Randy Dotinga

The gout drug colchicine appears to lower the severity of COVID-19, a small new Brazilian study finds, adding to evidence that the familiar medication holds promise as a treatment for hospitalized patients.

Patients who received colchicine in this randomized, double-blinded, placebo-controlled clinical trial presented better evolution in terms of the need for supplemental oxygen and the length of hospitalisation. ... Colchicine was safe and well tolerated,” the study authors wrote in RMD Open. However, deaths were rare in the trial, they added, and it is impossible to “evaluate the capacity of colchicine to avoid admission to ICU and reduce mortality.”

The oral anti-inflammatory colchicine, widely used as treatment in rheumatic disease, was first approved in the United States 60 years ago. Researchers began to explore its potential as a COVID-19 treatment in the early months of the pandemic.

On Jan. 25, an international team of researchers reported in a press release – but not yet a published paper – that the drug seemed to reduce hospitalizations, mechanical ventilation, and deaths in the ColCORONA trial. Earlier, a much-smaller, randomized, open-label, Greek trial linked the drug to reduced time to clinical deterioration and hospital stay.

The Brazilian authors of the new study, led by Maria Isabel Lopes of the University of São Paulo’s Ribeirão Preto Medical School, randomly assigned 75 hospitalized patients with moderate to severe COVID-19 to colchicine or placebo. A total of 72 subjects completed the April-August 2020 trial: 36 received colchicine (typically 0.5 mg three times for 5 days, then 0.5 mg twice daily for 5 days; doses were adjusted in low-weight patients and those with chronic kidney disease). The other 36 received the placebo.

(In the United States, 0.6-mg tablets of generic colchicine cost as little as $1.90 each with free coupons, according to goodrx.com.)

The median age in the groups was similar (55 years); and the placebo group had more women (61% vs. 47% in the colchicine group, P = .34). All 72 patients received the same COVID-19 treatment at the time of the trial: azithromycin, hydroxychloroquine, and unfractionated heparin. Most patients, about two-thirds in both groups, also received methylprednisolone because they needed higher amounts of supplemental oxygen.

Patients in the colchicine group needed supplemental oxygen for less time: Their median time of need was 4.0 days (interquartile range [IQR], 2.0-6.0) vs. 6.5 days (IQR, 4.0-9.0) for the placebo group (P < .001). The median time for hospitalization was also lower at 7.0 days (IQR, 5.0–9.0) for the colchicine group vs. 9.0 (IQR, 7.0–12.0) for the placebo group (log rank test, 10.6; P = .001).

The researchers also reported the percentage of patients who needed supplemental oxygen at day 2 as 67% with colchicine vs. 86% with placebo, and at day 7 as 9% vs. 42% (log rank test, 10.6; P = .001). Two patients in the placebo group died, both from ventilator-associated pneumonia.

As for side effects, new or worsened diarrhea was reported more often in the colchicine group (17% vs. 6% with placebo), but the difference was not statistically significant (P = .26), and diarrhea was controlled via medication.

The researchers reported that limitations include the exclusion criteria and their inability to link colchicine to rates of ICU admissions and death.

The drug appears to help patients with COVID-19, the study authors wrote, by “inhibiting inflammasome, reducing neutrophil migration and activation, or preventing endothelial damage.”

A “well-conceived and well-designed” study

In an interview, NYU Langone Health rheumatologist Michael H. Pillinger, MD – an investigator with the ColCORONA trial – praised the Brazilian study. It “appears well-conceived and well-designed, and was enrolled at a rate that was greater than the sample size that was estimated to be needed based on power analysis,” he said.

The Brazilian study is small, he noted. (In contrast, the ColCORONA trial had 4,488 outpatient participants.) “This study differs from ColCORONA in several ways – the most important being that it is a study of inpatients with moderate to severe COVID (really mostly moderate),” he added. “ColCORONA is looking at a target audience that is much larger – outpatients with mild to moderate COVID with risk factors for hospitalization. Both questions are really important and certainly not mutually exclusive, since our care remains inadequate in both venues. This study also adds value in that several other studies have been conducted in hospital patients with enrollment criteria relatively similar to this one, and all showed benefit, but those were open-label or retrospective, and this is blinded and placebo-controlled.”
 

Using colchicine in patients with COVID-19

Should physicians turn to colchicine in patients with COVID-19? “I would rather that it still be used in the context of research until formal recommendations can be made by bodies like the NIH and CDC,” Dr. Pillinger said. “But certainly, there may be times when physicians feel compelled to treat patients off label.”

He cautioned, however, that colchicine should never be used with some other drugs. Its interaction with the antibiotic clarithromycin can be fatal, he noted. And, he said, the drug must be monitored in general since it can cause rare, severe problems.

“Overall, colchicine probably works on the overabundant inflammatory response to COVID, and it may be that it can be combined with other drugs that affect viral replication or promote immunity – e.g. vaccines,” Dr. Pillinger said. “So far, it seems as if there is no safety problem with combining colchicine with other approaches, but this has not been studied in a rigorous manner.”

Moving forward, he said, the drug’s very low price outside of the United States “could provide resource-poor countries with a way to help keep patients out of precious hospital beds – or help them go home sooner once admitted.” For now, however, “we need a large-scale inpatient study, and one is currently going on in Great Britain. We also need validation of the outpatient ColCORONA study, and studies to look at whether colchicine can work in conjunction with other strategies.”

The study was funded by grants from the São Paulo Research Foundation, Brazilian National Council for Scientific and Technological Development, and CAPES Foundation. No disclosures are reported. Dr. Pillinger reports serving as an investigator for the ColCORONA trial and receiving a unrelated investigator-initiated grant from Hikma, a colchicine manufacturer.

The gout drug colchicine appears to lower the severity of COVID-19, a small new Brazilian study finds, adding to evidence that the familiar medication holds promise as a treatment for hospitalized patients.

Patients who received colchicine in this randomized, double-blinded, placebo-controlled clinical trial presented better evolution in terms of the need for supplemental oxygen and the length of hospitalisation. ... Colchicine was safe and well tolerated,” the study authors wrote in RMD Open. However, deaths were rare in the trial, they added, and it is impossible to “evaluate the capacity of colchicine to avoid admission to ICU and reduce mortality.”

The oral anti-inflammatory colchicine, widely used as treatment in rheumatic disease, was first approved in the United States 60 years ago. Researchers began to explore its potential as a COVID-19 treatment in the early months of the pandemic.

On Jan. 25, an international team of researchers reported in a press release – but not yet a published paper – that the drug seemed to reduce hospitalizations, mechanical ventilation, and deaths in the ColCORONA trial. Earlier, a much-smaller, randomized, open-label, Greek trial linked the drug to reduced time to clinical deterioration and hospital stay.

The Brazilian authors of the new study, led by Maria Isabel Lopes of the University of São Paulo’s Ribeirão Preto Medical School, randomly assigned 75 hospitalized patients with moderate to severe COVID-19 to colchicine or placebo. A total of 72 subjects completed the April-August 2020 trial: 36 received colchicine (typically 0.5 mg three times for 5 days, then 0.5 mg twice daily for 5 days; doses were adjusted in low-weight patients and those with chronic kidney disease). The other 36 received the placebo.

(In the United States, 0.6-mg tablets of generic colchicine cost as little as $1.90 each with free coupons, according to goodrx.com.)

The median age in the groups was similar (55 years); and the placebo group had more women (61% vs. 47% in the colchicine group, P = .34). All 72 patients received the same COVID-19 treatment at the time of the trial: azithromycin, hydroxychloroquine, and unfractionated heparin. Most patients, about two-thirds in both groups, also received methylprednisolone because they needed higher amounts of supplemental oxygen.

Patients in the colchicine group needed supplemental oxygen for less time: Their median time of need was 4.0 days (interquartile range [IQR], 2.0-6.0) vs. 6.5 days (IQR, 4.0-9.0) for the placebo group (P < .001). The median time for hospitalization was also lower at 7.0 days (IQR, 5.0–9.0) for the colchicine group vs. 9.0 (IQR, 7.0–12.0) for the placebo group (log rank test, 10.6; P = .001).

The researchers also reported the percentage of patients who needed supplemental oxygen at day 2 as 67% with colchicine vs. 86% with placebo, and at day 7 as 9% vs. 42% (log rank test, 10.6; P = .001). Two patients in the placebo group died, both from ventilator-associated pneumonia.

As for side effects, new or worsened diarrhea was reported more often in the colchicine group (17% vs. 6% with placebo), but the difference was not statistically significant (P = .26), and diarrhea was controlled via medication.

The researchers reported that limitations include the exclusion criteria and their inability to link colchicine to rates of ICU admissions and death.

The drug appears to help patients with COVID-19, the study authors wrote, by “inhibiting inflammasome, reducing neutrophil migration and activation, or preventing endothelial damage.”

A “well-conceived and well-designed” study

In an interview, NYU Langone Health rheumatologist Michael H. Pillinger, MD – an investigator with the ColCORONA trial – praised the Brazilian study. It “appears well-conceived and well-designed, and was enrolled at a rate that was greater than the sample size that was estimated to be needed based on power analysis,” he said.

The Brazilian study is small, he noted. (In contrast, the ColCORONA trial had 4,488 outpatient participants.) “This study differs from ColCORONA in several ways – the most important being that it is a study of inpatients with moderate to severe COVID (really mostly moderate),” he added. “ColCORONA is looking at a target audience that is much larger – outpatients with mild to moderate COVID with risk factors for hospitalization. Both questions are really important and certainly not mutually exclusive, since our care remains inadequate in both venues. This study also adds value in that several other studies have been conducted in hospital patients with enrollment criteria relatively similar to this one, and all showed benefit, but those were open-label or retrospective, and this is blinded and placebo-controlled.”
 

Using colchicine in patients with COVID-19

Should physicians turn to colchicine in patients with COVID-19? “I would rather that it still be used in the context of research until formal recommendations can be made by bodies like the NIH and CDC,” Dr. Pillinger said. “But certainly, there may be times when physicians feel compelled to treat patients off label.”

He cautioned, however, that colchicine should never be used with some other drugs. Its interaction with the antibiotic clarithromycin can be fatal, he noted. And, he said, the drug must be monitored in general since it can cause rare, severe problems.

“Overall, colchicine probably works on the overabundant inflammatory response to COVID, and it may be that it can be combined with other drugs that affect viral replication or promote immunity – e.g. vaccines,” Dr. Pillinger said. “So far, it seems as if there is no safety problem with combining colchicine with other approaches, but this has not been studied in a rigorous manner.”

Moving forward, he said, the drug’s very low price outside of the United States “could provide resource-poor countries with a way to help keep patients out of precious hospital beds – or help them go home sooner once admitted.” For now, however, “we need a large-scale inpatient study, and one is currently going on in Great Britain. We also need validation of the outpatient ColCORONA study, and studies to look at whether colchicine can work in conjunction with other strategies.”

The study was funded by grants from the São Paulo Research Foundation, Brazilian National Council for Scientific and Technological Development, and CAPES Foundation. No disclosures are reported. Dr. Pillinger reports serving as an investigator for the ColCORONA trial and receiving a unrelated investigator-initiated grant from Hikma, a colchicine manufacturer.

The gout drug colchicine appears to lower the severity of COVID-19, a small new Brazilian study finds, adding to evidence that the familiar medication holds promise as a treatment for hospitalized patients.

Patients who received colchicine in this randomized, double-blinded, placebo-controlled clinical trial presented better evolution in terms of the need for supplemental oxygen and the length of hospitalisation. ... Colchicine was safe and well tolerated,” the study authors wrote in RMD Open. However, deaths were rare in the trial, they added, and it is impossible to “evaluate the capacity of colchicine to avoid admission to ICU and reduce mortality.”

The oral anti-inflammatory colchicine, widely used as treatment in rheumatic disease, was first approved in the United States 60 years ago. Researchers began to explore its potential as a COVID-19 treatment in the early months of the pandemic.

On Jan. 25, an international team of researchers reported in a press release – but not yet a published paper – that the drug seemed to reduce hospitalizations, mechanical ventilation, and deaths in the ColCORONA trial. Earlier, a much-smaller, randomized, open-label, Greek trial linked the drug to reduced time to clinical deterioration and hospital stay.

The Brazilian authors of the new study, led by Maria Isabel Lopes of the University of São Paulo’s Ribeirão Preto Medical School, randomly assigned 75 hospitalized patients with moderate to severe COVID-19 to colchicine or placebo. A total of 72 subjects completed the April-August 2020 trial: 36 received colchicine (typically 0.5 mg three times for 5 days, then 0.5 mg twice daily for 5 days; doses were adjusted in low-weight patients and those with chronic kidney disease). The other 36 received the placebo.

(In the United States, 0.6-mg tablets of generic colchicine cost as little as $1.90 each with free coupons, according to goodrx.com.)

The median age in the groups was similar (55 years); and the placebo group had more women (61% vs. 47% in the colchicine group, P = .34). All 72 patients received the same COVID-19 treatment at the time of the trial: azithromycin, hydroxychloroquine, and unfractionated heparin. Most patients, about two-thirds in both groups, also received methylprednisolone because they needed higher amounts of supplemental oxygen.

Patients in the colchicine group needed supplemental oxygen for less time: Their median time of need was 4.0 days (interquartile range [IQR], 2.0-6.0) vs. 6.5 days (IQR, 4.0-9.0) for the placebo group (P < .001). The median time for hospitalization was also lower at 7.0 days (IQR, 5.0–9.0) for the colchicine group vs. 9.0 (IQR, 7.0–12.0) for the placebo group (log rank test, 10.6; P = .001).

The researchers also reported the percentage of patients who needed supplemental oxygen at day 2 as 67% with colchicine vs. 86% with placebo, and at day 7 as 9% vs. 42% (log rank test, 10.6; P = .001). Two patients in the placebo group died, both from ventilator-associated pneumonia.

As for side effects, new or worsened diarrhea was reported more often in the colchicine group (17% vs. 6% with placebo), but the difference was not statistically significant (P = .26), and diarrhea was controlled via medication.

The researchers reported that limitations include the exclusion criteria and their inability to link colchicine to rates of ICU admissions and death.

The drug appears to help patients with COVID-19, the study authors wrote, by “inhibiting inflammasome, reducing neutrophil migration and activation, or preventing endothelial damage.”

A “well-conceived and well-designed” study

In an interview, NYU Langone Health rheumatologist Michael H. Pillinger, MD – an investigator with the ColCORONA trial – praised the Brazilian study. It “appears well-conceived and well-designed, and was enrolled at a rate that was greater than the sample size that was estimated to be needed based on power analysis,” he said.

The Brazilian study is small, he noted. (In contrast, the ColCORONA trial had 4,488 outpatient participants.) “This study differs from ColCORONA in several ways – the most important being that it is a study of inpatients with moderate to severe COVID (really mostly moderate),” he added. “ColCORONA is looking at a target audience that is much larger – outpatients with mild to moderate COVID with risk factors for hospitalization. Both questions are really important and certainly not mutually exclusive, since our care remains inadequate in both venues. This study also adds value in that several other studies have been conducted in hospital patients with enrollment criteria relatively similar to this one, and all showed benefit, but those were open-label or retrospective, and this is blinded and placebo-controlled.”
 

Using colchicine in patients with COVID-19

Should physicians turn to colchicine in patients with COVID-19? “I would rather that it still be used in the context of research until formal recommendations can be made by bodies like the NIH and CDC,” Dr. Pillinger said. “But certainly, there may be times when physicians feel compelled to treat patients off label.”

He cautioned, however, that colchicine should never be used with some other drugs. Its interaction with the antibiotic clarithromycin can be fatal, he noted. And, he said, the drug must be monitored in general since it can cause rare, severe problems.

“Overall, colchicine probably works on the overabundant inflammatory response to COVID, and it may be that it can be combined with other drugs that affect viral replication or promote immunity – e.g. vaccines,” Dr. Pillinger said. “So far, it seems as if there is no safety problem with combining colchicine with other approaches, but this has not been studied in a rigorous manner.”

Moving forward, he said, the drug’s very low price outside of the United States “could provide resource-poor countries with a way to help keep patients out of precious hospital beds – or help them go home sooner once admitted.” For now, however, “we need a large-scale inpatient study, and one is currently going on in Great Britain. We also need validation of the outpatient ColCORONA study, and studies to look at whether colchicine can work in conjunction with other strategies.”

The study was funded by grants from the São Paulo Research Foundation, Brazilian National Council for Scientific and Technological Development, and CAPES Foundation. No disclosures are reported. Dr. Pillinger reports serving as an investigator for the ColCORONA trial and receiving a unrelated investigator-initiated grant from Hikma, a colchicine manufacturer.

While some guidelines support serotonin norepinephrine reuptake inhibitors (SNRIs) as treatments for back pain, a new systematic review and meta-analysis of existing research found no firm evidence of a benefit. Adverse effects, however, are common.

“Our review shows that, although these medicines are effective, the effect is small and unlikely to be considered clinically important by most patients,” wrote the authors of the review, which appeared Jan. 20 in the BMJ. “Our review also showed that about two-thirds of patients using SNRIs experience adverse events.”

However, the report hinted that certain classes of antidepressants may provide significant relief in knee OA and sciatica.

According to a 2018 review, 10 of 15 clinical guidelines from around the world – including those of the American College of Physicians – recommended antidepressants as treatments for low back pain, and 2 advised against them. “Evidence supporting the use of antidepressants is, however, uncertain,” wrote the authors of the new review, led by Giovanni E. Ferreira, PhD, of the University of Sydney. “Systematic reviews of antidepressants for back pain and osteoarthritis have either not included several published trials, considered only one type of antidepressant (e.g., duloxetine), or failed to assess the certainty of evidence.”

For the new review, the authors analyzed 33 randomized, controlled trials with a total of 5,318 subjects. Both published data and unpublished data from clinical trial registries were included.
 

Back pain trials

A total of 19 trials examined back pain, mostly lower back pain (16 trials), and none lasted more than 1 year. Fifteen examined SNRIs while others looked at other kinds of antidepressants.

The researchers found that “the effect of SNRIs was small [on back pain] and below this review’s predetermined threshold of clinical importance. ... Evidence ranging from low to very low certainty showed no benefit of a range of antidepressant classes, including SSRIs [selective serotonin reuptake inhibitors], tetracyclic antidepressants, SARIs [serotonin antagonist and reuptake inhibitors], and NDRIs [norepinephrine and dopamine reuptake inhibitors] for pain and disability across follow-ups of 2 weeks or less, 3-13 weeks, and 3-12 months.”
 

Sciatica trials

Six trials examined antidepressants as treatments for sciatica. Very-low-certainty evidence suggested that SNRIs reduced pain at up to 2 weeks (1 trial, n = 50) but not at 3-13 weeks (3 trials, n = 96). The results of trials of tricyclic antidepressants (TCAs) were the opposite: low- to very-low-certainty evidence suggested the drugs didn’t reduce pain at up to 2 weeks (2 trials, n = 94) but did at 3-13 weeks (2 trials, n = 114) and 3-12 months (1 trial, n = 60).

“All sciatica trials were small, had imprecise estimates, and were at high risk of bias, which reduced the certainty of evidence to low and very low,” the authors cautioned. “This level of uncertainty indicates that the true estimate of effect of TCAs and SNRIs for sciatica is likely to be substantially different from what we estimated in our review.”
 

Knee OA trials

Eight trials examined SNRIs in knee OA. Moderate-certainty evidence linked the drugs to less pain at up to 2 weeks (four trials, n = 1,328) and low-certainty evidence linked them to less pain at 3-13 weeks (eight trials, n = 1,941). Low-certainty evidence also linked the drugs to less disability at 2 weeks or less (one trial, n = 353) and 3-13 weeks (seven trials, n = 1,810).

In knee OA, “the effect of SNRIs was small and below this review’s predetermined threshold of clinical importance,” the researchers wrote. “However, the lower limit of the confidence interval did contain clinically important effects for pain, but not for disability.”
 

Antidepressant side effects in trials

A total of 21 trials (n = 4,107) looked at side effects when antidepressants were studied as treatments for back pain and OA. Low-certainty evidence in 13 SNRI trials (n = 3,447) suggested a higher risk of any adverse events in antidepressant versus placebo (62.5% vs. 49.7%; relative risk, 1.23, 95% confidence interval, 1.16-1.30), but there was no significantly higher risk of serious adverse events in 10 SNRI trials with 3,309 subjects (1.6% vs. 1.3%; RR, 1.12, 95% CI, 0.61-2.07).

As for adverse effects of non-SNRIs, “the number of studies evaluating the safety of other antidepressant classes was small, trials were underpowered to detect harm, and the certainty of evidence ranged from low to very low,” the researchers wrote.

Going forward, the authors said that “large, definitive randomized trials that are free of industry ties are urgently needed to resolve uncertainties about the efficacy of antidepressants for sciatica and osteoarthritis highlighted by this review.”
 

‘Largely ineffective’ drug treatments

In an accompanying commentary, Martin Underwood, of the University of Warwick in Coventry, England, and Colin Tysall, of the University Hospitals of Coventry and Warwickshire, also in Coventry, noted that “drug treatments are largely ineffective for back pain and osteoarthritis and have the potential for serious harm. We need to work harder to help people with these disorders to live better with their pain without recourse to the prescription pad.”

However, they noted that SNRIs may still be helpful for patients with back pain or OA. “Absolute effect sizes for physical treatments for low-back pain are of similar magnitudes to those reported here and translate into numbers needed to treat of between five and nine. If the same were true for SNRIs, some people might choose to a try that option for a 1 in 10 chance of a worthwhile reduction in pain after 3 months. They can easily stop if treatment is ineffective or does not suit them.”

The research received no specific funding. The review authors disclosed relationships with GlaxoSmithKline (postgraduate scholarship), Pfizer (investigational product for two trials), and Flexeze (provision of heat wraps for a trial). Mr. Underwood reported being a director and shareholder of Clinvivo. Mr. Tysall reported no disclosures.

While some guidelines support serotonin norepinephrine reuptake inhibitors (SNRIs) as treatments for back pain, a new systematic review and meta-analysis of existing research found no firm evidence of a benefit. Adverse effects, however, are common.

“Our review shows that, although these medicines are effective, the effect is small and unlikely to be considered clinically important by most patients,” wrote the authors of the review, which appeared Jan. 20 in the BMJ. “Our review also showed that about two-thirds of patients using SNRIs experience adverse events.”

However, the report hinted that certain classes of antidepressants may provide significant relief in knee OA and sciatica.

According to a 2018 review, 10 of 15 clinical guidelines from around the world – including those of the American College of Physicians – recommended antidepressants as treatments for low back pain, and 2 advised against them. “Evidence supporting the use of antidepressants is, however, uncertain,” wrote the authors of the new review, led by Giovanni E. Ferreira, PhD, of the University of Sydney. “Systematic reviews of antidepressants for back pain and osteoarthritis have either not included several published trials, considered only one type of antidepressant (e.g., duloxetine), or failed to assess the certainty of evidence.”

For the new review, the authors analyzed 33 randomized, controlled trials with a total of 5,318 subjects. Both published data and unpublished data from clinical trial registries were included.
 

Back pain trials

A total of 19 trials examined back pain, mostly lower back pain (16 trials), and none lasted more than 1 year. Fifteen examined SNRIs while others looked at other kinds of antidepressants.

The researchers found that “the effect of SNRIs was small [on back pain] and below this review’s predetermined threshold of clinical importance. ... Evidence ranging from low to very low certainty showed no benefit of a range of antidepressant classes, including SSRIs [selective serotonin reuptake inhibitors], tetracyclic antidepressants, SARIs [serotonin antagonist and reuptake inhibitors], and NDRIs [norepinephrine and dopamine reuptake inhibitors] for pain and disability across follow-ups of 2 weeks or less, 3-13 weeks, and 3-12 months.”
 

Sciatica trials

Six trials examined antidepressants as treatments for sciatica. Very-low-certainty evidence suggested that SNRIs reduced pain at up to 2 weeks (1 trial, n = 50) but not at 3-13 weeks (3 trials, n = 96). The results of trials of tricyclic antidepressants (TCAs) were the opposite: low- to very-low-certainty evidence suggested the drugs didn’t reduce pain at up to 2 weeks (2 trials, n = 94) but did at 3-13 weeks (2 trials, n = 114) and 3-12 months (1 trial, n = 60).

“All sciatica trials were small, had imprecise estimates, and were at high risk of bias, which reduced the certainty of evidence to low and very low,” the authors cautioned. “This level of uncertainty indicates that the true estimate of effect of TCAs and SNRIs for sciatica is likely to be substantially different from what we estimated in our review.”
 

Knee OA trials

Eight trials examined SNRIs in knee OA. Moderate-certainty evidence linked the drugs to less pain at up to 2 weeks (four trials, n = 1,328) and low-certainty evidence linked them to less pain at 3-13 weeks (eight trials, n = 1,941). Low-certainty evidence also linked the drugs to less disability at 2 weeks or less (one trial, n = 353) and 3-13 weeks (seven trials, n = 1,810).

In knee OA, “the effect of SNRIs was small and below this review’s predetermined threshold of clinical importance,” the researchers wrote. “However, the lower limit of the confidence interval did contain clinically important effects for pain, but not for disability.”
 

Antidepressant side effects in trials

A total of 21 trials (n = 4,107) looked at side effects when antidepressants were studied as treatments for back pain and OA. Low-certainty evidence in 13 SNRI trials (n = 3,447) suggested a higher risk of any adverse events in antidepressant versus placebo (62.5% vs. 49.7%; relative risk, 1.23, 95% confidence interval, 1.16-1.30), but there was no significantly higher risk of serious adverse events in 10 SNRI trials with 3,309 subjects (1.6% vs. 1.3%; RR, 1.12, 95% CI, 0.61-2.07).

As for adverse effects of non-SNRIs, “the number of studies evaluating the safety of other antidepressant classes was small, trials were underpowered to detect harm, and the certainty of evidence ranged from low to very low,” the researchers wrote.

Going forward, the authors said that “large, definitive randomized trials that are free of industry ties are urgently needed to resolve uncertainties about the efficacy of antidepressants for sciatica and osteoarthritis highlighted by this review.”
 

‘Largely ineffective’ drug treatments

In an accompanying commentary, Martin Underwood, of the University of Warwick in Coventry, England, and Colin Tysall, of the University Hospitals of Coventry and Warwickshire, also in Coventry, noted that “drug treatments are largely ineffective for back pain and osteoarthritis and have the potential for serious harm. We need to work harder to help people with these disorders to live better with their pain without recourse to the prescription pad.”

However, they noted that SNRIs may still be helpful for patients with back pain or OA. “Absolute effect sizes for physical treatments for low-back pain are of similar magnitudes to those reported here and translate into numbers needed to treat of between five and nine. If the same were true for SNRIs, some people might choose to a try that option for a 1 in 10 chance of a worthwhile reduction in pain after 3 months. They can easily stop if treatment is ineffective or does not suit them.”

The research received no specific funding. The review authors disclosed relationships with GlaxoSmithKline (postgraduate scholarship), Pfizer (investigational product for two trials), and Flexeze (provision of heat wraps for a trial). Mr. Underwood reported being a director and shareholder of Clinvivo. Mr. Tysall reported no disclosures.

While some guidelines support serotonin norepinephrine reuptake inhibitors (SNRIs) as treatments for back pain, a new systematic review and meta-analysis of existing research found no firm evidence of a benefit. Adverse effects, however, are common.

“Our review shows that, although these medicines are effective, the effect is small and unlikely to be considered clinically important by most patients,” wrote the authors of the review, which appeared Jan. 20 in the BMJ. “Our review also showed that about two-thirds of patients using SNRIs experience adverse events.”

However, the report hinted that certain classes of antidepressants may provide significant relief in knee OA and sciatica.

According to a 2018 review, 10 of 15 clinical guidelines from around the world – including those of the American College of Physicians – recommended antidepressants as treatments for low back pain, and 2 advised against them. “Evidence supporting the use of antidepressants is, however, uncertain,” wrote the authors of the new review, led by Giovanni E. Ferreira, PhD, of the University of Sydney. “Systematic reviews of antidepressants for back pain and osteoarthritis have either not included several published trials, considered only one type of antidepressant (e.g., duloxetine), or failed to assess the certainty of evidence.”

For the new review, the authors analyzed 33 randomized, controlled trials with a total of 5,318 subjects. Both published data and unpublished data from clinical trial registries were included.
 

Back pain trials

A total of 19 trials examined back pain, mostly lower back pain (16 trials), and none lasted more than 1 year. Fifteen examined SNRIs while others looked at other kinds of antidepressants.

The researchers found that “the effect of SNRIs was small [on back pain] and below this review’s predetermined threshold of clinical importance. ... Evidence ranging from low to very low certainty showed no benefit of a range of antidepressant classes, including SSRIs [selective serotonin reuptake inhibitors], tetracyclic antidepressants, SARIs [serotonin antagonist and reuptake inhibitors], and NDRIs [norepinephrine and dopamine reuptake inhibitors] for pain and disability across follow-ups of 2 weeks or less, 3-13 weeks, and 3-12 months.”
 

Sciatica trials

Six trials examined antidepressants as treatments for sciatica. Very-low-certainty evidence suggested that SNRIs reduced pain at up to 2 weeks (1 trial, n = 50) but not at 3-13 weeks (3 trials, n = 96). The results of trials of tricyclic antidepressants (TCAs) were the opposite: low- to very-low-certainty evidence suggested the drugs didn’t reduce pain at up to 2 weeks (2 trials, n = 94) but did at 3-13 weeks (2 trials, n = 114) and 3-12 months (1 trial, n = 60).

“All sciatica trials were small, had imprecise estimates, and were at high risk of bias, which reduced the certainty of evidence to low and very low,” the authors cautioned. “This level of uncertainty indicates that the true estimate of effect of TCAs and SNRIs for sciatica is likely to be substantially different from what we estimated in our review.”
 

Knee OA trials

Eight trials examined SNRIs in knee OA. Moderate-certainty evidence linked the drugs to less pain at up to 2 weeks (four trials, n = 1,328) and low-certainty evidence linked them to less pain at 3-13 weeks (eight trials, n = 1,941). Low-certainty evidence also linked the drugs to less disability at 2 weeks or less (one trial, n = 353) and 3-13 weeks (seven trials, n = 1,810).

In knee OA, “the effect of SNRIs was small and below this review’s predetermined threshold of clinical importance,” the researchers wrote. “However, the lower limit of the confidence interval did contain clinically important effects for pain, but not for disability.”
 

Antidepressant side effects in trials

A total of 21 trials (n = 4,107) looked at side effects when antidepressants were studied as treatments for back pain and OA. Low-certainty evidence in 13 SNRI trials (n = 3,447) suggested a higher risk of any adverse events in antidepressant versus placebo (62.5% vs. 49.7%; relative risk, 1.23, 95% confidence interval, 1.16-1.30), but there was no significantly higher risk of serious adverse events in 10 SNRI trials with 3,309 subjects (1.6% vs. 1.3%; RR, 1.12, 95% CI, 0.61-2.07).

As for adverse effects of non-SNRIs, “the number of studies evaluating the safety of other antidepressant classes was small, trials were underpowered to detect harm, and the certainty of evidence ranged from low to very low,” the researchers wrote.

Going forward, the authors said that “large, definitive randomized trials that are free of industry ties are urgently needed to resolve uncertainties about the efficacy of antidepressants for sciatica and osteoarthritis highlighted by this review.”
 

‘Largely ineffective’ drug treatments

In an accompanying commentary, Martin Underwood, of the University of Warwick in Coventry, England, and Colin Tysall, of the University Hospitals of Coventry and Warwickshire, also in Coventry, noted that “drug treatments are largely ineffective for back pain and osteoarthritis and have the potential for serious harm. We need to work harder to help people with these disorders to live better with their pain without recourse to the prescription pad.”

However, they noted that SNRIs may still be helpful for patients with back pain or OA. “Absolute effect sizes for physical treatments for low-back pain are of similar magnitudes to those reported here and translate into numbers needed to treat of between five and nine. If the same were true for SNRIs, some people might choose to a try that option for a 1 in 10 chance of a worthwhile reduction in pain after 3 months. They can easily stop if treatment is ineffective or does not suit them.”

The research received no specific funding. The review authors disclosed relationships with GlaxoSmithKline (postgraduate scholarship), Pfizer (investigational product for two trials), and Flexeze (provision of heat wraps for a trial). Mr. Underwood reported being a director and shareholder of Clinvivo. Mr. Tysall reported no disclosures.

Despite the lack of any Food and Drug Administration–approved medications for vitiligo, there are plenty of treatment options, and therapy can make a big difference in an individual’s quality of life, according to Seemal Desai, MD, of the University of Texas, Dallas.

“We have topical steroids. We have vitamin D analogs, calcineurin inhibitors, and depigmentation therapy. We also have systemic therapy, phototherapy, surgical treatment, and even psychological therapy, Dr. Desai said in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.

Head and neck vitiligo, which “tends to respond very nicely to treatment,” is one of the affected areas “where we have an important obligation to make sure our patients are effectively and aggressively treated,” he said.

According to Dr. Desai, there are three kinds of vitiligo. Active/unstable vitiligo is marked by depigmentation spreading across 1%-2% of body surface area per month, the size of about one to two palms. Refractory vitiligo responds poorly to therapy with less than 25% of affected areas experiencing repigmentation. And the third type is chronic vitiligo. “The majority of patients we see are in this phase, where depigmentation is present for at least 1 year with no history of spontaneous repigmentation.”

Before turning to therapy, he said, make sure to understand what the patient wants. “Are they even interested in being treated? I’ve had some patients with vitiligo, it’s only on their chest, and they’re always covered. They don’t even want anything. Then I have other patients who only want their face and hands treated because those are the only parts of their body that are exposed.”

To stabilize vitiligo, Dr. Desai recommends treating patients with “mini-pulse” oral therapy with systemic steroids. “I prescribe 4 milligrams of dexamethasone to be taken 2 consecutive days per week, such as Saturdays and Sundays. I usually halve the dose in children aged less than 16 years of age, so they’d be taking 2 milligrams.” Make sure, he said, to counsel patients on side effects.

He also recommends antioxidants, particularly polypodium leucotomos, “which has been shown in studies to increase the rates of head and neck repigmentation when combined with narrowband UVB.” He recommends 240 milligrams or higher, 2 or 3 times a day. He adds that alpha lipoic acid – in combination with vitamin C, vitamin E, and phototherapy – has also been shown to be effective in inducing repigmentation, especially on the head and neck.

As for newer drugs, Dr. Desai said afamelanotide, an analogue of alpha melanocyte-stimulating hormone combined with phototherapy, has shown promise. (It was approved in 2019 to increase pain free light exposure in adults with a history of phototoxic reactions related to erythropoietic protoporphyria.) Like other medications he mentioned, it isn’t FDA approved for treating vitiligo.

On another front, “Janus kinase inhibitors are our new frontier in treating vitiligo,” he said. “Tofacitinib can be dosed as an off-label usage in vitiligo in doses of 5 milligrams every other day, up to 5 milligrams daily. It’s half of the dose of rheumatoid arthritis, which is 5 milligrams b.i.d. You can actually start to see repigmentation as soon as 2 months, and then improvement up to 5 months.”

The drug requires laboratory monitoring and is expensive, he said, and JAK inhibitor side effects must be discussed with all patients.

Topical JAK inhibitors – tofacitinib 2% cream and ruxolitinib 1.5% cream – are also being evaluated as treatment for vitiligo. “I find that ruxolitinib works a little bit better, and the early bit of vitiligo data has shown that it tends to have more of a robust pigmentation response compared to tofacitinib,” said Dr. Desai, who gets these drugs compounded for topical use.

Dr. Desai added that he prefers to combine JAK inhibitors with phototherapy when possible.

For resistant vitiligo, he said, “lasers can help, especially Q-switched ruby and Q-switched Alexandrite laser. Q-switched Nd:Yag is very popular in Asia.”

In the big picture, he said, patients can benefit greatly from treatment. “Just think about the psychological improvement a patient would get by not having to get stares when walking in a mall and not having to deal with vitiligo lesions all over their cheek and neck.”

Dr. Desai disclosed performing clinical trials and/or consulting for numerous companies, including Pfizer, Allergan, AbbVie, and Dr. Reddy’s, among others. MedscapeLive and this news organization are owned by the same parent company.

Despite the lack of any Food and Drug Administration–approved medications for vitiligo, there are plenty of treatment options, and therapy can make a big difference in an individual’s quality of life, according to Seemal Desai, MD, of the University of Texas, Dallas.

“We have topical steroids. We have vitamin D analogs, calcineurin inhibitors, and depigmentation therapy. We also have systemic therapy, phototherapy, surgical treatment, and even psychological therapy, Dr. Desai said in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.

Head and neck vitiligo, which “tends to respond very nicely to treatment,” is one of the affected areas “where we have an important obligation to make sure our patients are effectively and aggressively treated,” he said.

According to Dr. Desai, there are three kinds of vitiligo. Active/unstable vitiligo is marked by depigmentation spreading across 1%-2% of body surface area per month, the size of about one to two palms. Refractory vitiligo responds poorly to therapy with less than 25% of affected areas experiencing repigmentation. And the third type is chronic vitiligo. “The majority of patients we see are in this phase, where depigmentation is present for at least 1 year with no history of spontaneous repigmentation.”

Before turning to therapy, he said, make sure to understand what the patient wants. “Are they even interested in being treated? I’ve had some patients with vitiligo, it’s only on their chest, and they’re always covered. They don’t even want anything. Then I have other patients who only want their face and hands treated because those are the only parts of their body that are exposed.”

To stabilize vitiligo, Dr. Desai recommends treating patients with “mini-pulse” oral therapy with systemic steroids. “I prescribe 4 milligrams of dexamethasone to be taken 2 consecutive days per week, such as Saturdays and Sundays. I usually halve the dose in children aged less than 16 years of age, so they’d be taking 2 milligrams.” Make sure, he said, to counsel patients on side effects.

He also recommends antioxidants, particularly polypodium leucotomos, “which has been shown in studies to increase the rates of head and neck repigmentation when combined with narrowband UVB.” He recommends 240 milligrams or higher, 2 or 3 times a day. He adds that alpha lipoic acid – in combination with vitamin C, vitamin E, and phototherapy – has also been shown to be effective in inducing repigmentation, especially on the head and neck.

As for newer drugs, Dr. Desai said afamelanotide, an analogue of alpha melanocyte-stimulating hormone combined with phototherapy, has shown promise. (It was approved in 2019 to increase pain free light exposure in adults with a history of phototoxic reactions related to erythropoietic protoporphyria.) Like other medications he mentioned, it isn’t FDA approved for treating vitiligo.

On another front, “Janus kinase inhibitors are our new frontier in treating vitiligo,” he said. “Tofacitinib can be dosed as an off-label usage in vitiligo in doses of 5 milligrams every other day, up to 5 milligrams daily. It’s half of the dose of rheumatoid arthritis, which is 5 milligrams b.i.d. You can actually start to see repigmentation as soon as 2 months, and then improvement up to 5 months.”

The drug requires laboratory monitoring and is expensive, he said, and JAK inhibitor side effects must be discussed with all patients.

Topical JAK inhibitors – tofacitinib 2% cream and ruxolitinib 1.5% cream – are also being evaluated as treatment for vitiligo. “I find that ruxolitinib works a little bit better, and the early bit of vitiligo data has shown that it tends to have more of a robust pigmentation response compared to tofacitinib,” said Dr. Desai, who gets these drugs compounded for topical use.

Dr. Desai added that he prefers to combine JAK inhibitors with phototherapy when possible.

For resistant vitiligo, he said, “lasers can help, especially Q-switched ruby and Q-switched Alexandrite laser. Q-switched Nd:Yag is very popular in Asia.”

In the big picture, he said, patients can benefit greatly from treatment. “Just think about the psychological improvement a patient would get by not having to get stares when walking in a mall and not having to deal with vitiligo lesions all over their cheek and neck.”

Dr. Desai disclosed performing clinical trials and/or consulting for numerous companies, including Pfizer, Allergan, AbbVie, and Dr. Reddy’s, among others. MedscapeLive and this news organization are owned by the same parent company.

Despite the lack of any Food and Drug Administration–approved medications for vitiligo, there are plenty of treatment options, and therapy can make a big difference in an individual’s quality of life, according to Seemal Desai, MD, of the University of Texas, Dallas.

“We have topical steroids. We have vitamin D analogs, calcineurin inhibitors, and depigmentation therapy. We also have systemic therapy, phototherapy, surgical treatment, and even psychological therapy, Dr. Desai said in a presentation at MedscapeLive’s virtual Women’s & Pediatric Dermatology Seminar.

Head and neck vitiligo, which “tends to respond very nicely to treatment,” is one of the affected areas “where we have an important obligation to make sure our patients are effectively and aggressively treated,” he said.

According to Dr. Desai, there are three kinds of vitiligo. Active/unstable vitiligo is marked by depigmentation spreading across 1%-2% of body surface area per month, the size of about one to two palms. Refractory vitiligo responds poorly to therapy with less than 25% of affected areas experiencing repigmentation. And the third type is chronic vitiligo. “The majority of patients we see are in this phase, where depigmentation is present for at least 1 year with no history of spontaneous repigmentation.”

Before turning to therapy, he said, make sure to understand what the patient wants. “Are they even interested in being treated? I’ve had some patients with vitiligo, it’s only on their chest, and they’re always covered. They don’t even want anything. Then I have other patients who only want their face and hands treated because those are the only parts of their body that are exposed.”

To stabilize vitiligo, Dr. Desai recommends treating patients with “mini-pulse” oral therapy with systemic steroids. “I prescribe 4 milligrams of dexamethasone to be taken 2 consecutive days per week, such as Saturdays and Sundays. I usually halve the dose in children aged less than 16 years of age, so they’d be taking 2 milligrams.” Make sure, he said, to counsel patients on side effects.

He also recommends antioxidants, particularly polypodium leucotomos, “which has been shown in studies to increase the rates of head and neck repigmentation when combined with narrowband UVB.” He recommends 240 milligrams or higher, 2 or 3 times a day. He adds that alpha lipoic acid – in combination with vitamin C, vitamin E, and phototherapy – has also been shown to be effective in inducing repigmentation, especially on the head and neck.

As for newer drugs, Dr. Desai said afamelanotide, an analogue of alpha melanocyte-stimulating hormone combined with phototherapy, has shown promise. (It was approved in 2019 to increase pain free light exposure in adults with a history of phototoxic reactions related to erythropoietic protoporphyria.) Like other medications he mentioned, it isn’t FDA approved for treating vitiligo.

On another front, “Janus kinase inhibitors are our new frontier in treating vitiligo,” he said. “Tofacitinib can be dosed as an off-label usage in vitiligo in doses of 5 milligrams every other day, up to 5 milligrams daily. It’s half of the dose of rheumatoid arthritis, which is 5 milligrams b.i.d. You can actually start to see repigmentation as soon as 2 months, and then improvement up to 5 months.”

The drug requires laboratory monitoring and is expensive, he said, and JAK inhibitor side effects must be discussed with all patients.

Topical JAK inhibitors – tofacitinib 2% cream and ruxolitinib 1.5% cream – are also being evaluated as treatment for vitiligo. “I find that ruxolitinib works a little bit better, and the early bit of vitiligo data has shown that it tends to have more of a robust pigmentation response compared to tofacitinib,” said Dr. Desai, who gets these drugs compounded for topical use.

Dr. Desai added that he prefers to combine JAK inhibitors with phototherapy when possible.

For resistant vitiligo, he said, “lasers can help, especially Q-switched ruby and Q-switched Alexandrite laser. Q-switched Nd:Yag is very popular in Asia.”

In the big picture, he said, patients can benefit greatly from treatment. “Just think about the psychological improvement a patient would get by not having to get stares when walking in a mall and not having to deal with vitiligo lesions all over their cheek and neck.”

Dr. Desai disclosed performing clinical trials and/or consulting for numerous companies, including Pfizer, Allergan, AbbVie, and Dr. Reddy’s, among others. MedscapeLive and this news organization are owned by the same parent company.

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.

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.

Prognoses remain extremely poor after hypomethylating agents (HMAs) fail in patients with higher-risk myelodysplastic syndromes (HR-MDS). But a hematologist-oncologist told colleagues that novel therapies are in the works, and some show promise.

Still, “the clinical development for drugs in this setting has been quite challenging, and we have had a lot of drugs that have died in this space over the years,” cautioned Amer Zeidan, MBBS, MHS, an associate professor at Yale University, New Haven, Conn., in a presentation at the virtual Acute Leukemia Forum of Hemedicus. For now, “the best way to manage HMA failure in MDS patients is by preventing HMA failure.”

Dr. Zeidan highlighted a 2016 study – which he led – that found the median overall survival from diagnosis was just a median of 17.0 months (95% confidence interval, 15.8-18.4) in 632 patients with HR-MDS. Another 2016 study, which he also led, reported median overall survival of 11 months (95% CI, 10-14) and 12 months (95% CI, 11-16; P = .26) for patients aged 66 or older who had HR-MDS and took azacitidine and decitabine, respectively. Median survival is even shorter after HMA failure, he said.

The most important obstacle to effective therapy is “the biologic and molecular heterogeneity of the disease,” he said. “Only a certain number of genes are altered in a significant number of patients. And then you have a very long tail, with so many alterations, but most of them are rare. That makes targeting all patients with the same mechanism quite challenging. Also, we poorly understand how hypomethylating agents work and the mechanism of primary and secondary failure. And many MDS patients are older with multiple conditions, multiple comorbidities. By the time of failure, they are generally beaten up and very difficult to enroll in clinical trials.”

Even so, he said, “the understanding of the molecular pathogenesis of MDS is starting to open the door for new drug development opportunities. What’s been changing over the last 5 years is an increased understanding of targeting some of the alterations that are specific to the patient – individualized targeting or precision medicine.”
 

Novel therapies

Dr. Zeidan said the novel therapies for HR-MDS after HMA failure fall into these categories: molecularly targeted agents, genetically agnostic small-molecule inhibitors, immunotherapies, and chemotherapy/epigenetic agents.

Multiple trials, for example, are examining a chemotherapy treatment CPX-351 (liposomal cytarabine-daunorubicin) in HR-MDS, and a 2018 study showed improvement in median survival in older patients with newly diagnosed secondary acute myeloid leukemia. “However, this remains an investigational treatment,” Dr. Zeidan cautioned.

Venetoclax is also being studied. Animal and cell culture data suggest there may be helpful synergistic activity between venetoclax and azacitidine in both the frontline and relapse settings. Dr. Zeidan highlighted his own 2019 report on a phase 1b study of venetoclax versus venetoclax and azacitidine in the HMA failure/HR-MDS setting. The results are “quite exciting,” he said.

The report noted that, “although the study is still ongoing, the 6-month OS [overall survival] estimate of 57% in monotherapy [patients] compares favorably to historical controls.”

Glasdegib is “another drug of interest,” although it’s mostly been studied in the frontline setting, he said, and “we don’t have much data with this drug in the refractory setting for MDS patients.” APR-246 is also intriguing, he said, but again lacks data in the refractory setting.

Dr. Zeidan noted research into other treatments – rigosertib (recent findings have been disappointing), ivosidenib for IDH1-mutated MDS, AG221-001 and enasidenib (targeting IDH2 mutations), trametinib (targeting RAS pathway mutations), and others. For now, “clinical trial participation should be the best way to manage these patients.”

Dr. Zeidan disclosed multiple disclosures, including relationships with Pfizer, Novartis, Abbvie, Pfizer, Medimmune/AstraZeneca and Boehringer Ingelheim, among others.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Prognoses remain extremely poor after hypomethylating agents (HMAs) fail in patients with higher-risk myelodysplastic syndromes (HR-MDS). But a hematologist-oncologist told colleagues that novel therapies are in the works, and some show promise.

Still, “the clinical development for drugs in this setting has been quite challenging, and we have had a lot of drugs that have died in this space over the years,” cautioned Amer Zeidan, MBBS, MHS, an associate professor at Yale University, New Haven, Conn., in a presentation at the virtual Acute Leukemia Forum of Hemedicus. For now, “the best way to manage HMA failure in MDS patients is by preventing HMA failure.”

Dr. Zeidan highlighted a 2016 study – which he led – that found the median overall survival from diagnosis was just a median of 17.0 months (95% confidence interval, 15.8-18.4) in 632 patients with HR-MDS. Another 2016 study, which he also led, reported median overall survival of 11 months (95% CI, 10-14) and 12 months (95% CI, 11-16; P = .26) for patients aged 66 or older who had HR-MDS and took azacitidine and decitabine, respectively. Median survival is even shorter after HMA failure, he said.

The most important obstacle to effective therapy is “the biologic and molecular heterogeneity of the disease,” he said. “Only a certain number of genes are altered in a significant number of patients. And then you have a very long tail, with so many alterations, but most of them are rare. That makes targeting all patients with the same mechanism quite challenging. Also, we poorly understand how hypomethylating agents work and the mechanism of primary and secondary failure. And many MDS patients are older with multiple conditions, multiple comorbidities. By the time of failure, they are generally beaten up and very difficult to enroll in clinical trials.”

Even so, he said, “the understanding of the molecular pathogenesis of MDS is starting to open the door for new drug development opportunities. What’s been changing over the last 5 years is an increased understanding of targeting some of the alterations that are specific to the patient – individualized targeting or precision medicine.”
 

Novel therapies

Dr. Zeidan said the novel therapies for HR-MDS after HMA failure fall into these categories: molecularly targeted agents, genetically agnostic small-molecule inhibitors, immunotherapies, and chemotherapy/epigenetic agents.

Multiple trials, for example, are examining a chemotherapy treatment CPX-351 (liposomal cytarabine-daunorubicin) in HR-MDS, and a 2018 study showed improvement in median survival in older patients with newly diagnosed secondary acute myeloid leukemia. “However, this remains an investigational treatment,” Dr. Zeidan cautioned.

Venetoclax is also being studied. Animal and cell culture data suggest there may be helpful synergistic activity between venetoclax and azacitidine in both the frontline and relapse settings. Dr. Zeidan highlighted his own 2019 report on a phase 1b study of venetoclax versus venetoclax and azacitidine in the HMA failure/HR-MDS setting. The results are “quite exciting,” he said.

The report noted that, “although the study is still ongoing, the 6-month OS [overall survival] estimate of 57% in monotherapy [patients] compares favorably to historical controls.”

Glasdegib is “another drug of interest,” although it’s mostly been studied in the frontline setting, he said, and “we don’t have much data with this drug in the refractory setting for MDS patients.” APR-246 is also intriguing, he said, but again lacks data in the refractory setting.

Dr. Zeidan noted research into other treatments – rigosertib (recent findings have been disappointing), ivosidenib for IDH1-mutated MDS, AG221-001 and enasidenib (targeting IDH2 mutations), trametinib (targeting RAS pathway mutations), and others. For now, “clinical trial participation should be the best way to manage these patients.”

Dr. Zeidan disclosed multiple disclosures, including relationships with Pfizer, Novartis, Abbvie, Pfizer, Medimmune/AstraZeneca and Boehringer Ingelheim, among others.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Prognoses remain extremely poor after hypomethylating agents (HMAs) fail in patients with higher-risk myelodysplastic syndromes (HR-MDS). But a hematologist-oncologist told colleagues that novel therapies are in the works, and some show promise.

Still, “the clinical development for drugs in this setting has been quite challenging, and we have had a lot of drugs that have died in this space over the years,” cautioned Amer Zeidan, MBBS, MHS, an associate professor at Yale University, New Haven, Conn., in a presentation at the virtual Acute Leukemia Forum of Hemedicus. For now, “the best way to manage HMA failure in MDS patients is by preventing HMA failure.”

Dr. Zeidan highlighted a 2016 study – which he led – that found the median overall survival from diagnosis was just a median of 17.0 months (95% confidence interval, 15.8-18.4) in 632 patients with HR-MDS. Another 2016 study, which he also led, reported median overall survival of 11 months (95% CI, 10-14) and 12 months (95% CI, 11-16; P = .26) for patients aged 66 or older who had HR-MDS and took azacitidine and decitabine, respectively. Median survival is even shorter after HMA failure, he said.

The most important obstacle to effective therapy is “the biologic and molecular heterogeneity of the disease,” he said. “Only a certain number of genes are altered in a significant number of patients. And then you have a very long tail, with so many alterations, but most of them are rare. That makes targeting all patients with the same mechanism quite challenging. Also, we poorly understand how hypomethylating agents work and the mechanism of primary and secondary failure. And many MDS patients are older with multiple conditions, multiple comorbidities. By the time of failure, they are generally beaten up and very difficult to enroll in clinical trials.”

Even so, he said, “the understanding of the molecular pathogenesis of MDS is starting to open the door for new drug development opportunities. What’s been changing over the last 5 years is an increased understanding of targeting some of the alterations that are specific to the patient – individualized targeting or precision medicine.”
 

Novel therapies

Dr. Zeidan said the novel therapies for HR-MDS after HMA failure fall into these categories: molecularly targeted agents, genetically agnostic small-molecule inhibitors, immunotherapies, and chemotherapy/epigenetic agents.

Multiple trials, for example, are examining a chemotherapy treatment CPX-351 (liposomal cytarabine-daunorubicin) in HR-MDS, and a 2018 study showed improvement in median survival in older patients with newly diagnosed secondary acute myeloid leukemia. “However, this remains an investigational treatment,” Dr. Zeidan cautioned.

Venetoclax is also being studied. Animal and cell culture data suggest there may be helpful synergistic activity between venetoclax and azacitidine in both the frontline and relapse settings. Dr. Zeidan highlighted his own 2019 report on a phase 1b study of venetoclax versus venetoclax and azacitidine in the HMA failure/HR-MDS setting. The results are “quite exciting,” he said.

The report noted that, “although the study is still ongoing, the 6-month OS [overall survival] estimate of 57% in monotherapy [patients] compares favorably to historical controls.”

Glasdegib is “another drug of interest,” although it’s mostly been studied in the frontline setting, he said, and “we don’t have much data with this drug in the refractory setting for MDS patients.” APR-246 is also intriguing, he said, but again lacks data in the refractory setting.

Dr. Zeidan noted research into other treatments – rigosertib (recent findings have been disappointing), ivosidenib for IDH1-mutated MDS, AG221-001 and enasidenib (targeting IDH2 mutations), trametinib (targeting RAS pathway mutations), and others. For now, “clinical trial participation should be the best way to manage these patients.”

Dr. Zeidan disclosed multiple disclosures, including relationships with Pfizer, Novartis, Abbvie, Pfizer, Medimmune/AstraZeneca and Boehringer Ingelheim, among others.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.

“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”

Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”

In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
 

A potential role

Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.

“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.

If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”

In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”

In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”

The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”

In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”

Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”

Dr. Appelbaum reports no disclosures.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.

“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”

Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”

In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
 

A potential role

Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.

“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.

If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”

In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”

In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”

The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”

In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”

Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”

Dr. Appelbaum reports no disclosures.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.

“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”

Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”

In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
 

A potential role

Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.

“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.

If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”

In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”

In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”

The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”

In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”

Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”

Dr. Appelbaum reports no disclosures.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Novel therapies are poised to dramatically change frontline therapy for acute myeloid leukemia (AML), and they have the potential to replace chemotherapy, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus.

But more work needs to be done, noted Alexander Perl, MD, MS, associate professor at the University of Pennsylvania, Philadelphia. While advances have transformed AML treatment in the relapsed/refractory setting, “we’re just not seeing that substantive improvement” for newly diagnosed patients, he said. “We need to find the disease-modifying drugs that work in the relapsed/refractory setting and move those frontline. That’s where we’re going to see the transformations.”

Research suggests that low-intensity therapy holds tremendous promise, he said, “with the idea that we could make therapy much more tolerable for the vast majority of patients affected by AML, who, as we know, are older patients.”

Dr. Perl highlighted the 2020 VIALE-A study – venetoclax/azacitidine versus azacitidine/placebo – which reported that “in previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone.”

Venetoclax promotes apoptosis in leukemia cells, Dr. Perl said. “To a certain extent, you can think of it as putting the rubber to the road in terms of what actually chemotherapy is designed to do, which is to make leukemic blasts apoptose. It does so without DNA damage and with much less toxicity to the patient. Therefore it can be added to any number of regimens – granted, with mild suppression, but with relatively little extramedullary toxicity.”

Dr. Perl noted that the venetoclax arm “showed a higher response rate than azacitidine in pretty much every subgroup that was looked at, whether patients had de novo leukemia, secondary leukemia, multiple mutational complements, various different karyotypes. The response rates on this study are as high as what we often will see with intensive chemotherapy.” He added that “the winning arm on this trial seems to hold up against any low-intensity therapy, and I would argue against many high-intensity therapies in older patients.”

As for other targeted agents, isocitrate dehydrogenase (IDH) inhibitors “are very promising drugs in the relapsed/refractory setting, which is primarily where these drugs are given. In regard to frontline treatment, “data are coming from a very small study, but they’re very encouraging. It’s hard to entirely say that we’re ready to change practice based on this. But it’s very encouraging – the idea that earlier use of a drug-targeting IDH mutation might lead to substantially better outcomes.”

Moving forward, he said, “we could put all of our eggs in one basket and use many active drugs [at] front line. Or we can perhaps be smart about sequencing these drugs one after another, or using more intensive approaches followed by maintenance approaches followed by more intensive approaches.”

This approach is similar to strategies in myeloma patients “who less and less are relying on an autologous transplant for durable control of their disease, and more and more are using low-intensity biologically targeted drugs,” he said.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Dr. Perl reported numerous disclosures, including relationships with Daiichi Sankyo, Abbvie, and Astellas.

Novel therapies are poised to dramatically change frontline therapy for acute myeloid leukemia (AML), and they have the potential to replace chemotherapy, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus.

But more work needs to be done, noted Alexander Perl, MD, MS, associate professor at the University of Pennsylvania, Philadelphia. While advances have transformed AML treatment in the relapsed/refractory setting, “we’re just not seeing that substantive improvement” for newly diagnosed patients, he said. “We need to find the disease-modifying drugs that work in the relapsed/refractory setting and move those frontline. That’s where we’re going to see the transformations.”

Research suggests that low-intensity therapy holds tremendous promise, he said, “with the idea that we could make therapy much more tolerable for the vast majority of patients affected by AML, who, as we know, are older patients.”

Dr. Perl highlighted the 2020 VIALE-A study – venetoclax/azacitidine versus azacitidine/placebo – which reported that “in previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone.”

Venetoclax promotes apoptosis in leukemia cells, Dr. Perl said. “To a certain extent, you can think of it as putting the rubber to the road in terms of what actually chemotherapy is designed to do, which is to make leukemic blasts apoptose. It does so without DNA damage and with much less toxicity to the patient. Therefore it can be added to any number of regimens – granted, with mild suppression, but with relatively little extramedullary toxicity.”

Dr. Perl noted that the venetoclax arm “showed a higher response rate than azacitidine in pretty much every subgroup that was looked at, whether patients had de novo leukemia, secondary leukemia, multiple mutational complements, various different karyotypes. The response rates on this study are as high as what we often will see with intensive chemotherapy.” He added that “the winning arm on this trial seems to hold up against any low-intensity therapy, and I would argue against many high-intensity therapies in older patients.”

As for other targeted agents, isocitrate dehydrogenase (IDH) inhibitors “are very promising drugs in the relapsed/refractory setting, which is primarily where these drugs are given. In regard to frontline treatment, “data are coming from a very small study, but they’re very encouraging. It’s hard to entirely say that we’re ready to change practice based on this. But it’s very encouraging – the idea that earlier use of a drug-targeting IDH mutation might lead to substantially better outcomes.”

Moving forward, he said, “we could put all of our eggs in one basket and use many active drugs [at] front line. Or we can perhaps be smart about sequencing these drugs one after another, or using more intensive approaches followed by maintenance approaches followed by more intensive approaches.”

This approach is similar to strategies in myeloma patients “who less and less are relying on an autologous transplant for durable control of their disease, and more and more are using low-intensity biologically targeted drugs,” he said.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Dr. Perl reported numerous disclosures, including relationships with Daiichi Sankyo, Abbvie, and Astellas.

Novel therapies are poised to dramatically change frontline therapy for acute myeloid leukemia (AML), and they have the potential to replace chemotherapy, a hematologist/oncologist told colleagues at the virtual Acute Leukemia Forum of Hemedicus.

But more work needs to be done, noted Alexander Perl, MD, MS, associate professor at the University of Pennsylvania, Philadelphia. While advances have transformed AML treatment in the relapsed/refractory setting, “we’re just not seeing that substantive improvement” for newly diagnosed patients, he said. “We need to find the disease-modifying drugs that work in the relapsed/refractory setting and move those frontline. That’s where we’re going to see the transformations.”

Research suggests that low-intensity therapy holds tremendous promise, he said, “with the idea that we could make therapy much more tolerable for the vast majority of patients affected by AML, who, as we know, are older patients.”

Dr. Perl highlighted the 2020 VIALE-A study – venetoclax/azacitidine versus azacitidine/placebo – which reported that “in previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone.”

Venetoclax promotes apoptosis in leukemia cells, Dr. Perl said. “To a certain extent, you can think of it as putting the rubber to the road in terms of what actually chemotherapy is designed to do, which is to make leukemic blasts apoptose. It does so without DNA damage and with much less toxicity to the patient. Therefore it can be added to any number of regimens – granted, with mild suppression, but with relatively little extramedullary toxicity.”

Dr. Perl noted that the venetoclax arm “showed a higher response rate than azacitidine in pretty much every subgroup that was looked at, whether patients had de novo leukemia, secondary leukemia, multiple mutational complements, various different karyotypes. The response rates on this study are as high as what we often will see with intensive chemotherapy.” He added that “the winning arm on this trial seems to hold up against any low-intensity therapy, and I would argue against many high-intensity therapies in older patients.”

As for other targeted agents, isocitrate dehydrogenase (IDH) inhibitors “are very promising drugs in the relapsed/refractory setting, which is primarily where these drugs are given. In regard to frontline treatment, “data are coming from a very small study, but they’re very encouraging. It’s hard to entirely say that we’re ready to change practice based on this. But it’s very encouraging – the idea that earlier use of a drug-targeting IDH mutation might lead to substantially better outcomes.”

Moving forward, he said, “we could put all of our eggs in one basket and use many active drugs [at] front line. Or we can perhaps be smart about sequencing these drugs one after another, or using more intensive approaches followed by maintenance approaches followed by more intensive approaches.”

This approach is similar to strategies in myeloma patients “who less and less are relying on an autologous transplant for durable control of their disease, and more and more are using low-intensity biologically targeted drugs,” he said.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Dr. Perl reported numerous disclosures, including relationships with Daiichi Sankyo, Abbvie, and Astellas.

Physicians are gaining a greater understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) in allo-hematopoietic cell transplantation (allo-HCT), a hematologist/oncologist told colleagues, and novel treatments are being tested.

However, options remain limited. There’s only one Food and Drug Administration–approved therapy for cGVHD that’s failed one or more treatments, and clinical trials remain a crucial option in some cases, said Mary E.D. Flowers, MD, professor of medicine at the University of Washington’s Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

According to Dr. Flowers, cGVHD – a product of a graft’s “immunological assault” against the person receiving a transplant – occurs in 40% of patients within a year after allo-HCT. The disorder “is associated with a poor quality of life, disability, and increased mortality after allo-transplantation,” she said. “It’s a syndrome that can be inflammatory and fibrotic. It involves several organs – the skin, the mouth, the eyes, the lungs, the GI tract.”

The median length of treatment after peripheral blood stem cell transplant is 3.5 years, Dr. Flowers said. Seven years after treatment, 10% of those who are alive – and have avoided relapse – will still need treatment. “Corticosteroids remain the first-line [treatment], at 0.5-1.0 [mg/kg], but they do not control at least 40% of the patients with cGVHD.”

In regard to pathophysiology, she highlighted a 2017 report that presented findings about the pathophysiology of cGVHD. The findings, the report authors wrote, “have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition.”

For now, no agents other than corticosteroids have shown benefit in cGVHD as initial therapy, Dr. Flowers said. In fact, several trials closed early from lack of benefit. But trials continue, she said: Results are pending for a completed phase 3 trial of ibrutinib, a Bruton tyrosine kinase inhibitor, plus steroids for initial treatment of cGVHD. Nearly 500 patients were enrolled, she said. And there’s an ongoing phase 2/3 trial of itacitinib, a Janus kinase 1 inhibitor plus steroids as initial treatment.

Dr. Flowers highlighted the case of a patient with moderate cGVHD. The patient was treated with infection prophylaxis, supportive care for oral and eyes manifestations, and prednisone 0.5 mg/kg (at a lower dose because of diabetes) plus a substitution of tacrolimus with sirolimus, a calcineurin inhibitor.

Why sirolimus? At this early point in progression, she said, the patient didn’t necessarily need systemwide chemo-suppression, and calcineurin inhibitors can be “quite effective” in management of inflammation in the liver. “It would be a completely different story once the patient develops severe cGVHR.” In that case, she said, calcineurin inhibitors wouldn’t be appropriate.

The patient’s status deteriorated to severe cGVHD, and sirolimus was replaced with ibrutinib. Other drugs were added to prevent infection and treat bronchiolitis obliterans syndrome.

In general, “the goal of the treatment is get adequate control of clinical manifestations and prevent more severe disease from developing,” Dr. Flowers said.

In response to a question about polypharmacy in patient with advanced disease – “we tend not to peel those drugs off” – Dr. Flowers said she does see new patients who appear to be taking too many medications. “They are on five drugs, and I say, ‘What are we doing?’ ”

Quite often, Dr. Flowers said, she doesn’t add therapies to existing ones but instead looks for substitutes. “A clinical lesson that I feel that I learned over time is: Ask your questions first. What would you like to see in 3 months? Or 6 months? Before you just add another therapy, do you really know what the trajectory of a disease might be?”

Dr. Flowers discloses research support (Pharmacyclics, Incyte), speaker honorarium (Janssen, Johnson & Johnson, Astellas, Mallinckrodt), and consulting relationships (Pharmacyclics, CSL Behring, Fresenius Kabi).

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Physicians are gaining a greater understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) in allo-hematopoietic cell transplantation (allo-HCT), a hematologist/oncologist told colleagues, and novel treatments are being tested.

However, options remain limited. There’s only one Food and Drug Administration–approved therapy for cGVHD that’s failed one or more treatments, and clinical trials remain a crucial option in some cases, said Mary E.D. Flowers, MD, professor of medicine at the University of Washington’s Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

According to Dr. Flowers, cGVHD – a product of a graft’s “immunological assault” against the person receiving a transplant – occurs in 40% of patients within a year after allo-HCT. The disorder “is associated with a poor quality of life, disability, and increased mortality after allo-transplantation,” she said. “It’s a syndrome that can be inflammatory and fibrotic. It involves several organs – the skin, the mouth, the eyes, the lungs, the GI tract.”

The median length of treatment after peripheral blood stem cell transplant is 3.5 years, Dr. Flowers said. Seven years after treatment, 10% of those who are alive – and have avoided relapse – will still need treatment. “Corticosteroids remain the first-line [treatment], at 0.5-1.0 [mg/kg], but they do not control at least 40% of the patients with cGVHD.”

In regard to pathophysiology, she highlighted a 2017 report that presented findings about the pathophysiology of cGVHD. The findings, the report authors wrote, “have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition.”

For now, no agents other than corticosteroids have shown benefit in cGVHD as initial therapy, Dr. Flowers said. In fact, several trials closed early from lack of benefit. But trials continue, she said: Results are pending for a completed phase 3 trial of ibrutinib, a Bruton tyrosine kinase inhibitor, plus steroids for initial treatment of cGVHD. Nearly 500 patients were enrolled, she said. And there’s an ongoing phase 2/3 trial of itacitinib, a Janus kinase 1 inhibitor plus steroids as initial treatment.

Dr. Flowers highlighted the case of a patient with moderate cGVHD. The patient was treated with infection prophylaxis, supportive care for oral and eyes manifestations, and prednisone 0.5 mg/kg (at a lower dose because of diabetes) plus a substitution of tacrolimus with sirolimus, a calcineurin inhibitor.

Why sirolimus? At this early point in progression, she said, the patient didn’t necessarily need systemwide chemo-suppression, and calcineurin inhibitors can be “quite effective” in management of inflammation in the liver. “It would be a completely different story once the patient develops severe cGVHR.” In that case, she said, calcineurin inhibitors wouldn’t be appropriate.

The patient’s status deteriorated to severe cGVHD, and sirolimus was replaced with ibrutinib. Other drugs were added to prevent infection and treat bronchiolitis obliterans syndrome.

In general, “the goal of the treatment is get adequate control of clinical manifestations and prevent more severe disease from developing,” Dr. Flowers said.

In response to a question about polypharmacy in patient with advanced disease – “we tend not to peel those drugs off” – Dr. Flowers said she does see new patients who appear to be taking too many medications. “They are on five drugs, and I say, ‘What are we doing?’ ”

Quite often, Dr. Flowers said, she doesn’t add therapies to existing ones but instead looks for substitutes. “A clinical lesson that I feel that I learned over time is: Ask your questions first. What would you like to see in 3 months? Or 6 months? Before you just add another therapy, do you really know what the trajectory of a disease might be?”

Dr. Flowers discloses research support (Pharmacyclics, Incyte), speaker honorarium (Janssen, Johnson & Johnson, Astellas, Mallinckrodt), and consulting relationships (Pharmacyclics, CSL Behring, Fresenius Kabi).

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Physicians are gaining a greater understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) in allo-hematopoietic cell transplantation (allo-HCT), a hematologist/oncologist told colleagues, and novel treatments are being tested.

However, options remain limited. There’s only one Food and Drug Administration–approved therapy for cGVHD that’s failed one or more treatments, and clinical trials remain a crucial option in some cases, said Mary E.D. Flowers, MD, professor of medicine at the University of Washington’s Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.

According to Dr. Flowers, cGVHD – a product of a graft’s “immunological assault” against the person receiving a transplant – occurs in 40% of patients within a year after allo-HCT. The disorder “is associated with a poor quality of life, disability, and increased mortality after allo-transplantation,” she said. “It’s a syndrome that can be inflammatory and fibrotic. It involves several organs – the skin, the mouth, the eyes, the lungs, the GI tract.”

The median length of treatment after peripheral blood stem cell transplant is 3.5 years, Dr. Flowers said. Seven years after treatment, 10% of those who are alive – and have avoided relapse – will still need treatment. “Corticosteroids remain the first-line [treatment], at 0.5-1.0 [mg/kg], but they do not control at least 40% of the patients with cGVHD.”

In regard to pathophysiology, she highlighted a 2017 report that presented findings about the pathophysiology of cGVHD. The findings, the report authors wrote, “have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition.”

For now, no agents other than corticosteroids have shown benefit in cGVHD as initial therapy, Dr. Flowers said. In fact, several trials closed early from lack of benefit. But trials continue, she said: Results are pending for a completed phase 3 trial of ibrutinib, a Bruton tyrosine kinase inhibitor, plus steroids for initial treatment of cGVHD. Nearly 500 patients were enrolled, she said. And there’s an ongoing phase 2/3 trial of itacitinib, a Janus kinase 1 inhibitor plus steroids as initial treatment.

Dr. Flowers highlighted the case of a patient with moderate cGVHD. The patient was treated with infection prophylaxis, supportive care for oral and eyes manifestations, and prednisone 0.5 mg/kg (at a lower dose because of diabetes) plus a substitution of tacrolimus with sirolimus, a calcineurin inhibitor.

Why sirolimus? At this early point in progression, she said, the patient didn’t necessarily need systemwide chemo-suppression, and calcineurin inhibitors can be “quite effective” in management of inflammation in the liver. “It would be a completely different story once the patient develops severe cGVHR.” In that case, she said, calcineurin inhibitors wouldn’t be appropriate.

The patient’s status deteriorated to severe cGVHD, and sirolimus was replaced with ibrutinib. Other drugs were added to prevent infection and treat bronchiolitis obliterans syndrome.

In general, “the goal of the treatment is get adequate control of clinical manifestations and prevent more severe disease from developing,” Dr. Flowers said.

In response to a question about polypharmacy in patient with advanced disease – “we tend not to peel those drugs off” – Dr. Flowers said she does see new patients who appear to be taking too many medications. “They are on five drugs, and I say, ‘What are we doing?’ ”

Quite often, Dr. Flowers said, she doesn’t add therapies to existing ones but instead looks for substitutes. “A clinical lesson that I feel that I learned over time is: Ask your questions first. What would you like to see in 3 months? Or 6 months? Before you just add another therapy, do you really know what the trajectory of a disease might be?”

Dr. Flowers discloses research support (Pharmacyclics, Incyte), speaker honorarium (Janssen, Johnson & Johnson, Astellas, Mallinckrodt), and consulting relationships (Pharmacyclics, CSL Behring, Fresenius Kabi).

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

Despite a variety of options, patients with relapsed/refractory acute myeloid leukemia (AML) continue to face poor prognoses, and a standard of care remains elusive, a hematologist/oncologist told colleagues.

“Clearly we have a problem with this group of patients,” Ehab Atallah, MD, professor of medicine at Medical College of Wisconsin, Milwaukee, said in a presentation at the virtual Acute Leukemia Forum of Hemedicus. In regard to treatments, he added, “we still have multiple unanswered questions.”

As Dr. Atallah noted, a 2018 study of 3,012 patients – in 9 successive ECOG‐ACRIN trials for newly diagnosed AML from 1984-2008 – showed poor outcomes for relapsed/refractory patients. At a median follow-up of 9.7 years, 59.1% reached first complete remission (CR1), and 58.9% of those relapsed. In the relapsed patients, the median overall survival from relapse was 0.5 years, and the overall survival (OS) over 5 years was 10%.

“Even among patients who relapsed with better prognostic factors – age < 40 and CR1 > 12 months – there was no significant OS difference between the studies,” the study noted. “In conclusion, this large cohort appears to confirm that the survival of AML patients post relapse continues to be dismal and has not improved during the past quarter of a century.”

There isn’t a clear standard of care, said Dr. Atallah, as shown by a 2014 phase 3 study of elacytarabine vs. investigator choice in relapsed/refractory AML patients. The investigators chose seven treatment options for the control arm.

So how can physicians make the best decisions about treatment? A 2018 report finds that some factors do offer guidance about how well relapsed patients will do, Dr. Atallah said, including worse prognoses for higher age (>50 years), time to relapse (< 1 year), number of cycles of treatment needed to achieve remission (more than 1), and unfavorable cytogenetics. And, he said, “practically no one is cured when their leukemia relapses without stem cell transplantation.”

Also keep comorbidities in mind, he said, and consider previous therapies – not just the ones implemented prior to their induction but from all treatments they received: “How much anthracycline did they get? Do they still have room to receive any more anthracycline? Do they have any pulmonary complications from GVHD [graft versus host disease]?”

Another tool may be helpful. A 2013 study found that geriatric assessment predicted survival for older adults with AML who took induction chemotherapy, he said. “I’m pretty sure that this geriatric assessment would also have significant prognostic information for patients with relapsed refractory AML.”

Molecular changes add to the complexity of treatment for relapsed/refractory AML, Dr. Atallah said, in light of new molecularly targeted drugs. He pointed to a 2019 study that showed a slight increase in median overall survival (9.3 months vs. 5.6 months) for gilteritinib vs. salvage chemotherapy in relapsed/refractory patients with FLT3-mutated AML. Other studies have shown limited effects of ID1 inhibitors, he said.

In the big picture, “there are many patient-, disease-, and prior-therapy-related variables that are involved in our decisions plus donor availability, social support, whether they have a transplant before, what kind of treatment they got before the functional assessment, and comorbidities. Even with the current choices for relapsed/refractory AML, the overall survival remains poor. Enrollment in clinical trials would be the best option for these patients.”

Dr. Atallah disclosed ties with Jazz, Abbvie, Takeda, Celgene, and Novartis.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

SOURCE: “Why Is There No Standard of Care for Relapsed AML?” Acute Leukemia Forum of Hemedicus, Oct. 15, 2020.

Despite a variety of options, patients with relapsed/refractory acute myeloid leukemia (AML) continue to face poor prognoses, and a standard of care remains elusive, a hematologist/oncologist told colleagues.

“Clearly we have a problem with this group of patients,” Ehab Atallah, MD, professor of medicine at Medical College of Wisconsin, Milwaukee, said in a presentation at the virtual Acute Leukemia Forum of Hemedicus. In regard to treatments, he added, “we still have multiple unanswered questions.”

As Dr. Atallah noted, a 2018 study of 3,012 patients – in 9 successive ECOG‐ACRIN trials for newly diagnosed AML from 1984-2008 – showed poor outcomes for relapsed/refractory patients. At a median follow-up of 9.7 years, 59.1% reached first complete remission (CR1), and 58.9% of those relapsed. In the relapsed patients, the median overall survival from relapse was 0.5 years, and the overall survival (OS) over 5 years was 10%.

“Even among patients who relapsed with better prognostic factors – age < 40 and CR1 > 12 months – there was no significant OS difference between the studies,” the study noted. “In conclusion, this large cohort appears to confirm that the survival of AML patients post relapse continues to be dismal and has not improved during the past quarter of a century.”

There isn’t a clear standard of care, said Dr. Atallah, as shown by a 2014 phase 3 study of elacytarabine vs. investigator choice in relapsed/refractory AML patients. The investigators chose seven treatment options for the control arm.

So how can physicians make the best decisions about treatment? A 2018 report finds that some factors do offer guidance about how well relapsed patients will do, Dr. Atallah said, including worse prognoses for higher age (>50 years), time to relapse (< 1 year), number of cycles of treatment needed to achieve remission (more than 1), and unfavorable cytogenetics. And, he said, “practically no one is cured when their leukemia relapses without stem cell transplantation.”

Also keep comorbidities in mind, he said, and consider previous therapies – not just the ones implemented prior to their induction but from all treatments they received: “How much anthracycline did they get? Do they still have room to receive any more anthracycline? Do they have any pulmonary complications from GVHD [graft versus host disease]?”

Another tool may be helpful. A 2013 study found that geriatric assessment predicted survival for older adults with AML who took induction chemotherapy, he said. “I’m pretty sure that this geriatric assessment would also have significant prognostic information for patients with relapsed refractory AML.”

Molecular changes add to the complexity of treatment for relapsed/refractory AML, Dr. Atallah said, in light of new molecularly targeted drugs. He pointed to a 2019 study that showed a slight increase in median overall survival (9.3 months vs. 5.6 months) for gilteritinib vs. salvage chemotherapy in relapsed/refractory patients with FLT3-mutated AML. Other studies have shown limited effects of ID1 inhibitors, he said.

In the big picture, “there are many patient-, disease-, and prior-therapy-related variables that are involved in our decisions plus donor availability, social support, whether they have a transplant before, what kind of treatment they got before the functional assessment, and comorbidities. Even with the current choices for relapsed/refractory AML, the overall survival remains poor. Enrollment in clinical trials would be the best option for these patients.”

Dr. Atallah disclosed ties with Jazz, Abbvie, Takeda, Celgene, and Novartis.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

SOURCE: “Why Is There No Standard of Care for Relapsed AML?” Acute Leukemia Forum of Hemedicus, Oct. 15, 2020.

Despite a variety of options, patients with relapsed/refractory acute myeloid leukemia (AML) continue to face poor prognoses, and a standard of care remains elusive, a hematologist/oncologist told colleagues.

“Clearly we have a problem with this group of patients,” Ehab Atallah, MD, professor of medicine at Medical College of Wisconsin, Milwaukee, said in a presentation at the virtual Acute Leukemia Forum of Hemedicus. In regard to treatments, he added, “we still have multiple unanswered questions.”

As Dr. Atallah noted, a 2018 study of 3,012 patients – in 9 successive ECOG‐ACRIN trials for newly diagnosed AML from 1984-2008 – showed poor outcomes for relapsed/refractory patients. At a median follow-up of 9.7 years, 59.1% reached first complete remission (CR1), and 58.9% of those relapsed. In the relapsed patients, the median overall survival from relapse was 0.5 years, and the overall survival (OS) over 5 years was 10%.

“Even among patients who relapsed with better prognostic factors – age < 40 and CR1 > 12 months – there was no significant OS difference between the studies,” the study noted. “In conclusion, this large cohort appears to confirm that the survival of AML patients post relapse continues to be dismal and has not improved during the past quarter of a century.”

There isn’t a clear standard of care, said Dr. Atallah, as shown by a 2014 phase 3 study of elacytarabine vs. investigator choice in relapsed/refractory AML patients. The investigators chose seven treatment options for the control arm.

So how can physicians make the best decisions about treatment? A 2018 report finds that some factors do offer guidance about how well relapsed patients will do, Dr. Atallah said, including worse prognoses for higher age (>50 years), time to relapse (< 1 year), number of cycles of treatment needed to achieve remission (more than 1), and unfavorable cytogenetics. And, he said, “practically no one is cured when their leukemia relapses without stem cell transplantation.”

Also keep comorbidities in mind, he said, and consider previous therapies – not just the ones implemented prior to their induction but from all treatments they received: “How much anthracycline did they get? Do they still have room to receive any more anthracycline? Do they have any pulmonary complications from GVHD [graft versus host disease]?”

Another tool may be helpful. A 2013 study found that geriatric assessment predicted survival for older adults with AML who took induction chemotherapy, he said. “I’m pretty sure that this geriatric assessment would also have significant prognostic information for patients with relapsed refractory AML.”

Molecular changes add to the complexity of treatment for relapsed/refractory AML, Dr. Atallah said, in light of new molecularly targeted drugs. He pointed to a 2019 study that showed a slight increase in median overall survival (9.3 months vs. 5.6 months) for gilteritinib vs. salvage chemotherapy in relapsed/refractory patients with FLT3-mutated AML. Other studies have shown limited effects of ID1 inhibitors, he said.

In the big picture, “there are many patient-, disease-, and prior-therapy-related variables that are involved in our decisions plus donor availability, social support, whether they have a transplant before, what kind of treatment they got before the functional assessment, and comorbidities. Even with the current choices for relapsed/refractory AML, the overall survival remains poor. Enrollment in clinical trials would be the best option for these patients.”

Dr. Atallah disclosed ties with Jazz, Abbvie, Takeda, Celgene, and Novartis.

The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.

SOURCE: “Why Is There No Standard of Care for Relapsed AML?” Acute Leukemia Forum of Hemedicus, Oct. 15, 2020.