The researchers’ follow-up study addressed two key questions: Whether this epidermal T cell immunity persists long term, and if it actually achieves a reduced risk of squamous cell carcinoma (SCC) over time. The answers were yes and yes.
Seventy of the original 130 patients were prospectively followed for 3 years. Only 2 of 30 (7%) in the short-course combination therapy group developed SCC in treated areas of the face and scalp, compared with 11 of 40 controls (28%), a statistically significant difference, which constitutes a 79% relative risk reduction. This chemopreventive effect was long lasting at the cellular level, as the combination therapy group still retained measurable T cell immunity in the skin at the 3-year mark. As expected, the topical therapy had no impact on the development of basal cell carcinoma. The question now becomes how long the chemopreventive effect extends beyond 3 years.
“These remarkable findings substantiate the use of immunotherapeutic agents with minimal side effects and high efficacy against precancerous lesions in order to reduce the risk of cancer development and recurrence, which may be broadly applicable to skin and internal malignancies,” the investigators wrote in the study (JCI Insight. 2019 Mar 21;4(6). pii: 125476. doi: 10.1172/jci.insight.125476). Dr. Nehal said that this study requires confirmation in light of its post hoc design and the relatively small numbers of patients and SCCs. But the potential public health implications are profound, since roughly 40 million Americans have AKs, subclinical AKs are 10 times more common than visible ones, AKs are known precursors for SCC, and high-risk SCC is the cause of roughly 10,000 deaths per year, an underappreciated mortality burden that’s actually comparable to that of melanoma.
While awaiting further studies, this short-course combination therapy also offers the ready appeal of a field therapy without much downtime due to treatment-induced inflammation. In the study, 4 days of combo therapy resulted in moderate inflammation which quickly resolved.
“Does treatment duration and severity affect patient compliance? I would argue that in 2020 it does. People have very active, busy lives and they don’t want a lot of downtime. I can tell you that in Manhattan they want no downtime,” said Dr. Nehal, professor of dermatology at Weill Cornell Medicine, New York.
Even though a traditional 4-week, twice-daily course of 5% 5-FU cream has been convincingly shown in a recent large randomized Dutch trial (N Engl J Med. 2019 Mar 7;380[10]:935-46) to be the most effective field therapy for eradicating AKs – outperforming in descending order of efficacy at 12 months of follow-up imiquimod (Zyclara), photodynamic therapy, and ingenol mebutate (Picato) – Dr. Nehal finds few takers for 5-FU. People balk at the downtime. Her female patients with a significant AK burden typically opt for photodynamic therapy because of the aesthetic side benefit and shorter downtime, while the men – even those who’ve already had a large SCC – are more likely to prefer a watch-and-wait approach, dealing with an SCC if and when it arises.
“I love the science behind using calcipotriol with 5-FU, but I wish it was more friendly to dermatologists,” said fellow panelist Paul Nghiem, MD, PhD. “Of all the things we should have a combination product for, the pharmaceutical industry should really prepare a [calcipotriol/5-FU] cream and market it with the improved efficacy data.”
He added that he has no use for the conventional 2- to 4-week, twice-daily 5-FU regimens employed by many dermatologists.
“I don’t understand this need to feel like you’ve got to treat patients until they look like they’ve fallen off a motorcycle at 50 mph. I just can’t see that,” said Dr. Nghiem, professor and chair of dermatology at the University of Washington, Seattle.
Instead, he routinely utilizes the nearly 3-decade-old Pearlman technique of weekly pulsed dosing of topical 5-FU (J Am Acad Dermatol. 1991 Oct;25[4]:665-7).
“I almost never even ask my patients, ‘Are you OK with having a bunch of downtime?’ I just say, ‘Treat with the 5-FU until you get some erythema, until you’re bothered by it, and then stop for a while,’ ” he explained. “I’ve treated many patients with that technique over the years. It might not be quite as effective, but I hardly have to do any treatment with liquid nitrogen.”
Session chair Ashfaq A. Marghoob, MD, is of a similar mind.
“I also don’t go to the point that you’re fire engine red. Once the irritation sets in, we stop,” said Dr. Marghoob, director of clinical dermatology, Memorial Sloan Kettering Skin Cancer Center Hauppauge (New York).
Neither Dr. Nehal nor Dr. Nghiem has used short-course calcipotriol plus 5-FU therapy. When they polled the large audience as to who has, only a few hands went up.
“I feel like residents who are keeping up with the literature are using it,” Dr. Nehal observed. “My fellows say, ‘Yup, that’s what we’re doing,’ but I’m not using it.”
“I use it,” volunteered fellow panelist Trilokraj Tejasvi, MBBS. “I was educated by one of my residents, and now I use it all the time, especially in my VA population. I’ve been using it for a year. Things get red, but it clears fast,” said Dr. Tejasvi, director of the cutaneous lymphoma program and director of teledermatology services at the University of Michigan, Ann Arbor, and chief of the dermatology service at Ann Arbor Veteran Affairs Hospital.
Dr. Nehal reported having no conflicts of interest regarding her presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
Isotretinoin data provide postmeal absorption guidance
LAHAINA, HAWAII – Recent , Hilary E. Baldwin, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
It is recommended that isotretinoin, which is fat-soluble, be taken with food, preferably high-fat foods. So it has been unclear what the effect would be when taken with lower-fat food, such as low-fat cereal and raspberries, for example, Dr. Baldwin, medical director of the Acne Treatment and Research Center in New York, pointed out.
“We’ve been trying for years to figure out how we’re going to get around this,” and there have not been any relevant data available until recently, other than in the setting of taking isotretinoin on an empty stomach or with a high-fat meal, she commented.
She referred to a open-label, single-dose, randomized crossover study that compared the bioavailability of the lidose formulation of isotretinoin (Absorica) and brand name Accutane, at a dose of 40 mg either on top of a fatty meal (the Food and Drug Administration-stipulated high-fat, high-calorie diet) or after a 10-hour fast; 60 patients did all four arms, with a 21-day washout period between them (J Am Acad Dermatol. 2013 Nov;69[5]:762-7).
In the fed state, both isotretinoin formulations were absorbed to the same extent, “but in the fasting state, there was a considerable difference,” Dr. Baldwin said. Absorption of both dropped in the fasting state, but the drop was more extreme with Accutane, “about a 50% difference between the two, in terms of how much drug was getting into the system,” she noted.
That is important because weight-based dosing is considered with isotretinoin, so at the end of treatment, a patient who has been taking it on an empty stomach may be getting a 60% lower dose than prescribed, “which could lead to a lessening of the effectiveness of the drug and also an increase in relapse over time.”
But how would a low-fat meal, like low-fat cereal and raspberries, affect the absorption, and ultimate efficacy?
This question was addressed in an open-label, single-arm study of 163 patients with acne, who were taking the lidose isotretinoin formulation without food, at the standard dose, for no longer than 20 weeks. Whether they relapsed was evaluated in a 2-year observational phase of the study, Dr. Baldwin said.
At the end of the trial, the drug was considered effective, with improvements in IGA (the 5-point Investigator’s Global Assessment scale). But the change from baseline was maintained at the 2-year posttreatment period, so the benefits of treatment lasted, which indicates that patients can take it “on top of absolutely no food whatsoever ... so if they eat anything, we are headed in the right direction,” including a low-fat meal. During the 2-year period, most patients did not need to be retreated. Of those people who needed treatment, only 4.2% needed treatment with isotretinoin, which is better than the historical relapse rates with isotretinoin, she noted.
Dr. Baldwin’s disclosures included being on the speakers’ bureau, serving as an advisor, and/or an investigator for companies that include Almirall, BioPharmx, Foamix, Galderma, Ortho Dermatologics, Sun Pharmaceuticals, Johnson & Johnson, and La Roche–Posay.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – Recent , Hilary E. Baldwin, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
It is recommended that isotretinoin, which is fat-soluble, be taken with food, preferably high-fat foods. So it has been unclear what the effect would be when taken with lower-fat food, such as low-fat cereal and raspberries, for example, Dr. Baldwin, medical director of the Acne Treatment and Research Center in New York, pointed out.
“We’ve been trying for years to figure out how we’re going to get around this,” and there have not been any relevant data available until recently, other than in the setting of taking isotretinoin on an empty stomach or with a high-fat meal, she commented.
She referred to a open-label, single-dose, randomized crossover study that compared the bioavailability of the lidose formulation of isotretinoin (Absorica) and brand name Accutane, at a dose of 40 mg either on top of a fatty meal (the Food and Drug Administration-stipulated high-fat, high-calorie diet) or after a 10-hour fast; 60 patients did all four arms, with a 21-day washout period between them (J Am Acad Dermatol. 2013 Nov;69[5]:762-7).
In the fed state, both isotretinoin formulations were absorbed to the same extent, “but in the fasting state, there was a considerable difference,” Dr. Baldwin said. Absorption of both dropped in the fasting state, but the drop was more extreme with Accutane, “about a 50% difference between the two, in terms of how much drug was getting into the system,” she noted.
That is important because weight-based dosing is considered with isotretinoin, so at the end of treatment, a patient who has been taking it on an empty stomach may be getting a 60% lower dose than prescribed, “which could lead to a lessening of the effectiveness of the drug and also an increase in relapse over time.”
But how would a low-fat meal, like low-fat cereal and raspberries, affect the absorption, and ultimate efficacy?
This question was addressed in an open-label, single-arm study of 163 patients with acne, who were taking the lidose isotretinoin formulation without food, at the standard dose, for no longer than 20 weeks. Whether they relapsed was evaluated in a 2-year observational phase of the study, Dr. Baldwin said.
At the end of the trial, the drug was considered effective, with improvements in IGA (the 5-point Investigator’s Global Assessment scale). But the change from baseline was maintained at the 2-year posttreatment period, so the benefits of treatment lasted, which indicates that patients can take it “on top of absolutely no food whatsoever ... so if they eat anything, we are headed in the right direction,” including a low-fat meal. During the 2-year period, most patients did not need to be retreated. Of those people who needed treatment, only 4.2% needed treatment with isotretinoin, which is better than the historical relapse rates with isotretinoin, she noted.
Dr. Baldwin’s disclosures included being on the speakers’ bureau, serving as an advisor, and/or an investigator for companies that include Almirall, BioPharmx, Foamix, Galderma, Ortho Dermatologics, Sun Pharmaceuticals, Johnson & Johnson, and La Roche–Posay.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – Recent , Hilary E. Baldwin, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
It is recommended that isotretinoin, which is fat-soluble, be taken with food, preferably high-fat foods. So it has been unclear what the effect would be when taken with lower-fat food, such as low-fat cereal and raspberries, for example, Dr. Baldwin, medical director of the Acne Treatment and Research Center in New York, pointed out.
“We’ve been trying for years to figure out how we’re going to get around this,” and there have not been any relevant data available until recently, other than in the setting of taking isotretinoin on an empty stomach or with a high-fat meal, she commented.
She referred to a open-label, single-dose, randomized crossover study that compared the bioavailability of the lidose formulation of isotretinoin (Absorica) and brand name Accutane, at a dose of 40 mg either on top of a fatty meal (the Food and Drug Administration-stipulated high-fat, high-calorie diet) or after a 10-hour fast; 60 patients did all four arms, with a 21-day washout period between them (J Am Acad Dermatol. 2013 Nov;69[5]:762-7).
In the fed state, both isotretinoin formulations were absorbed to the same extent, “but in the fasting state, there was a considerable difference,” Dr. Baldwin said. Absorption of both dropped in the fasting state, but the drop was more extreme with Accutane, “about a 50% difference between the two, in terms of how much drug was getting into the system,” she noted.
That is important because weight-based dosing is considered with isotretinoin, so at the end of treatment, a patient who has been taking it on an empty stomach may be getting a 60% lower dose than prescribed, “which could lead to a lessening of the effectiveness of the drug and also an increase in relapse over time.”
But how would a low-fat meal, like low-fat cereal and raspberries, affect the absorption, and ultimate efficacy?
This question was addressed in an open-label, single-arm study of 163 patients with acne, who were taking the lidose isotretinoin formulation without food, at the standard dose, for no longer than 20 weeks. Whether they relapsed was evaluated in a 2-year observational phase of the study, Dr. Baldwin said.
At the end of the trial, the drug was considered effective, with improvements in IGA (the 5-point Investigator’s Global Assessment scale). But the change from baseline was maintained at the 2-year posttreatment period, so the benefits of treatment lasted, which indicates that patients can take it “on top of absolutely no food whatsoever ... so if they eat anything, we are headed in the right direction,” including a low-fat meal. During the 2-year period, most patients did not need to be retreated. Of those people who needed treatment, only 4.2% needed treatment with isotretinoin, which is better than the historical relapse rates with isotretinoin, she noted.
Dr. Baldwin’s disclosures included being on the speakers’ bureau, serving as an advisor, and/or an investigator for companies that include Almirall, BioPharmx, Foamix, Galderma, Ortho Dermatologics, Sun Pharmaceuticals, Johnson & Johnson, and La Roche–Posay.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM SDEF HAWAII DERMATOLOGY SEMINAR
Keep your eye on tapinarof, a topical antipsoriatic therapy
LAHAINA, HAWAII – Tapinarof is an investigational drug whose novel mechanism of action – and encouraging performance in phase 2 studies – are making waves for the topical treatment of both psoriasis and atopic dermatitis, Linda F. Stein Gold, MD, observed at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Tapinarof is a first-in-class agonist of the aryl hydrocarbon receptor.
“An aryl hydrocarbon receptor agonist – what in the world does that mean? It means that this drug actually acts at the receptor level inside the cell, and it does a lot of different things,” explained Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Health System in Detroit.
For one, tapinarof down-regulates Th17 cytokines, an attribute that positions the drug very well as a potential topical treatment for psoriasis. But in addition, the drug has a skin barrier repair element through up-regulation of the filaggrin and involucrin genes in keratinocytes, and it also down-regulates Th2 cytokines, actions desirable in a treatment for atopic dermatitis.
Dr. Stein Gold focused mainly on tapinarof’s potential as a novel treatment for psoriasis, a disease that hasn’t seen approval of a new nonsteroidal topical therapy in decades. There is a huge unmet need for safe and effective new topical therapies for this disease; despite all the attention devoted to biologics and other systemic therapies, the great majority of psoriasis patients are managed via topical therapy only.
The definitive trial was initiated based upon the results of a phase 2b, double-blind, six-arm study including 141 adults with body surface involvement of 1%-15% and a baseline Physician Global Assessment (PGA) score of 2 or more who were assigned to tapinarof at 0.5% or 1% once or twice daily or placebo. The phase 2b results, she commented, were very encouraging.
“When we look at the clinical efficacy, it looks like this drug has legs. It does work even as monotherapy to get patients clear,” she said.
The phase 2b, dose-finding study showed dose-dependent treatment efficacy. At week 12, the proportion of participants with a PGA of 0-1 and at least a 2-grade improvement – that is, clear or almost clear – was 36% with tapinarof monotherapy at 0.5% once daily, 46% with 0.5% twice daily, 56% with 1% once daily, and 65% with 1% twice daily, compared with 5% in controls on once-daily application of vehicle and 11% with twice-daily vehicle. Moreover, the improvement was maintained for 4 weeks post treatment. The drug was well tolerated other than some mild to moderate folliculitis and contact dermatitis (J Am Acad Dermatol. 2019 Mar;80[3]:714-21).
“With such small numbers in phase 2, we don’t necessarily need to see statistical significance, but we want to see a trend in the right direction. But every one of the active treatment arms was statistically significantly better than with vehicle. And at higher concentrations, greater efficacy,” noted Dr. Stein Gold.
A phase 2 study of tapinarof cream has also been completed in adults and adolescents with atopic dermatitis, again with positive results. A phase 3 study in atopic dermatitis is still in the planning stages.
Dr. Stein Gold wasn’t involved in the tapinarof psoriasis phase 2b study, sponsored by GlaxoSmithKline. She reported research funding from nine other pharmaceutical companies and serves as a consultant and/or scientific to more than a dozen companies.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – Tapinarof is an investigational drug whose novel mechanism of action – and encouraging performance in phase 2 studies – are making waves for the topical treatment of both psoriasis and atopic dermatitis, Linda F. Stein Gold, MD, observed at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Tapinarof is a first-in-class agonist of the aryl hydrocarbon receptor.
“An aryl hydrocarbon receptor agonist – what in the world does that mean? It means that this drug actually acts at the receptor level inside the cell, and it does a lot of different things,” explained Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Health System in Detroit.
For one, tapinarof down-regulates Th17 cytokines, an attribute that positions the drug very well as a potential topical treatment for psoriasis. But in addition, the drug has a skin barrier repair element through up-regulation of the filaggrin and involucrin genes in keratinocytes, and it also down-regulates Th2 cytokines, actions desirable in a treatment for atopic dermatitis.
Dr. Stein Gold focused mainly on tapinarof’s potential as a novel treatment for psoriasis, a disease that hasn’t seen approval of a new nonsteroidal topical therapy in decades. There is a huge unmet need for safe and effective new topical therapies for this disease; despite all the attention devoted to biologics and other systemic therapies, the great majority of psoriasis patients are managed via topical therapy only.
The definitive trial was initiated based upon the results of a phase 2b, double-blind, six-arm study including 141 adults with body surface involvement of 1%-15% and a baseline Physician Global Assessment (PGA) score of 2 or more who were assigned to tapinarof at 0.5% or 1% once or twice daily or placebo. The phase 2b results, she commented, were very encouraging.
“When we look at the clinical efficacy, it looks like this drug has legs. It does work even as monotherapy to get patients clear,” she said.
The phase 2b, dose-finding study showed dose-dependent treatment efficacy. At week 12, the proportion of participants with a PGA of 0-1 and at least a 2-grade improvement – that is, clear or almost clear – was 36% with tapinarof monotherapy at 0.5% once daily, 46% with 0.5% twice daily, 56% with 1% once daily, and 65% with 1% twice daily, compared with 5% in controls on once-daily application of vehicle and 11% with twice-daily vehicle. Moreover, the improvement was maintained for 4 weeks post treatment. The drug was well tolerated other than some mild to moderate folliculitis and contact dermatitis (J Am Acad Dermatol. 2019 Mar;80[3]:714-21).
“With such small numbers in phase 2, we don’t necessarily need to see statistical significance, but we want to see a trend in the right direction. But every one of the active treatment arms was statistically significantly better than with vehicle. And at higher concentrations, greater efficacy,” noted Dr. Stein Gold.
A phase 2 study of tapinarof cream has also been completed in adults and adolescents with atopic dermatitis, again with positive results. A phase 3 study in atopic dermatitis is still in the planning stages.
Dr. Stein Gold wasn’t involved in the tapinarof psoriasis phase 2b study, sponsored by GlaxoSmithKline. She reported research funding from nine other pharmaceutical companies and serves as a consultant and/or scientific to more than a dozen companies.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – Tapinarof is an investigational drug whose novel mechanism of action – and encouraging performance in phase 2 studies – are making waves for the topical treatment of both psoriasis and atopic dermatitis, Linda F. Stein Gold, MD, observed at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Tapinarof is a first-in-class agonist of the aryl hydrocarbon receptor.
“An aryl hydrocarbon receptor agonist – what in the world does that mean? It means that this drug actually acts at the receptor level inside the cell, and it does a lot of different things,” explained Dr. Stein Gold, director of dermatology clinical research at the Henry Ford Health System in Detroit.
For one, tapinarof down-regulates Th17 cytokines, an attribute that positions the drug very well as a potential topical treatment for psoriasis. But in addition, the drug has a skin barrier repair element through up-regulation of the filaggrin and involucrin genes in keratinocytes, and it also down-regulates Th2 cytokines, actions desirable in a treatment for atopic dermatitis.
Dr. Stein Gold focused mainly on tapinarof’s potential as a novel treatment for psoriasis, a disease that hasn’t seen approval of a new nonsteroidal topical therapy in decades. There is a huge unmet need for safe and effective new topical therapies for this disease; despite all the attention devoted to biologics and other systemic therapies, the great majority of psoriasis patients are managed via topical therapy only.
The definitive trial was initiated based upon the results of a phase 2b, double-blind, six-arm study including 141 adults with body surface involvement of 1%-15% and a baseline Physician Global Assessment (PGA) score of 2 or more who were assigned to tapinarof at 0.5% or 1% once or twice daily or placebo. The phase 2b results, she commented, were very encouraging.
“When we look at the clinical efficacy, it looks like this drug has legs. It does work even as monotherapy to get patients clear,” she said.
The phase 2b, dose-finding study showed dose-dependent treatment efficacy. At week 12, the proportion of participants with a PGA of 0-1 and at least a 2-grade improvement – that is, clear or almost clear – was 36% with tapinarof monotherapy at 0.5% once daily, 46% with 0.5% twice daily, 56% with 1% once daily, and 65% with 1% twice daily, compared with 5% in controls on once-daily application of vehicle and 11% with twice-daily vehicle. Moreover, the improvement was maintained for 4 weeks post treatment. The drug was well tolerated other than some mild to moderate folliculitis and contact dermatitis (J Am Acad Dermatol. 2019 Mar;80[3]:714-21).
“With such small numbers in phase 2, we don’t necessarily need to see statistical significance, but we want to see a trend in the right direction. But every one of the active treatment arms was statistically significantly better than with vehicle. And at higher concentrations, greater efficacy,” noted Dr. Stein Gold.
A phase 2 study of tapinarof cream has also been completed in adults and adolescents with atopic dermatitis, again with positive results. A phase 3 study in atopic dermatitis is still in the planning stages.
Dr. Stein Gold wasn’t involved in the tapinarof psoriasis phase 2b study, sponsored by GlaxoSmithKline. She reported research funding from nine other pharmaceutical companies and serves as a consultant and/or scientific to more than a dozen companies.
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REPORTING FROM THE SDEF HAWAII DERMATOLOGY SEMINAR