Treat acne from near birth to adulthood with a growing level of aggressiveness as a child ages, a dermatologist urged colleagues.

No treatment may be necessary for acne in the first few months of life, but the condition can leave scars in children as young as ages 3-6 months, said Andrea L. Zaenglein, MD, professor of dermatology and pediatric dermatology, Penn State University, Hershey, Penn., said in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.

Neonatal acne occurs in more than 20% of newborns aged 2 weeks to 3 months. “Typically we don’t need to treat it. But if you do, you could use a topical antifungal like clotrimazole cream twice a day,” but in most babies, “this will just improve over time and resolve without any scarring or sequelae,” she said.

Infantile acne begins about 3-6 months of age typically, or a little bit older, and lasts up to 2 years of age, Dr. Zaenglein said. “You will see comedones in infantile acne, so this is actually a true form of acne. It’s due to increased adrenal production of androgens.”

She added: “The scarring can be permanent. It’s important that you recognize infantile acne and treat it, even though it seems pretty mild.”

For infantile acne, she recommends performing a full-skin exam to rule out hyperandrogenic disorders such as Cushing syndrome, congenital adrenal hyperplasia, premature adrenarche, a gonadal/adrenal tumor and precocious puberty.

Treatments are similar to those in teenagers, she said, “but make sure you use baby-friendly formulations,” with lower concentrations of active ingredients – and avoid tetracyclines and benzoyl peroxide (BPO) washes. BPO can be used in leave-on formulations/creams at lower strengths (2.5%-5%).

One possible combination option is tretinoin 0.025% cream or adapalene 0.1% gel plus BPO 2.5% cream or clindamycin/BPO gel. Another combination is adapalene/BPO 2.5% gel.

Erythromycin can be appropriate at 30-50 mg/kg per day divided in two or three doses a day, but beware of possible gastrointestinal upset. Azithromycin at 5 mg/kg per day is another option.

“Rarely do we have to go to isotretinoin,” Dr. Zaenglein said. “I think in all my years, I’ve only treated one baby with isotretinoin for infantile acne. But severe forms can occur.”

Midchildhood and preadolescent acne conditions occur in children starting at ages 1 up to 10 years, Dr. Zaenglein said. In this population, she also recommends ruling out hyperandrogenism by looking for secondary sexual characteristics with full-body skin exams. “The workup can be broad and includes looking at adrenal androgens and total and free testosterone, as well as looking at growth charts and bone age. Typically, you’ll refer these kids to pediatric endocrinology.”

Keep in mind, she said, that early adrenarche starts at ages 6-7 years in girls and 7-8 years in boys. “That’s when we expect to start seeing that very early acne. You can see it even earlier in patients with elevated BMI, and it’s more common in Hispanic and Black children as well.”

She added that it’s important to remember that early adrenarche is a risk factor for polycystic ovarian syndrome (PCOS). “So ask patients about their family history and look for other signs of PCOS as they move further into adolescence.”

Milder cases of acne in this age group can be treated with “salicylic acid wipes and things that are kind of a rite of passage. But if they have any more severe acne, you’re going to want to treat it more or less like you do adolescent acne.”

MedscapeLive and this news organization are owned by the same parent company. Dr. Zaenglein disclosed receiving consulting fees from Cassiopea, Dermata, and Regeneron and fees for contracted research support from Incyte.

Treat acne from near birth to adulthood with a growing level of aggressiveness as a child ages, a dermatologist urged colleagues.

No treatment may be necessary for acne in the first few months of life, but the condition can leave scars in children as young as ages 3-6 months, said Andrea L. Zaenglein, MD, professor of dermatology and pediatric dermatology, Penn State University, Hershey, Penn., said in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.

Neonatal acne occurs in more than 20% of newborns aged 2 weeks to 3 months. “Typically we don’t need to treat it. But if you do, you could use a topical antifungal like clotrimazole cream twice a day,” but in most babies, “this will just improve over time and resolve without any scarring or sequelae,” she said.

Infantile acne begins about 3-6 months of age typically, or a little bit older, and lasts up to 2 years of age, Dr. Zaenglein said. “You will see comedones in infantile acne, so this is actually a true form of acne. It’s due to increased adrenal production of androgens.”

She added: “The scarring can be permanent. It’s important that you recognize infantile acne and treat it, even though it seems pretty mild.”

For infantile acne, she recommends performing a full-skin exam to rule out hyperandrogenic disorders such as Cushing syndrome, congenital adrenal hyperplasia, premature adrenarche, a gonadal/adrenal tumor and precocious puberty.

Treatments are similar to those in teenagers, she said, “but make sure you use baby-friendly formulations,” with lower concentrations of active ingredients – and avoid tetracyclines and benzoyl peroxide (BPO) washes. BPO can be used in leave-on formulations/creams at lower strengths (2.5%-5%).

One possible combination option is tretinoin 0.025% cream or adapalene 0.1% gel plus BPO 2.5% cream or clindamycin/BPO gel. Another combination is adapalene/BPO 2.5% gel.

Erythromycin can be appropriate at 30-50 mg/kg per day divided in two or three doses a day, but beware of possible gastrointestinal upset. Azithromycin at 5 mg/kg per day is another option.

“Rarely do we have to go to isotretinoin,” Dr. Zaenglein said. “I think in all my years, I’ve only treated one baby with isotretinoin for infantile acne. But severe forms can occur.”

Midchildhood and preadolescent acne conditions occur in children starting at ages 1 up to 10 years, Dr. Zaenglein said. In this population, she also recommends ruling out hyperandrogenism by looking for secondary sexual characteristics with full-body skin exams. “The workup can be broad and includes looking at adrenal androgens and total and free testosterone, as well as looking at growth charts and bone age. Typically, you’ll refer these kids to pediatric endocrinology.”

Keep in mind, she said, that early adrenarche starts at ages 6-7 years in girls and 7-8 years in boys. “That’s when we expect to start seeing that very early acne. You can see it even earlier in patients with elevated BMI, and it’s more common in Hispanic and Black children as well.”

She added that it’s important to remember that early adrenarche is a risk factor for polycystic ovarian syndrome (PCOS). “So ask patients about their family history and look for other signs of PCOS as they move further into adolescence.”

Milder cases of acne in this age group can be treated with “salicylic acid wipes and things that are kind of a rite of passage. But if they have any more severe acne, you’re going to want to treat it more or less like you do adolescent acne.”

MedscapeLive and this news organization are owned by the same parent company. Dr. Zaenglein disclosed receiving consulting fees from Cassiopea, Dermata, and Regeneron and fees for contracted research support from Incyte.

Treat acne from near birth to adulthood with a growing level of aggressiveness as a child ages, a dermatologist urged colleagues.

No treatment may be necessary for acne in the first few months of life, but the condition can leave scars in children as young as ages 3-6 months, said Andrea L. Zaenglein, MD, professor of dermatology and pediatric dermatology, Penn State University, Hershey, Penn., said in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.

Neonatal acne occurs in more than 20% of newborns aged 2 weeks to 3 months. “Typically we don’t need to treat it. But if you do, you could use a topical antifungal like clotrimazole cream twice a day,” but in most babies, “this will just improve over time and resolve without any scarring or sequelae,” she said.

Infantile acne begins about 3-6 months of age typically, or a little bit older, and lasts up to 2 years of age, Dr. Zaenglein said. “You will see comedones in infantile acne, so this is actually a true form of acne. It’s due to increased adrenal production of androgens.”

She added: “The scarring can be permanent. It’s important that you recognize infantile acne and treat it, even though it seems pretty mild.”

For infantile acne, she recommends performing a full-skin exam to rule out hyperandrogenic disorders such as Cushing syndrome, congenital adrenal hyperplasia, premature adrenarche, a gonadal/adrenal tumor and precocious puberty.

Treatments are similar to those in teenagers, she said, “but make sure you use baby-friendly formulations,” with lower concentrations of active ingredients – and avoid tetracyclines and benzoyl peroxide (BPO) washes. BPO can be used in leave-on formulations/creams at lower strengths (2.5%-5%).

One possible combination option is tretinoin 0.025% cream or adapalene 0.1% gel plus BPO 2.5% cream or clindamycin/BPO gel. Another combination is adapalene/BPO 2.5% gel.

Erythromycin can be appropriate at 30-50 mg/kg per day divided in two or three doses a day, but beware of possible gastrointestinal upset. Azithromycin at 5 mg/kg per day is another option.

“Rarely do we have to go to isotretinoin,” Dr. Zaenglein said. “I think in all my years, I’ve only treated one baby with isotretinoin for infantile acne. But severe forms can occur.”

Midchildhood and preadolescent acne conditions occur in children starting at ages 1 up to 10 years, Dr. Zaenglein said. In this population, she also recommends ruling out hyperandrogenism by looking for secondary sexual characteristics with full-body skin exams. “The workup can be broad and includes looking at adrenal androgens and total and free testosterone, as well as looking at growth charts and bone age. Typically, you’ll refer these kids to pediatric endocrinology.”

Keep in mind, she said, that early adrenarche starts at ages 6-7 years in girls and 7-8 years in boys. “That’s when we expect to start seeing that very early acne. You can see it even earlier in patients with elevated BMI, and it’s more common in Hispanic and Black children as well.”

She added that it’s important to remember that early adrenarche is a risk factor for polycystic ovarian syndrome (PCOS). “So ask patients about their family history and look for other signs of PCOS as they move further into adolescence.”

Milder cases of acne in this age group can be treated with “salicylic acid wipes and things that are kind of a rite of passage. But if they have any more severe acne, you’re going to want to treat it more or less like you do adolescent acne.”

MedscapeLive and this news organization are owned by the same parent company. Dr. Zaenglein disclosed receiving consulting fees from Cassiopea, Dermata, and Regeneron and fees for contracted research support from Incyte.

Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.

There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).

“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.

Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).

The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.

For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.

In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).

PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.

A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.

Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.

Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”

She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”

Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.

Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”

Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
 

Study details

For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.

They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.

Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.

Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.

Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.

The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.

After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.

This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.

The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.

Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.

Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.

In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.

Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”

This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.

A version of this article first appeared on Medscape.com.

Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.

There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).

“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.

Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).

The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.

For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.

In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).

PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.

A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.

Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.

Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”

She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”

Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.

Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”

Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
 

Study details

For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.

They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.

Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.

Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.

Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.

The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.

After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.

This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.

The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.

Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.

Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.

In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.

Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”

This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.

A version of this article first appeared on Medscape.com.

Adding pembrolizumab to chemotherapy substantially increases progression-free survival (PFS) in treatment-naive advanced or metastatic triple-negative breast cancer (TNBC) regardless of chemotherapy type, suggests an analysis of the clinical trial KEYNOTE-355.

There was also a trend for improved outcomes with increasing programmed death–ligand 1 (PD-L1) expression in the tumor, as measured by combined positive score (CPS).

“These data further support a role for the addition of pembro to standard chemo for the first-line treatment of metastatic TNBC,” said study presenter Hope S. Rugo, MD, from the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

The research was presented at the 2020 San Antonio Breast Cancer Symposium on Dec. 10.

Last month, pembrolizumab was granted accelerated approval by the Food and Drug Administration in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10).

The approval was based on data from KEYNOTE-355, which involved almost 850 women with previously untreated locally recurrent inoperable or metastatic TNBC randomized 2:1 to pembrolizumab plus investigator’s choice of chemotherapy who were followed for 2 years.

For the current analysis, patients were stratified by PD-L1 CPS in the tumor, including over 320 patients with CPS ≥10, and by accompanying chemotherapy regimen.

In the overall intention-to-treat (ITT) population (n = 847), median PFS was longer with pembrolizumab plus chemotherapy versus placebo plus chemotherapy, at 9.7 months versus 5.6 months (hazard ratio, 0.82).

PFS improved step-wise with increased PD-L1 expression. In patients with PD-L1 CPS ≥1, the HR was 0.74, and in those with PD-L1 CPS ≥10, it was 0.65.

A similar incremental improvement by PD-L1 expression was seen in the overall response rate, with the rate topping out at 53.2% in the pembrolizumab plus chemotherapy arm, among the PD-L1 CPS ≥10 group.

Duration of response told a similar story, with the pembro-chemo combination providing superior results and the treatment effect increasing with PD-L1 enrichment.

Study discussant Sylvia Adams, MD, New York University Perlmutter Cancer Center, New York, said the “consistency of treatment effect” with different chemotherapy backbones seen in the study is “very important, as it is currently unknown what the optimal backbone is.”

She also noted that the chemotherapy analysis presented by Dr. Rugo was “exploratory” and “not powered to show the winner of the chemotherapy backbone.”

Nevertheless, in the postpresentation debate, Ian Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, said that there are “several questions over the chemotherapy partner,” including whether there were differences in the populations who received each type of regimen.

Dr. Rugo replied that “because the trial wasn’t powered to look at the separate chemotherapy groups with any statistical significance ... it’s really impossible to draw any specific conclusions because it’s the overall population that’s evaluated.”

Asked about when overall survival results will be presented, Dr. Rugo said that “everybody is very interested” in that, “and we expect these results to be available next year.”
 

Study details

For KEYNOTE-355, researchers recruited women with previously untreated metastatic TNBC who had completed treatment with curative intent ≥6 months prior to their first disease recurrence.

They were randomized 2:1 to pembrolizumab or placebo plus investigator’s choice of chemotherapy from nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin for up to 35 administrations of pembrolizumab or placebo or until progression, intolerable toxicity, or cessation of treatment.

Crossover was not allowed. Patients were stratified by type of chemotherapy, PD-L1 expression in the tumor, and prior treatment in the neoadjuvant or adjuvant setting with the same class of chemotherapy.

Response was assessed with imaging every 8 weeks until week 24, then every 9 weeks during the first year of follow-up, and then every 12 weeks.

Of 847 randomized patients, 566 received pembrolizumab plus chemotherapy and 281 were assigned to the placebo group. The median age was 53 years in both groups.

The majority (75.1%) of patients in both groups were PD-L1 positive with a centrally assessed CPS ≥1, while 38.9% of patients in the pembrolizumab arm and 36.7% of those given placebo had a CPS ≥10.

After a median follow-up of 25.9 months, 16 patients given pembrolizumab had completed the study and 33 were still ongoing.

This compares with five patients having completed the placebo arm, and 12 still ongoing, after a median follow-up of 26.3 months.

The overall response rate was higher with pembrolizumab plus chemotherapy in the ITT population, at 41.0% versus 35.9%, rising to 45.2% versus 37.9% in patients with PD-L1 CPS ≥1 and 53.2% versus 39.8% in the PD-L1 CPS ≥10 group.

Again, when the groups were stratified by on-study chemotherapy, the overall response rate was higher with pembrolizumab versus placebo regardless of the chemotherapy partner.

Finally, the duration of response with pembrolizumab plus chemotherapy was longer than that seen with placebo, at a median of 10.1 months versus 6.4 months in the ITT population.

In the PD-L1 CPS ≥1 group, the duration of response was 10.1 months versus 6.5 months, rising to 19.3 months versus 7.3 months in the PD-L1 CPS ≥10 group.

Dr. Adams nevertheless said that PD-L1 remains an “imperfect” biomarker in metastatic TNBC, although it is “the best to date.” Furthermore, the IMpassion130 trial, featuring atezolizumab, showed that there is “very poor” analytic and clinical concordance between assays, which “complicates clinical decision-making.”

This study was sponsored by Merck. Dr. Rugo, Dr. Adams, and Dr. Krop have disclosed financial ties to multiple pharmaceutical companies, including Merck.

A version of this article first appeared on Medscape.com.

Treatment with etanercept does not appear to achieve significant clinical improvement in patients suspected of having nonradiographic axial spondyloarthritis (nr-axSpA) but without positive MRI signs of sacroiliitis and/or elevated C-reactive protein (CRP) levels, research suggests.

A paper published in Arthritis & Rheumatology presents the outcomes of a randomized, double-blind, placebo-controlled trial of a 16-week course of etanercept at 25 mg twice weekly in 80 tumor necrosis factor inhibitor (TNFi)–naive patients with suspected nr-axSpA. Patients all had chronic inflammatory back pain, at least two spondyloarthritis features – such as HLA-B27 positivity, asymmetrical arthritis, or family history of ankylosing spondylitis – as well as high disease activity and insufficient response to at least two NSAIDs. These patients meet the “clinical arm” of Assessment of SpondyloArthritis international Society (ASAS) criteria for classifying axSpA at an early stage of disease but not “imaging-arm” requirements for the presence of active inflammatory lesions of the sacroiliac joints (SIJ) on MRI and one additional SpA feature.

Whether these imaging criteria and objective evidence of elevated inflammation are necessary to fulfill when considering TNFi treatment for patients with suspected nr-axSpA in daily practice is an important question to address, the authors pointed out, because “in many studies, the presence of a positive MRI-SIJ is one of the prerequisites to start a TNF inhibitor treatment in patients with nr-axSpA.” In addition, starting a TNFi is dependent on failure of at least two NSAIDs and an elevated CRP level when the MRI is negative, which is problematic since in some studies raised CRP levels were found in only 30% of the nr-axSpA patients and 59%-64% of nr-axSpA patients with high disease activity do not have active inflammatory SIJ lesions on MRI. On top of these concerns is the fact that many people who do not have axSpA show false-positive results of bone marrow edema on MRI of the SIJ, such as postpartum women, recreational runners, professional athletes, and army recruits undergoing physical training, they added.

In the current study at the end of the 16-week course of treatment, researchers found no statistically significant difference between the treatment and placebo group in the number of patients who achieved a 20% improvement in ASAS response criteria (16.7% vs. 11.1%; P = .5), nor in those who had at least 40% improvement (8.3% in both groups). This was regardless of sex, age, NSAID or disease-modifying antirheumatic drug use, HLA-B27 status, or other clinical factors.

Similarly, there was no statistically significant difference between the two groups in the number of patients who met response criteria for the Ankylosing Spondylitis Disease Activity Score based on CRP for either clinical improvement or major improvement.

Participants underwent MRI at baseline and at 16 and 24 weeks, which revealed similar numbers of active inflammatory SIJ lesions in each group. The two groups also had similar Spondyloarthritis Research Consortium of Canada scores at baseline and 16 weeks, but a slightly – yet statistically significant – higher score in the etanercept group at 24 weeks.

However, during the first 16 weeks of the study, patients in the etanercept group showed greater improvements in pain and erythrocyte sedimentation rate (ESR), compared with those in the placebo group.

After the 16-week treatment course, participants were followed for another 8 weeks. During this time, participants in the etanercept group showed a worsening in their mean Bath Ankylosing Spondylitis Metrology Index score, CRP level, and ESR, compared with the placebo group.

While the number of participants who experienced an adverse event by 16 weeks was similar in both groups, more patients in the etanercept group experienced an adverse effect likely related to the study drug.

Study results in the context of previous findings

Commenting on their findings, first author Tamara Rusman, of the Amsterdam University Medical Center, and coauthors wrote that the results suggested early treatment with etanercept in patients without a positive MRI and raised CRP levels was not effective.

However, they acknowledged that two previous placebo-controlled studies had specifically included patients with nr-axSpA and found a significantly better treatment response to TNF inhibitors than to placebo. One of these studies included a significant number of patients with MRI-detected active inflammatory SIJ lesions at baseline, which is a known predictor of treatment response.

“The relatively low number of patients with either a positive MRI-SIJ (23%) and/or elevated CRP level (13%) at baseline in our study could be an explanation for the absence of a treatment effect in favor of etanercept,” they wrote.

They also raised the possibility that their choice of study population didn’t truly capture patients with nr-axSpA, and that it was not powered to compare patients with or without a positive MRI or raised CRP level at baseline.

“It would be interesting to know whether our study results will be replicated by others in comparable study populations with equal numbers of patients with and without a positive MRI-SIJ and raised CRP in the future,” they wrote.

The study was supported by an unrestricted financial grant from Pfizer and ReumaNederland. No conflicts of interest were declared.

SOURCE: Rusman T et al. Arthritis Rheumatol. 2020 Dec 5. doi: 10.1002/art.41607.

Treatment with etanercept does not appear to achieve significant clinical improvement in patients suspected of having nonradiographic axial spondyloarthritis (nr-axSpA) but without positive MRI signs of sacroiliitis and/or elevated C-reactive protein (CRP) levels, research suggests.

A paper published in Arthritis & Rheumatology presents the outcomes of a randomized, double-blind, placebo-controlled trial of a 16-week course of etanercept at 25 mg twice weekly in 80 tumor necrosis factor inhibitor (TNFi)–naive patients with suspected nr-axSpA. Patients all had chronic inflammatory back pain, at least two spondyloarthritis features – such as HLA-B27 positivity, asymmetrical arthritis, or family history of ankylosing spondylitis – as well as high disease activity and insufficient response to at least two NSAIDs. These patients meet the “clinical arm” of Assessment of SpondyloArthritis international Society (ASAS) criteria for classifying axSpA at an early stage of disease but not “imaging-arm” requirements for the presence of active inflammatory lesions of the sacroiliac joints (SIJ) on MRI and one additional SpA feature.

Whether these imaging criteria and objective evidence of elevated inflammation are necessary to fulfill when considering TNFi treatment for patients with suspected nr-axSpA in daily practice is an important question to address, the authors pointed out, because “in many studies, the presence of a positive MRI-SIJ is one of the prerequisites to start a TNF inhibitor treatment in patients with nr-axSpA.” In addition, starting a TNFi is dependent on failure of at least two NSAIDs and an elevated CRP level when the MRI is negative, which is problematic since in some studies raised CRP levels were found in only 30% of the nr-axSpA patients and 59%-64% of nr-axSpA patients with high disease activity do not have active inflammatory SIJ lesions on MRI. On top of these concerns is the fact that many people who do not have axSpA show false-positive results of bone marrow edema on MRI of the SIJ, such as postpartum women, recreational runners, professional athletes, and army recruits undergoing physical training, they added.

In the current study at the end of the 16-week course of treatment, researchers found no statistically significant difference between the treatment and placebo group in the number of patients who achieved a 20% improvement in ASAS response criteria (16.7% vs. 11.1%; P = .5), nor in those who had at least 40% improvement (8.3% in both groups). This was regardless of sex, age, NSAID or disease-modifying antirheumatic drug use, HLA-B27 status, or other clinical factors.

Similarly, there was no statistically significant difference between the two groups in the number of patients who met response criteria for the Ankylosing Spondylitis Disease Activity Score based on CRP for either clinical improvement or major improvement.

Participants underwent MRI at baseline and at 16 and 24 weeks, which revealed similar numbers of active inflammatory SIJ lesions in each group. The two groups also had similar Spondyloarthritis Research Consortium of Canada scores at baseline and 16 weeks, but a slightly – yet statistically significant – higher score in the etanercept group at 24 weeks.

However, during the first 16 weeks of the study, patients in the etanercept group showed greater improvements in pain and erythrocyte sedimentation rate (ESR), compared with those in the placebo group.

After the 16-week treatment course, participants were followed for another 8 weeks. During this time, participants in the etanercept group showed a worsening in their mean Bath Ankylosing Spondylitis Metrology Index score, CRP level, and ESR, compared with the placebo group.

While the number of participants who experienced an adverse event by 16 weeks was similar in both groups, more patients in the etanercept group experienced an adverse effect likely related to the study drug.

Study results in the context of previous findings

Commenting on their findings, first author Tamara Rusman, of the Amsterdam University Medical Center, and coauthors wrote that the results suggested early treatment with etanercept in patients without a positive MRI and raised CRP levels was not effective.

However, they acknowledged that two previous placebo-controlled studies had specifically included patients with nr-axSpA and found a significantly better treatment response to TNF inhibitors than to placebo. One of these studies included a significant number of patients with MRI-detected active inflammatory SIJ lesions at baseline, which is a known predictor of treatment response.

“The relatively low number of patients with either a positive MRI-SIJ (23%) and/or elevated CRP level (13%) at baseline in our study could be an explanation for the absence of a treatment effect in favor of etanercept,” they wrote.

They also raised the possibility that their choice of study population didn’t truly capture patients with nr-axSpA, and that it was not powered to compare patients with or without a positive MRI or raised CRP level at baseline.

“It would be interesting to know whether our study results will be replicated by others in comparable study populations with equal numbers of patients with and without a positive MRI-SIJ and raised CRP in the future,” they wrote.

The study was supported by an unrestricted financial grant from Pfizer and ReumaNederland. No conflicts of interest were declared.

SOURCE: Rusman T et al. Arthritis Rheumatol. 2020 Dec 5. doi: 10.1002/art.41607.

Treatment with etanercept does not appear to achieve significant clinical improvement in patients suspected of having nonradiographic axial spondyloarthritis (nr-axSpA) but without positive MRI signs of sacroiliitis and/or elevated C-reactive protein (CRP) levels, research suggests.

A paper published in Arthritis & Rheumatology presents the outcomes of a randomized, double-blind, placebo-controlled trial of a 16-week course of etanercept at 25 mg twice weekly in 80 tumor necrosis factor inhibitor (TNFi)–naive patients with suspected nr-axSpA. Patients all had chronic inflammatory back pain, at least two spondyloarthritis features – such as HLA-B27 positivity, asymmetrical arthritis, or family history of ankylosing spondylitis – as well as high disease activity and insufficient response to at least two NSAIDs. These patients meet the “clinical arm” of Assessment of SpondyloArthritis international Society (ASAS) criteria for classifying axSpA at an early stage of disease but not “imaging-arm” requirements for the presence of active inflammatory lesions of the sacroiliac joints (SIJ) on MRI and one additional SpA feature.

Whether these imaging criteria and objective evidence of elevated inflammation are necessary to fulfill when considering TNFi treatment for patients with suspected nr-axSpA in daily practice is an important question to address, the authors pointed out, because “in many studies, the presence of a positive MRI-SIJ is one of the prerequisites to start a TNF inhibitor treatment in patients with nr-axSpA.” In addition, starting a TNFi is dependent on failure of at least two NSAIDs and an elevated CRP level when the MRI is negative, which is problematic since in some studies raised CRP levels were found in only 30% of the nr-axSpA patients and 59%-64% of nr-axSpA patients with high disease activity do not have active inflammatory SIJ lesions on MRI. On top of these concerns is the fact that many people who do not have axSpA show false-positive results of bone marrow edema on MRI of the SIJ, such as postpartum women, recreational runners, professional athletes, and army recruits undergoing physical training, they added.

In the current study at the end of the 16-week course of treatment, researchers found no statistically significant difference between the treatment and placebo group in the number of patients who achieved a 20% improvement in ASAS response criteria (16.7% vs. 11.1%; P = .5), nor in those who had at least 40% improvement (8.3% in both groups). This was regardless of sex, age, NSAID or disease-modifying antirheumatic drug use, HLA-B27 status, or other clinical factors.

Similarly, there was no statistically significant difference between the two groups in the number of patients who met response criteria for the Ankylosing Spondylitis Disease Activity Score based on CRP for either clinical improvement or major improvement.

Participants underwent MRI at baseline and at 16 and 24 weeks, which revealed similar numbers of active inflammatory SIJ lesions in each group. The two groups also had similar Spondyloarthritis Research Consortium of Canada scores at baseline and 16 weeks, but a slightly – yet statistically significant – higher score in the etanercept group at 24 weeks.

However, during the first 16 weeks of the study, patients in the etanercept group showed greater improvements in pain and erythrocyte sedimentation rate (ESR), compared with those in the placebo group.

After the 16-week treatment course, participants were followed for another 8 weeks. During this time, participants in the etanercept group showed a worsening in their mean Bath Ankylosing Spondylitis Metrology Index score, CRP level, and ESR, compared with the placebo group.

While the number of participants who experienced an adverse event by 16 weeks was similar in both groups, more patients in the etanercept group experienced an adverse effect likely related to the study drug.

Study results in the context of previous findings

Commenting on their findings, first author Tamara Rusman, of the Amsterdam University Medical Center, and coauthors wrote that the results suggested early treatment with etanercept in patients without a positive MRI and raised CRP levels was not effective.

However, they acknowledged that two previous placebo-controlled studies had specifically included patients with nr-axSpA and found a significantly better treatment response to TNF inhibitors than to placebo. One of these studies included a significant number of patients with MRI-detected active inflammatory SIJ lesions at baseline, which is a known predictor of treatment response.

“The relatively low number of patients with either a positive MRI-SIJ (23%) and/or elevated CRP level (13%) at baseline in our study could be an explanation for the absence of a treatment effect in favor of etanercept,” they wrote.

They also raised the possibility that their choice of study population didn’t truly capture patients with nr-axSpA, and that it was not powered to compare patients with or without a positive MRI or raised CRP level at baseline.

“It would be interesting to know whether our study results will be replicated by others in comparable study populations with equal numbers of patients with and without a positive MRI-SIJ and raised CRP in the future,” they wrote.

The study was supported by an unrestricted financial grant from Pfizer and ReumaNederland. No conflicts of interest were declared.

SOURCE: Rusman T et al. Arthritis Rheumatol. 2020 Dec 5. doi: 10.1002/art.41607.

A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.

In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.

“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
 

Inconsistent criteria

There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.

“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.

A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.

To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.

They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.

For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.

The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).

Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.

In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.

Rituximab was administered to 91% of U.S. and 95% of international patients.
 

Higher survival rates outside US

Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.

In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.

Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.

In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).

“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.

Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.

“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).

Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).

Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).

There were no significant differences in either PFS or OS when either LDH or stage was added into the model.

The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.

As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
 

Why the CNS discrepancy?

In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.

“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.

Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”

Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”

He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”

No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.

SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.

A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.

In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.

“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
 

Inconsistent criteria

There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.

“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.

A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.

To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.

They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.

For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.

The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).

Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.

In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.

Rituximab was administered to 91% of U.S. and 95% of international patients.
 

Higher survival rates outside US

Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.

In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.

Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.

In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).

“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.

Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.

“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).

Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).

Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).

There were no significant differences in either PFS or OS when either LDH or stage was added into the model.

The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.

As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
 

Why the CNS discrepancy?

In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.

“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.

Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”

Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”

He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”

No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.

SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.

A newly devised, validated prognostic tool – the Burkitt Lymphoma International Prognostic Index – can consistently identify low-risk patients who might benefit from treatment de-escalation, and high-risk patients who are unlikely to be cured with current therapies and may require novel approaches, investigators said.

In a cohort of patients treated at international sites, patients with a low-risk score on the BL-IPI had a 3-year progression-free survival (PFS) rate of 96%, and 3-year overall survival rate (OS) of 99%. In contrast, the 3-year PFS rate for patients in the high-risk category was 63%, and the 3-year OS rate was 64%, reported Adam J Olszewski, MD, from the Lifespan Cancer Institute at Rhode Island Hospital and The Miriam Hospital, both in Providence.

“The Burkitt Lymphoma International Prognostic Index – or the ‘BLI-PI’ [‘blippy’] as it was inevitably called – is a novel prognostic index that is specific to Burkitt lymphoma. It has been validated with sufficient calibration and discrimination in external data sets to allow for simple stratification and comparison of risk distribution in geographically diverse cohorts,” he said in an oral abstract presented virtually during the annual meeting of the American Society of Hematology.
 

Inconsistent criteria

There is a need for a Burkitt-specific index, he said, because of significant differences in age, stage at presentation, and abnormal lactate dehydrogenase (LDH) levels between patients with Burkitt and those with diffuse large B-cell lymphoma (DLBCL), and because historical definitions of “low-risk” Burkitt lymphoma have been inconsistent, with less than 10% of patients falling into this group, leaving the remainder in a undifferentiated “high-risk” category.

“Burkitt lymphoma is considered highly curable, but current therapy requires administration of dose-intense chemoimmunotherapy for which there are many chemotherapy backbone regimens developed across the world, and used mostly locally. These are often studied in phase 2 studies with limited sample sizes, which makes it difficult to compare populations across trials,” Dr. Olszewski said.

A validated prognostic index can help clinicians and researchers compare cohorts and can be used to help design future trials, he added.

To devise the BL-IPI, the investigators first selected a retrospective cohort of 570 adults with Burkitt lymphoma treated at 30 U.S. centers for whom data on outcomes were available.

They determined the best prognostic cutoffs for age, LDH, hemoglobin and albumin levels, and identified independent risk factors using stepwise selection in Cox regression and lasso regression analysis, a machine learning approach. The variables included age; sex; HIV-positivity status; loss of MYC rearrangement; performance status; stage; nodal involvement; marrow involvement; central nervous system involvement; and LDH, hemoglobin, and albumin levels.

For validation, they pooled data from European, Canadian, Australian, and U.K. studies to identify 457 patients for whom retrospective treatment and outcomes data were available.

The derivation and validation cohorts were similar in most respects, expect for a higher proportion of patients with Eastern Cooperative Oncology Group performance status scores of 2 or higher in the validation cohort (22% vs. 35%), and a higher proportion of patients with CNS involvement in the U.S.-based derivation cohort (19% vs. 10%, respectively).

Therapy also differed markedly between the U.S. and international cohorts, with about 30% each of U.S. patients receiving either the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) regimen, DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) regimen, or hCVAD/MA (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen, and the remaining 10% receiving other, unspecified therapy.

In contrast, 65% of the patients in the international (validation) cohort received CODOX-M/IVAC, 10% and 9%, respectively, received DA-EPOCH-R and hCVAD/MA, and 16% receiving other regimens.

Rituximab was administered to 91% of U.S. and 95% of international patients.
 

Higher survival rates outside US

Both PFS and OS were higher in the international versus U.S. cohort. At a median follow-up of 45 months, the PFS rate in the United States was 65%, and the OS rate was 70%.

In the international cohort, after a median follow-up of 52 months, the PFS rate was 75%, and the OS rate was 76%, the investigators found.

Reasons for the differences may be because of differences in treatment regimens, socioeconomic and racial disparities in the United States versus other countries, or to decentralized Burkitt lymphoma therapy in the United States, Dr. Olszewski said.

In univariate analysis, factors significantly predictive of worse PFS included age 40 years or older, ECOG performance status 2 or greater, stage 3 or 4 disease, marrow involvement, CNS involvement, LDH more than three times the upper limit of normal, and hemoglobin <11.5 g/dL (P < .001 for all preceding), as well as albumin <3.5 g/dL (P = .001).

“However, the multivariable analysis was more complicated, because many of these factors were overlapping, and most patients with high LDH also had advanced disease, and this group also encompassed patients who had bone marrow and CNS involvement,” he said.

Using the two types of regression analysis mentioned before, investigators identified ECOG performance status 2 or greater (P = .001), age 40 and older (P = .005), LDH greater than three times the upper limit of normal (P < .001) and CNS involvement (P = .002) as significant predictors for worse outcomes in multivariable analysis, and were included in the final model.

“We initially had five groups according to the number of these factors, but we observed that the survival curves for patients with two, three, or four factors were overlapping, and not significantly different, so ultimately we had three risk groups. In the derivation (U.S.) cohort, patients in the low-risk group, with no risk factors, a 3-year PFS of 92%, compared with 72% for patients with one risk factor (intermediate risk), and 53% for patients with two to four risk factors (high risk).

Respective hazard ratios for worse PFS in the low-, intermediate-, and high-risk groups were 1 (reference), 4.15 (95% confidence interval, 1.99-8.68), and 8.83 (95% CI, 4.32-18.03).

Respective HR for worse OS was 1, 7.06 (95% CI, 2.55-19.53), and 15.12 (95% CI, 5.58-40.99).

There were no significant differences in either PFS or OS when either LDH or stage was added into the model.

The BL-IPI was prognostic for PFS and OS in all subgroups, including HIV-positive or -negative patients, those with MYC rearrangements, stage 1 or 2 versus stage 3 or 4, or those treated with rituximab versus those who were not.

As noted before, 3-year PFS rates in the validation cohort for low, intermediate, high-risk groups were 96%, 82%, and 63% respectively, and 3-year OS rates were 99%, 85%, and 64%.
 

Why the CNS discrepancy?

In the question and answer session following the presentation, comoderator Christopher J. Melani, MD, from the Lymphoid Malignancies Branch at the National Cancer Institute in Bethesda, Md., said that “it was interesting to see the difference between CNS involvement in both the U.S. and the international cohort,” and asked whether Dr. Olszweski could elaborate on whether baseline CNS involvement was assessed by contrast-enhanced MRI of flow cytometry studies of cerebrospinal fluid.

“Could some of these differences between the U.S. and the international cohort be from the baseline assessment differing between the two?” he asked.

Dr. Olszewski replied that the retrospective nature of the data precluded capturing those data, but added that “I do suspect there may be some differences in the way that central nervous system is staged in different countries. In the United States the use of flow cytometry is more commonly employed, but we don’t know how it is used internationally. We do not know how often this is staged radiographically.”

Asked by others who viewed the presentation whether extranodal disease or peripheral blood involvement were prognostic in the final model, Dr. Olszewski replied that “one has to understand that, when one constructs a prognostic index, there is a balance between trying to input as much information as possible and to create something that is useful, clinically meaningful, and accurate.”

He said that, despite trying different models with different factors, “we couldn’t get the discrimination to be much better than the basic model that we ultimately created, so we favored using a more parsimonious model.”

No study funding source was reported. Dr. Olszewski reported research funding from Spectrum Pharmaceuticals, Genentech, TG Therapeutics, and Adaptive Biotechnologies. Dr. Melani reported having no relevant conflicts of interest.

SOURCE: Olszewski AJ et al. ASH 2020, Abstract 705.

In heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), venetoclax plus navitoclax with chemotherapy was well tolerated with promising responses, according to results of a phase 1 trial. Delayed count recovery, however, stated lead author Jeffrey E. Rubnitz, MD, PhD, St. Jude’s Children’s Research Hospital, Memphis, remained a key safety concern.
 

Unmet medical need

Despite intensive chemotherapy and novel therapeutics, Dr. Rubnitz said in a virtual oral presentation at the annual meeting of the American Society of Hematology, patients with relapsed or refractory ALL and LL have a poor prognosis and represent an unmet medical need. Venetoclax, a potent, highly selective oral B-cell lymphoma 2 inhibitor, and navitoclax, an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. In ALL preclinical models, venetoclax and navitoclax have demonstrated antileukemic effects, which suggests dependence on BCL-2 family members. Venetoclax efficacy associated with BCL-2 family inhibition may be potentiated and dose-limiting thrombocytopenia associated with standard-dose navitoclax monotherapy may be avoided by adding venetoclax to low-dose navitoclax. Previous reports of an ongoing phase 1, multicenter, open-label, dose-escalation study in an adult and pediatric population (NCT03181126), Dr. Rubnitz noted, showed the venetoclax/navitoclax/chemotherapy combination to be well tolerated with promising response rates. In the current report, Dr. Rubnitz presented data on the safety, tolerability, pharmacokinetics, and antitumor activity of the triplet regimen in the subgroup of pediatric patients.

The study included pediatric patients (ages, 4-18 years and weight ≥20 kg) receiving venetoclax (weight-adjusted equivalent of 400 mg daily) and navitoclax at three dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and two dose levels (25, 50 mg) for patients weighing <45 kg. At investigator’s discretion, patients could receive chemotherapy (polyethylene glycosylated–asparaginase, vincristine, and dexamethasone). The primary outcomes were safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetics. A safety expansion cohort assessed a 21-day dosing schedule of venetoclax at 400 mg followed by 7 days off plus navitoclax at 50 mg (patients ≥45 kg) or 25 mg (patients <45 kg).

Investigators enrolled 18 patients <18 years (median age, 10 years; range, 6-16; 56% male), with 12 in the dose-escalation cohort and 6 in the safety-expansion cohort. Three patients had prior chimeric antigen receptor (CAR) T treatment and four had received prior stem cell transplantation. In the overall cohort, B-cell ALL was most common (n = 13, 72%), with T-cell ALL (n = 3, 17%) and LL (n = 2, 11%) following. The median number of prior therapies was 2 (range 1-6). All patients received chemotherapy.
 

Grade 3-4 adverse events

Venetoclax-related grade 3-4 adverse events occurred in 56% of patients. Similarly, navitoclax-related grade 3-4 events were reported in 56% of patients. Navitoclax dose-limiting toxicities occurred in two patients (11%), delayed count recovery on 25 mg and sepsis on 50 mg. No grade 5 adverse events and tumor lysis syndrome were reported.

Among secondary endpoint efficacy parameters, complete responses, CRs with incomplete marrow recovery (CRi) and CRs without platelet recovery (CRp) combined occurred in 62% of B-ALL patients (8/13), 33% of T-cell ALL patients (1/3) and in 50% of LL patients (1/2). Separately, CRs/CRis/CRps occurred in 33%/22%/0% of all patients, respectively.

Subsequently, 5 of 18 (28%) of patients proceeded to stem cell transplantation and 3 (17%) to CAR T. Eight patients (44%) died from disease progression.
 

BH3 profiling

BH3 profiling revealed that at baseline, patients with B-cell ALL had more diversity in BCL-2 and BCL-XL dependency than did patients with T-cell ALL or early T-cell precursor ALL. The fact that responses were observed in patients who were BCL-2 or BCL-XL dependent, Dr. Rubnitz said, supports the use of venetoclax plus navitoclax in these patients. Analysis of these results led to a recommended phase 2 dose for pediatric patients of 400 mg venetoclax with 25 mg navitoclax (for patients weighing <45 kg) or 50 mg navitoclax (for patients weighing 45 kg or more).

Dr. Rubnitz concluded: “Venetoclax plus navitoclax plus chemotherapy was well tolerated in pediatric patients with relapsed/refractory ALL or LL, with promising response rates observed in a heavily pretreated pediatric population.”

Asked whether the combination might be used also before the refractory setting, in a minimal residual disease (MRD) setting, Dr. Rubnitz replied: “We have a lot of safety data on venetoclax but very little on navitoclax. The next trial, being developed by Seth Karol, MD, will include relapsed patients. MRD-positive patients will also be eligible for enrollment.” To a further question as to whether guiding titration via BH3 profiling would lead to improved outcomes, Dr. Rubnitz said, “I think BH3 profiling can be used to identify which patients will respond to these drugs, but we are still a long way from using it for titrating the doses and dose ratios for the two drugs.”

Dr. Rubnitz disclosed research funding from AbbVie.

SOURCE: Rubnitz JE et al. ASH 2020, Abstract 466.

In heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), venetoclax plus navitoclax with chemotherapy was well tolerated with promising responses, according to results of a phase 1 trial. Delayed count recovery, however, stated lead author Jeffrey E. Rubnitz, MD, PhD, St. Jude’s Children’s Research Hospital, Memphis, remained a key safety concern.
 

Unmet medical need

Despite intensive chemotherapy and novel therapeutics, Dr. Rubnitz said in a virtual oral presentation at the annual meeting of the American Society of Hematology, patients with relapsed or refractory ALL and LL have a poor prognosis and represent an unmet medical need. Venetoclax, a potent, highly selective oral B-cell lymphoma 2 inhibitor, and navitoclax, an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. In ALL preclinical models, venetoclax and navitoclax have demonstrated antileukemic effects, which suggests dependence on BCL-2 family members. Venetoclax efficacy associated with BCL-2 family inhibition may be potentiated and dose-limiting thrombocytopenia associated with standard-dose navitoclax monotherapy may be avoided by adding venetoclax to low-dose navitoclax. Previous reports of an ongoing phase 1, multicenter, open-label, dose-escalation study in an adult and pediatric population (NCT03181126), Dr. Rubnitz noted, showed the venetoclax/navitoclax/chemotherapy combination to be well tolerated with promising response rates. In the current report, Dr. Rubnitz presented data on the safety, tolerability, pharmacokinetics, and antitumor activity of the triplet regimen in the subgroup of pediatric patients.

The study included pediatric patients (ages, 4-18 years and weight ≥20 kg) receiving venetoclax (weight-adjusted equivalent of 400 mg daily) and navitoclax at three dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and two dose levels (25, 50 mg) for patients weighing <45 kg. At investigator’s discretion, patients could receive chemotherapy (polyethylene glycosylated–asparaginase, vincristine, and dexamethasone). The primary outcomes were safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetics. A safety expansion cohort assessed a 21-day dosing schedule of venetoclax at 400 mg followed by 7 days off plus navitoclax at 50 mg (patients ≥45 kg) or 25 mg (patients <45 kg).

Investigators enrolled 18 patients <18 years (median age, 10 years; range, 6-16; 56% male), with 12 in the dose-escalation cohort and 6 in the safety-expansion cohort. Three patients had prior chimeric antigen receptor (CAR) T treatment and four had received prior stem cell transplantation. In the overall cohort, B-cell ALL was most common (n = 13, 72%), with T-cell ALL (n = 3, 17%) and LL (n = 2, 11%) following. The median number of prior therapies was 2 (range 1-6). All patients received chemotherapy.
 

Grade 3-4 adverse events

Venetoclax-related grade 3-4 adverse events occurred in 56% of patients. Similarly, navitoclax-related grade 3-4 events were reported in 56% of patients. Navitoclax dose-limiting toxicities occurred in two patients (11%), delayed count recovery on 25 mg and sepsis on 50 mg. No grade 5 adverse events and tumor lysis syndrome were reported.

Among secondary endpoint efficacy parameters, complete responses, CRs with incomplete marrow recovery (CRi) and CRs without platelet recovery (CRp) combined occurred in 62% of B-ALL patients (8/13), 33% of T-cell ALL patients (1/3) and in 50% of LL patients (1/2). Separately, CRs/CRis/CRps occurred in 33%/22%/0% of all patients, respectively.

Subsequently, 5 of 18 (28%) of patients proceeded to stem cell transplantation and 3 (17%) to CAR T. Eight patients (44%) died from disease progression.
 

BH3 profiling

BH3 profiling revealed that at baseline, patients with B-cell ALL had more diversity in BCL-2 and BCL-XL dependency than did patients with T-cell ALL or early T-cell precursor ALL. The fact that responses were observed in patients who were BCL-2 or BCL-XL dependent, Dr. Rubnitz said, supports the use of venetoclax plus navitoclax in these patients. Analysis of these results led to a recommended phase 2 dose for pediatric patients of 400 mg venetoclax with 25 mg navitoclax (for patients weighing <45 kg) or 50 mg navitoclax (for patients weighing 45 kg or more).

Dr. Rubnitz concluded: “Venetoclax plus navitoclax plus chemotherapy was well tolerated in pediatric patients with relapsed/refractory ALL or LL, with promising response rates observed in a heavily pretreated pediatric population.”

Asked whether the combination might be used also before the refractory setting, in a minimal residual disease (MRD) setting, Dr. Rubnitz replied: “We have a lot of safety data on venetoclax but very little on navitoclax. The next trial, being developed by Seth Karol, MD, will include relapsed patients. MRD-positive patients will also be eligible for enrollment.” To a further question as to whether guiding titration via BH3 profiling would lead to improved outcomes, Dr. Rubnitz said, “I think BH3 profiling can be used to identify which patients will respond to these drugs, but we are still a long way from using it for titrating the doses and dose ratios for the two drugs.”

Dr. Rubnitz disclosed research funding from AbbVie.

SOURCE: Rubnitz JE et al. ASH 2020, Abstract 466.

In heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), venetoclax plus navitoclax with chemotherapy was well tolerated with promising responses, according to results of a phase 1 trial. Delayed count recovery, however, stated lead author Jeffrey E. Rubnitz, MD, PhD, St. Jude’s Children’s Research Hospital, Memphis, remained a key safety concern.
 

Unmet medical need

Despite intensive chemotherapy and novel therapeutics, Dr. Rubnitz said in a virtual oral presentation at the annual meeting of the American Society of Hematology, patients with relapsed or refractory ALL and LL have a poor prognosis and represent an unmet medical need. Venetoclax, a potent, highly selective oral B-cell lymphoma 2 inhibitor, and navitoclax, an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. In ALL preclinical models, venetoclax and navitoclax have demonstrated antileukemic effects, which suggests dependence on BCL-2 family members. Venetoclax efficacy associated with BCL-2 family inhibition may be potentiated and dose-limiting thrombocytopenia associated with standard-dose navitoclax monotherapy may be avoided by adding venetoclax to low-dose navitoclax. Previous reports of an ongoing phase 1, multicenter, open-label, dose-escalation study in an adult and pediatric population (NCT03181126), Dr. Rubnitz noted, showed the venetoclax/navitoclax/chemotherapy combination to be well tolerated with promising response rates. In the current report, Dr. Rubnitz presented data on the safety, tolerability, pharmacokinetics, and antitumor activity of the triplet regimen in the subgroup of pediatric patients.

The study included pediatric patients (ages, 4-18 years and weight ≥20 kg) receiving venetoclax (weight-adjusted equivalent of 400 mg daily) and navitoclax at three dose levels (25, 50, 100 mg) for patients weighing ≥45 kg and two dose levels (25, 50 mg) for patients weighing <45 kg. At investigator’s discretion, patients could receive chemotherapy (polyethylene glycosylated–asparaginase, vincristine, and dexamethasone). The primary outcomes were safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetics. A safety expansion cohort assessed a 21-day dosing schedule of venetoclax at 400 mg followed by 7 days off plus navitoclax at 50 mg (patients ≥45 kg) or 25 mg (patients <45 kg).

Investigators enrolled 18 patients <18 years (median age, 10 years; range, 6-16; 56% male), with 12 in the dose-escalation cohort and 6 in the safety-expansion cohort. Three patients had prior chimeric antigen receptor (CAR) T treatment and four had received prior stem cell transplantation. In the overall cohort, B-cell ALL was most common (n = 13, 72%), with T-cell ALL (n = 3, 17%) and LL (n = 2, 11%) following. The median number of prior therapies was 2 (range 1-6). All patients received chemotherapy.
 

Grade 3-4 adverse events

Venetoclax-related grade 3-4 adverse events occurred in 56% of patients. Similarly, navitoclax-related grade 3-4 events were reported in 56% of patients. Navitoclax dose-limiting toxicities occurred in two patients (11%), delayed count recovery on 25 mg and sepsis on 50 mg. No grade 5 adverse events and tumor lysis syndrome were reported.

Among secondary endpoint efficacy parameters, complete responses, CRs with incomplete marrow recovery (CRi) and CRs without platelet recovery (CRp) combined occurred in 62% of B-ALL patients (8/13), 33% of T-cell ALL patients (1/3) and in 50% of LL patients (1/2). Separately, CRs/CRis/CRps occurred in 33%/22%/0% of all patients, respectively.

Subsequently, 5 of 18 (28%) of patients proceeded to stem cell transplantation and 3 (17%) to CAR T. Eight patients (44%) died from disease progression.
 

BH3 profiling

BH3 profiling revealed that at baseline, patients with B-cell ALL had more diversity in BCL-2 and BCL-XL dependency than did patients with T-cell ALL or early T-cell precursor ALL. The fact that responses were observed in patients who were BCL-2 or BCL-XL dependent, Dr. Rubnitz said, supports the use of venetoclax plus navitoclax in these patients. Analysis of these results led to a recommended phase 2 dose for pediatric patients of 400 mg venetoclax with 25 mg navitoclax (for patients weighing <45 kg) or 50 mg navitoclax (for patients weighing 45 kg or more).

Dr. Rubnitz concluded: “Venetoclax plus navitoclax plus chemotherapy was well tolerated in pediatric patients with relapsed/refractory ALL or LL, with promising response rates observed in a heavily pretreated pediatric population.”

Asked whether the combination might be used also before the refractory setting, in a minimal residual disease (MRD) setting, Dr. Rubnitz replied: “We have a lot of safety data on venetoclax but very little on navitoclax. The next trial, being developed by Seth Karol, MD, will include relapsed patients. MRD-positive patients will also be eligible for enrollment.” To a further question as to whether guiding titration via BH3 profiling would lead to improved outcomes, Dr. Rubnitz said, “I think BH3 profiling can be used to identify which patients will respond to these drugs, but we are still a long way from using it for titrating the doses and dose ratios for the two drugs.”

Dr. Rubnitz disclosed research funding from AbbVie.

SOURCE: Rubnitz JE et al. ASH 2020, Abstract 466.

The Food and Drug Administration has issued an emergency-use authorization (EUA) for the first COVID-19 diagnostic test that can be completed at home without a prescription.

Authorization of the Ellume COVID-19 Home Test is “a major milestone in diagnostic testing for COVID-19,” FDA Commissioner Stephen M. Hahn, MD, said in a news release.

“By authorizing a test for over-the-counter use, the FDA allows it to be sold in places like drug stores, where a patient can buy it, swab their nose, run the test, and find out their results in as little as 20 minutes,” said Dr. Hahn.

The Ellume COVID-19 Home Test is a rapid antigen test that detects fragments of the SARS-CoV-2 virus from a nasal swab sample taken from anyone aged 2 years and older, including those not showing any symptoms.

In testing, the Ellume COVID-19 Home Test correctly identified 96% of positive samples and 100% of negative samples in individuals with symptoms.

In people without symptoms, the test correctly identified 91% of positive samples and 96% of negative samples, the FDA said.

The test includes a sterile nasal swab, a dropper, processing fluid, and a Bluetooth-connected analyzer for use with an app on the user’s smartphone. The sample is analyzed and results are automatically transmitted to the user’s smartphone.

“The Ellume COVID-19 home test’s core technology combines ultra-sensitive optics, electronics, and proprietary software to leverage best-in-class digital immunoassay technology with next-generation multi-quantum dot fluorescence technology,” the company said in a news release.

The mobile app requires individuals to input their ZIP code and date of birth, with optional fields including name and email address. The app automatically reports the results as appropriate to public health authorities to monitor disease prevalence.

Ellume expects to produce more than 3 million tests in January 2021. The company said the test will cost around $30.

FDA authorization of this first fully at-home nonprescription COVID-19 diagnostic test follows last month’s EUA for the first prescription COVID-19 test for home use, as reported this news organization.

Since the start of the pandemic, the FDA has authorized more than 225 diagnostic tests for COVID-19, including more than 25 tests that allow for home collection of samples, which are then sent to a lab for testing.

“As we continue to authorize additional tests for home use, we are helping expand Americans’ access to testing, reducing the burden on laboratories and test supplies, and giving Americans more testing options from the comfort and safety of their own homes,” Dr. Hahn said.

“This test, like other antigen tests, is less sensitive and less specific than typical molecular tests run in a lab,” said Jeffrey Shuren, MD, JD, director of FDA’s Center for Devices and Radiological Health, in the release. “However, the fact that it can be used completely at home and return results quickly means that it can play an important role in response to the pandemic.”

As with other antigen tests, a small percentage of positive and negative results from the Ellume test may be false. In patients without symptoms, positive results should be treated as presumptively positive until confirmed by another test as soon as possible, the FDA advised.

This is especially true if there are fewer infections in a particular community, as false-positive results can be more common when antigen tests are used in populations where there is a low prevalence of COVID-19, the agency said.

Because all tests can give false-negative and false-positive results, individuals with positive results should self-isolate and seek additional care from their health care provider.

Individuals who test negative and have symptoms of COVID-19 should follow up with their health care provider, as negative results don’t preclude an individual from SARS-CoV-2 infection.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has issued an emergency-use authorization (EUA) for the first COVID-19 diagnostic test that can be completed at home without a prescription.

Authorization of the Ellume COVID-19 Home Test is “a major milestone in diagnostic testing for COVID-19,” FDA Commissioner Stephen M. Hahn, MD, said in a news release.

“By authorizing a test for over-the-counter use, the FDA allows it to be sold in places like drug stores, where a patient can buy it, swab their nose, run the test, and find out their results in as little as 20 minutes,” said Dr. Hahn.

The Ellume COVID-19 Home Test is a rapid antigen test that detects fragments of the SARS-CoV-2 virus from a nasal swab sample taken from anyone aged 2 years and older, including those not showing any symptoms.

In testing, the Ellume COVID-19 Home Test correctly identified 96% of positive samples and 100% of negative samples in individuals with symptoms.

In people without symptoms, the test correctly identified 91% of positive samples and 96% of negative samples, the FDA said.

The test includes a sterile nasal swab, a dropper, processing fluid, and a Bluetooth-connected analyzer for use with an app on the user’s smartphone. The sample is analyzed and results are automatically transmitted to the user’s smartphone.

“The Ellume COVID-19 home test’s core technology combines ultra-sensitive optics, electronics, and proprietary software to leverage best-in-class digital immunoassay technology with next-generation multi-quantum dot fluorescence technology,” the company said in a news release.

The mobile app requires individuals to input their ZIP code and date of birth, with optional fields including name and email address. The app automatically reports the results as appropriate to public health authorities to monitor disease prevalence.

Ellume expects to produce more than 3 million tests in January 2021. The company said the test will cost around $30.

FDA authorization of this first fully at-home nonprescription COVID-19 diagnostic test follows last month’s EUA for the first prescription COVID-19 test for home use, as reported this news organization.

Since the start of the pandemic, the FDA has authorized more than 225 diagnostic tests for COVID-19, including more than 25 tests that allow for home collection of samples, which are then sent to a lab for testing.

“As we continue to authorize additional tests for home use, we are helping expand Americans’ access to testing, reducing the burden on laboratories and test supplies, and giving Americans more testing options from the comfort and safety of their own homes,” Dr. Hahn said.

“This test, like other antigen tests, is less sensitive and less specific than typical molecular tests run in a lab,” said Jeffrey Shuren, MD, JD, director of FDA’s Center for Devices and Radiological Health, in the release. “However, the fact that it can be used completely at home and return results quickly means that it can play an important role in response to the pandemic.”

As with other antigen tests, a small percentage of positive and negative results from the Ellume test may be false. In patients without symptoms, positive results should be treated as presumptively positive until confirmed by another test as soon as possible, the FDA advised.

This is especially true if there are fewer infections in a particular community, as false-positive results can be more common when antigen tests are used in populations where there is a low prevalence of COVID-19, the agency said.

Because all tests can give false-negative and false-positive results, individuals with positive results should self-isolate and seek additional care from their health care provider.

Individuals who test negative and have symptoms of COVID-19 should follow up with their health care provider, as negative results don’t preclude an individual from SARS-CoV-2 infection.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has issued an emergency-use authorization (EUA) for the first COVID-19 diagnostic test that can be completed at home without a prescription.

Authorization of the Ellume COVID-19 Home Test is “a major milestone in diagnostic testing for COVID-19,” FDA Commissioner Stephen M. Hahn, MD, said in a news release.

“By authorizing a test for over-the-counter use, the FDA allows it to be sold in places like drug stores, where a patient can buy it, swab their nose, run the test, and find out their results in as little as 20 minutes,” said Dr. Hahn.

The Ellume COVID-19 Home Test is a rapid antigen test that detects fragments of the SARS-CoV-2 virus from a nasal swab sample taken from anyone aged 2 years and older, including those not showing any symptoms.

In testing, the Ellume COVID-19 Home Test correctly identified 96% of positive samples and 100% of negative samples in individuals with symptoms.

In people without symptoms, the test correctly identified 91% of positive samples and 96% of negative samples, the FDA said.

The test includes a sterile nasal swab, a dropper, processing fluid, and a Bluetooth-connected analyzer for use with an app on the user’s smartphone. The sample is analyzed and results are automatically transmitted to the user’s smartphone.

“The Ellume COVID-19 home test’s core technology combines ultra-sensitive optics, electronics, and proprietary software to leverage best-in-class digital immunoassay technology with next-generation multi-quantum dot fluorescence technology,” the company said in a news release.

The mobile app requires individuals to input their ZIP code and date of birth, with optional fields including name and email address. The app automatically reports the results as appropriate to public health authorities to monitor disease prevalence.

Ellume expects to produce more than 3 million tests in January 2021. The company said the test will cost around $30.

FDA authorization of this first fully at-home nonprescription COVID-19 diagnostic test follows last month’s EUA for the first prescription COVID-19 test for home use, as reported this news organization.

Since the start of the pandemic, the FDA has authorized more than 225 diagnostic tests for COVID-19, including more than 25 tests that allow for home collection of samples, which are then sent to a lab for testing.

“As we continue to authorize additional tests for home use, we are helping expand Americans’ access to testing, reducing the burden on laboratories and test supplies, and giving Americans more testing options from the comfort and safety of their own homes,” Dr. Hahn said.

“This test, like other antigen tests, is less sensitive and less specific than typical molecular tests run in a lab,” said Jeffrey Shuren, MD, JD, director of FDA’s Center for Devices and Radiological Health, in the release. “However, the fact that it can be used completely at home and return results quickly means that it can play an important role in response to the pandemic.”

As with other antigen tests, a small percentage of positive and negative results from the Ellume test may be false. In patients without symptoms, positive results should be treated as presumptively positive until confirmed by another test as soon as possible, the FDA advised.

This is especially true if there are fewer infections in a particular community, as false-positive results can be more common when antigen tests are used in populations where there is a low prevalence of COVID-19, the agency said.

Because all tests can give false-negative and false-positive results, individuals with positive results should self-isolate and seek additional care from their health care provider.

Individuals who test negative and have symptoms of COVID-19 should follow up with their health care provider, as negative results don’t preclude an individual from SARS-CoV-2 infection.

A version of this article first appeared on Medscape.com.

Researchers have worked at record-breaking speed to not only identify and characterize the novel coronavirus, but also to develop potential vaccines; it is a race that another trio of scientists, awarded the 2020 Nobel Prize in Medicine, know well after their own decades-long marathon to crack the code of hepatitis C.

The RNA virus vexed researchers like Harvey J. Alter, MD; Michael Houghton, PhD; and Charles M. Rice, PhD, for years. Unlike today’s parallel sequencing and polymerase chain reaction, screening at the time was tedious and painstaking. But they were all in for some big highs, some dead-ends, and a little inspiration by way of author Lewis Carroll.

“Our undertaking was a success,” Dr. Alter said in an interview, “because everyone got on board.” Investigators, the Food and Drug Administration, and blood banks all worked together. It was a national effort, he added.

The Laureates will share the $1 million prize that recognizes their achievement. This is the second time that scientists who have devoted their time to the pursuit of viral hepatitis have been honored.

Two main types of infectious hepatitis were identified in the 1940s. The first, hepatitis A, is transmitted by polluted water or food and generally has little long-term effect on the patient. The second, transmitted through blood and other bodily fluids, is a much more serious threat.

In the 1960s, Baruch Blumberg, MD, ascertained that blood-borne hepatitis was caused by an insidious virus – hepatitis B – which silently causes liver complications in otherwise healthy people years after infection. Dr. Blumberg’s discovery led to the development of diagnostic tests and an effective vaccine; he was awarded the Nobel Prize in Physiology or Medicine in 1976.

At that time, Dr. Alter was working at the National Institutes of Health in Bethesda, Md., studying the occurrence of hepatitis in patients who had received blood transfusions. Globally, blood-borne hepatitis was causing more than a million deaths each year.

When screening began in 1969 to prevent people with hepatitis A or hepatitis B from donating blood, many recipients were spared from developing liver inflammation after transfusion. However, some people were still getting sick and researchers began to suspect that something dubbed “non-A, non-B” was lurking in donated blood.

As scientists were tracking it down in the micro world, public health officials and others tried to block the presumed virus in the macro world. In the United States, this meant changing blood-donation practices. When it became clear that as many as one in five transfusion recipients developed hepatitis, probably as the result of a virus, the blood donation system switched from being a paid enterprise to a volunteer activity.

It was anticipated that this would eliminate one source of the virus – users of street drugs – and it did; rates of transmission after transfusion dropped by half. By the 1980s, researchers had figured out that donors carrying the mysterious pathogen often had elevated levels of antibodies to the hepatitis B virus or elevated levels of ALT. Blood banks then began testing prospective donors and cut the incidence of non-A, non-B hepatitis by another half.

When Dr. Alter and his team got to work studying chimpanzees, they were able to confirm that the non-A, non-B agent was transmittable by blood transfusion. But the next step proved insurmountable. “People knew what the virus would look like if we found it, but we couldn’t find it,” Dr. Alter said.

“Then Chiron came along and cloned it,” he recounts.

The tiny start-up company was housed in a few rented rooms in an abandoned plant in Emeryville, Calif. This is where Nobel Laureate Dr. Houghton and coworkers Qui-Lim Choo, PhD, and George Kuo, PhD, spent 7 years chasing the mystery pathogen. When every traditional method to pin it down failed, the team tried some nontraditional approaches.

They found success when they painstakingly cloned genomic fragments from the blood of an infected chimpanzee and then screened this library using serum isolated from affected patients. The hope was that antibodies in the serum samples would stick to the viral genetic material and create a signpost indicating its presence.

This “fishing expedition” was disappointing at first, said Dr. Choo, now vice president of research at Nansha Biologics Limited in Hong Kong. “We didn’t catch any fish.”

He likened the pursuit, which took place under growing pressure from upper management, to that in “The Imitation Game,” the film that depicted Alan Turing’s effort to decrypt German intelligence messages for the British government during World War II.

The effort wasn’t working out and the team was down. So to keep spirits up, Dr. Kuo shared a snippet of the Lewis Carroll poem “The Hunting of the Snark.” It just happened to encapsulate the frustrations of their pursuit while also encouraging perseverance: “For the Snark’s a peculiar creature, that won’t / Be caught in a commonplace way. / Do all that you know, and try all that you don’t: / Not a chance must be wasted today!”

Those words motivated the team to keep going, to try different approaches and, ultimately, to find the hepatitis C virus, said Dr. Kuo, now retired.

During the tedious process of screening millions of clones, Dr. Choo spotted a single likely area on one of the plates that his “gut feeling” told him would contain the viral material. And it did. The pathogen – RNA packed in a lipid coat – was a member of the Flaviviridae family.

In 1989, the team reported that they’d identified a new flavivirus associated with posttransfusion hepatitis, and published their findings in Science. Later that year, an antibody test for it was described in Science by the team, which included Dr. Alter.

The success was a “fantastic feeling,” mused Dr. Houghton, now a virologist at the University of Alberta, Edmonton. “I’ve often said that, from 1989 to 1991, I was high just on the discovery.” After that, “researchers and the pharmaceutical industry did a great job coming up with really effective antivirals.”

“Mike, with his team, took 7 years to get this tiny little piece of viral genome, which reacted with convalescent patient serum, and used that to build up the sequence. That’s where I come into it,” said Dr. Rice, professor of virology at Rockefeller University, New York, and the third scientist in the Nobel Prize–winning trio.

The next step was to confirm that this was causing the hepatitis in patients who received blood transfusions. Over the course of several years, Dr. Rice and colleagues at the Washington University, St. Louis, engineered a version of the virus that retained its replicating capacity and injected it into chimpanzees. The animals developed hepatitis, confirming that this flavivirus was indeed the cause. More than 8 years after the virus was identified, scientists had proof of its infectiousness.

“We finally knew the structure of the viral genome,” said Dr. Rice. “We showed that the sequence was sufficient to initiate infection and cause disease.”

Those findings, published in 1997 in Science, were the key final step in the search for a molecular target for therapies and, maybe someday, a vaccine.

For the first time in history, hepatitis C can now be cured, raising hopes that the virus will be eradicated from the world population. But obstacles remain as the World Health Organization works toward its goal of eliminating hepatitis C–related disease by 2030.

Rates have actually risen in the United States as the opioid epidemic has taken hold because the virus is common in people who use street drugs and are at increased risk for behaviors that lead to transmission.

The prevalence of chronic hepatitis C now hovers around 1%. In 2019, it affected an estimated 3.8 million Americans, and more than 39,000 people died of hepatitis C–related causes. Of all deaths from liver cancer in 2019, 39% were attributable to hepatitis C.

This “silent killer” can take years to develop, which dampens the sense of immediacy to help, said Jean-Michel Piedagnel, director of the Drugs for Neglected Diseases nonprofit initiative.

People infected with hepatitis C are often part of marginalized groups. There isn’t typically a common demographic factor to unite them in advocacy.

And even though treatment can cost as little as $200 in countries where generic drugs are available, money can still be an issue, Mr. Piedagnel pointed out.

The COVID-19 response shows how quickly health systems can evolve in a crisis and adapt. “If there is political will, means can be found, said Cary James, CEO at the World Hepatitis Alliance.

The incredible speed of vaccine development for SARS-CoV-2 has impressed the Nobel Laureates, who have yet to see a vaccine for hepatitis C.

Dr. Houghton said he hopes this momentum will perpetuate new emergency filings for hepatitis C vaccines.

If even a tiny fraction of the money that’s gone into COVID-19 were used, Dr. Rice pointed out, “we’d have a hep C vaccine by now.”

A version of this article first appeared on Medscape.com

Researchers have worked at record-breaking speed to not only identify and characterize the novel coronavirus, but also to develop potential vaccines; it is a race that another trio of scientists, awarded the 2020 Nobel Prize in Medicine, know well after their own decades-long marathon to crack the code of hepatitis C.

The RNA virus vexed researchers like Harvey J. Alter, MD; Michael Houghton, PhD; and Charles M. Rice, PhD, for years. Unlike today’s parallel sequencing and polymerase chain reaction, screening at the time was tedious and painstaking. But they were all in for some big highs, some dead-ends, and a little inspiration by way of author Lewis Carroll.

“Our undertaking was a success,” Dr. Alter said in an interview, “because everyone got on board.” Investigators, the Food and Drug Administration, and blood banks all worked together. It was a national effort, he added.

The Laureates will share the $1 million prize that recognizes their achievement. This is the second time that scientists who have devoted their time to the pursuit of viral hepatitis have been honored.

Two main types of infectious hepatitis were identified in the 1940s. The first, hepatitis A, is transmitted by polluted water or food and generally has little long-term effect on the patient. The second, transmitted through blood and other bodily fluids, is a much more serious threat.

In the 1960s, Baruch Blumberg, MD, ascertained that blood-borne hepatitis was caused by an insidious virus – hepatitis B – which silently causes liver complications in otherwise healthy people years after infection. Dr. Blumberg’s discovery led to the development of diagnostic tests and an effective vaccine; he was awarded the Nobel Prize in Physiology or Medicine in 1976.

At that time, Dr. Alter was working at the National Institutes of Health in Bethesda, Md., studying the occurrence of hepatitis in patients who had received blood transfusions. Globally, blood-borne hepatitis was causing more than a million deaths each year.

When screening began in 1969 to prevent people with hepatitis A or hepatitis B from donating blood, many recipients were spared from developing liver inflammation after transfusion. However, some people were still getting sick and researchers began to suspect that something dubbed “non-A, non-B” was lurking in donated blood.

As scientists were tracking it down in the micro world, public health officials and others tried to block the presumed virus in the macro world. In the United States, this meant changing blood-donation practices. When it became clear that as many as one in five transfusion recipients developed hepatitis, probably as the result of a virus, the blood donation system switched from being a paid enterprise to a volunteer activity.

It was anticipated that this would eliminate one source of the virus – users of street drugs – and it did; rates of transmission after transfusion dropped by half. By the 1980s, researchers had figured out that donors carrying the mysterious pathogen often had elevated levels of antibodies to the hepatitis B virus or elevated levels of ALT. Blood banks then began testing prospective donors and cut the incidence of non-A, non-B hepatitis by another half.

When Dr. Alter and his team got to work studying chimpanzees, they were able to confirm that the non-A, non-B agent was transmittable by blood transfusion. But the next step proved insurmountable. “People knew what the virus would look like if we found it, but we couldn’t find it,” Dr. Alter said.

“Then Chiron came along and cloned it,” he recounts.

The tiny start-up company was housed in a few rented rooms in an abandoned plant in Emeryville, Calif. This is where Nobel Laureate Dr. Houghton and coworkers Qui-Lim Choo, PhD, and George Kuo, PhD, spent 7 years chasing the mystery pathogen. When every traditional method to pin it down failed, the team tried some nontraditional approaches.

They found success when they painstakingly cloned genomic fragments from the blood of an infected chimpanzee and then screened this library using serum isolated from affected patients. The hope was that antibodies in the serum samples would stick to the viral genetic material and create a signpost indicating its presence.

This “fishing expedition” was disappointing at first, said Dr. Choo, now vice president of research at Nansha Biologics Limited in Hong Kong. “We didn’t catch any fish.”

He likened the pursuit, which took place under growing pressure from upper management, to that in “The Imitation Game,” the film that depicted Alan Turing’s effort to decrypt German intelligence messages for the British government during World War II.

The effort wasn’t working out and the team was down. So to keep spirits up, Dr. Kuo shared a snippet of the Lewis Carroll poem “The Hunting of the Snark.” It just happened to encapsulate the frustrations of their pursuit while also encouraging perseverance: “For the Snark’s a peculiar creature, that won’t / Be caught in a commonplace way. / Do all that you know, and try all that you don’t: / Not a chance must be wasted today!”

Those words motivated the team to keep going, to try different approaches and, ultimately, to find the hepatitis C virus, said Dr. Kuo, now retired.

During the tedious process of screening millions of clones, Dr. Choo spotted a single likely area on one of the plates that his “gut feeling” told him would contain the viral material. And it did. The pathogen – RNA packed in a lipid coat – was a member of the Flaviviridae family.

In 1989, the team reported that they’d identified a new flavivirus associated with posttransfusion hepatitis, and published their findings in Science. Later that year, an antibody test for it was described in Science by the team, which included Dr. Alter.

The success was a “fantastic feeling,” mused Dr. Houghton, now a virologist at the University of Alberta, Edmonton. “I’ve often said that, from 1989 to 1991, I was high just on the discovery.” After that, “researchers and the pharmaceutical industry did a great job coming up with really effective antivirals.”

“Mike, with his team, took 7 years to get this tiny little piece of viral genome, which reacted with convalescent patient serum, and used that to build up the sequence. That’s where I come into it,” said Dr. Rice, professor of virology at Rockefeller University, New York, and the third scientist in the Nobel Prize–winning trio.

The next step was to confirm that this was causing the hepatitis in patients who received blood transfusions. Over the course of several years, Dr. Rice and colleagues at the Washington University, St. Louis, engineered a version of the virus that retained its replicating capacity and injected it into chimpanzees. The animals developed hepatitis, confirming that this flavivirus was indeed the cause. More than 8 years after the virus was identified, scientists had proof of its infectiousness.

“We finally knew the structure of the viral genome,” said Dr. Rice. “We showed that the sequence was sufficient to initiate infection and cause disease.”

Those findings, published in 1997 in Science, were the key final step in the search for a molecular target for therapies and, maybe someday, a vaccine.

For the first time in history, hepatitis C can now be cured, raising hopes that the virus will be eradicated from the world population. But obstacles remain as the World Health Organization works toward its goal of eliminating hepatitis C–related disease by 2030.

Rates have actually risen in the United States as the opioid epidemic has taken hold because the virus is common in people who use street drugs and are at increased risk for behaviors that lead to transmission.

The prevalence of chronic hepatitis C now hovers around 1%. In 2019, it affected an estimated 3.8 million Americans, and more than 39,000 people died of hepatitis C–related causes. Of all deaths from liver cancer in 2019, 39% were attributable to hepatitis C.

This “silent killer” can take years to develop, which dampens the sense of immediacy to help, said Jean-Michel Piedagnel, director of the Drugs for Neglected Diseases nonprofit initiative.

People infected with hepatitis C are often part of marginalized groups. There isn’t typically a common demographic factor to unite them in advocacy.

And even though treatment can cost as little as $200 in countries where generic drugs are available, money can still be an issue, Mr. Piedagnel pointed out.

The COVID-19 response shows how quickly health systems can evolve in a crisis and adapt. “If there is political will, means can be found, said Cary James, CEO at the World Hepatitis Alliance.

The incredible speed of vaccine development for SARS-CoV-2 has impressed the Nobel Laureates, who have yet to see a vaccine for hepatitis C.

Dr. Houghton said he hopes this momentum will perpetuate new emergency filings for hepatitis C vaccines.

If even a tiny fraction of the money that’s gone into COVID-19 were used, Dr. Rice pointed out, “we’d have a hep C vaccine by now.”

A version of this article first appeared on Medscape.com

Researchers have worked at record-breaking speed to not only identify and characterize the novel coronavirus, but also to develop potential vaccines; it is a race that another trio of scientists, awarded the 2020 Nobel Prize in Medicine, know well after their own decades-long marathon to crack the code of hepatitis C.

The RNA virus vexed researchers like Harvey J. Alter, MD; Michael Houghton, PhD; and Charles M. Rice, PhD, for years. Unlike today’s parallel sequencing and polymerase chain reaction, screening at the time was tedious and painstaking. But they were all in for some big highs, some dead-ends, and a little inspiration by way of author Lewis Carroll.

“Our undertaking was a success,” Dr. Alter said in an interview, “because everyone got on board.” Investigators, the Food and Drug Administration, and blood banks all worked together. It was a national effort, he added.

The Laureates will share the $1 million prize that recognizes their achievement. This is the second time that scientists who have devoted their time to the pursuit of viral hepatitis have been honored.

Two main types of infectious hepatitis were identified in the 1940s. The first, hepatitis A, is transmitted by polluted water or food and generally has little long-term effect on the patient. The second, transmitted through blood and other bodily fluids, is a much more serious threat.

In the 1960s, Baruch Blumberg, MD, ascertained that blood-borne hepatitis was caused by an insidious virus – hepatitis B – which silently causes liver complications in otherwise healthy people years after infection. Dr. Blumberg’s discovery led to the development of diagnostic tests and an effective vaccine; he was awarded the Nobel Prize in Physiology or Medicine in 1976.

At that time, Dr. Alter was working at the National Institutes of Health in Bethesda, Md., studying the occurrence of hepatitis in patients who had received blood transfusions. Globally, blood-borne hepatitis was causing more than a million deaths each year.

When screening began in 1969 to prevent people with hepatitis A or hepatitis B from donating blood, many recipients were spared from developing liver inflammation after transfusion. However, some people were still getting sick and researchers began to suspect that something dubbed “non-A, non-B” was lurking in donated blood.

As scientists were tracking it down in the micro world, public health officials and others tried to block the presumed virus in the macro world. In the United States, this meant changing blood-donation practices. When it became clear that as many as one in five transfusion recipients developed hepatitis, probably as the result of a virus, the blood donation system switched from being a paid enterprise to a volunteer activity.

It was anticipated that this would eliminate one source of the virus – users of street drugs – and it did; rates of transmission after transfusion dropped by half. By the 1980s, researchers had figured out that donors carrying the mysterious pathogen often had elevated levels of antibodies to the hepatitis B virus or elevated levels of ALT. Blood banks then began testing prospective donors and cut the incidence of non-A, non-B hepatitis by another half.

When Dr. Alter and his team got to work studying chimpanzees, they were able to confirm that the non-A, non-B agent was transmittable by blood transfusion. But the next step proved insurmountable. “People knew what the virus would look like if we found it, but we couldn’t find it,” Dr. Alter said.

“Then Chiron came along and cloned it,” he recounts.

The tiny start-up company was housed in a few rented rooms in an abandoned plant in Emeryville, Calif. This is where Nobel Laureate Dr. Houghton and coworkers Qui-Lim Choo, PhD, and George Kuo, PhD, spent 7 years chasing the mystery pathogen. When every traditional method to pin it down failed, the team tried some nontraditional approaches.

They found success when they painstakingly cloned genomic fragments from the blood of an infected chimpanzee and then screened this library using serum isolated from affected patients. The hope was that antibodies in the serum samples would stick to the viral genetic material and create a signpost indicating its presence.

This “fishing expedition” was disappointing at first, said Dr. Choo, now vice president of research at Nansha Biologics Limited in Hong Kong. “We didn’t catch any fish.”

He likened the pursuit, which took place under growing pressure from upper management, to that in “The Imitation Game,” the film that depicted Alan Turing’s effort to decrypt German intelligence messages for the British government during World War II.

The effort wasn’t working out and the team was down. So to keep spirits up, Dr. Kuo shared a snippet of the Lewis Carroll poem “The Hunting of the Snark.” It just happened to encapsulate the frustrations of their pursuit while also encouraging perseverance: “For the Snark’s a peculiar creature, that won’t / Be caught in a commonplace way. / Do all that you know, and try all that you don’t: / Not a chance must be wasted today!”

Those words motivated the team to keep going, to try different approaches and, ultimately, to find the hepatitis C virus, said Dr. Kuo, now retired.

During the tedious process of screening millions of clones, Dr. Choo spotted a single likely area on one of the plates that his “gut feeling” told him would contain the viral material. And it did. The pathogen – RNA packed in a lipid coat – was a member of the Flaviviridae family.

In 1989, the team reported that they’d identified a new flavivirus associated with posttransfusion hepatitis, and published their findings in Science. Later that year, an antibody test for it was described in Science by the team, which included Dr. Alter.

The success was a “fantastic feeling,” mused Dr. Houghton, now a virologist at the University of Alberta, Edmonton. “I’ve often said that, from 1989 to 1991, I was high just on the discovery.” After that, “researchers and the pharmaceutical industry did a great job coming up with really effective antivirals.”

“Mike, with his team, took 7 years to get this tiny little piece of viral genome, which reacted with convalescent patient serum, and used that to build up the sequence. That’s where I come into it,” said Dr. Rice, professor of virology at Rockefeller University, New York, and the third scientist in the Nobel Prize–winning trio.

The next step was to confirm that this was causing the hepatitis in patients who received blood transfusions. Over the course of several years, Dr. Rice and colleagues at the Washington University, St. Louis, engineered a version of the virus that retained its replicating capacity and injected it into chimpanzees. The animals developed hepatitis, confirming that this flavivirus was indeed the cause. More than 8 years after the virus was identified, scientists had proof of its infectiousness.

“We finally knew the structure of the viral genome,” said Dr. Rice. “We showed that the sequence was sufficient to initiate infection and cause disease.”

Those findings, published in 1997 in Science, were the key final step in the search for a molecular target for therapies and, maybe someday, a vaccine.

For the first time in history, hepatitis C can now be cured, raising hopes that the virus will be eradicated from the world population. But obstacles remain as the World Health Organization works toward its goal of eliminating hepatitis C–related disease by 2030.

Rates have actually risen in the United States as the opioid epidemic has taken hold because the virus is common in people who use street drugs and are at increased risk for behaviors that lead to transmission.

The prevalence of chronic hepatitis C now hovers around 1%. In 2019, it affected an estimated 3.8 million Americans, and more than 39,000 people died of hepatitis C–related causes. Of all deaths from liver cancer in 2019, 39% were attributable to hepatitis C.

This “silent killer” can take years to develop, which dampens the sense of immediacy to help, said Jean-Michel Piedagnel, director of the Drugs for Neglected Diseases nonprofit initiative.

People infected with hepatitis C are often part of marginalized groups. There isn’t typically a common demographic factor to unite them in advocacy.

And even though treatment can cost as little as $200 in countries where generic drugs are available, money can still be an issue, Mr. Piedagnel pointed out.

The COVID-19 response shows how quickly health systems can evolve in a crisis and adapt. “If there is political will, means can be found, said Cary James, CEO at the World Hepatitis Alliance.

The incredible speed of vaccine development for SARS-CoV-2 has impressed the Nobel Laureates, who have yet to see a vaccine for hepatitis C.

Dr. Houghton said he hopes this momentum will perpetuate new emergency filings for hepatitis C vaccines.

If even a tiny fraction of the money that’s gone into COVID-19 were used, Dr. Rice pointed out, “we’d have a hep C vaccine by now.”

A version of this article first appeared on Medscape.com

Recently I posted a simple question on several social media pages and internet blogs populated exclusively by board-certified dermatologists and dermatologic surgeons: How would you respond to a patient asking (or demanding) to record all or part of their office visit? (Or, if you have encountered such a situation, how did you respond?)

The question was simple, but the answers were somewhat complicated.

First, I noticed a fundamental misunderstanding of applicable laws: Many practitioners apparently believe that taping or recording a private conversation is per se illegal. Perhaps they are conflating with wiretapping laws, which don’t apply in this situation. HIPAA laws don’t apply either, because the patient, by definition, is waiving the right to privacy by initiating the recording in the first place.

In fact, every U.S. jurisdiction permits the taping or recording of doctor-patient conversations; and only 11 states (California, Florida, Illinois, Maryland, Massachusetts, Michigan, Montana, New Hampshire, Oregon, Pennsylvania, and Washington) require the consent of both parties. All other states and territories actually allow it even if one party has not given consent. And some patients don’t ask permission at all; they just do it.

Another misconception was the perceived frequency of such situations. Recordings of conversations in the doctor’s office are by no means rare. A 2014 survey in the United Kingdom revealed that 15% of the public had secretly recorded a clinic visit, and a further 11% were aware of someone else doing the same, a topic discussed by a Dartmouth group in the Aug. 8, 2017, issue of JAMA.

In general, younger respondents to my (admittedly unscientific) informal survey tended to be less receptive to being recorded. “I do not allow recordings by patients because I can’t control how they may be used later and it’s just creepy,” wrote one. “It just seems a strange way to begin a trusting, transparent patient/doctor relationship … this is not Instagram.”

“I will sometimes let them take a photo of a specimen or a defect but I don’t allow recording,” wrote another. “Same reasons; creepy and out of my control. I worry about it happening surreptitiously, but what can you do?”

You can proactively prohibit all office recordings by posting a “no recording” sign in your waiting room in the name of confidentiality and privacy. Should a patient initiate a covert recording anyway, you have the option of terminating the visit with a warning that a repeat attempt will result in discharge. If you practice in one of the 39 one-party states, the recording would still be admissible, but your notice gives your attorney an argument – specifically, that the patient made the recording after being expressly directed not to do so – if anyone ever tries to use the recording against you, or without your permission.

Older, more experienced practitioners in the survey tended to be more sanguine about recordings. “I have allowed patients to record all or parts of the visit,” wrote one. “I even allowed a patient to film a [liposuction] procedure. My decision … was that the patient might think I had something to hide, which I [did not].”

Another reported, “I have no problem with patients or family recording office visits or procedures. When someone is recording a procedure, I have no problem ignoring them.”

“We don’t have anything to hide, after all,” affirmed another. “In the era of telemedicine, many things can be recorded, even without permission.”

Several other veteran practitioners summarized my own philosophy on the subject: Patients have a right to record visits in my state (New Jersey), whether I like it or not, so I simply assume I’m being recorded during every visit, and conduct myself accordingly.

Risk managers and malpractice carriers are divided on recordings. At one neurology clinic in Arizona, patients are routinely offered videos of their visits, and clinicians who participate in these recordings receive a 10% reduction in the cost of their medical defense and extra liability coverage. There are clear advantages to having a permanent record of a doctor’s professional opinion. Other carriers are not as supportive, discouraging their insureds from allowing recordings to be made.

In the end, like it or not, recordings are here to stay, and the omnipresence of modern communications devices such as smartphones, tablets, etc., will only increase their prevalence. My advice: Familiarize yourself with the laws in your state, and never say anything during an office visit that you would not stand behind, if it ever turns out to have been recorded.
 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

Recently I posted a simple question on several social media pages and internet blogs populated exclusively by board-certified dermatologists and dermatologic surgeons: How would you respond to a patient asking (or demanding) to record all or part of their office visit? (Or, if you have encountered such a situation, how did you respond?)

The question was simple, but the answers were somewhat complicated.

First, I noticed a fundamental misunderstanding of applicable laws: Many practitioners apparently believe that taping or recording a private conversation is per se illegal. Perhaps they are conflating with wiretapping laws, which don’t apply in this situation. HIPAA laws don’t apply either, because the patient, by definition, is waiving the right to privacy by initiating the recording in the first place.

In fact, every U.S. jurisdiction permits the taping or recording of doctor-patient conversations; and only 11 states (California, Florida, Illinois, Maryland, Massachusetts, Michigan, Montana, New Hampshire, Oregon, Pennsylvania, and Washington) require the consent of both parties. All other states and territories actually allow it even if one party has not given consent. And some patients don’t ask permission at all; they just do it.

Another misconception was the perceived frequency of such situations. Recordings of conversations in the doctor’s office are by no means rare. A 2014 survey in the United Kingdom revealed that 15% of the public had secretly recorded a clinic visit, and a further 11% were aware of someone else doing the same, a topic discussed by a Dartmouth group in the Aug. 8, 2017, issue of JAMA.

In general, younger respondents to my (admittedly unscientific) informal survey tended to be less receptive to being recorded. “I do not allow recordings by patients because I can’t control how they may be used later and it’s just creepy,” wrote one. “It just seems a strange way to begin a trusting, transparent patient/doctor relationship … this is not Instagram.”

“I will sometimes let them take a photo of a specimen or a defect but I don’t allow recording,” wrote another. “Same reasons; creepy and out of my control. I worry about it happening surreptitiously, but what can you do?”

You can proactively prohibit all office recordings by posting a “no recording” sign in your waiting room in the name of confidentiality and privacy. Should a patient initiate a covert recording anyway, you have the option of terminating the visit with a warning that a repeat attempt will result in discharge. If you practice in one of the 39 one-party states, the recording would still be admissible, but your notice gives your attorney an argument – specifically, that the patient made the recording after being expressly directed not to do so – if anyone ever tries to use the recording against you, or without your permission.

Older, more experienced practitioners in the survey tended to be more sanguine about recordings. “I have allowed patients to record all or parts of the visit,” wrote one. “I even allowed a patient to film a [liposuction] procedure. My decision … was that the patient might think I had something to hide, which I [did not].”

Another reported, “I have no problem with patients or family recording office visits or procedures. When someone is recording a procedure, I have no problem ignoring them.”

“We don’t have anything to hide, after all,” affirmed another. “In the era of telemedicine, many things can be recorded, even without permission.”

Several other veteran practitioners summarized my own philosophy on the subject: Patients have a right to record visits in my state (New Jersey), whether I like it or not, so I simply assume I’m being recorded during every visit, and conduct myself accordingly.

Risk managers and malpractice carriers are divided on recordings. At one neurology clinic in Arizona, patients are routinely offered videos of their visits, and clinicians who participate in these recordings receive a 10% reduction in the cost of their medical defense and extra liability coverage. There are clear advantages to having a permanent record of a doctor’s professional opinion. Other carriers are not as supportive, discouraging their insureds from allowing recordings to be made.

In the end, like it or not, recordings are here to stay, and the omnipresence of modern communications devices such as smartphones, tablets, etc., will only increase their prevalence. My advice: Familiarize yourself with the laws in your state, and never say anything during an office visit that you would not stand behind, if it ever turns out to have been recorded.
 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

Recently I posted a simple question on several social media pages and internet blogs populated exclusively by board-certified dermatologists and dermatologic surgeons: How would you respond to a patient asking (or demanding) to record all or part of their office visit? (Or, if you have encountered such a situation, how did you respond?)

The question was simple, but the answers were somewhat complicated.

First, I noticed a fundamental misunderstanding of applicable laws: Many practitioners apparently believe that taping or recording a private conversation is per se illegal. Perhaps they are conflating with wiretapping laws, which don’t apply in this situation. HIPAA laws don’t apply either, because the patient, by definition, is waiving the right to privacy by initiating the recording in the first place.

In fact, every U.S. jurisdiction permits the taping or recording of doctor-patient conversations; and only 11 states (California, Florida, Illinois, Maryland, Massachusetts, Michigan, Montana, New Hampshire, Oregon, Pennsylvania, and Washington) require the consent of both parties. All other states and territories actually allow it even if one party has not given consent. And some patients don’t ask permission at all; they just do it.

Another misconception was the perceived frequency of such situations. Recordings of conversations in the doctor’s office are by no means rare. A 2014 survey in the United Kingdom revealed that 15% of the public had secretly recorded a clinic visit, and a further 11% were aware of someone else doing the same, a topic discussed by a Dartmouth group in the Aug. 8, 2017, issue of JAMA.

In general, younger respondents to my (admittedly unscientific) informal survey tended to be less receptive to being recorded. “I do not allow recordings by patients because I can’t control how they may be used later and it’s just creepy,” wrote one. “It just seems a strange way to begin a trusting, transparent patient/doctor relationship … this is not Instagram.”

“I will sometimes let them take a photo of a specimen or a defect but I don’t allow recording,” wrote another. “Same reasons; creepy and out of my control. I worry about it happening surreptitiously, but what can you do?”

You can proactively prohibit all office recordings by posting a “no recording” sign in your waiting room in the name of confidentiality and privacy. Should a patient initiate a covert recording anyway, you have the option of terminating the visit with a warning that a repeat attempt will result in discharge. If you practice in one of the 39 one-party states, the recording would still be admissible, but your notice gives your attorney an argument – specifically, that the patient made the recording after being expressly directed not to do so – if anyone ever tries to use the recording against you, or without your permission.

Older, more experienced practitioners in the survey tended to be more sanguine about recordings. “I have allowed patients to record all or parts of the visit,” wrote one. “I even allowed a patient to film a [liposuction] procedure. My decision … was that the patient might think I had something to hide, which I [did not].”

Another reported, “I have no problem with patients or family recording office visits or procedures. When someone is recording a procedure, I have no problem ignoring them.”

“We don’t have anything to hide, after all,” affirmed another. “In the era of telemedicine, many things can be recorded, even without permission.”

Several other veteran practitioners summarized my own philosophy on the subject: Patients have a right to record visits in my state (New Jersey), whether I like it or not, so I simply assume I’m being recorded during every visit, and conduct myself accordingly.

Risk managers and malpractice carriers are divided on recordings. At one neurology clinic in Arizona, patients are routinely offered videos of their visits, and clinicians who participate in these recordings receive a 10% reduction in the cost of their medical defense and extra liability coverage. There are clear advantages to having a permanent record of a doctor’s professional opinion. Other carriers are not as supportive, discouraging their insureds from allowing recordings to be made.

In the end, like it or not, recordings are here to stay, and the omnipresence of modern communications devices such as smartphones, tablets, etc., will only increase their prevalence. My advice: Familiarize yourself with the laws in your state, and never say anything during an office visit that you would not stand behind, if it ever turns out to have been recorded.
 

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

Science should be the cornerstone for health policy, and decisions on medical care of transgender and gender-diverse (TGD) individuals should be between a patient and their doctor.

That’s according to a joint policy statement from the Endocrine Society and Pediatric Endocrine Society published in the Journal of Clinical Endocrinology & Metabolism expressing concern about recent proposed legislation that would limit access to medical care for TGD individuals.

“The main emphasis is that we are simply medical people trying to be conservative and science driven in the care of our patients,” Joshua D. Safer, MD, coauthor and executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System, and professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Why the health care for a particular group of people should be considered political is a mystery to me.”

TGD individuals have seen a recent uptick in efforts to limit or restrict their access to medical care at the federal and state levels. In June 2020, the Department of Health & Human Services finalized a revision to Section 1557 of the Affordable Care Act, rolling back a 2016 rule that determined the phrase “on the basis of sex” included nondiscrimination based on a person’s sex and gender identity. The Endocrine Society opposed this rule revision, arguing that it would allow “providers to deny care to TGD persons as well as discourage patients from seeking routine and gender-affirming care or reporting discrimination.”

Over a dozen U.S. states have introduced proposed legislation concerning medical care of TGD individuals that contain erroneous and misleading information. Proposed laws in Alabama, Missouri, and Texas, for example, would prohibit any use of medical treatments for minors for the purpose of gender-affirming medical care, including “gonadotropin-releasing hormone agonist therapy for pubertal suppression and gender-affirming hormonal therapy,” the authors of the joint statement wrote. In some cases, medical professionals who provide medical care for TGD patients could face criminal charges.

Outside the United States, three High Court judges in the United Kingdom recently ruled that minors aged under 16 years could not legally consent to pubertal suppression. “The recent U.K. court decision could be very disruptive because it would raise a barrier to transgender children receiving puberty blockers at exactly the ages that puberty blockers would be typically used,” Dr. Safer said.

Misleading characterizations of gender-affirming medical care for TGD individuals have also been spread to the general public. A recent Republican primary ballot proposition in Texas asked whether the state should ban “chemical castration, puberty blockers, cross-sex hormones, and genital mutilation surgery on all minor children for transition purposes,” falsely asserting that “Texas children as young as 3 are being transitioned from their biological sex to the opposite sex,” referencing a high-profile custody battle of a transgender child in Texas.

There are several tiers of misinformation that exist within these statements, Dr. Safer noted. “Some statements have suggested that gender-affirming treatment for young children can include hormone therapy or even surgery. Of course, there are no medical treatments for transgender and gender-diverse children prior to puberty.”

For adolescents aged under 18 years, Endocrine Society guidelines released in 2017 state that pubertal suppression is fully reversible and “offered to adolescents who meet diagnostic and treatment criteria, and are requesting care, for gender dysphoria/gender incongruence after they exhibit physical changes of puberty,” Dr. Safer and coauthors wrote in the joint policy statement. Other, more permanent – but still partially reversible – treatments such as hormone therapy are available as options for adolescents with confirmed and persistent gender dysphoria/gender incongruence, after meeting with a team of medical and mental health professionals and giving informed consent, according to the guidelines.

Dr. Safer expressed surprise at the opposition to puberty blockers in proposed state legislation. “Puberty blockers are the conservative option so that we can avoid permanent changes while thoughtful decisions are being made by our adolescent patients with their families and health care providers,” he said.

The perception that puberty blockers will lead to hormone therapy is another misunderstanding and source of misinformation, Dr. Safer explained.

“The fear is that these data suggest that puberty blockers are a ‘gateway drug’ of some sort. But that is false. The reason that most adolescents who take puberty blockers go on to hormone therapy is because most of the adolescents who are identified in our conservative systems are actually transgender and interested in more gender-affirming care as they age,” he said.
 

Effects of discrimination on TGD persons

Many of these proposed state bills have not advanced through state legislatures, but a few – such as the proposed laws in Alabama, Missouri, and Texas – are still currently under consideration.

“In the United States, most recent efforts to single out transgender and gender-diverse people for discrimination in health care have failed. However, the demonization of trans people and attempts to disrupt care have been the source of much stress among our patients,” Dr. Safer said.

Restricting access to health care has “multiple implications” for TGD patients. “In the era when we did not provide care to transgender youth, we had a situation where approximately 40% of transgender people had considered suicide in their lives,” Dr. Safer said. In contrast, having access to these treatments has been shown to improve mental health outcomes in these patients, according to an Endocrine Society position statement.

The purpose of earlier interventions such as puberty blockers is to allow an adolescent to “explore options and live in the experienced gender before making a decision to proceed with gender-affirming hormone therapy,” the authors of the Endocrine Society and Pediatric Endocrine Society joint statement said.

Blocking access to puberty blockers, on the other hand, forces transgender youth to experience a puberty that doesn’t match their gender identity, Dr. Safer noted. “The puberty will include permanent changes which will then have to be reversed with surgery. Why would we intentionally allow that to happen?”

Dr. Safer reported that his spouse is an employee of Parexel. Dr. Tangpricha is the current president of the World Association for Transgender Health and a board member of the American Association of Clinical Endocrinology. The other authors reported no relevant conflicts of interests.

SOURCE: Safer JD et al. J Clin Endocrinol Metab. 2020. doi: 10.1210/clinem/dgaa816.

Science should be the cornerstone for health policy, and decisions on medical care of transgender and gender-diverse (TGD) individuals should be between a patient and their doctor.

That’s according to a joint policy statement from the Endocrine Society and Pediatric Endocrine Society published in the Journal of Clinical Endocrinology & Metabolism expressing concern about recent proposed legislation that would limit access to medical care for TGD individuals.

“The main emphasis is that we are simply medical people trying to be conservative and science driven in the care of our patients,” Joshua D. Safer, MD, coauthor and executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System, and professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Why the health care for a particular group of people should be considered political is a mystery to me.”

TGD individuals have seen a recent uptick in efforts to limit or restrict their access to medical care at the federal and state levels. In June 2020, the Department of Health & Human Services finalized a revision to Section 1557 of the Affordable Care Act, rolling back a 2016 rule that determined the phrase “on the basis of sex” included nondiscrimination based on a person’s sex and gender identity. The Endocrine Society opposed this rule revision, arguing that it would allow “providers to deny care to TGD persons as well as discourage patients from seeking routine and gender-affirming care or reporting discrimination.”

Over a dozen U.S. states have introduced proposed legislation concerning medical care of TGD individuals that contain erroneous and misleading information. Proposed laws in Alabama, Missouri, and Texas, for example, would prohibit any use of medical treatments for minors for the purpose of gender-affirming medical care, including “gonadotropin-releasing hormone agonist therapy for pubertal suppression and gender-affirming hormonal therapy,” the authors of the joint statement wrote. In some cases, medical professionals who provide medical care for TGD patients could face criminal charges.

Outside the United States, three High Court judges in the United Kingdom recently ruled that minors aged under 16 years could not legally consent to pubertal suppression. “The recent U.K. court decision could be very disruptive because it would raise a barrier to transgender children receiving puberty blockers at exactly the ages that puberty blockers would be typically used,” Dr. Safer said.

Misleading characterizations of gender-affirming medical care for TGD individuals have also been spread to the general public. A recent Republican primary ballot proposition in Texas asked whether the state should ban “chemical castration, puberty blockers, cross-sex hormones, and genital mutilation surgery on all minor children for transition purposes,” falsely asserting that “Texas children as young as 3 are being transitioned from their biological sex to the opposite sex,” referencing a high-profile custody battle of a transgender child in Texas.

There are several tiers of misinformation that exist within these statements, Dr. Safer noted. “Some statements have suggested that gender-affirming treatment for young children can include hormone therapy or even surgery. Of course, there are no medical treatments for transgender and gender-diverse children prior to puberty.”

For adolescents aged under 18 years, Endocrine Society guidelines released in 2017 state that pubertal suppression is fully reversible and “offered to adolescents who meet diagnostic and treatment criteria, and are requesting care, for gender dysphoria/gender incongruence after they exhibit physical changes of puberty,” Dr. Safer and coauthors wrote in the joint policy statement. Other, more permanent – but still partially reversible – treatments such as hormone therapy are available as options for adolescents with confirmed and persistent gender dysphoria/gender incongruence, after meeting with a team of medical and mental health professionals and giving informed consent, according to the guidelines.

Dr. Safer expressed surprise at the opposition to puberty blockers in proposed state legislation. “Puberty blockers are the conservative option so that we can avoid permanent changes while thoughtful decisions are being made by our adolescent patients with their families and health care providers,” he said.

The perception that puberty blockers will lead to hormone therapy is another misunderstanding and source of misinformation, Dr. Safer explained.

“The fear is that these data suggest that puberty blockers are a ‘gateway drug’ of some sort. But that is false. The reason that most adolescents who take puberty blockers go on to hormone therapy is because most of the adolescents who are identified in our conservative systems are actually transgender and interested in more gender-affirming care as they age,” he said.
 

Effects of discrimination on TGD persons

Many of these proposed state bills have not advanced through state legislatures, but a few – such as the proposed laws in Alabama, Missouri, and Texas – are still currently under consideration.

“In the United States, most recent efforts to single out transgender and gender-diverse people for discrimination in health care have failed. However, the demonization of trans people and attempts to disrupt care have been the source of much stress among our patients,” Dr. Safer said.

Restricting access to health care has “multiple implications” for TGD patients. “In the era when we did not provide care to transgender youth, we had a situation where approximately 40% of transgender people had considered suicide in their lives,” Dr. Safer said. In contrast, having access to these treatments has been shown to improve mental health outcomes in these patients, according to an Endocrine Society position statement.

The purpose of earlier interventions such as puberty blockers is to allow an adolescent to “explore options and live in the experienced gender before making a decision to proceed with gender-affirming hormone therapy,” the authors of the Endocrine Society and Pediatric Endocrine Society joint statement said.

Blocking access to puberty blockers, on the other hand, forces transgender youth to experience a puberty that doesn’t match their gender identity, Dr. Safer noted. “The puberty will include permanent changes which will then have to be reversed with surgery. Why would we intentionally allow that to happen?”

Dr. Safer reported that his spouse is an employee of Parexel. Dr. Tangpricha is the current president of the World Association for Transgender Health and a board member of the American Association of Clinical Endocrinology. The other authors reported no relevant conflicts of interests.

SOURCE: Safer JD et al. J Clin Endocrinol Metab. 2020. doi: 10.1210/clinem/dgaa816.

Science should be the cornerstone for health policy, and decisions on medical care of transgender and gender-diverse (TGD) individuals should be between a patient and their doctor.

That’s according to a joint policy statement from the Endocrine Society and Pediatric Endocrine Society published in the Journal of Clinical Endocrinology & Metabolism expressing concern about recent proposed legislation that would limit access to medical care for TGD individuals.

“The main emphasis is that we are simply medical people trying to be conservative and science driven in the care of our patients,” Joshua D. Safer, MD, coauthor and executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System, and professor of medicine at Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Why the health care for a particular group of people should be considered political is a mystery to me.”

TGD individuals have seen a recent uptick in efforts to limit or restrict their access to medical care at the federal and state levels. In June 2020, the Department of Health & Human Services finalized a revision to Section 1557 of the Affordable Care Act, rolling back a 2016 rule that determined the phrase “on the basis of sex” included nondiscrimination based on a person’s sex and gender identity. The Endocrine Society opposed this rule revision, arguing that it would allow “providers to deny care to TGD persons as well as discourage patients from seeking routine and gender-affirming care or reporting discrimination.”

Over a dozen U.S. states have introduced proposed legislation concerning medical care of TGD individuals that contain erroneous and misleading information. Proposed laws in Alabama, Missouri, and Texas, for example, would prohibit any use of medical treatments for minors for the purpose of gender-affirming medical care, including “gonadotropin-releasing hormone agonist therapy for pubertal suppression and gender-affirming hormonal therapy,” the authors of the joint statement wrote. In some cases, medical professionals who provide medical care for TGD patients could face criminal charges.

Outside the United States, three High Court judges in the United Kingdom recently ruled that minors aged under 16 years could not legally consent to pubertal suppression. “The recent U.K. court decision could be very disruptive because it would raise a barrier to transgender children receiving puberty blockers at exactly the ages that puberty blockers would be typically used,” Dr. Safer said.

Misleading characterizations of gender-affirming medical care for TGD individuals have also been spread to the general public. A recent Republican primary ballot proposition in Texas asked whether the state should ban “chemical castration, puberty blockers, cross-sex hormones, and genital mutilation surgery on all minor children for transition purposes,” falsely asserting that “Texas children as young as 3 are being transitioned from their biological sex to the opposite sex,” referencing a high-profile custody battle of a transgender child in Texas.

There are several tiers of misinformation that exist within these statements, Dr. Safer noted. “Some statements have suggested that gender-affirming treatment for young children can include hormone therapy or even surgery. Of course, there are no medical treatments for transgender and gender-diverse children prior to puberty.”

For adolescents aged under 18 years, Endocrine Society guidelines released in 2017 state that pubertal suppression is fully reversible and “offered to adolescents who meet diagnostic and treatment criteria, and are requesting care, for gender dysphoria/gender incongruence after they exhibit physical changes of puberty,” Dr. Safer and coauthors wrote in the joint policy statement. Other, more permanent – but still partially reversible – treatments such as hormone therapy are available as options for adolescents with confirmed and persistent gender dysphoria/gender incongruence, after meeting with a team of medical and mental health professionals and giving informed consent, according to the guidelines.

Dr. Safer expressed surprise at the opposition to puberty blockers in proposed state legislation. “Puberty blockers are the conservative option so that we can avoid permanent changes while thoughtful decisions are being made by our adolescent patients with their families and health care providers,” he said.

The perception that puberty blockers will lead to hormone therapy is another misunderstanding and source of misinformation, Dr. Safer explained.

“The fear is that these data suggest that puberty blockers are a ‘gateway drug’ of some sort. But that is false. The reason that most adolescents who take puberty blockers go on to hormone therapy is because most of the adolescents who are identified in our conservative systems are actually transgender and interested in more gender-affirming care as they age,” he said.
 

Effects of discrimination on TGD persons

Many of these proposed state bills have not advanced through state legislatures, but a few – such as the proposed laws in Alabama, Missouri, and Texas – are still currently under consideration.

“In the United States, most recent efforts to single out transgender and gender-diverse people for discrimination in health care have failed. However, the demonization of trans people and attempts to disrupt care have been the source of much stress among our patients,” Dr. Safer said.

Restricting access to health care has “multiple implications” for TGD patients. “In the era when we did not provide care to transgender youth, we had a situation where approximately 40% of transgender people had considered suicide in their lives,” Dr. Safer said. In contrast, having access to these treatments has been shown to improve mental health outcomes in these patients, according to an Endocrine Society position statement.

The purpose of earlier interventions such as puberty blockers is to allow an adolescent to “explore options and live in the experienced gender before making a decision to proceed with gender-affirming hormone therapy,” the authors of the Endocrine Society and Pediatric Endocrine Society joint statement said.

Blocking access to puberty blockers, on the other hand, forces transgender youth to experience a puberty that doesn’t match their gender identity, Dr. Safer noted. “The puberty will include permanent changes which will then have to be reversed with surgery. Why would we intentionally allow that to happen?”

Dr. Safer reported that his spouse is an employee of Parexel. Dr. Tangpricha is the current president of the World Association for Transgender Health and a board member of the American Association of Clinical Endocrinology. The other authors reported no relevant conflicts of interests.

SOURCE: Safer JD et al. J Clin Endocrinol Metab. 2020. doi: 10.1210/clinem/dgaa816.

Eczema herpeticum and staphylococcal scalded skin syndrome can be emergencies in children and require immediate care, warned dermatologist George Hightower, MD, PhD, in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.

Eczema herpeticum is a condition in which a herpes simplex virus (HSV-1 or HSV-2) is superimposed over preexisting eczema. “The infection may be primary and sustained from a close contact or result in some of our older patients from reactivation and spread through autoinoculation,” said Dr. Hightower, of Rady Children’s Hospital and the University of California, both in San Diego.

Signs, he said, include acute worsening of atopic dermatitis with new-onset vesicles, pustules, and “punched-out” hemorrhagic crusted erosions. “Presentation ranges from mild to transient to life threatening.”

Potential complications include meningitis, encephalitis, hepatitis, and chronic conjunctivitis. “That’s why immediate ophthalmological evaluation is needed when there’s involvement on the face near the eye,” he said.

As for management and care, “where I have concern for HSV patients, I get HSV [polymerase chain reaction] as well as a bacterial culture,” he said. But even before the results are available, empiric treatment with acyclovir can be appropriate. “It’s got to be systemic for these kids with severe involvement,” he said, and they should also be started on medication for staphylococci and streptococci.

During his presentation, Dr. Hightower also highlighted staphylococcal scalded skin syndrome. Patients with the disease commonly have concurrent skin pain (which can appear to be fussiness), fever, irritability, malaise, and poor feeding. Examination may reveal widespread erythema with accentuation at folds/peeling at hands and large sheets of superficial peeling scale with diffuse erythema.

Widespread skin involvement “results not from the presence of staph throughout the skin, but the exotoxin that it produces that becomes systemic,” he said. “Clinical diagnosis is supported by presence of S. aureus on bacterial culture, but the presence of staph is not necessary to make the diagnosis. When in doubt, histopathology is helpful. But again, it’s not necessary to make the diagnosis.”

Cases can be managed with a first- or second-generation cephalosporin, he said. Alternative therapies include antistaphylococcus penicillinase-resistant penicillins (oxacillin or nafcillin) or vancomycin.

While Dr. Hightower doesn’t use clindamycin in these patients, he said it’s an option that some dermatologists consider because of its antistaphylococcus activity. “Historically, people thought it may decrease exotoxin production. The big concern if you are going to use clindamycin is that there are high rates of community resistance,” he said. “So you want to be careful that you know your resistance patterns wherever you are. Follow up on culture to make sure that you have adequate coverage for the bug that the kiddo in front of you has.”

Dr. Hightower reported no relevant disclosures. MedscapeLive and this news organization are owned by the same parent company.

Eczema herpeticum and staphylococcal scalded skin syndrome can be emergencies in children and require immediate care, warned dermatologist George Hightower, MD, PhD, in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.

Eczema herpeticum is a condition in which a herpes simplex virus (HSV-1 or HSV-2) is superimposed over preexisting eczema. “The infection may be primary and sustained from a close contact or result in some of our older patients from reactivation and spread through autoinoculation,” said Dr. Hightower, of Rady Children’s Hospital and the University of California, both in San Diego.

Signs, he said, include acute worsening of atopic dermatitis with new-onset vesicles, pustules, and “punched-out” hemorrhagic crusted erosions. “Presentation ranges from mild to transient to life threatening.”

Potential complications include meningitis, encephalitis, hepatitis, and chronic conjunctivitis. “That’s why immediate ophthalmological evaluation is needed when there’s involvement on the face near the eye,” he said.

As for management and care, “where I have concern for HSV patients, I get HSV [polymerase chain reaction] as well as a bacterial culture,” he said. But even before the results are available, empiric treatment with acyclovir can be appropriate. “It’s got to be systemic for these kids with severe involvement,” he said, and they should also be started on medication for staphylococci and streptococci.

During his presentation, Dr. Hightower also highlighted staphylococcal scalded skin syndrome. Patients with the disease commonly have concurrent skin pain (which can appear to be fussiness), fever, irritability, malaise, and poor feeding. Examination may reveal widespread erythema with accentuation at folds/peeling at hands and large sheets of superficial peeling scale with diffuse erythema.

Widespread skin involvement “results not from the presence of staph throughout the skin, but the exotoxin that it produces that becomes systemic,” he said. “Clinical diagnosis is supported by presence of S. aureus on bacterial culture, but the presence of staph is not necessary to make the diagnosis. When in doubt, histopathology is helpful. But again, it’s not necessary to make the diagnosis.”

Cases can be managed with a first- or second-generation cephalosporin, he said. Alternative therapies include antistaphylococcus penicillinase-resistant penicillins (oxacillin or nafcillin) or vancomycin.

While Dr. Hightower doesn’t use clindamycin in these patients, he said it’s an option that some dermatologists consider because of its antistaphylococcus activity. “Historically, people thought it may decrease exotoxin production. The big concern if you are going to use clindamycin is that there are high rates of community resistance,” he said. “So you want to be careful that you know your resistance patterns wherever you are. Follow up on culture to make sure that you have adequate coverage for the bug that the kiddo in front of you has.”

Dr. Hightower reported no relevant disclosures. MedscapeLive and this news organization are owned by the same parent company.

Eczema herpeticum and staphylococcal scalded skin syndrome can be emergencies in children and require immediate care, warned dermatologist George Hightower, MD, PhD, in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.

Eczema herpeticum is a condition in which a herpes simplex virus (HSV-1 or HSV-2) is superimposed over preexisting eczema. “The infection may be primary and sustained from a close contact or result in some of our older patients from reactivation and spread through autoinoculation,” said Dr. Hightower, of Rady Children’s Hospital and the University of California, both in San Diego.

Signs, he said, include acute worsening of atopic dermatitis with new-onset vesicles, pustules, and “punched-out” hemorrhagic crusted erosions. “Presentation ranges from mild to transient to life threatening.”

Potential complications include meningitis, encephalitis, hepatitis, and chronic conjunctivitis. “That’s why immediate ophthalmological evaluation is needed when there’s involvement on the face near the eye,” he said.

As for management and care, “where I have concern for HSV patients, I get HSV [polymerase chain reaction] as well as a bacterial culture,” he said. But even before the results are available, empiric treatment with acyclovir can be appropriate. “It’s got to be systemic for these kids with severe involvement,” he said, and they should also be started on medication for staphylococci and streptococci.

During his presentation, Dr. Hightower also highlighted staphylococcal scalded skin syndrome. Patients with the disease commonly have concurrent skin pain (which can appear to be fussiness), fever, irritability, malaise, and poor feeding. Examination may reveal widespread erythema with accentuation at folds/peeling at hands and large sheets of superficial peeling scale with diffuse erythema.

Widespread skin involvement “results not from the presence of staph throughout the skin, but the exotoxin that it produces that becomes systemic,” he said. “Clinical diagnosis is supported by presence of S. aureus on bacterial culture, but the presence of staph is not necessary to make the diagnosis. When in doubt, histopathology is helpful. But again, it’s not necessary to make the diagnosis.”

Cases can be managed with a first- or second-generation cephalosporin, he said. Alternative therapies include antistaphylococcus penicillinase-resistant penicillins (oxacillin or nafcillin) or vancomycin.

While Dr. Hightower doesn’t use clindamycin in these patients, he said it’s an option that some dermatologists consider because of its antistaphylococcus activity. “Historically, people thought it may decrease exotoxin production. The big concern if you are going to use clindamycin is that there are high rates of community resistance,” he said. “So you want to be careful that you know your resistance patterns wherever you are. Follow up on culture to make sure that you have adequate coverage for the bug that the kiddo in front of you has.”

Dr. Hightower reported no relevant disclosures. MedscapeLive and this news organization are owned by the same parent company.