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Tips for avoiding, taming most postlaser complications
SAN DIEGO – Do not use the fractional laser on tanned skin or skin that will be getting sun exposure soon after the treatment, Tina Alster, MD, advised as one of her cardinal rules for avoiding hyperpigmentation complications.
Melanocytes are already activated and ready to deposit pigment in such patients. Also, use strict posttreatment sun protection with a mineral sunscreen, she said.
Fractional lasers – both ablative and nonablative – are remarkably safe, said Dr. Alster of Georgetown University Medical Center, Washington.
Her own 2008 study found side effects and complications in just 7.6% of 961 patients. The most frequent were acneiform eruptions (1.8%) and herpes simplex virus outbreaks (1.7%).
A more recent study comprising 730 patients treated with three different fractional lasers found an even lower complication rate of 4%. Complications included 5 herpes simplex virus breakouts, 13 acne eruptions, one abrasion, one bacterial infection, 9 cases of dermatitis, one drug eruption, 4 cases of prolonged erythema, one case of hyperpigmentation, one case of increased swelling and one of telangiectasia.
“We consistently find these very low incidences of less than 10%, and most of these I would term ‘side effects’ and not true complications,” Dr. Alster said at the annual meeting of the American Academy of Dermatology.
Still, if a clinician performs enough laser procedures, these outcomes will eventually occur. Dr. Alster gave her “top tips” for dealing with them when they do arise.
Tip #1: Adequate preoperative assessment
“You must be thorough in assessing all of these things: the type and location of the lesion, the Fitzpatrick skin phototype, any prior treatments the patient has had for the condition (and many have had them). We need to know of any pre-existing medical conditions, particularly autoimmune, and whether the patient has a history of scarring or delayed wound healing.”
Another part of this assessment is managing patient expectations upfront to avoid postprocedural dissatisfaction. “If someone comes to me and says ‘I want you to get rid of every acne scar on my face,’ I tell them right there, ‘I can’t do that,’” she said.
Tip #2: Prepare the patient for the expected – and the unexpected
“The overall risk of even the most common side effects, like prolonged erythema, is relatively small. But they can happen and patients need to be prepared for them.” The most common are prolonged erythema of more than 4 days for nonablative fractional lasers and more than a month for ablative lasers. But dermatitis may appear, as well as reactivation of acne, especially in patients who are having acne scars removed. There is also always the risk of infection and pigmentary alteration.”
Tip #3: Proper technique and close follow-up
The most expensive laser in the world still relies on good technique during deployment, she said. “I always stress, do not ‘pulse stack.’ Use side-by-side, nonoverlapping passes.”
Another key for success is to avoid using the laser on any tanned skin, or skin that will soon have sun exposure. “Any skin phototype with recent sun exposure has activated melanocytes and will have a higher tendency to develop postinflammatory hyperpigmentation. The cells are already activated and in the presence of any other damage – including a laser – they are programmed to produce more pigment.”
Individualize your treatment plan, she advised. “Do additional passes on the most severe areas, like cheek scars and perioral rhytides, and fewer passes and lower density on scar-prone areas, like the infraorbital area, mandible neck, and chest.”
Tip #4: Recognize and address complications
“Complications run the full spectrum from mild erythema to disseminated infections. I am always careful to figure out if it’s a true complication or an expected side effect. The greatest risk profiles are patients with darker skin phototypes, treatments in more sensitive areas, and patients with predisposing medical conditions like collagen or vascular diseases. You don’t need to avoid treating them, just be prepared for the higher risks.”
Dr. Alster also shared her techniques for managing some of the more common adverse events following a fractional laser procedure.
Prolonged erythema isn’t clinically serious, but it really bothers patients. They should be counseled to avoid putting any potentially irritating or allergenic product on their face, and that includes chemical sunscreens. A mineral sunscreen is a much better choice. “For management, postoperative cooling with ice packs is important. A mild topical corticosteroid and a nonsteroidal anti-inflammatory can help, too.”
Acne exacerbation is not uncommon, especially among patients being treated for acne scars. “In people who are prone to acne, I write a script for doxycycline. They don’t have to take it unless they break out. And I always avoid laser skin resurfacing in active acne.”
If a breakout does happen, stick to the well-trodden path, she advised. “We know how to treat acne. Discontinue any occlusive topical, start the patent on an antibiotic, treat topically with a clay masque to help dry things out.”
Infections can be alarming but are manageable when promptly treated. “The main thing is to diagnose and treat early. In those patients who are proven to have herpes simplex virus, I give an antiviral, like valacyclovir. I give 1 gram twice a day for a week, starting on the day of the procedure. I think a bigger question is, ‘Does everyone need a prophylactic antibiotic?’ There is probably no reason to start one routinely, and in fact, there is some evidence that if you do, you may get a more pathogenic organism if you do get an infection.”
Hyperpigmentation is always a concern. Dr Alster repeated her cardinal rule: Do not use the fractional laser on tanned skin or skin that will be getting sun exposure soon after the treatment, as melanocytes are already activated and ready to deposit pigment. Use strict posttreatment sun protection with a mineral sunscreen. While she is not “a big fan” of hydroquinone, Dr. Alster does employ other bleaching agents for postoperative hyperpigmentation, including alpha hydroxyl acid, retinoic acid, kojic acid, and lignin peroxidase.
Good technique and aftercare reduce the risk of hypertrophic scarring. This means avoiding excessive fluences and aggressive lasering techniques and early treatment of any suspected infection. “My main treatment is the 585nm pulsed dye laser, but the main thing is to avoid aggressive techniques with overlapping or stacking of pulses, strict wound care, and early treatment of any infections.”
Dr. Alster disclosed that she is a consultant to L’Oréal USA, an investigator for Revance Therapeutics and Sente Labs, and a medical advisor to Merz Aesthetics, and has investments/commercial interests in Home Skinovations.
SOURCE: Alster, T. et al, PREVENTION & MANAGEMENT OF
SAN DIEGO – Do not use the fractional laser on tanned skin or skin that will be getting sun exposure soon after the treatment, Tina Alster, MD, advised as one of her cardinal rules for avoiding hyperpigmentation complications.
Melanocytes are already activated and ready to deposit pigment in such patients. Also, use strict posttreatment sun protection with a mineral sunscreen, she said.
Fractional lasers – both ablative and nonablative – are remarkably safe, said Dr. Alster of Georgetown University Medical Center, Washington.
Her own 2008 study found side effects and complications in just 7.6% of 961 patients. The most frequent were acneiform eruptions (1.8%) and herpes simplex virus outbreaks (1.7%).
A more recent study comprising 730 patients treated with three different fractional lasers found an even lower complication rate of 4%. Complications included 5 herpes simplex virus breakouts, 13 acne eruptions, one abrasion, one bacterial infection, 9 cases of dermatitis, one drug eruption, 4 cases of prolonged erythema, one case of hyperpigmentation, one case of increased swelling and one of telangiectasia.
“We consistently find these very low incidences of less than 10%, and most of these I would term ‘side effects’ and not true complications,” Dr. Alster said at the annual meeting of the American Academy of Dermatology.
Still, if a clinician performs enough laser procedures, these outcomes will eventually occur. Dr. Alster gave her “top tips” for dealing with them when they do arise.
Tip #1: Adequate preoperative assessment
“You must be thorough in assessing all of these things: the type and location of the lesion, the Fitzpatrick skin phototype, any prior treatments the patient has had for the condition (and many have had them). We need to know of any pre-existing medical conditions, particularly autoimmune, and whether the patient has a history of scarring or delayed wound healing.”
Another part of this assessment is managing patient expectations upfront to avoid postprocedural dissatisfaction. “If someone comes to me and says ‘I want you to get rid of every acne scar on my face,’ I tell them right there, ‘I can’t do that,’” she said.
Tip #2: Prepare the patient for the expected – and the unexpected
“The overall risk of even the most common side effects, like prolonged erythema, is relatively small. But they can happen and patients need to be prepared for them.” The most common are prolonged erythema of more than 4 days for nonablative fractional lasers and more than a month for ablative lasers. But dermatitis may appear, as well as reactivation of acne, especially in patients who are having acne scars removed. There is also always the risk of infection and pigmentary alteration.”
Tip #3: Proper technique and close follow-up
The most expensive laser in the world still relies on good technique during deployment, she said. “I always stress, do not ‘pulse stack.’ Use side-by-side, nonoverlapping passes.”
Another key for success is to avoid using the laser on any tanned skin, or skin that will soon have sun exposure. “Any skin phototype with recent sun exposure has activated melanocytes and will have a higher tendency to develop postinflammatory hyperpigmentation. The cells are already activated and in the presence of any other damage – including a laser – they are programmed to produce more pigment.”
Individualize your treatment plan, she advised. “Do additional passes on the most severe areas, like cheek scars and perioral rhytides, and fewer passes and lower density on scar-prone areas, like the infraorbital area, mandible neck, and chest.”
Tip #4: Recognize and address complications
“Complications run the full spectrum from mild erythema to disseminated infections. I am always careful to figure out if it’s a true complication or an expected side effect. The greatest risk profiles are patients with darker skin phototypes, treatments in more sensitive areas, and patients with predisposing medical conditions like collagen or vascular diseases. You don’t need to avoid treating them, just be prepared for the higher risks.”
Dr. Alster also shared her techniques for managing some of the more common adverse events following a fractional laser procedure.
Prolonged erythema isn’t clinically serious, but it really bothers patients. They should be counseled to avoid putting any potentially irritating or allergenic product on their face, and that includes chemical sunscreens. A mineral sunscreen is a much better choice. “For management, postoperative cooling with ice packs is important. A mild topical corticosteroid and a nonsteroidal anti-inflammatory can help, too.”
Acne exacerbation is not uncommon, especially among patients being treated for acne scars. “In people who are prone to acne, I write a script for doxycycline. They don’t have to take it unless they break out. And I always avoid laser skin resurfacing in active acne.”
If a breakout does happen, stick to the well-trodden path, she advised. “We know how to treat acne. Discontinue any occlusive topical, start the patent on an antibiotic, treat topically with a clay masque to help dry things out.”
Infections can be alarming but are manageable when promptly treated. “The main thing is to diagnose and treat early. In those patients who are proven to have herpes simplex virus, I give an antiviral, like valacyclovir. I give 1 gram twice a day for a week, starting on the day of the procedure. I think a bigger question is, ‘Does everyone need a prophylactic antibiotic?’ There is probably no reason to start one routinely, and in fact, there is some evidence that if you do, you may get a more pathogenic organism if you do get an infection.”
Hyperpigmentation is always a concern. Dr Alster repeated her cardinal rule: Do not use the fractional laser on tanned skin or skin that will be getting sun exposure soon after the treatment, as melanocytes are already activated and ready to deposit pigment. Use strict posttreatment sun protection with a mineral sunscreen. While she is not “a big fan” of hydroquinone, Dr. Alster does employ other bleaching agents for postoperative hyperpigmentation, including alpha hydroxyl acid, retinoic acid, kojic acid, and lignin peroxidase.
Good technique and aftercare reduce the risk of hypertrophic scarring. This means avoiding excessive fluences and aggressive lasering techniques and early treatment of any suspected infection. “My main treatment is the 585nm pulsed dye laser, but the main thing is to avoid aggressive techniques with overlapping or stacking of pulses, strict wound care, and early treatment of any infections.”
Dr. Alster disclosed that she is a consultant to L’Oréal USA, an investigator for Revance Therapeutics and Sente Labs, and a medical advisor to Merz Aesthetics, and has investments/commercial interests in Home Skinovations.
SOURCE: Alster, T. et al, PREVENTION & MANAGEMENT OF
SAN DIEGO – Do not use the fractional laser on tanned skin or skin that will be getting sun exposure soon after the treatment, Tina Alster, MD, advised as one of her cardinal rules for avoiding hyperpigmentation complications.
Melanocytes are already activated and ready to deposit pigment in such patients. Also, use strict posttreatment sun protection with a mineral sunscreen, she said.
Fractional lasers – both ablative and nonablative – are remarkably safe, said Dr. Alster of Georgetown University Medical Center, Washington.
Her own 2008 study found side effects and complications in just 7.6% of 961 patients. The most frequent were acneiform eruptions (1.8%) and herpes simplex virus outbreaks (1.7%).
A more recent study comprising 730 patients treated with three different fractional lasers found an even lower complication rate of 4%. Complications included 5 herpes simplex virus breakouts, 13 acne eruptions, one abrasion, one bacterial infection, 9 cases of dermatitis, one drug eruption, 4 cases of prolonged erythema, one case of hyperpigmentation, one case of increased swelling and one of telangiectasia.
“We consistently find these very low incidences of less than 10%, and most of these I would term ‘side effects’ and not true complications,” Dr. Alster said at the annual meeting of the American Academy of Dermatology.
Still, if a clinician performs enough laser procedures, these outcomes will eventually occur. Dr. Alster gave her “top tips” for dealing with them when they do arise.
Tip #1: Adequate preoperative assessment
“You must be thorough in assessing all of these things: the type and location of the lesion, the Fitzpatrick skin phototype, any prior treatments the patient has had for the condition (and many have had them). We need to know of any pre-existing medical conditions, particularly autoimmune, and whether the patient has a history of scarring or delayed wound healing.”
Another part of this assessment is managing patient expectations upfront to avoid postprocedural dissatisfaction. “If someone comes to me and says ‘I want you to get rid of every acne scar on my face,’ I tell them right there, ‘I can’t do that,’” she said.
Tip #2: Prepare the patient for the expected – and the unexpected
“The overall risk of even the most common side effects, like prolonged erythema, is relatively small. But they can happen and patients need to be prepared for them.” The most common are prolonged erythema of more than 4 days for nonablative fractional lasers and more than a month for ablative lasers. But dermatitis may appear, as well as reactivation of acne, especially in patients who are having acne scars removed. There is also always the risk of infection and pigmentary alteration.”
Tip #3: Proper technique and close follow-up
The most expensive laser in the world still relies on good technique during deployment, she said. “I always stress, do not ‘pulse stack.’ Use side-by-side, nonoverlapping passes.”
Another key for success is to avoid using the laser on any tanned skin, or skin that will soon have sun exposure. “Any skin phototype with recent sun exposure has activated melanocytes and will have a higher tendency to develop postinflammatory hyperpigmentation. The cells are already activated and in the presence of any other damage – including a laser – they are programmed to produce more pigment.”
Individualize your treatment plan, she advised. “Do additional passes on the most severe areas, like cheek scars and perioral rhytides, and fewer passes and lower density on scar-prone areas, like the infraorbital area, mandible neck, and chest.”
Tip #4: Recognize and address complications
“Complications run the full spectrum from mild erythema to disseminated infections. I am always careful to figure out if it’s a true complication or an expected side effect. The greatest risk profiles are patients with darker skin phototypes, treatments in more sensitive areas, and patients with predisposing medical conditions like collagen or vascular diseases. You don’t need to avoid treating them, just be prepared for the higher risks.”
Dr. Alster also shared her techniques for managing some of the more common adverse events following a fractional laser procedure.
Prolonged erythema isn’t clinically serious, but it really bothers patients. They should be counseled to avoid putting any potentially irritating or allergenic product on their face, and that includes chemical sunscreens. A mineral sunscreen is a much better choice. “For management, postoperative cooling with ice packs is important. A mild topical corticosteroid and a nonsteroidal anti-inflammatory can help, too.”
Acne exacerbation is not uncommon, especially among patients being treated for acne scars. “In people who are prone to acne, I write a script for doxycycline. They don’t have to take it unless they break out. And I always avoid laser skin resurfacing in active acne.”
If a breakout does happen, stick to the well-trodden path, she advised. “We know how to treat acne. Discontinue any occlusive topical, start the patent on an antibiotic, treat topically with a clay masque to help dry things out.”
Infections can be alarming but are manageable when promptly treated. “The main thing is to diagnose and treat early. In those patients who are proven to have herpes simplex virus, I give an antiviral, like valacyclovir. I give 1 gram twice a day for a week, starting on the day of the procedure. I think a bigger question is, ‘Does everyone need a prophylactic antibiotic?’ There is probably no reason to start one routinely, and in fact, there is some evidence that if you do, you may get a more pathogenic organism if you do get an infection.”
Hyperpigmentation is always a concern. Dr Alster repeated her cardinal rule: Do not use the fractional laser on tanned skin or skin that will be getting sun exposure soon after the treatment, as melanocytes are already activated and ready to deposit pigment. Use strict posttreatment sun protection with a mineral sunscreen. While she is not “a big fan” of hydroquinone, Dr. Alster does employ other bleaching agents for postoperative hyperpigmentation, including alpha hydroxyl acid, retinoic acid, kojic acid, and lignin peroxidase.
Good technique and aftercare reduce the risk of hypertrophic scarring. This means avoiding excessive fluences and aggressive lasering techniques and early treatment of any suspected infection. “My main treatment is the 585nm pulsed dye laser, but the main thing is to avoid aggressive techniques with overlapping or stacking of pulses, strict wound care, and early treatment of any infections.”
Dr. Alster disclosed that she is a consultant to L’Oréal USA, an investigator for Revance Therapeutics and Sente Labs, and a medical advisor to Merz Aesthetics, and has investments/commercial interests in Home Skinovations.
SOURCE: Alster, T. et al, PREVENTION & MANAGEMENT OF
EXPERT ANALYSIS AT AAD 18
Biologics gaining traction in children with moderate to severe psoriasis
SAN DIEGO – Systemic therapies are increasingly being used for children with moderate to severe psoriasis; methotrexate is still the mainstay of systemic treatment, but biologics appear to achieve superior results with fewer side effects, Amy S. Paller, MD, said at the annual meeting of the American Academy of Dermatology.
Etanercept was approved in 2016 for children ages 6 and up, and ustekinumab was approved for use in patients aged 12 years or older in October 2017. Ongoing trials are examining adalimumab, apremilast, ustekinumab, and ixekizumab for use in adolescents and younger children. Trials are also being planned for other therapies that inhibit the Th17/IL-23 pathway, said Dr. Paller, the Walter J. Hamlin Professor and chair of dermatology at Northwestern University Feinberg School of Medicine, Chicago.
Further, the study found that biologic agents, primarily etanercept, were used by 27%, acitretin by nearly 15%, cyclosporine by about 8%, and fumaric acid esters by 5%. More than 1 medication was used by 19%, according to the study results.
Adverse events affected the ability to tolerate therapy, and methotrexate and biologic agents were taken for a mean duration that was 2-fold greater than the mean duration for cyclosporine or fumaric acid esters. “A prospective registry is needed to track the long-term risks of systemic agents for pediatric psoriasis,” the authors concluded.
Dr. Paller reported that, in her practice, "we're still primarily using methotrexate. It takes time to see an effect with methotrexate, and you have to let people know this up front.” She pointed to a 2015 single-site prospective study of 25 children that found just 40% achieved Psoriasis Area and Severity Index 50 at 12 weeks, with that number rising to 80% by 36 weeks. (J Derm Treat 2015; 26: 406-12)
Dr. Paller recommends baseline and annual TB testing, updated vaccinations and pregnancy counseling for all patients taking immunosuppressant therapies.
"I don't use a lot of retinoids for plaque psoriasis in kids," Dr. Paller said, "but for pustular psoriasis, I use (them) quite a bit. The beauty of retinoids is that they are not immunosuppressants, and you can start and stop them without loss of efficacy. There are many potential side effects, primarily skin and mucosal dryness."
Cyclosporine "has the greatest potential toxicity, which leaves it lower on the therapeutic ladder," Dr. Paller said. "But it has a pretty good safety record. The nice thing we can say is that (cyclosporine has) been around a long time. We have decades of experience in children, and we're using a low dose."
Benefits of biologics include convenience, infrequent dosing, and, potentially, fewer lab tests, Dr. Paller said. She added that there's no consensus about whether lab tests beyond annual TB tests are a good idea for patients on biologics.
Long-term risks are unclear, however, and drug holidays could spell trouble for efficacy when kids return to the medications.
Dr. Paller noted that biologics can cost tens of thousands of dollars for several weeks of treatment, and insurers may not cover them.
A 2014 meta-analysis of 48 randomized, controlled trials of 16,696 adult patients with psoriasis put biologics as the most effective therapies, with infliximab at the top (risk difference 76%), followed by adalimumab (RD 61%) and ustekinumab (RD 63%).
“These biologics are more effective than etanercept and all conventional treatments. Head-to-head trials indicate the superiority of adalimumab and infliximab over methotrexate (MTX), the superiority of ustekinumab over etanercept …” the meta-analysis concluded. (Br J Dermatol. 2014 Feb;170(2):274-303)
Dr. Paller disclosed that she is an investigator for Abbvie; Celgene; Eli Lilly, Janssen, Leo Foundation; Novartis. She is a consultant with honorarium for Amgen; Celgene; Eli Lilly; and Novartis.
SOURCE: Paller, A. et al, Session F025 Update on systemic therapies and emerging treatments
SAN DIEGO – Systemic therapies are increasingly being used for children with moderate to severe psoriasis; methotrexate is still the mainstay of systemic treatment, but biologics appear to achieve superior results with fewer side effects, Amy S. Paller, MD, said at the annual meeting of the American Academy of Dermatology.
Etanercept was approved in 2016 for children ages 6 and up, and ustekinumab was approved for use in patients aged 12 years or older in October 2017. Ongoing trials are examining adalimumab, apremilast, ustekinumab, and ixekizumab for use in adolescents and younger children. Trials are also being planned for other therapies that inhibit the Th17/IL-23 pathway, said Dr. Paller, the Walter J. Hamlin Professor and chair of dermatology at Northwestern University Feinberg School of Medicine, Chicago.
Further, the study found that biologic agents, primarily etanercept, were used by 27%, acitretin by nearly 15%, cyclosporine by about 8%, and fumaric acid esters by 5%. More than 1 medication was used by 19%, according to the study results.
Adverse events affected the ability to tolerate therapy, and methotrexate and biologic agents were taken for a mean duration that was 2-fold greater than the mean duration for cyclosporine or fumaric acid esters. “A prospective registry is needed to track the long-term risks of systemic agents for pediatric psoriasis,” the authors concluded.
Dr. Paller reported that, in her practice, "we're still primarily using methotrexate. It takes time to see an effect with methotrexate, and you have to let people know this up front.” She pointed to a 2015 single-site prospective study of 25 children that found just 40% achieved Psoriasis Area and Severity Index 50 at 12 weeks, with that number rising to 80% by 36 weeks. (J Derm Treat 2015; 26: 406-12)
Dr. Paller recommends baseline and annual TB testing, updated vaccinations and pregnancy counseling for all patients taking immunosuppressant therapies.
"I don't use a lot of retinoids for plaque psoriasis in kids," Dr. Paller said, "but for pustular psoriasis, I use (them) quite a bit. The beauty of retinoids is that they are not immunosuppressants, and you can start and stop them without loss of efficacy. There are many potential side effects, primarily skin and mucosal dryness."
Cyclosporine "has the greatest potential toxicity, which leaves it lower on the therapeutic ladder," Dr. Paller said. "But it has a pretty good safety record. The nice thing we can say is that (cyclosporine has) been around a long time. We have decades of experience in children, and we're using a low dose."
Benefits of biologics include convenience, infrequent dosing, and, potentially, fewer lab tests, Dr. Paller said. She added that there's no consensus about whether lab tests beyond annual TB tests are a good idea for patients on biologics.
Long-term risks are unclear, however, and drug holidays could spell trouble for efficacy when kids return to the medications.
Dr. Paller noted that biologics can cost tens of thousands of dollars for several weeks of treatment, and insurers may not cover them.
A 2014 meta-analysis of 48 randomized, controlled trials of 16,696 adult patients with psoriasis put biologics as the most effective therapies, with infliximab at the top (risk difference 76%), followed by adalimumab (RD 61%) and ustekinumab (RD 63%).
“These biologics are more effective than etanercept and all conventional treatments. Head-to-head trials indicate the superiority of adalimumab and infliximab over methotrexate (MTX), the superiority of ustekinumab over etanercept …” the meta-analysis concluded. (Br J Dermatol. 2014 Feb;170(2):274-303)
Dr. Paller disclosed that she is an investigator for Abbvie; Celgene; Eli Lilly, Janssen, Leo Foundation; Novartis. She is a consultant with honorarium for Amgen; Celgene; Eli Lilly; and Novartis.
SOURCE: Paller, A. et al, Session F025 Update on systemic therapies and emerging treatments
SAN DIEGO – Systemic therapies are increasingly being used for children with moderate to severe psoriasis; methotrexate is still the mainstay of systemic treatment, but biologics appear to achieve superior results with fewer side effects, Amy S. Paller, MD, said at the annual meeting of the American Academy of Dermatology.
Etanercept was approved in 2016 for children ages 6 and up, and ustekinumab was approved for use in patients aged 12 years or older in October 2017. Ongoing trials are examining adalimumab, apremilast, ustekinumab, and ixekizumab for use in adolescents and younger children. Trials are also being planned for other therapies that inhibit the Th17/IL-23 pathway, said Dr. Paller, the Walter J. Hamlin Professor and chair of dermatology at Northwestern University Feinberg School of Medicine, Chicago.
Further, the study found that biologic agents, primarily etanercept, were used by 27%, acitretin by nearly 15%, cyclosporine by about 8%, and fumaric acid esters by 5%. More than 1 medication was used by 19%, according to the study results.
Adverse events affected the ability to tolerate therapy, and methotrexate and biologic agents were taken for a mean duration that was 2-fold greater than the mean duration for cyclosporine or fumaric acid esters. “A prospective registry is needed to track the long-term risks of systemic agents for pediatric psoriasis,” the authors concluded.
Dr. Paller reported that, in her practice, "we're still primarily using methotrexate. It takes time to see an effect with methotrexate, and you have to let people know this up front.” She pointed to a 2015 single-site prospective study of 25 children that found just 40% achieved Psoriasis Area and Severity Index 50 at 12 weeks, with that number rising to 80% by 36 weeks. (J Derm Treat 2015; 26: 406-12)
Dr. Paller recommends baseline and annual TB testing, updated vaccinations and pregnancy counseling for all patients taking immunosuppressant therapies.
"I don't use a lot of retinoids for plaque psoriasis in kids," Dr. Paller said, "but for pustular psoriasis, I use (them) quite a bit. The beauty of retinoids is that they are not immunosuppressants, and you can start and stop them without loss of efficacy. There are many potential side effects, primarily skin and mucosal dryness."
Cyclosporine "has the greatest potential toxicity, which leaves it lower on the therapeutic ladder," Dr. Paller said. "But it has a pretty good safety record. The nice thing we can say is that (cyclosporine has) been around a long time. We have decades of experience in children, and we're using a low dose."
Benefits of biologics include convenience, infrequent dosing, and, potentially, fewer lab tests, Dr. Paller said. She added that there's no consensus about whether lab tests beyond annual TB tests are a good idea for patients on biologics.
Long-term risks are unclear, however, and drug holidays could spell trouble for efficacy when kids return to the medications.
Dr. Paller noted that biologics can cost tens of thousands of dollars for several weeks of treatment, and insurers may not cover them.
A 2014 meta-analysis of 48 randomized, controlled trials of 16,696 adult patients with psoriasis put biologics as the most effective therapies, with infliximab at the top (risk difference 76%), followed by adalimumab (RD 61%) and ustekinumab (RD 63%).
“These biologics are more effective than etanercept and all conventional treatments. Head-to-head trials indicate the superiority of adalimumab and infliximab over methotrexate (MTX), the superiority of ustekinumab over etanercept …” the meta-analysis concluded. (Br J Dermatol. 2014 Feb;170(2):274-303)
Dr. Paller disclosed that she is an investigator for Abbvie; Celgene; Eli Lilly, Janssen, Leo Foundation; Novartis. She is a consultant with honorarium for Amgen; Celgene; Eli Lilly; and Novartis.
SOURCE: Paller, A. et al, Session F025 Update on systemic therapies and emerging treatments
EXPERT ANALYSIS AT AAD 18
FDA grants ivosidenib NDA priority review
The US Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for ivosidenib, a targeted inhibitor of mutant IDH1.
With this NDA, Agios Pharmaceuticals, Inc., is seeking approval for ivosidenib (formerly AG-120) to treat patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.
The FDA expects to make a decision on the NDA by August 21, 2018.
The agency aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 1 data
The priority review for the ivosidenib NDA is based on results from AG120-C-001, a phase 1 trial of patients with advanced hematologic malignancies and an IDH1 mutation. Data from this study were presented at the 2017 ASH Annual Meeting (abstract 725).
This ongoing trial includes a dose-escalation phase and 4 expansion arms. Ivosidenib doses ranged from 200 mg to 1200 mg in the dose-escalation phase. Patients in the dose-expansion arms received a 500 mg daily dose of the drug.
Arm 1 includes IDH1-mutant-positive AML patients who relapsed after bone marrow transplant, were in second or later relapse, were refractory to initial induction or re-induction treatment, or who relapsed within a year of initial treatment, excluding patients with favorable-risk status.
Arms 2, 3 and 4 were not included in the primary efficacy analysis.
The primary analysis set consists of 125 relapsed/refractory AML patients—92 from arm 1 of the expansion and 33 patients from the dose-escalation who met the eligibility criteria for arm 1 and received ivosidenib at 500 mg once daily.
The median age of these patients was 67 (range, 18-87), and the median number of prior regimens they received was 2 (range, 1-6).
The primary endpoint for these patients is the rate of complete response (CR) and CR with partial hematologic recovery (CRh), which was 30.4%. The CR rate was 21.6% (27/125), and the CRh rate was 8.8% (11/125).
The overall response rate was 41.6% (52/125). The median duration of response was 6.5 months for all patients, 9.3 months for those who achieved a CR, and 8.2 months for those who had a CR/CRh.
At the time of the data cut-off, the median overall survival was 8.8 months. The median overall survival was not reached for patients who achieved a CR/CRh, was 9.3 months for non-CR/CRh responders, and was 3.9 months for non-responders.
There were a few adverse events of interest. Eight percent of patients reported grade 3 or higher leukocytosis, which was managed with hydroxyurea, and none of the cases were fatal.
Eight percent of patients reported grade 3 QT prolongation. Ivosidenib was reduced in 1 patient and held in 5 patients (for any grade of QT prolongation). There were no grade 4 or 5 cases of QT prolongation.
Finally, 9.6% of patients reported IDH-differentiation syndrome, which was managed with corticosteroids and diuretics. None of the cases were grade 4 or 5.
Companion diagnostic
Abbott has submitted a premarket approval application to the FDA for an IDH1 assay to be used on the Abbott m2000 RealTime System, an automated sample preparation and batch analyzer system for nucleic acid amplification and detection.
In 2014, Abbott and Agios entered into an exclusive agreement under which Abbott is responsible for the development and commercialization of a RealTime PCR assay for detection of the IDH1 mutation in bone marrow and blood. The Abbott assay is intended to serve as a companion diagnostic for ivosidenib.
The US Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for ivosidenib, a targeted inhibitor of mutant IDH1.
With this NDA, Agios Pharmaceuticals, Inc., is seeking approval for ivosidenib (formerly AG-120) to treat patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.
The FDA expects to make a decision on the NDA by August 21, 2018.
The agency aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 1 data
The priority review for the ivosidenib NDA is based on results from AG120-C-001, a phase 1 trial of patients with advanced hematologic malignancies and an IDH1 mutation. Data from this study were presented at the 2017 ASH Annual Meeting (abstract 725).
This ongoing trial includes a dose-escalation phase and 4 expansion arms. Ivosidenib doses ranged from 200 mg to 1200 mg in the dose-escalation phase. Patients in the dose-expansion arms received a 500 mg daily dose of the drug.
Arm 1 includes IDH1-mutant-positive AML patients who relapsed after bone marrow transplant, were in second or later relapse, were refractory to initial induction or re-induction treatment, or who relapsed within a year of initial treatment, excluding patients with favorable-risk status.
Arms 2, 3 and 4 were not included in the primary efficacy analysis.
The primary analysis set consists of 125 relapsed/refractory AML patients—92 from arm 1 of the expansion and 33 patients from the dose-escalation who met the eligibility criteria for arm 1 and received ivosidenib at 500 mg once daily.
The median age of these patients was 67 (range, 18-87), and the median number of prior regimens they received was 2 (range, 1-6).
The primary endpoint for these patients is the rate of complete response (CR) and CR with partial hematologic recovery (CRh), which was 30.4%. The CR rate was 21.6% (27/125), and the CRh rate was 8.8% (11/125).
The overall response rate was 41.6% (52/125). The median duration of response was 6.5 months for all patients, 9.3 months for those who achieved a CR, and 8.2 months for those who had a CR/CRh.
At the time of the data cut-off, the median overall survival was 8.8 months. The median overall survival was not reached for patients who achieved a CR/CRh, was 9.3 months for non-CR/CRh responders, and was 3.9 months for non-responders.
There were a few adverse events of interest. Eight percent of patients reported grade 3 or higher leukocytosis, which was managed with hydroxyurea, and none of the cases were fatal.
Eight percent of patients reported grade 3 QT prolongation. Ivosidenib was reduced in 1 patient and held in 5 patients (for any grade of QT prolongation). There were no grade 4 or 5 cases of QT prolongation.
Finally, 9.6% of patients reported IDH-differentiation syndrome, which was managed with corticosteroids and diuretics. None of the cases were grade 4 or 5.
Companion diagnostic
Abbott has submitted a premarket approval application to the FDA for an IDH1 assay to be used on the Abbott m2000 RealTime System, an automated sample preparation and batch analyzer system for nucleic acid amplification and detection.
In 2014, Abbott and Agios entered into an exclusive agreement under which Abbott is responsible for the development and commercialization of a RealTime PCR assay for detection of the IDH1 mutation in bone marrow and blood. The Abbott assay is intended to serve as a companion diagnostic for ivosidenib.
The US Food and Drug Administration (FDA) has accepted for priority review the new drug application (NDA) for ivosidenib, a targeted inhibitor of mutant IDH1.
With this NDA, Agios Pharmaceuticals, Inc., is seeking approval for ivosidenib (formerly AG-120) to treat patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.
The FDA expects to make a decision on the NDA by August 21, 2018.
The agency aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.
Phase 1 data
The priority review for the ivosidenib NDA is based on results from AG120-C-001, a phase 1 trial of patients with advanced hematologic malignancies and an IDH1 mutation. Data from this study were presented at the 2017 ASH Annual Meeting (abstract 725).
This ongoing trial includes a dose-escalation phase and 4 expansion arms. Ivosidenib doses ranged from 200 mg to 1200 mg in the dose-escalation phase. Patients in the dose-expansion arms received a 500 mg daily dose of the drug.
Arm 1 includes IDH1-mutant-positive AML patients who relapsed after bone marrow transplant, were in second or later relapse, were refractory to initial induction or re-induction treatment, or who relapsed within a year of initial treatment, excluding patients with favorable-risk status.
Arms 2, 3 and 4 were not included in the primary efficacy analysis.
The primary analysis set consists of 125 relapsed/refractory AML patients—92 from arm 1 of the expansion and 33 patients from the dose-escalation who met the eligibility criteria for arm 1 and received ivosidenib at 500 mg once daily.
The median age of these patients was 67 (range, 18-87), and the median number of prior regimens they received was 2 (range, 1-6).
The primary endpoint for these patients is the rate of complete response (CR) and CR with partial hematologic recovery (CRh), which was 30.4%. The CR rate was 21.6% (27/125), and the CRh rate was 8.8% (11/125).
The overall response rate was 41.6% (52/125). The median duration of response was 6.5 months for all patients, 9.3 months for those who achieved a CR, and 8.2 months for those who had a CR/CRh.
At the time of the data cut-off, the median overall survival was 8.8 months. The median overall survival was not reached for patients who achieved a CR/CRh, was 9.3 months for non-CR/CRh responders, and was 3.9 months for non-responders.
There were a few adverse events of interest. Eight percent of patients reported grade 3 or higher leukocytosis, which was managed with hydroxyurea, and none of the cases were fatal.
Eight percent of patients reported grade 3 QT prolongation. Ivosidenib was reduced in 1 patient and held in 5 patients (for any grade of QT prolongation). There were no grade 4 or 5 cases of QT prolongation.
Finally, 9.6% of patients reported IDH-differentiation syndrome, which was managed with corticosteroids and diuretics. None of the cases were grade 4 or 5.
Companion diagnostic
Abbott has submitted a premarket approval application to the FDA for an IDH1 assay to be used on the Abbott m2000 RealTime System, an automated sample preparation and batch analyzer system for nucleic acid amplification and detection.
In 2014, Abbott and Agios entered into an exclusive agreement under which Abbott is responsible for the development and commercialization of a RealTime PCR assay for detection of the IDH1 mutation in bone marrow and blood. The Abbott assay is intended to serve as a companion diagnostic for ivosidenib.
DDW® 2018 general registration is now open
General registration and housing for Digestive Disease Week® (DDW) 2018 are now open. Registering during the early-bird period (until April 18) guarantees a savings of at least $80 on your registration.
Why DDW?
Just as monumental as this year’s host city, Washington, D.C., DDW is the premier meeting for GI professionals. Come to DDW 2018, taking place June 2-5, to:
- • Choose from an extensive program of high-quality education presented in a variety of learning formats.
- • Explore research unveiled in more than 4,000 poster presentations and over 1,000 abstract presentations.
- • Network and share capital ideas with more than 14,000 other attendees from around the world.
- • Browse an extensive Exhibit Hall featuring the latest products and services in gastroenterology and related fields.
Whether your area of expertise is in patient care, research, education, or administration, DDW has something for you. Register today
General registration and housing for Digestive Disease Week® (DDW) 2018 are now open. Registering during the early-bird period (until April 18) guarantees a savings of at least $80 on your registration.
Why DDW?
Just as monumental as this year’s host city, Washington, D.C., DDW is the premier meeting for GI professionals. Come to DDW 2018, taking place June 2-5, to:
- • Choose from an extensive program of high-quality education presented in a variety of learning formats.
- • Explore research unveiled in more than 4,000 poster presentations and over 1,000 abstract presentations.
- • Network and share capital ideas with more than 14,000 other attendees from around the world.
- • Browse an extensive Exhibit Hall featuring the latest products and services in gastroenterology and related fields.
Whether your area of expertise is in patient care, research, education, or administration, DDW has something for you. Register today
General registration and housing for Digestive Disease Week® (DDW) 2018 are now open. Registering during the early-bird period (until April 18) guarantees a savings of at least $80 on your registration.
Why DDW?
Just as monumental as this year’s host city, Washington, D.C., DDW is the premier meeting for GI professionals. Come to DDW 2018, taking place June 2-5, to:
- • Choose from an extensive program of high-quality education presented in a variety of learning formats.
- • Explore research unveiled in more than 4,000 poster presentations and over 1,000 abstract presentations.
- • Network and share capital ideas with more than 14,000 other attendees from around the world.
- • Browse an extensive Exhibit Hall featuring the latest products and services in gastroenterology and related fields.
Whether your area of expertise is in patient care, research, education, or administration, DDW has something for you. Register today
AGA’s Fecal Microbiota Transplantation National Registry enrolls first patient
The AGA Fecal Microbiota Transplantation (FMT) National Registry is officially underway! The first patient enrolled in the FMT National Registry received a fecal transplant through the Gastroenterology Center of Connecticut/Medical Research Center of Connecticut by Paul Feuerstadt, MD. The patient being treated had experienced multiple recurrences of C. difficile infection. As part of the registry, Dr. Feuerstadt will follow up with the patient four times over the next 2 years and report back on the patient’s health post-FMT. The patient will also provide yearly reports for up to 10 years.
The AGA FMT National Registry, a program of the AGA Center for Gut Microbiome Research and Education, was established in August 2016 after receiving funding from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH (award number R24AI118629). The registry aims to enroll 75 sites and track 4,000 patients for 5-10 years after their FMT procedure. The data collected from this registry will guide physicians in determining when to use FMT on their patients and will provide much-needed information on the potential risks associated with stool transplants.
If you’re interested in participating in the registry, email [email protected].
New registry collaborators
AGA will collaborate with the American Gut Project – an academic effort run by the laboratory of Rob Knight, PhD, professor and director of the Center for Microbiome Innovation at the University of California, San Diego – to build a biobank of stool samples from participants in the FMT National Registry. American Gut will receive stool samples from registry participants before and after their FMT. The microbiota will be sequenced in each sample, and remaining material will be frozen to be made available for future research. Eventually, this information could help doctors screen and select the best donor samples for individual patients.
AGA will also collaborate with OpenBiome, a public stool bank and nonprofit research organization that provides clinicians with rigorously screened, ready-to-use stool preparations for fecal transplant procedures. As the only public stool bank in the country, OpenBiome serves as the source of stool preparations for nearly 1,000 clinical partners performing FMT across the U.S. For patients enrolled in the registry who receive OpenBiome FMT material, OpenBiome will provide screening information and samples to support the registry’s research analyses. Learn more at www.gastro.org/FMTRegistry.
The AGA Fecal Microbiota Transplantation (FMT) National Registry is officially underway! The first patient enrolled in the FMT National Registry received a fecal transplant through the Gastroenterology Center of Connecticut/Medical Research Center of Connecticut by Paul Feuerstadt, MD. The patient being treated had experienced multiple recurrences of C. difficile infection. As part of the registry, Dr. Feuerstadt will follow up with the patient four times over the next 2 years and report back on the patient’s health post-FMT. The patient will also provide yearly reports for up to 10 years.
The AGA FMT National Registry, a program of the AGA Center for Gut Microbiome Research and Education, was established in August 2016 after receiving funding from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH (award number R24AI118629). The registry aims to enroll 75 sites and track 4,000 patients for 5-10 years after their FMT procedure. The data collected from this registry will guide physicians in determining when to use FMT on their patients and will provide much-needed information on the potential risks associated with stool transplants.
If you’re interested in participating in the registry, email [email protected].
New registry collaborators
AGA will collaborate with the American Gut Project – an academic effort run by the laboratory of Rob Knight, PhD, professor and director of the Center for Microbiome Innovation at the University of California, San Diego – to build a biobank of stool samples from participants in the FMT National Registry. American Gut will receive stool samples from registry participants before and after their FMT. The microbiota will be sequenced in each sample, and remaining material will be frozen to be made available for future research. Eventually, this information could help doctors screen and select the best donor samples for individual patients.
AGA will also collaborate with OpenBiome, a public stool bank and nonprofit research organization that provides clinicians with rigorously screened, ready-to-use stool preparations for fecal transplant procedures. As the only public stool bank in the country, OpenBiome serves as the source of stool preparations for nearly 1,000 clinical partners performing FMT across the U.S. For patients enrolled in the registry who receive OpenBiome FMT material, OpenBiome will provide screening information and samples to support the registry’s research analyses. Learn more at www.gastro.org/FMTRegistry.
The AGA Fecal Microbiota Transplantation (FMT) National Registry is officially underway! The first patient enrolled in the FMT National Registry received a fecal transplant through the Gastroenterology Center of Connecticut/Medical Research Center of Connecticut by Paul Feuerstadt, MD. The patient being treated had experienced multiple recurrences of C. difficile infection. As part of the registry, Dr. Feuerstadt will follow up with the patient four times over the next 2 years and report back on the patient’s health post-FMT. The patient will also provide yearly reports for up to 10 years.
The AGA FMT National Registry, a program of the AGA Center for Gut Microbiome Research and Education, was established in August 2016 after receiving funding from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH (award number R24AI118629). The registry aims to enroll 75 sites and track 4,000 patients for 5-10 years after their FMT procedure. The data collected from this registry will guide physicians in determining when to use FMT on their patients and will provide much-needed information on the potential risks associated with stool transplants.
If you’re interested in participating in the registry, email [email protected].
New registry collaborators
AGA will collaborate with the American Gut Project – an academic effort run by the laboratory of Rob Knight, PhD, professor and director of the Center for Microbiome Innovation at the University of California, San Diego – to build a biobank of stool samples from participants in the FMT National Registry. American Gut will receive stool samples from registry participants before and after their FMT. The microbiota will be sequenced in each sample, and remaining material will be frozen to be made available for future research. Eventually, this information could help doctors screen and select the best donor samples for individual patients.
AGA will also collaborate with OpenBiome, a public stool bank and nonprofit research organization that provides clinicians with rigorously screened, ready-to-use stool preparations for fecal transplant procedures. As the only public stool bank in the country, OpenBiome serves as the source of stool preparations for nearly 1,000 clinical partners performing FMT across the U.S. For patients enrolled in the registry who receive OpenBiome FMT material, OpenBiome will provide screening information and samples to support the registry’s research analyses. Learn more at www.gastro.org/FMTRegistry.
Long-term effects of ketamine uncertain
LAS VEGAS – Low doses of ketamine, an N-methyl-D-asparate glutamate receptor antagonist, can produce benefits that are unprecedented in the history of treating major depression, according to David Feifel, MD, PhD.
“When have we ever had the ability to be sitting in front of a patient who is extremely suicidal and have an intervention that will work within [an] hour that will remediate that?” he asked at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Ketamine is that tool. If nothing else, that’s what ketamine already presents to us in this field.”
Then there’s the potential for abuse. he asked. “What about other long-term side effects?”
A recent consensus statement authored by Gerard Sanacora, PhD, MD, and associates acknowledged that data on the long-term effects of using ketamine in psychiatry practice are limited or nonexistent (JAMA Psychiatry. 2017 Apr 1;74[4]:399-405), even though an increasing number of clinicians are providing off-label ketamine for depression and other psychiatric disorders. First synthesized in the 1960s, ketamine’s primary site of action in the central nervous system seems to be the thalamocortical projection system, said Dr. Feifel, who has been providing the drug to patients since 2008. In a handout that accompanied his talk, he wrote that ketamine “selectively depresses neuronal function in parts of the cortex and thalamus while stimulating parts of the limbic system, including the hippocampus. This process creates what is termed a functional disorganization of nonspecific pathways in midbrain and thalamic areas.”
Ketamine creates acute subjective experiences that vary with doses, including a sense of “melting into people or things” at lower doses, and visions and hallucinations at higher doses. “Patients will tell me that they deliberately tried to move their hands and feet, to make sure they were still connected to their bodies,” Dr. Feifel said. “There’s often a sensation of moving through space. At higher doses, they often experience a profound sense of connection to all things, an ineffable universal unity that can change their perspective on themselves and their depression. It’s very profound.”
Antidepressant benefits with ketamine are usually dramatic, said Dr. Feifel, who also is founder and director of the Kadima Neuropsychiatry Institute in La Jolla, Calif. The drug is most commonly administered as an IV infusion over a 40 minute period at a dosage of 0.5 mg/kg. It also can be administered orally, intranasally, and intramuscularly. “Patients may achieve response and even remission of depression within a day, even when the depression was previously medication refractory,” he said. “The benefits are usually lost in 3-21 days. Maintenance treatment with ketamine, scheduled once every 2-4 weeks, can maintain the treatment gains. Dissociative and psychotomimetic effects are common but very seldom problematic.”
Dr. Feifel noted that ketamine’s remarkable results have piqued the interest of pharmaceutical companies. “But it is off patent – non proprietary,” he said. “Several novel agents by different pharmaceutical companies quickly have been developed and are in development. Some have modified pharmacology and are claimed to produce less acute dissociative/psychedelic effects. Janssen is developing intranasal esketamine for acutely suicidal patients that has been fast-tracked by the FDA.”
Dr. Feifel reported having no financial disclosures.
LAS VEGAS – Low doses of ketamine, an N-methyl-D-asparate glutamate receptor antagonist, can produce benefits that are unprecedented in the history of treating major depression, according to David Feifel, MD, PhD.
“When have we ever had the ability to be sitting in front of a patient who is extremely suicidal and have an intervention that will work within [an] hour that will remediate that?” he asked at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Ketamine is that tool. If nothing else, that’s what ketamine already presents to us in this field.”
Then there’s the potential for abuse. he asked. “What about other long-term side effects?”
A recent consensus statement authored by Gerard Sanacora, PhD, MD, and associates acknowledged that data on the long-term effects of using ketamine in psychiatry practice are limited or nonexistent (JAMA Psychiatry. 2017 Apr 1;74[4]:399-405), even though an increasing number of clinicians are providing off-label ketamine for depression and other psychiatric disorders. First synthesized in the 1960s, ketamine’s primary site of action in the central nervous system seems to be the thalamocortical projection system, said Dr. Feifel, who has been providing the drug to patients since 2008. In a handout that accompanied his talk, he wrote that ketamine “selectively depresses neuronal function in parts of the cortex and thalamus while stimulating parts of the limbic system, including the hippocampus. This process creates what is termed a functional disorganization of nonspecific pathways in midbrain and thalamic areas.”
Ketamine creates acute subjective experiences that vary with doses, including a sense of “melting into people or things” at lower doses, and visions and hallucinations at higher doses. “Patients will tell me that they deliberately tried to move their hands and feet, to make sure they were still connected to their bodies,” Dr. Feifel said. “There’s often a sensation of moving through space. At higher doses, they often experience a profound sense of connection to all things, an ineffable universal unity that can change their perspective on themselves and their depression. It’s very profound.”
Antidepressant benefits with ketamine are usually dramatic, said Dr. Feifel, who also is founder and director of the Kadima Neuropsychiatry Institute in La Jolla, Calif. The drug is most commonly administered as an IV infusion over a 40 minute period at a dosage of 0.5 mg/kg. It also can be administered orally, intranasally, and intramuscularly. “Patients may achieve response and even remission of depression within a day, even when the depression was previously medication refractory,” he said. “The benefits are usually lost in 3-21 days. Maintenance treatment with ketamine, scheduled once every 2-4 weeks, can maintain the treatment gains. Dissociative and psychotomimetic effects are common but very seldom problematic.”
Dr. Feifel noted that ketamine’s remarkable results have piqued the interest of pharmaceutical companies. “But it is off patent – non proprietary,” he said. “Several novel agents by different pharmaceutical companies quickly have been developed and are in development. Some have modified pharmacology and are claimed to produce less acute dissociative/psychedelic effects. Janssen is developing intranasal esketamine for acutely suicidal patients that has been fast-tracked by the FDA.”
Dr. Feifel reported having no financial disclosures.
LAS VEGAS – Low doses of ketamine, an N-methyl-D-asparate glutamate receptor antagonist, can produce benefits that are unprecedented in the history of treating major depression, according to David Feifel, MD, PhD.
“When have we ever had the ability to be sitting in front of a patient who is extremely suicidal and have an intervention that will work within [an] hour that will remediate that?” he asked at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Ketamine is that tool. If nothing else, that’s what ketamine already presents to us in this field.”
Then there’s the potential for abuse. he asked. “What about other long-term side effects?”
A recent consensus statement authored by Gerard Sanacora, PhD, MD, and associates acknowledged that data on the long-term effects of using ketamine in psychiatry practice are limited or nonexistent (JAMA Psychiatry. 2017 Apr 1;74[4]:399-405), even though an increasing number of clinicians are providing off-label ketamine for depression and other psychiatric disorders. First synthesized in the 1960s, ketamine’s primary site of action in the central nervous system seems to be the thalamocortical projection system, said Dr. Feifel, who has been providing the drug to patients since 2008. In a handout that accompanied his talk, he wrote that ketamine “selectively depresses neuronal function in parts of the cortex and thalamus while stimulating parts of the limbic system, including the hippocampus. This process creates what is termed a functional disorganization of nonspecific pathways in midbrain and thalamic areas.”
Ketamine creates acute subjective experiences that vary with doses, including a sense of “melting into people or things” at lower doses, and visions and hallucinations at higher doses. “Patients will tell me that they deliberately tried to move their hands and feet, to make sure they were still connected to their bodies,” Dr. Feifel said. “There’s often a sensation of moving through space. At higher doses, they often experience a profound sense of connection to all things, an ineffable universal unity that can change their perspective on themselves and their depression. It’s very profound.”
Antidepressant benefits with ketamine are usually dramatic, said Dr. Feifel, who also is founder and director of the Kadima Neuropsychiatry Institute in La Jolla, Calif. The drug is most commonly administered as an IV infusion over a 40 minute period at a dosage of 0.5 mg/kg. It also can be administered orally, intranasally, and intramuscularly. “Patients may achieve response and even remission of depression within a day, even when the depression was previously medication refractory,” he said. “The benefits are usually lost in 3-21 days. Maintenance treatment with ketamine, scheduled once every 2-4 weeks, can maintain the treatment gains. Dissociative and psychotomimetic effects are common but very seldom problematic.”
Dr. Feifel noted that ketamine’s remarkable results have piqued the interest of pharmaceutical companies. “But it is off patent – non proprietary,” he said. “Several novel agents by different pharmaceutical companies quickly have been developed and are in development. Some have modified pharmacology and are claimed to produce less acute dissociative/psychedelic effects. Janssen is developing intranasal esketamine for acutely suicidal patients that has been fast-tracked by the FDA.”
Dr. Feifel reported having no financial disclosures.
REPORTING FROM NPA 2018
Embrace the complexity of marijuana use in adolescents
Las Vegas – When talking with adolescents and their families about marijuana use, Kevin M. Gray, MD, recommends embracing the complexity of the issue.
“Avoid polarizing this topic and avoid vilifying cannabis,” he advised at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Take an interest in what they have to say about cannabis. Work in a gentle, nonconfrontational way where you avoid polarization and find some common ground where you can agree that maybe there’s some good and some bad [about cannabis], but the overwhelming evidence in adolescents is that there’s more harm than good with cannabis use, particularly recreationally.”
Dr. Gray, professor and director of child and adolescent psychiatry at the Medical University of South Carolina, Charleston, acknowledged that clinicians face a delicate balance between risk and benefit, even among Food and Drug Administration–approved medications. However, teens and families may struggle with these nuances, especially in light of the term “medical marijuana.” Some assume that “medical” implies “beneficial.” Others may equate “marijuana” with “natural,” which they may, in turn, equate with being “harmless.”
“Perception is critically important,” Dr. Gray said at an annual psychopharmacology update held by the Nevada Psychiatric Association.
Cannabis initiation typically occurs during adolescence, and rates of initiation and use are increasing. According to Dr. Gray, 55% of U.S. high school seniors have used marijuana, 23% use currently, and 6% use daily. “Those are the ones who have adverse outcomes,” he said. Young users are particularly prone to dependence symptoms and an inability to cut back their use. The odds of meeting criteria for cannabis use disorder are substantially greater in adolescent users than they are in adults regardless of time frame or intensity of use.
“In a dose-dependent manner, adolescent cannabis use is associated with adverse academic, occupational, cognitive, psychiatric, and substance use outcomes,” Dr. Gray said, adding that the average potency of delta-9-tetrahydrocannabinol (THC) in seized cannabis increased from 3% in 1992 to 11% in 2010. “Cannabis use in adolescence is associated with increased incidence and worsened course of psychotic, mood, and anxiety disorders. Serious cannabis-associated risks are well recognized and are particularly striking in adolescents. Adult-onset cannabis users may experience fewer adverse effects.”
Evidence-based psychosocial approaches for adolescents with cannabis use disorder include motivational enhancement therapy, which involves building rapport in a gentle way, with phrasing such as “Tell me what you like about marijuana use” and “What don’t you like about it?” Dr. Gray described motivational enhancement therapy as “a gentle nudge for behavior change” that serves as a bridge to cognitive-behavioral therapy, family therapy, and contingency management. “That said, long-term abstinence outcomes are generally poor,” he said. “People tend to go back to use.”
N-acetylcysteine (NAC) shows promise as a medication for adolescents with cannabis use disorder. NAC activates the cystine/glutamate exchanger and upregulates the GLT-1 receptor, which leads to reduction in reinstatement of drug seeking in animal models. One trial of NAC supported efficacy in 116 cannabis-dependent adolescents (Am J Psychiatry. 2012 Aug;169[8]:805-12). Led by Dr. Gray, the trial consisted of 8 weeks of active treatment on placebo or NAC 1,200 mg BID. All participants received weekly brief cessation counseling and twice-weekly contingency management. The researchers found that adolescents in the NAC group were more than twice as likely to submit a negative urine specimen during treatment than were their counterparts in the placebo group (odds ratio, 2.4; P = .029). In addition, those in the NAC group also were significantly more likely than were those in the placebo group to achieve end-of-treatment abstinence, which was defined as self-reported abstinence confirmed by negative urine testing throughout the last 2 weeks of treatment (OR, 2.3; P = .054).
A similarly designed adult trial indicated that adolescent findings did not translate to adults (Drug Alcohol Depend. 2017 Aug 1;177:249-57). “Whether this may be due to developmental differences in the course and phenomenology of cannabis use disorder, we don’t know,” Dr. Gray said. “For now, NAC remains the only pharmacotherapy with positive published intent-to-treat clinical trial abstinence findings for cannabis use disorder in adolescents. Positive adolescent findings must be replicated, but the necessary behavioral treatment platform must be clarified to translate successfully to real-world practice.”
Dr. Gray disclosed that he receives research funding from the National Institutes of Health.
[email protected]
Las Vegas – When talking with adolescents and their families about marijuana use, Kevin M. Gray, MD, recommends embracing the complexity of the issue.
“Avoid polarizing this topic and avoid vilifying cannabis,” he advised at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Take an interest in what they have to say about cannabis. Work in a gentle, nonconfrontational way where you avoid polarization and find some common ground where you can agree that maybe there’s some good and some bad [about cannabis], but the overwhelming evidence in adolescents is that there’s more harm than good with cannabis use, particularly recreationally.”
Dr. Gray, professor and director of child and adolescent psychiatry at the Medical University of South Carolina, Charleston, acknowledged that clinicians face a delicate balance between risk and benefit, even among Food and Drug Administration–approved medications. However, teens and families may struggle with these nuances, especially in light of the term “medical marijuana.” Some assume that “medical” implies “beneficial.” Others may equate “marijuana” with “natural,” which they may, in turn, equate with being “harmless.”
“Perception is critically important,” Dr. Gray said at an annual psychopharmacology update held by the Nevada Psychiatric Association.
Cannabis initiation typically occurs during adolescence, and rates of initiation and use are increasing. According to Dr. Gray, 55% of U.S. high school seniors have used marijuana, 23% use currently, and 6% use daily. “Those are the ones who have adverse outcomes,” he said. Young users are particularly prone to dependence symptoms and an inability to cut back their use. The odds of meeting criteria for cannabis use disorder are substantially greater in adolescent users than they are in adults regardless of time frame or intensity of use.
“In a dose-dependent manner, adolescent cannabis use is associated with adverse academic, occupational, cognitive, psychiatric, and substance use outcomes,” Dr. Gray said, adding that the average potency of delta-9-tetrahydrocannabinol (THC) in seized cannabis increased from 3% in 1992 to 11% in 2010. “Cannabis use in adolescence is associated with increased incidence and worsened course of psychotic, mood, and anxiety disorders. Serious cannabis-associated risks are well recognized and are particularly striking in adolescents. Adult-onset cannabis users may experience fewer adverse effects.”
Evidence-based psychosocial approaches for adolescents with cannabis use disorder include motivational enhancement therapy, which involves building rapport in a gentle way, with phrasing such as “Tell me what you like about marijuana use” and “What don’t you like about it?” Dr. Gray described motivational enhancement therapy as “a gentle nudge for behavior change” that serves as a bridge to cognitive-behavioral therapy, family therapy, and contingency management. “That said, long-term abstinence outcomes are generally poor,” he said. “People tend to go back to use.”
N-acetylcysteine (NAC) shows promise as a medication for adolescents with cannabis use disorder. NAC activates the cystine/glutamate exchanger and upregulates the GLT-1 receptor, which leads to reduction in reinstatement of drug seeking in animal models. One trial of NAC supported efficacy in 116 cannabis-dependent adolescents (Am J Psychiatry. 2012 Aug;169[8]:805-12). Led by Dr. Gray, the trial consisted of 8 weeks of active treatment on placebo or NAC 1,200 mg BID. All participants received weekly brief cessation counseling and twice-weekly contingency management. The researchers found that adolescents in the NAC group were more than twice as likely to submit a negative urine specimen during treatment than were their counterparts in the placebo group (odds ratio, 2.4; P = .029). In addition, those in the NAC group also were significantly more likely than were those in the placebo group to achieve end-of-treatment abstinence, which was defined as self-reported abstinence confirmed by negative urine testing throughout the last 2 weeks of treatment (OR, 2.3; P = .054).
A similarly designed adult trial indicated that adolescent findings did not translate to adults (Drug Alcohol Depend. 2017 Aug 1;177:249-57). “Whether this may be due to developmental differences in the course and phenomenology of cannabis use disorder, we don’t know,” Dr. Gray said. “For now, NAC remains the only pharmacotherapy with positive published intent-to-treat clinical trial abstinence findings for cannabis use disorder in adolescents. Positive adolescent findings must be replicated, but the necessary behavioral treatment platform must be clarified to translate successfully to real-world practice.”
Dr. Gray disclosed that he receives research funding from the National Institutes of Health.
[email protected]
Las Vegas – When talking with adolescents and their families about marijuana use, Kevin M. Gray, MD, recommends embracing the complexity of the issue.
“Avoid polarizing this topic and avoid vilifying cannabis,” he advised at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Take an interest in what they have to say about cannabis. Work in a gentle, nonconfrontational way where you avoid polarization and find some common ground where you can agree that maybe there’s some good and some bad [about cannabis], but the overwhelming evidence in adolescents is that there’s more harm than good with cannabis use, particularly recreationally.”
Dr. Gray, professor and director of child and adolescent psychiatry at the Medical University of South Carolina, Charleston, acknowledged that clinicians face a delicate balance between risk and benefit, even among Food and Drug Administration–approved medications. However, teens and families may struggle with these nuances, especially in light of the term “medical marijuana.” Some assume that “medical” implies “beneficial.” Others may equate “marijuana” with “natural,” which they may, in turn, equate with being “harmless.”
“Perception is critically important,” Dr. Gray said at an annual psychopharmacology update held by the Nevada Psychiatric Association.
Cannabis initiation typically occurs during adolescence, and rates of initiation and use are increasing. According to Dr. Gray, 55% of U.S. high school seniors have used marijuana, 23% use currently, and 6% use daily. “Those are the ones who have adverse outcomes,” he said. Young users are particularly prone to dependence symptoms and an inability to cut back their use. The odds of meeting criteria for cannabis use disorder are substantially greater in adolescent users than they are in adults regardless of time frame or intensity of use.
“In a dose-dependent manner, adolescent cannabis use is associated with adverse academic, occupational, cognitive, psychiatric, and substance use outcomes,” Dr. Gray said, adding that the average potency of delta-9-tetrahydrocannabinol (THC) in seized cannabis increased from 3% in 1992 to 11% in 2010. “Cannabis use in adolescence is associated with increased incidence and worsened course of psychotic, mood, and anxiety disorders. Serious cannabis-associated risks are well recognized and are particularly striking in adolescents. Adult-onset cannabis users may experience fewer adverse effects.”
Evidence-based psychosocial approaches for adolescents with cannabis use disorder include motivational enhancement therapy, which involves building rapport in a gentle way, with phrasing such as “Tell me what you like about marijuana use” and “What don’t you like about it?” Dr. Gray described motivational enhancement therapy as “a gentle nudge for behavior change” that serves as a bridge to cognitive-behavioral therapy, family therapy, and contingency management. “That said, long-term abstinence outcomes are generally poor,” he said. “People tend to go back to use.”
N-acetylcysteine (NAC) shows promise as a medication for adolescents with cannabis use disorder. NAC activates the cystine/glutamate exchanger and upregulates the GLT-1 receptor, which leads to reduction in reinstatement of drug seeking in animal models. One trial of NAC supported efficacy in 116 cannabis-dependent adolescents (Am J Psychiatry. 2012 Aug;169[8]:805-12). Led by Dr. Gray, the trial consisted of 8 weeks of active treatment on placebo or NAC 1,200 mg BID. All participants received weekly brief cessation counseling and twice-weekly contingency management. The researchers found that adolescents in the NAC group were more than twice as likely to submit a negative urine specimen during treatment than were their counterparts in the placebo group (odds ratio, 2.4; P = .029). In addition, those in the NAC group also were significantly more likely than were those in the placebo group to achieve end-of-treatment abstinence, which was defined as self-reported abstinence confirmed by negative urine testing throughout the last 2 weeks of treatment (OR, 2.3; P = .054).
A similarly designed adult trial indicated that adolescent findings did not translate to adults (Drug Alcohol Depend. 2017 Aug 1;177:249-57). “Whether this may be due to developmental differences in the course and phenomenology of cannabis use disorder, we don’t know,” Dr. Gray said. “For now, NAC remains the only pharmacotherapy with positive published intent-to-treat clinical trial abstinence findings for cannabis use disorder in adolescents. Positive adolescent findings must be replicated, but the necessary behavioral treatment platform must be clarified to translate successfully to real-world practice.”
Dr. Gray disclosed that he receives research funding from the National Institutes of Health.
[email protected]
REPORTING FROM NPA 2018
NF-kappaB pathway could help solve resistance problem in mantle cell lymphoma
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
FROM CELL DEATH & DISEASE
Axitinib/pembrolizumab combo safe, effective against mRCC
A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.
Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.
“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.
Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.
The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).
“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.
As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.
There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.
Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.
Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.
Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.
The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.
At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.
Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.
This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.
Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.
Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.
In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.
Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).
This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.
Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.
Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.
In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.
Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).
This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.
Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.
Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.
In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.
Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).
A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.
Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.
“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.
Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.
The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).
“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.
As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.
There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.
Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.
Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.
Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.
The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.
At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.
Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.
A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.
Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.
“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.
Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.
The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).
“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.
As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.
There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.
Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.
Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.
Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.
The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.
At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.
Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.
FROM THE LANCET ONCOLOGY
Key clinical point: A combination of axitinib and pembrolizumab was tolerable and showed activity against advanced/metastatic renal cell carcinoma.
Major finding: At a median of 20.4 months of follow-up, the overall response rate was 73%.
Study details: Open-label phase 1b dose-finding trial and expansion in 52 patients with advanced RCC.
Disclosures: Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
Source: Atkins MB et al. Lancet Oncol 2018 Feb 10. doi: 10.1016/S1470-2045(18)30081-0.
Sexual aids not available to cancer survivors despite recommendations
ORLANDO – Therapeutic aids for sexual rehabilitation were not available at most major cancer centers, according to results of a structured telephone survey presented at the Cancer Survivorship Symposium.
Of the centers reached, 87% said they had no sexual aids available for men, and 72% said they had no such aids for women, said lead study author Sharon Bober, PhD, a psychologist at the Dana-Farber Cancer Institute in Boston, Massachusetts.
“I think the scarcity of all of these products really underscores the cultural taboos around sexual dysfunction, as did some of the discomfort of the staff responding to our calls,” Dr. Bober said in a press conference at the symposium, which was sponsored by the American Academy of Family Physicians, the American College of Physicians, and the American Society of Clinical Oncology.
Cancer treatment guidelines from the National Comprehensive Cancer Network (NCCN) recommend therapeutic aids for sexual health rehabilitation including vaginal dilators, moisturizers, and vacuum erection devices, Dr. Bober said.
Dr. Bober and her colleagues surveyed 25 NCI-designated Cancer Centers/National Comprehensive Cancer Network–member institutions about on-site availability of sexual aids and resources for cancer survivors.
After conducting internet searches and phone calls designed to identify potential sources of sexual aids at each center, study staff posed as relatives of patients and used a structured script to query cancer center staff about on-site availability of sexual aids.
Separate calls were conducted to query on availability of men and women’s sexual aids.
Of 23 centers that responded about men, 87% reported having no sexual aids, and of 22 centers that responded about women, 72% reported having no sexual aids, Dr. Bober reported at the symposium.
The lack of sexual aids was particularly notable given the wide availability of wigs, prosthetics, sunscreen, and other cancer care products at leading cancer centers, she added.
“Only one center of the 25 had an extensive list of products and resources for both men and women, which may well serve as a model when we think about the needs for cancer survivors in general,” said Dr. Bober.
These results suggest that leading cancer centers are not meeting the needs of cancer survivors in terms of recommended sexual therapeutic aids and informational resources, according to Timothy Gilligan, MD, an American Society of Clinical Oncology expert and member of the Cancer Survivorship news planning team.
“You sort of wonder where a cancer patient’s supposed to go to get this information if not at the Cancer Center,” said Dr. Gilligan, who moderated the press conference. “We’re really kind of leaving them shortchanged here, and the good news is I think we could easily do better if we just decide that we want to.”
The study was funded by Dana-Farber Cancer Institute. Dr. Bober reported research funding from Apex Neuro.
SOURCE: Bober S. et al. Cancer Survivorship Symposium Abstract #134
ORLANDO – Therapeutic aids for sexual rehabilitation were not available at most major cancer centers, according to results of a structured telephone survey presented at the Cancer Survivorship Symposium.
Of the centers reached, 87% said they had no sexual aids available for men, and 72% said they had no such aids for women, said lead study author Sharon Bober, PhD, a psychologist at the Dana-Farber Cancer Institute in Boston, Massachusetts.
“I think the scarcity of all of these products really underscores the cultural taboos around sexual dysfunction, as did some of the discomfort of the staff responding to our calls,” Dr. Bober said in a press conference at the symposium, which was sponsored by the American Academy of Family Physicians, the American College of Physicians, and the American Society of Clinical Oncology.
Cancer treatment guidelines from the National Comprehensive Cancer Network (NCCN) recommend therapeutic aids for sexual health rehabilitation including vaginal dilators, moisturizers, and vacuum erection devices, Dr. Bober said.
Dr. Bober and her colleagues surveyed 25 NCI-designated Cancer Centers/National Comprehensive Cancer Network–member institutions about on-site availability of sexual aids and resources for cancer survivors.
After conducting internet searches and phone calls designed to identify potential sources of sexual aids at each center, study staff posed as relatives of patients and used a structured script to query cancer center staff about on-site availability of sexual aids.
Separate calls were conducted to query on availability of men and women’s sexual aids.
Of 23 centers that responded about men, 87% reported having no sexual aids, and of 22 centers that responded about women, 72% reported having no sexual aids, Dr. Bober reported at the symposium.
The lack of sexual aids was particularly notable given the wide availability of wigs, prosthetics, sunscreen, and other cancer care products at leading cancer centers, she added.
“Only one center of the 25 had an extensive list of products and resources for both men and women, which may well serve as a model when we think about the needs for cancer survivors in general,” said Dr. Bober.
These results suggest that leading cancer centers are not meeting the needs of cancer survivors in terms of recommended sexual therapeutic aids and informational resources, according to Timothy Gilligan, MD, an American Society of Clinical Oncology expert and member of the Cancer Survivorship news planning team.
“You sort of wonder where a cancer patient’s supposed to go to get this information if not at the Cancer Center,” said Dr. Gilligan, who moderated the press conference. “We’re really kind of leaving them shortchanged here, and the good news is I think we could easily do better if we just decide that we want to.”
The study was funded by Dana-Farber Cancer Institute. Dr. Bober reported research funding from Apex Neuro.
SOURCE: Bober S. et al. Cancer Survivorship Symposium Abstract #134
ORLANDO – Therapeutic aids for sexual rehabilitation were not available at most major cancer centers, according to results of a structured telephone survey presented at the Cancer Survivorship Symposium.
Of the centers reached, 87% said they had no sexual aids available for men, and 72% said they had no such aids for women, said lead study author Sharon Bober, PhD, a psychologist at the Dana-Farber Cancer Institute in Boston, Massachusetts.
“I think the scarcity of all of these products really underscores the cultural taboos around sexual dysfunction, as did some of the discomfort of the staff responding to our calls,” Dr. Bober said in a press conference at the symposium, which was sponsored by the American Academy of Family Physicians, the American College of Physicians, and the American Society of Clinical Oncology.
Cancer treatment guidelines from the National Comprehensive Cancer Network (NCCN) recommend therapeutic aids for sexual health rehabilitation including vaginal dilators, moisturizers, and vacuum erection devices, Dr. Bober said.
Dr. Bober and her colleagues surveyed 25 NCI-designated Cancer Centers/National Comprehensive Cancer Network–member institutions about on-site availability of sexual aids and resources for cancer survivors.
After conducting internet searches and phone calls designed to identify potential sources of sexual aids at each center, study staff posed as relatives of patients and used a structured script to query cancer center staff about on-site availability of sexual aids.
Separate calls were conducted to query on availability of men and women’s sexual aids.
Of 23 centers that responded about men, 87% reported having no sexual aids, and of 22 centers that responded about women, 72% reported having no sexual aids, Dr. Bober reported at the symposium.
The lack of sexual aids was particularly notable given the wide availability of wigs, prosthetics, sunscreen, and other cancer care products at leading cancer centers, she added.
“Only one center of the 25 had an extensive list of products and resources for both men and women, which may well serve as a model when we think about the needs for cancer survivors in general,” said Dr. Bober.
These results suggest that leading cancer centers are not meeting the needs of cancer survivors in terms of recommended sexual therapeutic aids and informational resources, according to Timothy Gilligan, MD, an American Society of Clinical Oncology expert and member of the Cancer Survivorship news planning team.
“You sort of wonder where a cancer patient’s supposed to go to get this information if not at the Cancer Center,” said Dr. Gilligan, who moderated the press conference. “We’re really kind of leaving them shortchanged here, and the good news is I think we could easily do better if we just decide that we want to.”
The study was funded by Dana-Farber Cancer Institute. Dr. Bober reported research funding from Apex Neuro.
SOURCE: Bober S. et al. Cancer Survivorship Symposium Abstract #134
FROM THE CSC 2018
Key clinical point: Therapeutic aids for sexual health rehabilitation were not available at most leading cancer centers, despite clinical practice guidelines recommending their use.
Major finding: Of the centers reached, 87% said they had no sexual aids available for men, and 72% said they had no aids for women.
Data source: Analysis of responses from cancer center staff at 25 NCI-designated cancer centers to telephone queries that used a structured script.
Disclosures: Study funding came from Dana-Farber Cancer Institute. Dr. Bober reported research funding from Apex Neuro.
Source: Bober S. et al. Cancer Survivorship Symposium, Abstract #134.