User login
Hydroxychloroquine confers dose-dependent survival benefits in elderly-onset RA
Key clinical point: Hydroxychloroquine treatment conferred survival benefits in a dose-dependent manner in patients with elderly-onset rheumatoid arthritis (RA), with patients receiving a monthly cumulative dose of 1374.5-5778.5 mg or more showing better survival than those receiving <1374.5 mg.
Major finding: Hydroxychloroquine treatment was a protective factor against mortality in patients with elderly-onset RA (hazard ratio 0.30; P = .002), with a cumulative dose of <1374.5 mg vs 1374.5-5,778.5 mg or more leading to the lowest survival rate (P < .001).
Study details: Findings are from a retrospective observational study including 980 patients with elderly-onset RA (disease onset after 60 years of age) who had received conventional synthetic, biologic, or targeted synthetic disease-modifying antirheumatic drugs.
Disclosures: This study was supported by the National Science and Technology Council, Taiwan, and other sources. The authors declared no conflicts of interest.
Source: Lin CT et al. Association of hydroxychloroquine use with a dose-dependent decrease in mortality risk in patients with elderly-onset rheumatoid arthritis. Rheumatol Ther. 2023 (May 12). Doi: 10.1007/s40744-023-00561-1
Key clinical point: Hydroxychloroquine treatment conferred survival benefits in a dose-dependent manner in patients with elderly-onset rheumatoid arthritis (RA), with patients receiving a monthly cumulative dose of 1374.5-5778.5 mg or more showing better survival than those receiving <1374.5 mg.
Major finding: Hydroxychloroquine treatment was a protective factor against mortality in patients with elderly-onset RA (hazard ratio 0.30; P = .002), with a cumulative dose of <1374.5 mg vs 1374.5-5,778.5 mg or more leading to the lowest survival rate (P < .001).
Study details: Findings are from a retrospective observational study including 980 patients with elderly-onset RA (disease onset after 60 years of age) who had received conventional synthetic, biologic, or targeted synthetic disease-modifying antirheumatic drugs.
Disclosures: This study was supported by the National Science and Technology Council, Taiwan, and other sources. The authors declared no conflicts of interest.
Source: Lin CT et al. Association of hydroxychloroquine use with a dose-dependent decrease in mortality risk in patients with elderly-onset rheumatoid arthritis. Rheumatol Ther. 2023 (May 12). Doi: 10.1007/s40744-023-00561-1
Key clinical point: Hydroxychloroquine treatment conferred survival benefits in a dose-dependent manner in patients with elderly-onset rheumatoid arthritis (RA), with patients receiving a monthly cumulative dose of 1374.5-5778.5 mg or more showing better survival than those receiving <1374.5 mg.
Major finding: Hydroxychloroquine treatment was a protective factor against mortality in patients with elderly-onset RA (hazard ratio 0.30; P = .002), with a cumulative dose of <1374.5 mg vs 1374.5-5,778.5 mg or more leading to the lowest survival rate (P < .001).
Study details: Findings are from a retrospective observational study including 980 patients with elderly-onset RA (disease onset after 60 years of age) who had received conventional synthetic, biologic, or targeted synthetic disease-modifying antirheumatic drugs.
Disclosures: This study was supported by the National Science and Technology Council, Taiwan, and other sources. The authors declared no conflicts of interest.
Source: Lin CT et al. Association of hydroxychloroquine use with a dose-dependent decrease in mortality risk in patients with elderly-onset rheumatoid arthritis. Rheumatol Ther. 2023 (May 12). Doi: 10.1007/s40744-023-00561-1
Higher risk for herpes zoster with tofacitinib vs TNFi in RA
Key clinical point: Tofacitinib use increased the risk for herpes zoster (HZ) in patients with rheumatoid arthritis (RA) compared with tumor necrosis factor inhibitor (TNFi); however, the rate of serious HZ or tofacitinib discontinuation due to HZ was low.
Major finding: The incidence of HZ was significantly higher among patients receiving tofacitinib vs TNFi (incidence rate ratio 8.33; P < .001). However, the incidence of serious HZ was not significantly different between the groups (P = .452), with HZ leading to only one case of permanent tofacitinib discontinuation.
Study details: This study included 912 patients with RA from two single-center prospective cohorts (tofacitinib cohort n = 200 and TNFi cohort n = 712).
Disclosures: This study was supported by the Ministry of Health and Welfare, Republic of Korea, and Pfizer. Two authors declared being employees and shareholders of Pfizer Inc. YK Sung declared receiving research grants from Pfizer and other sources. The other authors declared no conflicts of interest.
Source: Song YJ et al. Increased risk of herpes zoster with tofacitinib treatment in Korean patients with rheumatoid arthritis: A single‑center prospective study. Sci Rep. 2023;13:7877 (May 15). doi: 10.1038/s41598-023-33718-7
Key clinical point: Tofacitinib use increased the risk for herpes zoster (HZ) in patients with rheumatoid arthritis (RA) compared with tumor necrosis factor inhibitor (TNFi); however, the rate of serious HZ or tofacitinib discontinuation due to HZ was low.
Major finding: The incidence of HZ was significantly higher among patients receiving tofacitinib vs TNFi (incidence rate ratio 8.33; P < .001). However, the incidence of serious HZ was not significantly different between the groups (P = .452), with HZ leading to only one case of permanent tofacitinib discontinuation.
Study details: This study included 912 patients with RA from two single-center prospective cohorts (tofacitinib cohort n = 200 and TNFi cohort n = 712).
Disclosures: This study was supported by the Ministry of Health and Welfare, Republic of Korea, and Pfizer. Two authors declared being employees and shareholders of Pfizer Inc. YK Sung declared receiving research grants from Pfizer and other sources. The other authors declared no conflicts of interest.
Source: Song YJ et al. Increased risk of herpes zoster with tofacitinib treatment in Korean patients with rheumatoid arthritis: A single‑center prospective study. Sci Rep. 2023;13:7877 (May 15). doi: 10.1038/s41598-023-33718-7
Key clinical point: Tofacitinib use increased the risk for herpes zoster (HZ) in patients with rheumatoid arthritis (RA) compared with tumor necrosis factor inhibitor (TNFi); however, the rate of serious HZ or tofacitinib discontinuation due to HZ was low.
Major finding: The incidence of HZ was significantly higher among patients receiving tofacitinib vs TNFi (incidence rate ratio 8.33; P < .001). However, the incidence of serious HZ was not significantly different between the groups (P = .452), with HZ leading to only one case of permanent tofacitinib discontinuation.
Study details: This study included 912 patients with RA from two single-center prospective cohorts (tofacitinib cohort n = 200 and TNFi cohort n = 712).
Disclosures: This study was supported by the Ministry of Health and Welfare, Republic of Korea, and Pfizer. Two authors declared being employees and shareholders of Pfizer Inc. YK Sung declared receiving research grants from Pfizer and other sources. The other authors declared no conflicts of interest.
Source: Song YJ et al. Increased risk of herpes zoster with tofacitinib treatment in Korean patients with rheumatoid arthritis: A single‑center prospective study. Sci Rep. 2023;13:7877 (May 15). doi: 10.1038/s41598-023-33718-7
Frailty raises risk for methotrexate discontinuation due to adverse events in RA
Key clinical point: Frailty is a significant contributing factor leading to methotrexate discontinuation due to adverse events in long-term pretreated patients with rheumatoid arthritis (RA).
Major finding: Overall, 7.4% of the patients discontinued methotrexate due to adverse events during 2 years of follow-up, with methotrexate retention being significantly lower among patients with vs without frailty (P < .05) and frailty being a significant factor contributing to methotrexate discontinuation (adjusted hazard ratio 2.34; 95% CI 1.02-5.37).
Study details: This retrospective longitudinal study included 323 patients with RA who used methotrexate at baseline.
Disclosures: This study did not declare the funding source. The authors did not report conflicts of interest.
Source: Sobue Y et al. Relationship between frailty and methotrexate discontinuation due to adverse events in rheumatoid arthritis patients. Clin Rheumatol. 2023 (May 22). doi: 10.1007/s10067-023-06639-z
Key clinical point: Frailty is a significant contributing factor leading to methotrexate discontinuation due to adverse events in long-term pretreated patients with rheumatoid arthritis (RA).
Major finding: Overall, 7.4% of the patients discontinued methotrexate due to adverse events during 2 years of follow-up, with methotrexate retention being significantly lower among patients with vs without frailty (P < .05) and frailty being a significant factor contributing to methotrexate discontinuation (adjusted hazard ratio 2.34; 95% CI 1.02-5.37).
Study details: This retrospective longitudinal study included 323 patients with RA who used methotrexate at baseline.
Disclosures: This study did not declare the funding source. The authors did not report conflicts of interest.
Source: Sobue Y et al. Relationship between frailty and methotrexate discontinuation due to adverse events in rheumatoid arthritis patients. Clin Rheumatol. 2023 (May 22). doi: 10.1007/s10067-023-06639-z
Key clinical point: Frailty is a significant contributing factor leading to methotrexate discontinuation due to adverse events in long-term pretreated patients with rheumatoid arthritis (RA).
Major finding: Overall, 7.4% of the patients discontinued methotrexate due to adverse events during 2 years of follow-up, with methotrexate retention being significantly lower among patients with vs without frailty (P < .05) and frailty being a significant factor contributing to methotrexate discontinuation (adjusted hazard ratio 2.34; 95% CI 1.02-5.37).
Study details: This retrospective longitudinal study included 323 patients with RA who used methotrexate at baseline.
Disclosures: This study did not declare the funding source. The authors did not report conflicts of interest.
Source: Sobue Y et al. Relationship between frailty and methotrexate discontinuation due to adverse events in rheumatoid arthritis patients. Clin Rheumatol. 2023 (May 22). doi: 10.1007/s10067-023-06639-z
Antimalarials improve safety and persistence of bDMARD or JAKi treatment in RA
Key clinical point: Concomitant use of antimalarials with biologic disease-modifying antirheumatic drugs (bDMARD) or Janus kinase inhibitors (JAKi) improved the overall safety profile and persistence of treatment in patients with rheumatoid arthritis (RA).
Major finding: The concomitant use vs nonuse of antimalarials was associated with a reduced risk for serious adverse events (multivariate incidence rate ratios [mIRR] 0.49; P < .001), total adverse events (mIRR 0.68; P < .001), and serious infections (mIRR 0.53; P = .007) and with longer survival of treatment course (hazard ratio 0.72; P = .003).
Study details: Findings are from a registry-based cohort study including 1316 patients with RA who initiated their first bDMARD or JAKi with (n = 280) or without (n = 1,036) concomitant antimalarials.
Disclosures: This study was supported by the Brazilian Society of Rheumatology and other sources. The authors declared no conflicts of interest.
Source: Bredemeier M et al, for the Brazilian Society of Rheumatology and the Brazilian Registry of Biological Therapies in Rheumatic Diseases (BiobadaBrasil). The effect of antimalarials on the safety and persistence of treatment with biologic agents or JAK inhibitors in rheumatoid arthritis. Rheumatology (Oxford). 2023 (May 22). doi: 10.1093/rheumatology/kead232
Key clinical point: Concomitant use of antimalarials with biologic disease-modifying antirheumatic drugs (bDMARD) or Janus kinase inhibitors (JAKi) improved the overall safety profile and persistence of treatment in patients with rheumatoid arthritis (RA).
Major finding: The concomitant use vs nonuse of antimalarials was associated with a reduced risk for serious adverse events (multivariate incidence rate ratios [mIRR] 0.49; P < .001), total adverse events (mIRR 0.68; P < .001), and serious infections (mIRR 0.53; P = .007) and with longer survival of treatment course (hazard ratio 0.72; P = .003).
Study details: Findings are from a registry-based cohort study including 1316 patients with RA who initiated their first bDMARD or JAKi with (n = 280) or without (n = 1,036) concomitant antimalarials.
Disclosures: This study was supported by the Brazilian Society of Rheumatology and other sources. The authors declared no conflicts of interest.
Source: Bredemeier M et al, for the Brazilian Society of Rheumatology and the Brazilian Registry of Biological Therapies in Rheumatic Diseases (BiobadaBrasil). The effect of antimalarials on the safety and persistence of treatment with biologic agents or JAK inhibitors in rheumatoid arthritis. Rheumatology (Oxford). 2023 (May 22). doi: 10.1093/rheumatology/kead232
Key clinical point: Concomitant use of antimalarials with biologic disease-modifying antirheumatic drugs (bDMARD) or Janus kinase inhibitors (JAKi) improved the overall safety profile and persistence of treatment in patients with rheumatoid arthritis (RA).
Major finding: The concomitant use vs nonuse of antimalarials was associated with a reduced risk for serious adverse events (multivariate incidence rate ratios [mIRR] 0.49; P < .001), total adverse events (mIRR 0.68; P < .001), and serious infections (mIRR 0.53; P = .007) and with longer survival of treatment course (hazard ratio 0.72; P = .003).
Study details: Findings are from a registry-based cohort study including 1316 patients with RA who initiated their first bDMARD or JAKi with (n = 280) or without (n = 1,036) concomitant antimalarials.
Disclosures: This study was supported by the Brazilian Society of Rheumatology and other sources. The authors declared no conflicts of interest.
Source: Bredemeier M et al, for the Brazilian Society of Rheumatology and the Brazilian Registry of Biological Therapies in Rheumatic Diseases (BiobadaBrasil). The effect of antimalarials on the safety and persistence of treatment with biologic agents or JAK inhibitors in rheumatoid arthritis. Rheumatology (Oxford). 2023 (May 22). doi: 10.1093/rheumatology/kead232
Peresolimab shows efficacy as a new treatment approach for moderate-to-severe RA
Key clinical point: Peresolimab, a humanized antibody stimulating the programmed cell death protein 1 inhibitory pathway, showed significant efficacy compared with placebo in improving disease activity in patients with moderate-to-severe rheumatoid arthritis (RA).
Major finding: At week 12, 700 mg peresolimab vs placebo was associated with a significantly greater change in Disease Activity Scores for 28 joints based on C-reactive protein levels (between-group difference in change from baseline −1.09; P < .001). The safety profiles were similar in all treatment groups, and no deaths were reported.
Study details: This phase 2a trial included 98 patients with moderate-to-severe RA and inadequate or loss of response to or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs who were randomly assigned to receive peresolimab (300 or 700 mg) or placebo once every 4 weeks.
Disclosures: This study was supported by Eli Lilly. Five authors declared being employees of or owning stocks in Eli Lilly. Several authors declared ties with various sources, including Eli Lilly.
Source: Tuttle J et al. A phase 2 trial of peresolimab for adults with rheumatoid arthritis. N Engl J Med. 2023;388:1853-1862 (May 18). doi: 10.1056/NEJMoa2209856
Key clinical point: Peresolimab, a humanized antibody stimulating the programmed cell death protein 1 inhibitory pathway, showed significant efficacy compared with placebo in improving disease activity in patients with moderate-to-severe rheumatoid arthritis (RA).
Major finding: At week 12, 700 mg peresolimab vs placebo was associated with a significantly greater change in Disease Activity Scores for 28 joints based on C-reactive protein levels (between-group difference in change from baseline −1.09; P < .001). The safety profiles were similar in all treatment groups, and no deaths were reported.
Study details: This phase 2a trial included 98 patients with moderate-to-severe RA and inadequate or loss of response to or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs who were randomly assigned to receive peresolimab (300 or 700 mg) or placebo once every 4 weeks.
Disclosures: This study was supported by Eli Lilly. Five authors declared being employees of or owning stocks in Eli Lilly. Several authors declared ties with various sources, including Eli Lilly.
Source: Tuttle J et al. A phase 2 trial of peresolimab for adults with rheumatoid arthritis. N Engl J Med. 2023;388:1853-1862 (May 18). doi: 10.1056/NEJMoa2209856
Key clinical point: Peresolimab, a humanized antibody stimulating the programmed cell death protein 1 inhibitory pathway, showed significant efficacy compared with placebo in improving disease activity in patients with moderate-to-severe rheumatoid arthritis (RA).
Major finding: At week 12, 700 mg peresolimab vs placebo was associated with a significantly greater change in Disease Activity Scores for 28 joints based on C-reactive protein levels (between-group difference in change from baseline −1.09; P < .001). The safety profiles were similar in all treatment groups, and no deaths were reported.
Study details: This phase 2a trial included 98 patients with moderate-to-severe RA and inadequate or loss of response to or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs who were randomly assigned to receive peresolimab (300 or 700 mg) or placebo once every 4 weeks.
Disclosures: This study was supported by Eli Lilly. Five authors declared being employees of or owning stocks in Eli Lilly. Several authors declared ties with various sources, including Eli Lilly.
Source: Tuttle J et al. A phase 2 trial of peresolimab for adults with rheumatoid arthritis. N Engl J Med. 2023;388:1853-1862 (May 18). doi: 10.1056/NEJMoa2209856
Anabolic-steroid withdrawal regimens show promise in men
Men who illicitly used anabolic-androgenic steroids to bulk up and then turned to illegal, web-based regimens for treating their steroid withdrawal complications have provided important clues for new approaches to treating a growing worldwide population of men who abuse steroids.
A retrospective, observational study at one steroid addiction center in Glasgow examined 641 men who had stopped using steroids within the prior 3 years in 2015-2022 and who had self-administered certain agents, collectively known as post-cycle therapy (PCT) – within 3 months of stopping steroids.
They had a significant 3.8-fold increased rate of normalization of their levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), compared with men who either never used PCT or began it more than 3 months after stopping steroids, Channa N. Jayasena, PhD, MRCP, FRCPath, reported at the annual meeting of the Endocrine Society.
These testosterone, LH, and FSH levels served as a “surrogate marker of biochemical recovery from hypogonadism,” he explained. Normalization also occurred “slightly sooner” in men who began using PCT early after steroid cessation, added Dr. Jayasena, a reproductive endocrinologist at Imperial College, London.
When men recovered their endogenous testosterone-producing capacity, it occurred after an average of about 13 weeks on PCT and after an average of about 19 weeks without PCT, a significant difference.
“There is a vacuum of medical advice on what to do” when men stop taking steroids, said Dr. Jayasena during a press briefing at the meeting. “We can’t recommend anything yet because [our studies] have not proven causality” between the post-cycle therapy that many men start after stopping steroids and any symptom improvement they experience.”
The next step is to test the PCT agents in a prospective, controlled study, an investigation Dr. Jayasena and colleagues are eager to launch. The goal is to determine whether PCT is truly effective, the optimal doses, and whether the treatments are safe.
‘Incredibly sophisticated’ online community
The agents that constitute PCT include human chorionic gonadotropin (hCG, the “pregnancy hormone”), selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs). SERMs and AIs are licensed only for use in women, the former for osteoporosis and breast cancer and the latter for breast cancer.
All of these agents, as well as others, are advertised by various illegal websites as treatments that can restore endogenous testosterone production in men whose native testosterone shut down during their steroid self-medication.
Restored testosterone resolves many of the adverse effects of steroid withdrawal such as diminished libido and erections, and depressed mood and energy.
Men buy PCT agents illegally from various websites. “There is an enormous, incredibly sophisticated community online that influences” PCT, and an “incredibly refined worldwide distribution network,” Dr. Jayasena explained.
His study included 410 men who turned to PCT after steroid cessation and 170 who did not.
Largest study of hormone recovery when men stop taking steroids
In a further multivariate analysis of the observational data, men who had used four or more different steroid treatments fared worse – with a significant 75% reduced rate of testosterone normalization with PCT – compared with men who had used a single steroid agent.
And men who had been on a steroid regimen for more than 6 months also fared badly – with a significant 66% reduced rate of testosterone normalization with PCT, compared with men on a steroid regimen for 3 months or less.
“This is the largest study of hormone recovery when men stop taking steroids,” Dr. Jayasena noted.
And the data “require corroboration within an interventional study to determine causality.”
“We need further studies to help doctors and other health care professionals advise men about the risks of anabolic steroid use and support those who are motivated to stop,” Dr. Jayasena said.
He cautioned that the study has several limitations: biases were potentially introduced based on recruitment and on recall by participants; clinicians drew blood specimens used to measure hormone levels at random times; and participants may have engaged in concealed drug use and used steroid and PCT agents that did not contain the substances advertised.
Nevertheless,, and they “may have important therapeutic implications for the future treatment of men who are motivated to stop” steroids.
The study received no commercial funding. Dr. Jayasena has received research funding from Logixx Pharma.
A version of this article first appeared on Medscape.com.
Men who illicitly used anabolic-androgenic steroids to bulk up and then turned to illegal, web-based regimens for treating their steroid withdrawal complications have provided important clues for new approaches to treating a growing worldwide population of men who abuse steroids.
A retrospective, observational study at one steroid addiction center in Glasgow examined 641 men who had stopped using steroids within the prior 3 years in 2015-2022 and who had self-administered certain agents, collectively known as post-cycle therapy (PCT) – within 3 months of stopping steroids.
They had a significant 3.8-fold increased rate of normalization of their levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), compared with men who either never used PCT or began it more than 3 months after stopping steroids, Channa N. Jayasena, PhD, MRCP, FRCPath, reported at the annual meeting of the Endocrine Society.
These testosterone, LH, and FSH levels served as a “surrogate marker of biochemical recovery from hypogonadism,” he explained. Normalization also occurred “slightly sooner” in men who began using PCT early after steroid cessation, added Dr. Jayasena, a reproductive endocrinologist at Imperial College, London.
When men recovered their endogenous testosterone-producing capacity, it occurred after an average of about 13 weeks on PCT and after an average of about 19 weeks without PCT, a significant difference.
“There is a vacuum of medical advice on what to do” when men stop taking steroids, said Dr. Jayasena during a press briefing at the meeting. “We can’t recommend anything yet because [our studies] have not proven causality” between the post-cycle therapy that many men start after stopping steroids and any symptom improvement they experience.”
The next step is to test the PCT agents in a prospective, controlled study, an investigation Dr. Jayasena and colleagues are eager to launch. The goal is to determine whether PCT is truly effective, the optimal doses, and whether the treatments are safe.
‘Incredibly sophisticated’ online community
The agents that constitute PCT include human chorionic gonadotropin (hCG, the “pregnancy hormone”), selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs). SERMs and AIs are licensed only for use in women, the former for osteoporosis and breast cancer and the latter for breast cancer.
All of these agents, as well as others, are advertised by various illegal websites as treatments that can restore endogenous testosterone production in men whose native testosterone shut down during their steroid self-medication.
Restored testosterone resolves many of the adverse effects of steroid withdrawal such as diminished libido and erections, and depressed mood and energy.
Men buy PCT agents illegally from various websites. “There is an enormous, incredibly sophisticated community online that influences” PCT, and an “incredibly refined worldwide distribution network,” Dr. Jayasena explained.
His study included 410 men who turned to PCT after steroid cessation and 170 who did not.
Largest study of hormone recovery when men stop taking steroids
In a further multivariate analysis of the observational data, men who had used four or more different steroid treatments fared worse – with a significant 75% reduced rate of testosterone normalization with PCT – compared with men who had used a single steroid agent.
And men who had been on a steroid regimen for more than 6 months also fared badly – with a significant 66% reduced rate of testosterone normalization with PCT, compared with men on a steroid regimen for 3 months or less.
“This is the largest study of hormone recovery when men stop taking steroids,” Dr. Jayasena noted.
And the data “require corroboration within an interventional study to determine causality.”
“We need further studies to help doctors and other health care professionals advise men about the risks of anabolic steroid use and support those who are motivated to stop,” Dr. Jayasena said.
He cautioned that the study has several limitations: biases were potentially introduced based on recruitment and on recall by participants; clinicians drew blood specimens used to measure hormone levels at random times; and participants may have engaged in concealed drug use and used steroid and PCT agents that did not contain the substances advertised.
Nevertheless,, and they “may have important therapeutic implications for the future treatment of men who are motivated to stop” steroids.
The study received no commercial funding. Dr. Jayasena has received research funding from Logixx Pharma.
A version of this article first appeared on Medscape.com.
Men who illicitly used anabolic-androgenic steroids to bulk up and then turned to illegal, web-based regimens for treating their steroid withdrawal complications have provided important clues for new approaches to treating a growing worldwide population of men who abuse steroids.
A retrospective, observational study at one steroid addiction center in Glasgow examined 641 men who had stopped using steroids within the prior 3 years in 2015-2022 and who had self-administered certain agents, collectively known as post-cycle therapy (PCT) – within 3 months of stopping steroids.
They had a significant 3.8-fold increased rate of normalization of their levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), compared with men who either never used PCT or began it more than 3 months after stopping steroids, Channa N. Jayasena, PhD, MRCP, FRCPath, reported at the annual meeting of the Endocrine Society.
These testosterone, LH, and FSH levels served as a “surrogate marker of biochemical recovery from hypogonadism,” he explained. Normalization also occurred “slightly sooner” in men who began using PCT early after steroid cessation, added Dr. Jayasena, a reproductive endocrinologist at Imperial College, London.
When men recovered their endogenous testosterone-producing capacity, it occurred after an average of about 13 weeks on PCT and after an average of about 19 weeks without PCT, a significant difference.
“There is a vacuum of medical advice on what to do” when men stop taking steroids, said Dr. Jayasena during a press briefing at the meeting. “We can’t recommend anything yet because [our studies] have not proven causality” between the post-cycle therapy that many men start after stopping steroids and any symptom improvement they experience.”
The next step is to test the PCT agents in a prospective, controlled study, an investigation Dr. Jayasena and colleagues are eager to launch. The goal is to determine whether PCT is truly effective, the optimal doses, and whether the treatments are safe.
‘Incredibly sophisticated’ online community
The agents that constitute PCT include human chorionic gonadotropin (hCG, the “pregnancy hormone”), selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs). SERMs and AIs are licensed only for use in women, the former for osteoporosis and breast cancer and the latter for breast cancer.
All of these agents, as well as others, are advertised by various illegal websites as treatments that can restore endogenous testosterone production in men whose native testosterone shut down during their steroid self-medication.
Restored testosterone resolves many of the adverse effects of steroid withdrawal such as diminished libido and erections, and depressed mood and energy.
Men buy PCT agents illegally from various websites. “There is an enormous, incredibly sophisticated community online that influences” PCT, and an “incredibly refined worldwide distribution network,” Dr. Jayasena explained.
His study included 410 men who turned to PCT after steroid cessation and 170 who did not.
Largest study of hormone recovery when men stop taking steroids
In a further multivariate analysis of the observational data, men who had used four or more different steroid treatments fared worse – with a significant 75% reduced rate of testosterone normalization with PCT – compared with men who had used a single steroid agent.
And men who had been on a steroid regimen for more than 6 months also fared badly – with a significant 66% reduced rate of testosterone normalization with PCT, compared with men on a steroid regimen for 3 months or less.
“This is the largest study of hormone recovery when men stop taking steroids,” Dr. Jayasena noted.
And the data “require corroboration within an interventional study to determine causality.”
“We need further studies to help doctors and other health care professionals advise men about the risks of anabolic steroid use and support those who are motivated to stop,” Dr. Jayasena said.
He cautioned that the study has several limitations: biases were potentially introduced based on recruitment and on recall by participants; clinicians drew blood specimens used to measure hormone levels at random times; and participants may have engaged in concealed drug use and used steroid and PCT agents that did not contain the substances advertised.
Nevertheless,, and they “may have important therapeutic implications for the future treatment of men who are motivated to stop” steroids.
The study received no commercial funding. Dr. Jayasena has received research funding from Logixx Pharma.
A version of this article first appeared on Medscape.com.
FROM ENDO 2023
PV: Novel rusfertide shows ‘impressive’ efficacy
“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.
“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.
“The results are surprisingly positive,” said senior author Ronald Hoffman, MD, of the Icahn School of Medicine at Mount Sinai, New York, in discussing the late-breaking research at a press briefing during the European Hematology Association Hybrid Congress 2023.
“Importantly, the study met all of its efficacy endpoints, including the proportion of responders, absence of phlebotomy eligibility, and hematocrit control,” Dr. Hoffman said.
PV, a relatively common clonal myeloproliferative neoplasm, is characterized by uncontrolled erythrocytosis, or excessive production of red blood cells, increasing the risk for serious complications such as thromboembolic and cardiovascular events – the most common causes of morbidity and mortality in this blood cancer.
To treat PV, the maintenance of hematocrit levels at below 45% is critical. However, the current standard of care, therapeutic phlebotomy, with or without cytoreductive agents, falls short in maintaining those lower levels in the majority of patients, Dr. Hoffman explained.
To improve responses, rusfertide was developed as a novel, synthetic form of hepcidin, a peptide hormone that is produced by the liver and functions to maintain iron homeostasis and control the formation of red blood cells.
“This is somewhat of a paradigm shift,” said Dr. Hoffman in the press briefing. “We’re trying to use a hormone made by the liver to control excessive red blood cell production from polycythemia vera.”
For the phase 2 REVIVE study evaluating rusfertide in PV, the authors enrolled 53 patients with PV who had a high phlebotomy burden while receiving the current standard of care. The study’s criteria called for patients to have received at least three therapeutic phlebotomies in the 28 weeks prior to enrollment, with or without concurrent cytoreductive agents.
During a first part of the study, patients received subcutaneous rusfertide once weekly over 28 weeks, during which period the dose was adjusted individually to achieve control of HCT levels below 45%.
The second part was a withdrawal phase extending from weeks 29 to 41, in which patients were randomized in a blinded fashion to either continue on rusfertide (n = 26) or receive a placebo (n = 27).
The patients had a median age of 58; they were 71.7% male, and 54.7% had previously been treated with therapeutic phlebotomy alone while 45.3% received therapeutic phlebotomy plus cytoreductive agents.
Patients were considered to be responders if they met three criteria, including having HCT control without phlebotomy eligibility, no therapeutic phlebotomy, and having completed 12 weeks of treatment.
At the end of the second phase, 69.2% of patients receiving rusfertide were responders versus just 18.5% in the placebo group (P = .0003).
Notably, the improvement with rusfertide was observed among those receiving therapeutic phlebotomy alone, as well as with cytoreductive agents (both P = .02).
Compared with placebo, rusfertide provided significant improvement in measures including the maintenance of response, the absence of the need for therapeutic phlebotomy, and persistent HCT control (P < .0001 for all).
Whereas the phlebotomy-free rate with rusfertide during the dose-finding weeks of 1-17 was 76.9% and in weeks 17-29, 87.3%, the rate increased in part 2 of the study to 92.3%.
Additional symptom benefits reported with rusfertide at week 29 versus baseline in part 1 of the study included significant improvements in concentration (P = .0018), itching (P = .0054), fatigue (P = .0074), and inactivity (P = .0005).
In terms of safety, rusfertide was generally well tolerated, with 83% of treatment-emergent adverse events (TEAEs) being grade 1-2, while 17% were grade 3, and none were grade 4 or 5.
The most common TEAEs consisted of injection-site reactions, which were localized, and grade 1-2 in severity. The incidence of reactions decreased with ongoing treatment. There were only two discontinuations resulting from TEAEs.
Among a total of 70 patients who were enrolled, 52 (74.3%) have continued to receive rusfertide for at least 1 year, 32 (45.7%) for at least 1.5 years, and 10 (14.3%) for at least 2 years, indicating the long-term tolerability of rusfertide.
Further commenting, first author Marina Kremyanskaya, MD, PhD, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, added that a key benefit is rusfertide’s tolerability with combination therapies, which is important in enabling the avoidance of phlebotomies.
“Many patients on cytoreductive therapies still require phlebotomies, and they can’t tolerate a dose increase, either due to cytopenias or other adverse reactions,” she said in an interview. “So adding rusfertide allows for better control of their hematocrits on a lower dose of their respective cytoreductive drug.”
“The combination treatment thus allows for elimination of phlebotomy requirements and potentially improves their symptoms,” Dr. Kremyanskaya said, adding that “using a lower dose of cytoreductive drug such as interferon or hydroxyurea could offer a symptomatic relief to patients as well.”
Overall, she agreed that the responses are remarkably positive.
“I think this is what is so impressive about this agent – basically everybody responds,” Dr. Kremyanskaya said. “When we first started treating patients, we were so impressed, as none of the other drugs we use to treat PV, or any other hematologic malignancy, come anywhere close to this response rate.”
In commenting on the study, Claire Harrison, MD, a professor of myeloproliferative neoplasms and deputy medical director of research at Guy’s and St Thomas’ NHS Foundation Trust in London, agreed that “these data show a strong signal for effectiveness of this therapy in controlling red cell proliferation in PV without inducing iron deficiency and adding to the symptom burden of patients.”
The alternative of phlebotomy “is painful and consumes patient time and hospital resources,” she said in an interview.
Dr. Harrison noted that an earlier signal suggested squamous cell cancer might be of potential concern, but the signal “has not re-emerged [suggesting] this does indeed seem to be a safe and extremely effective therapy.”
Further commenting on the study during the press briefing, Konstanze Döhner, MD, of the University of Ulm (Germany) added that “this is exciting data.”
“For a long time, we had no therapeutic options for PV, and now the field is rapidly developing,” she said.
In ongoing research, rusfertide is currently being studied in the phase 3, placebo-controlled VERIFY randomized trial.
The study was sponsored by Protagonist Therapeutics. Dr. Hoffman reports being on the advisory board for Protagonist Therapeutics, and Dr. Kremyanskaya is a consultant for Protagonist Therapeutics. Dr. Harrison had no disclosures to report.
FROM EHA 2023
FDA warns of tattoo ink tied to dangerous infections
The Food and Drug Administration draft guidance released recently on possible contamination of tattoo ink was not concerning Whitney Donohue, 34, owner of Forget Me Not Tattoo in Billings, Mont.
“I get our ink directly through the manufacturer – not at a store or through Amazon or eBay,” she said. “You never know if it’s going to be repackaged.”
Tattoo artists themselves, she said, regulate the quality of ink they use.
Still, the threat is real, said Bruce Brod, MD, a clinical professor of dermatology at the University of Pennsylvania Health System. “I’ve seen several different infections from tattooing, and they are from organisms that tend to contaminate things in damp, liquid-type environments.”
, dermatologists said.
“Tattooing involves puncturing the epidermis about 100 times per second with needles and depositing ink 1.5 to 2 millimeters below the surface of the skin, deep into the dermis,” the guidance states. “Contaminated tattoo ink can cause infections and serious injuries. Because these inks are injected, pathogens or other harmful substances in these inks can travel from the injection site through the blood and lymphatic systems to other parts of the body.”
The guidance comes as body art continues to get more popular. According to a 2019 poll, 30% of Americans had at least one tattoo – up from 21% in 2012. Forty percent of people 18-34 and 36% of those ages 35-54 had at least one tattoo. And though they are commonplace, tattoos come with medical risks that should be known beforehand, doctors said.
Commonly reported symptoms of tattoo ink–associated infections include rashes, blisters, painful nodules, and severe abscesses. One of the most common bacteria found in contaminated tattoo ink is nontuberculous mycobacteria, which is related to the bacteria that causes tuberculosis and can be found in soil and water.
The guidance lists several unsanitary manufacturing conditions that may lead to ink contamination, including:
- Preparing or packing of tattoo inks in facilities that are hard to sanitize, such as carpeted areas
- Ink or ink components left uncovered, especially near open air ducts
- Unsanitary mixing of tattoo inks, including with unclean utensils or containers
- Lack of appropriate attire by staff, failure to use hairnets, lab coats, aprons, gowns, masks, or gloves
“Infections will often spread along the drainage channels in the skin and create squiggly, uneven lines of big red, lumpy nodules,” Dr. Brod said.
Between 2003 and 2023, there were 18 recalls of tattoo inks that were contaminated with various microorganisms, according to the FDA. In May 2019, the FDA issued a safety alert advising consumers, tattoo artists, and retailers to avoid using or selling certain tattoo inks contaminated with microorganisms.
Reputable ink manufacturers use a process called gamma radiation, which refers to electromagnetic radiation of high frequencies to kill microorganisms in the ink and its packaging.
Most of the trustworthy, high-quality ink manufacturers are well-known among tattoo artists, Ms. Donohue said.
While she has seen customers with sensitive skin have allergic reactions, she has not seen someone come back with an infection in her 9 years working in the tattoo industry.
Because tattoo ink is considered a cosmetic product, there is not much regulatory oversight involved, which means the sterility and quality of ingredients vary, said Teo Soleymani, MD, an assistant clinical professor of dermatology and dermatological surgery at the UCLA David Geffen School of Medicine.
“Cosmeceuticals aren’t regulated by the FDA like prescription medication,” he said. “What we’ve seen many times is inadvertent contamination during the application process or contamination while the inks are being made.”
In years past, unclean needles spreading hepatitis and HIV were more of a concern, but those rates have dropped significantly, Dr. Soleymani said.
The infections that have increased are from rare bacteria that exist in stagnant water. And they are injected into a part of the body that allows them to evade the immune system, he said: shallow enough that there aren’t many associated blood vessels, but not still below the layer of skin that gets sloughed off every 28 days.
Sometimes, antibiotics alone won’t cut it, and the tattoo will require surgical removal.
“The aesthetic you were going for has to be not only removed, but you’re left with a surgical scar,” Dr. Soleymani said. “Tattoos can be beautiful, but they can come with unwanted visitors that can cause months of misery.”
A version of this article first appeared on WebMD.com.
The Food and Drug Administration draft guidance released recently on possible contamination of tattoo ink was not concerning Whitney Donohue, 34, owner of Forget Me Not Tattoo in Billings, Mont.
“I get our ink directly through the manufacturer – not at a store or through Amazon or eBay,” she said. “You never know if it’s going to be repackaged.”
Tattoo artists themselves, she said, regulate the quality of ink they use.
Still, the threat is real, said Bruce Brod, MD, a clinical professor of dermatology at the University of Pennsylvania Health System. “I’ve seen several different infections from tattooing, and they are from organisms that tend to contaminate things in damp, liquid-type environments.”
, dermatologists said.
“Tattooing involves puncturing the epidermis about 100 times per second with needles and depositing ink 1.5 to 2 millimeters below the surface of the skin, deep into the dermis,” the guidance states. “Contaminated tattoo ink can cause infections and serious injuries. Because these inks are injected, pathogens or other harmful substances in these inks can travel from the injection site through the blood and lymphatic systems to other parts of the body.”
The guidance comes as body art continues to get more popular. According to a 2019 poll, 30% of Americans had at least one tattoo – up from 21% in 2012. Forty percent of people 18-34 and 36% of those ages 35-54 had at least one tattoo. And though they are commonplace, tattoos come with medical risks that should be known beforehand, doctors said.
Commonly reported symptoms of tattoo ink–associated infections include rashes, blisters, painful nodules, and severe abscesses. One of the most common bacteria found in contaminated tattoo ink is nontuberculous mycobacteria, which is related to the bacteria that causes tuberculosis and can be found in soil and water.
The guidance lists several unsanitary manufacturing conditions that may lead to ink contamination, including:
- Preparing or packing of tattoo inks in facilities that are hard to sanitize, such as carpeted areas
- Ink or ink components left uncovered, especially near open air ducts
- Unsanitary mixing of tattoo inks, including with unclean utensils or containers
- Lack of appropriate attire by staff, failure to use hairnets, lab coats, aprons, gowns, masks, or gloves
“Infections will often spread along the drainage channels in the skin and create squiggly, uneven lines of big red, lumpy nodules,” Dr. Brod said.
Between 2003 and 2023, there were 18 recalls of tattoo inks that were contaminated with various microorganisms, according to the FDA. In May 2019, the FDA issued a safety alert advising consumers, tattoo artists, and retailers to avoid using or selling certain tattoo inks contaminated with microorganisms.
Reputable ink manufacturers use a process called gamma radiation, which refers to electromagnetic radiation of high frequencies to kill microorganisms in the ink and its packaging.
Most of the trustworthy, high-quality ink manufacturers are well-known among tattoo artists, Ms. Donohue said.
While she has seen customers with sensitive skin have allergic reactions, she has not seen someone come back with an infection in her 9 years working in the tattoo industry.
Because tattoo ink is considered a cosmetic product, there is not much regulatory oversight involved, which means the sterility and quality of ingredients vary, said Teo Soleymani, MD, an assistant clinical professor of dermatology and dermatological surgery at the UCLA David Geffen School of Medicine.
“Cosmeceuticals aren’t regulated by the FDA like prescription medication,” he said. “What we’ve seen many times is inadvertent contamination during the application process or contamination while the inks are being made.”
In years past, unclean needles spreading hepatitis and HIV were more of a concern, but those rates have dropped significantly, Dr. Soleymani said.
The infections that have increased are from rare bacteria that exist in stagnant water. And they are injected into a part of the body that allows them to evade the immune system, he said: shallow enough that there aren’t many associated blood vessels, but not still below the layer of skin that gets sloughed off every 28 days.
Sometimes, antibiotics alone won’t cut it, and the tattoo will require surgical removal.
“The aesthetic you were going for has to be not only removed, but you’re left with a surgical scar,” Dr. Soleymani said. “Tattoos can be beautiful, but they can come with unwanted visitors that can cause months of misery.”
A version of this article first appeared on WebMD.com.
The Food and Drug Administration draft guidance released recently on possible contamination of tattoo ink was not concerning Whitney Donohue, 34, owner of Forget Me Not Tattoo in Billings, Mont.
“I get our ink directly through the manufacturer – not at a store or through Amazon or eBay,” she said. “You never know if it’s going to be repackaged.”
Tattoo artists themselves, she said, regulate the quality of ink they use.
Still, the threat is real, said Bruce Brod, MD, a clinical professor of dermatology at the University of Pennsylvania Health System. “I’ve seen several different infections from tattooing, and they are from organisms that tend to contaminate things in damp, liquid-type environments.”
, dermatologists said.
“Tattooing involves puncturing the epidermis about 100 times per second with needles and depositing ink 1.5 to 2 millimeters below the surface of the skin, deep into the dermis,” the guidance states. “Contaminated tattoo ink can cause infections and serious injuries. Because these inks are injected, pathogens or other harmful substances in these inks can travel from the injection site through the blood and lymphatic systems to other parts of the body.”
The guidance comes as body art continues to get more popular. According to a 2019 poll, 30% of Americans had at least one tattoo – up from 21% in 2012. Forty percent of people 18-34 and 36% of those ages 35-54 had at least one tattoo. And though they are commonplace, tattoos come with medical risks that should be known beforehand, doctors said.
Commonly reported symptoms of tattoo ink–associated infections include rashes, blisters, painful nodules, and severe abscesses. One of the most common bacteria found in contaminated tattoo ink is nontuberculous mycobacteria, which is related to the bacteria that causes tuberculosis and can be found in soil and water.
The guidance lists several unsanitary manufacturing conditions that may lead to ink contamination, including:
- Preparing or packing of tattoo inks in facilities that are hard to sanitize, such as carpeted areas
- Ink or ink components left uncovered, especially near open air ducts
- Unsanitary mixing of tattoo inks, including with unclean utensils or containers
- Lack of appropriate attire by staff, failure to use hairnets, lab coats, aprons, gowns, masks, or gloves
“Infections will often spread along the drainage channels in the skin and create squiggly, uneven lines of big red, lumpy nodules,” Dr. Brod said.
Between 2003 and 2023, there were 18 recalls of tattoo inks that were contaminated with various microorganisms, according to the FDA. In May 2019, the FDA issued a safety alert advising consumers, tattoo artists, and retailers to avoid using or selling certain tattoo inks contaminated with microorganisms.
Reputable ink manufacturers use a process called gamma radiation, which refers to electromagnetic radiation of high frequencies to kill microorganisms in the ink and its packaging.
Most of the trustworthy, high-quality ink manufacturers are well-known among tattoo artists, Ms. Donohue said.
While she has seen customers with sensitive skin have allergic reactions, she has not seen someone come back with an infection in her 9 years working in the tattoo industry.
Because tattoo ink is considered a cosmetic product, there is not much regulatory oversight involved, which means the sterility and quality of ingredients vary, said Teo Soleymani, MD, an assistant clinical professor of dermatology and dermatological surgery at the UCLA David Geffen School of Medicine.
“Cosmeceuticals aren’t regulated by the FDA like prescription medication,” he said. “What we’ve seen many times is inadvertent contamination during the application process or contamination while the inks are being made.”
In years past, unclean needles spreading hepatitis and HIV were more of a concern, but those rates have dropped significantly, Dr. Soleymani said.
The infections that have increased are from rare bacteria that exist in stagnant water. And they are injected into a part of the body that allows them to evade the immune system, he said: shallow enough that there aren’t many associated blood vessels, but not still below the layer of skin that gets sloughed off every 28 days.
Sometimes, antibiotics alone won’t cut it, and the tattoo will require surgical removal.
“The aesthetic you were going for has to be not only removed, but you’re left with a surgical scar,” Dr. Soleymani said. “Tattoos can be beautiful, but they can come with unwanted visitors that can cause months of misery.”
A version of this article first appeared on WebMD.com.
CLL: Venetoclax-obinutuzumab combo effective long term
Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.
They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.
On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.
The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.
Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.
Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”
Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”
He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.
“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”
Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”
He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.
This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.
He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.
“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.
“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”
Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.
“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”
Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.
The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”
A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.
“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.
He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”
Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.
Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.
One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.
“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.
He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”
Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).
The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.
Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.
Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.
There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.
Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.
“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”
He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.
This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.
That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.
Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”
“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”
The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.
Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.
They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.
On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.
The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.
Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.
Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”
Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”
He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.
“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”
Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”
He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.
This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.
He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.
“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.
“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”
Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.
“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”
Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.
The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”
A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.
“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.
He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”
Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.
Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.
One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.
“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.
He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”
Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).
The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.
Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.
Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.
There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.
Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.
“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”
He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.
This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.
That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.
Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”
“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”
The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.
Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.
They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.
On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.
The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.
Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.
Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”
Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”
He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.
“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”
Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”
He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.
This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.
He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.
“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.
“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”
Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.
“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”
Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.
The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”
A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.
“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.
He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”
Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.
Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.
One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.
“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.
He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”
Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).
The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.
Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.
Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.
There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.
Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.
“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”
He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.
This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.
That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.
Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”
“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”
The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.
FROM EHA 2023
Teen depression and dyslipidemia: New data
TOPLINE
Mean lipid levels are similar among adolescents with and without major depressive disorder (MDD), as is the proportion of adolescents with borderline-high lipid levels.
METHODOLOGY
Teen depression is associated with an increased likelihood of experiencing cardiovascular (CV) events, with dyslipidemia being a potentially modifiable risk factor.
Only a few studies have examined the association between depression and lipids during adolescence, when confounding comorbidities such as obesity and diabetes are less common.
The study included 243 adolescents (186 with MDD and 57 healthy controls [HCs]) who were mostly female and had a mean age of 15 years.
Researchers assessed CV risk factors including body mass index (BMI), blood pressure, smoking status, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride (TG), which were classified as acceptable or borderline high.
Dyslipidemia was defined as having concentration of at least one lipid outside the acceptable range.
TAKEAWAY
Most participants in both groups had lipid concentrations within the acceptable range.
There were no differences between study groups in mean lipid levels after adjusting for age, sex, and standardized BMI.
There were also no differences in the proportion of adolescents with borderline-high lipid concentrations.
IN PRACTICE
“Taken together, results of the current study support the need for further examination of the relationship between gender, depression, and cholesterol,” the authors write.
STUDY DETAILS
The study was conducted by Anisa F. Khalfan, Neurosciences and Mental Health research program, SickKids Research Institute, Toronto, Canada, and colleagues. It was published online in the Journal of Affective Disorders.
LIMITATIONS
The HC group was relatively small, which might have contributed to the null findings. The mean Center for Epidemiologic Studies Depression Scale for Children (CES-DC) score was 8.3 among healthy youth, compared with 37.5 among MDD youth, limiting detection of an association related to depression severity.
DISCLOSURES
The study was supported by the Lunenfeld Summer Studentship. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE
Mean lipid levels are similar among adolescents with and without major depressive disorder (MDD), as is the proportion of adolescents with borderline-high lipid levels.
METHODOLOGY
Teen depression is associated with an increased likelihood of experiencing cardiovascular (CV) events, with dyslipidemia being a potentially modifiable risk factor.
Only a few studies have examined the association between depression and lipids during adolescence, when confounding comorbidities such as obesity and diabetes are less common.
The study included 243 adolescents (186 with MDD and 57 healthy controls [HCs]) who were mostly female and had a mean age of 15 years.
Researchers assessed CV risk factors including body mass index (BMI), blood pressure, smoking status, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride (TG), which were classified as acceptable or borderline high.
Dyslipidemia was defined as having concentration of at least one lipid outside the acceptable range.
TAKEAWAY
Most participants in both groups had lipid concentrations within the acceptable range.
There were no differences between study groups in mean lipid levels after adjusting for age, sex, and standardized BMI.
There were also no differences in the proportion of adolescents with borderline-high lipid concentrations.
IN PRACTICE
“Taken together, results of the current study support the need for further examination of the relationship between gender, depression, and cholesterol,” the authors write.
STUDY DETAILS
The study was conducted by Anisa F. Khalfan, Neurosciences and Mental Health research program, SickKids Research Institute, Toronto, Canada, and colleagues. It was published online in the Journal of Affective Disorders.
LIMITATIONS
The HC group was relatively small, which might have contributed to the null findings. The mean Center for Epidemiologic Studies Depression Scale for Children (CES-DC) score was 8.3 among healthy youth, compared with 37.5 among MDD youth, limiting detection of an association related to depression severity.
DISCLOSURES
The study was supported by the Lunenfeld Summer Studentship. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE
Mean lipid levels are similar among adolescents with and without major depressive disorder (MDD), as is the proportion of adolescents with borderline-high lipid levels.
METHODOLOGY
Teen depression is associated with an increased likelihood of experiencing cardiovascular (CV) events, with dyslipidemia being a potentially modifiable risk factor.
Only a few studies have examined the association between depression and lipids during adolescence, when confounding comorbidities such as obesity and diabetes are less common.
The study included 243 adolescents (186 with MDD and 57 healthy controls [HCs]) who were mostly female and had a mean age of 15 years.
Researchers assessed CV risk factors including body mass index (BMI), blood pressure, smoking status, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride (TG), which were classified as acceptable or borderline high.
Dyslipidemia was defined as having concentration of at least one lipid outside the acceptable range.
TAKEAWAY
Most participants in both groups had lipid concentrations within the acceptable range.
There were no differences between study groups in mean lipid levels after adjusting for age, sex, and standardized BMI.
There were also no differences in the proportion of adolescents with borderline-high lipid concentrations.
IN PRACTICE
“Taken together, results of the current study support the need for further examination of the relationship between gender, depression, and cholesterol,” the authors write.
STUDY DETAILS
The study was conducted by Anisa F. Khalfan, Neurosciences and Mental Health research program, SickKids Research Institute, Toronto, Canada, and colleagues. It was published online in the Journal of Affective Disorders.
LIMITATIONS
The HC group was relatively small, which might have contributed to the null findings. The mean Center for Epidemiologic Studies Depression Scale for Children (CES-DC) score was 8.3 among healthy youth, compared with 37.5 among MDD youth, limiting detection of an association related to depression severity.
DISCLOSURES
The study was supported by the Lunenfeld Summer Studentship. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.