User login
Vitiligo linked to moles, tanning ability, blistering sunburn
Upper extremity moles were associated with a 37% increase in the likelihood of vitiligo among white women, according to an analysis of the prospective Nurses’ Health Study.
“Women with a higher tanning ability and women who had a history of blistering sunburns in childhood were also found to have a higher risk of developing vitiligo,” Rachel Dunlap, MD, of the department of dermatology, Brown University in Providence, R.I., and her associates wrote in the Journal of Investigative Dermatology.
Vitiligo is the most common cutaneous depigmentation disorder, but associated risk factors are poorly understood, the investigators noted. They examined ties between skin pigmentation, reactions to sun exposure, and new onset vitiligo in the Nurses’ Health Study, a population-based prospective cohort study. Study participants were asked to report the number of moles on their left arms measuring at least 3 mm in diameter, their reactions to sunburn and ability to tan during childhood, and whether they had vitiligo diagnosed by a physician. A total of 51,337 women answered the question about moles, and 68,590 women answered the question about vitiligo, the investigators said (J Invest Dermatol. 2017 Feb 14. doi: 10.1016/j.jid.2017.02.004).
A total of 271 cases of vitiligo developed over 835,594 person-years. Women who reported at least one left arm mole larger than 3 mm were significantly more likely to report incident vitiligo, compared with women without moles (hazard ratio, 1.37; 95% confidence interval, 1.02-1.83), even after controlling for age, hair color, history of exposure to direct sunlight, skin tanning ability, and severity of reaction to sunburn. Developing an “average” tan or a “deep” tan after prolonged sun exposure also were significantly associated with vitiligo with hazard ratios of 2.28 (95% CI, 1.12-4.65) and 2.59 (95% CI, 1.21-5.54), respectively, “when compared to those who had minimal skin reactions or less severe burns when exposed to the sun,” the authors wrote.
A history of at least one blistering sunburn after 2 hours of sun exposure also predicted vitiligo (HR, 2.17; 95% CI, 1.15-4.10), while hair color did not.
“The benefits of good sun protection can be expanded to include potential vitiligo prevention, which may be particularly applicable to adult patients with vitiligo who are concerned about their children developing the condition,” the investigators commented. “Future studies will examine the incidence of other influencing factors, such as melanoma and melanoma associated leukoderma in this population.”
External funding sources included the National Institutes of Health and Dermatology Foundation. The investigators reported having no conflicts of interest.
Upper extremity moles were associated with a 37% increase in the likelihood of vitiligo among white women, according to an analysis of the prospective Nurses’ Health Study.
“Women with a higher tanning ability and women who had a history of blistering sunburns in childhood were also found to have a higher risk of developing vitiligo,” Rachel Dunlap, MD, of the department of dermatology, Brown University in Providence, R.I., and her associates wrote in the Journal of Investigative Dermatology.
Vitiligo is the most common cutaneous depigmentation disorder, but associated risk factors are poorly understood, the investigators noted. They examined ties between skin pigmentation, reactions to sun exposure, and new onset vitiligo in the Nurses’ Health Study, a population-based prospective cohort study. Study participants were asked to report the number of moles on their left arms measuring at least 3 mm in diameter, their reactions to sunburn and ability to tan during childhood, and whether they had vitiligo diagnosed by a physician. A total of 51,337 women answered the question about moles, and 68,590 women answered the question about vitiligo, the investigators said (J Invest Dermatol. 2017 Feb 14. doi: 10.1016/j.jid.2017.02.004).
A total of 271 cases of vitiligo developed over 835,594 person-years. Women who reported at least one left arm mole larger than 3 mm were significantly more likely to report incident vitiligo, compared with women without moles (hazard ratio, 1.37; 95% confidence interval, 1.02-1.83), even after controlling for age, hair color, history of exposure to direct sunlight, skin tanning ability, and severity of reaction to sunburn. Developing an “average” tan or a “deep” tan after prolonged sun exposure also were significantly associated with vitiligo with hazard ratios of 2.28 (95% CI, 1.12-4.65) and 2.59 (95% CI, 1.21-5.54), respectively, “when compared to those who had minimal skin reactions or less severe burns when exposed to the sun,” the authors wrote.
A history of at least one blistering sunburn after 2 hours of sun exposure also predicted vitiligo (HR, 2.17; 95% CI, 1.15-4.10), while hair color did not.
“The benefits of good sun protection can be expanded to include potential vitiligo prevention, which may be particularly applicable to adult patients with vitiligo who are concerned about their children developing the condition,” the investigators commented. “Future studies will examine the incidence of other influencing factors, such as melanoma and melanoma associated leukoderma in this population.”
External funding sources included the National Institutes of Health and Dermatology Foundation. The investigators reported having no conflicts of interest.
Upper extremity moles were associated with a 37% increase in the likelihood of vitiligo among white women, according to an analysis of the prospective Nurses’ Health Study.
“Women with a higher tanning ability and women who had a history of blistering sunburns in childhood were also found to have a higher risk of developing vitiligo,” Rachel Dunlap, MD, of the department of dermatology, Brown University in Providence, R.I., and her associates wrote in the Journal of Investigative Dermatology.
Vitiligo is the most common cutaneous depigmentation disorder, but associated risk factors are poorly understood, the investigators noted. They examined ties between skin pigmentation, reactions to sun exposure, and new onset vitiligo in the Nurses’ Health Study, a population-based prospective cohort study. Study participants were asked to report the number of moles on their left arms measuring at least 3 mm in diameter, their reactions to sunburn and ability to tan during childhood, and whether they had vitiligo diagnosed by a physician. A total of 51,337 women answered the question about moles, and 68,590 women answered the question about vitiligo, the investigators said (J Invest Dermatol. 2017 Feb 14. doi: 10.1016/j.jid.2017.02.004).
A total of 271 cases of vitiligo developed over 835,594 person-years. Women who reported at least one left arm mole larger than 3 mm were significantly more likely to report incident vitiligo, compared with women without moles (hazard ratio, 1.37; 95% confidence interval, 1.02-1.83), even after controlling for age, hair color, history of exposure to direct sunlight, skin tanning ability, and severity of reaction to sunburn. Developing an “average” tan or a “deep” tan after prolonged sun exposure also were significantly associated with vitiligo with hazard ratios of 2.28 (95% CI, 1.12-4.65) and 2.59 (95% CI, 1.21-5.54), respectively, “when compared to those who had minimal skin reactions or less severe burns when exposed to the sun,” the authors wrote.
A history of at least one blistering sunburn after 2 hours of sun exposure also predicted vitiligo (HR, 2.17; 95% CI, 1.15-4.10), while hair color did not.
“The benefits of good sun protection can be expanded to include potential vitiligo prevention, which may be particularly applicable to adult patients with vitiligo who are concerned about their children developing the condition,” the investigators commented. “Future studies will examine the incidence of other influencing factors, such as melanoma and melanoma associated leukoderma in this population.”
External funding sources included the National Institutes of Health and Dermatology Foundation. The investigators reported having no conflicts of interest.
FROM THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Key clinical point: Upper extremity moles, tanning ability, and a history of blistering sunburn were significant risk factors for vitiligo among white women.
Major finding: In the multivariate analysis, hazard ratios were 1.37 (95% confidence interval, 1.02-1.83), 2.28 (95% CI, 1.12-4.65), 2.59 (95% CI, 1.21-5.54), and 2.17 (95% CI, 1.15-4.10), respectively.
Data source: An analysis of 51,337 white women from the Nurses’ Health Study.
Disclosures: Funding sources included the National Institutes of Health and Dermatology Foundation. The investigators reported having no conflicts of interest.
Low-volume PEG linked to hypokalemia in at-risk patients
FROM GASTROINTESTINAL ENDOSCOPY
Bowel preparation with low-volume polyethylene glycol led to hypokalemia in nearly 25% of high-risk patients who were normokalemic at baseline, according to a first-in-kind large single-center prospective study.
“Hypokalemia is frequently encountered after low-volume PEG bowel cleansing in high-risk patients,” wrote Ankie Reumkens, MD, and her associates at Maastricht University Medical Center, Maastricht, the Netherlands. The report was published online in Gastrointestinal Endoscopy. “Additional large-scale studies are needed on the prevalence of hypokalemia in nonselected populations undergoing bowel cleansing and on the occurrence of potentially very serious side effects in order to decide on screening of high-risk groups in daily clinical practice.”
Good bowel preparation is crucial to colonoscopy. Bowel preparation with both sodium phosphate and high-volume polyethylene glycol (PEG) has caused hypokalemia, but whether this is true of low-volume PEG is unclear, the investigators said. Recently, at their institution, two colonoscopy patients developed severe hypokalemia and died of ventricular arrhythmias after receiving low-volume PEG. These deaths spurred the researchers to prospectively study 1,822 colonoscopy patients who underwent bowel preparation with low-volume PEG in 2014 and who were considered at high risk of hypokalemia by their gastroenterologists or because of hospitalization or diuretic use.
The researchers measured serum potassium levels of all patients before bowel cleansing. After bowel testing, they retested a subgroup of 301 patients who were normokalemic (3.5-5 mmol/L) at baseline (Gastrointest Endosc. 2017 Feb 7. doi: 10.1016/j.gie.2017.01.040).
In all, 77 patients (4%) were hypokalemic before bowel cleansing, the researchers said. Fully one-third were hospitalized, and hospitalization remained a significant risk factor for baseline hypokalemia even after the researchers controlled for diuretic use, age, sex, and reason for colonoscopy (odds ratio, 2.5; 95% confidence interval, 1.5 to 4.2; P less than .001).
Follow-up testing showed that 71 patients (24%) who were normokalemic at baseline became hypokalemic (serum potassium less than 3.5 mmol/L) after bowel preparation with low-volume PEG. Only diuretic use remained significantly associated with this outcome after researchers accounted for age, sex, reason for colonoscopy, and hospitalization status (odds ratio, 2.3; 95% confidence interval, 1.3 to 4.0; P = .004).
This study included preselected groups of diuretic users and hospitalized patients, making it difficult to assess specific and detailed risk factors for hypokalemia, the researchers said. “Despite this limitation, our study clearly shows that hypokalemia may develop in a substantial percentage of patients after the ingestion of low-volume PEG,” they emphasized. But they recommended population-based studies to determine the true prevalence of hypokalemia after colonoscopy, examine risk factors for this outcome, and consider whether it makes sense to screen subgroups at risk.
The protocol at their hospital is to measure serum potassium before bowel cleansing in hospitalized patients and those on diuretics, they noted. Hypokalemic patients then receive oral potassium if their potassium level was 2.5-3.0 mmol/L, and intravenous potassium if their level was below 2.5 mmol/L.
The investigators reported having no funding sources and no competing interests.
FROM GASTROINTESTINAL ENDOSCOPY
Bowel preparation with low-volume polyethylene glycol led to hypokalemia in nearly 25% of high-risk patients who were normokalemic at baseline, according to a first-in-kind large single-center prospective study.
“Hypokalemia is frequently encountered after low-volume PEG bowel cleansing in high-risk patients,” wrote Ankie Reumkens, MD, and her associates at Maastricht University Medical Center, Maastricht, the Netherlands. The report was published online in Gastrointestinal Endoscopy. “Additional large-scale studies are needed on the prevalence of hypokalemia in nonselected populations undergoing bowel cleansing and on the occurrence of potentially very serious side effects in order to decide on screening of high-risk groups in daily clinical practice.”
Good bowel preparation is crucial to colonoscopy. Bowel preparation with both sodium phosphate and high-volume polyethylene glycol (PEG) has caused hypokalemia, but whether this is true of low-volume PEG is unclear, the investigators said. Recently, at their institution, two colonoscopy patients developed severe hypokalemia and died of ventricular arrhythmias after receiving low-volume PEG. These deaths spurred the researchers to prospectively study 1,822 colonoscopy patients who underwent bowel preparation with low-volume PEG in 2014 and who were considered at high risk of hypokalemia by their gastroenterologists or because of hospitalization or diuretic use.
The researchers measured serum potassium levels of all patients before bowel cleansing. After bowel testing, they retested a subgroup of 301 patients who were normokalemic (3.5-5 mmol/L) at baseline (Gastrointest Endosc. 2017 Feb 7. doi: 10.1016/j.gie.2017.01.040).
In all, 77 patients (4%) were hypokalemic before bowel cleansing, the researchers said. Fully one-third were hospitalized, and hospitalization remained a significant risk factor for baseline hypokalemia even after the researchers controlled for diuretic use, age, sex, and reason for colonoscopy (odds ratio, 2.5; 95% confidence interval, 1.5 to 4.2; P less than .001).
Follow-up testing showed that 71 patients (24%) who were normokalemic at baseline became hypokalemic (serum potassium less than 3.5 mmol/L) after bowel preparation with low-volume PEG. Only diuretic use remained significantly associated with this outcome after researchers accounted for age, sex, reason for colonoscopy, and hospitalization status (odds ratio, 2.3; 95% confidence interval, 1.3 to 4.0; P = .004).
This study included preselected groups of diuretic users and hospitalized patients, making it difficult to assess specific and detailed risk factors for hypokalemia, the researchers said. “Despite this limitation, our study clearly shows that hypokalemia may develop in a substantial percentage of patients after the ingestion of low-volume PEG,” they emphasized. But they recommended population-based studies to determine the true prevalence of hypokalemia after colonoscopy, examine risk factors for this outcome, and consider whether it makes sense to screen subgroups at risk.
The protocol at their hospital is to measure serum potassium before bowel cleansing in hospitalized patients and those on diuretics, they noted. Hypokalemic patients then receive oral potassium if their potassium level was 2.5-3.0 mmol/L, and intravenous potassium if their level was below 2.5 mmol/L.
The investigators reported having no funding sources and no competing interests.
FROM GASTROINTESTINAL ENDOSCOPY
Bowel preparation with low-volume polyethylene glycol led to hypokalemia in nearly 25% of high-risk patients who were normokalemic at baseline, according to a first-in-kind large single-center prospective study.
“Hypokalemia is frequently encountered after low-volume PEG bowel cleansing in high-risk patients,” wrote Ankie Reumkens, MD, and her associates at Maastricht University Medical Center, Maastricht, the Netherlands. The report was published online in Gastrointestinal Endoscopy. “Additional large-scale studies are needed on the prevalence of hypokalemia in nonselected populations undergoing bowel cleansing and on the occurrence of potentially very serious side effects in order to decide on screening of high-risk groups in daily clinical practice.”
Good bowel preparation is crucial to colonoscopy. Bowel preparation with both sodium phosphate and high-volume polyethylene glycol (PEG) has caused hypokalemia, but whether this is true of low-volume PEG is unclear, the investigators said. Recently, at their institution, two colonoscopy patients developed severe hypokalemia and died of ventricular arrhythmias after receiving low-volume PEG. These deaths spurred the researchers to prospectively study 1,822 colonoscopy patients who underwent bowel preparation with low-volume PEG in 2014 and who were considered at high risk of hypokalemia by their gastroenterologists or because of hospitalization or diuretic use.
The researchers measured serum potassium levels of all patients before bowel cleansing. After bowel testing, they retested a subgroup of 301 patients who were normokalemic (3.5-5 mmol/L) at baseline (Gastrointest Endosc. 2017 Feb 7. doi: 10.1016/j.gie.2017.01.040).
In all, 77 patients (4%) were hypokalemic before bowel cleansing, the researchers said. Fully one-third were hospitalized, and hospitalization remained a significant risk factor for baseline hypokalemia even after the researchers controlled for diuretic use, age, sex, and reason for colonoscopy (odds ratio, 2.5; 95% confidence interval, 1.5 to 4.2; P less than .001).
Follow-up testing showed that 71 patients (24%) who were normokalemic at baseline became hypokalemic (serum potassium less than 3.5 mmol/L) after bowel preparation with low-volume PEG. Only diuretic use remained significantly associated with this outcome after researchers accounted for age, sex, reason for colonoscopy, and hospitalization status (odds ratio, 2.3; 95% confidence interval, 1.3 to 4.0; P = .004).
This study included preselected groups of diuretic users and hospitalized patients, making it difficult to assess specific and detailed risk factors for hypokalemia, the researchers said. “Despite this limitation, our study clearly shows that hypokalemia may develop in a substantial percentage of patients after the ingestion of low-volume PEG,” they emphasized. But they recommended population-based studies to determine the true prevalence of hypokalemia after colonoscopy, examine risk factors for this outcome, and consider whether it makes sense to screen subgroups at risk.
The protocol at their hospital is to measure serum potassium before bowel cleansing in hospitalized patients and those on diuretics, they noted. Hypokalemic patients then receive oral potassium if their potassium level was 2.5-3.0 mmol/L, and intravenous potassium if their level was below 2.5 mmol/L.
The investigators reported having no funding sources and no competing interests.
Key clinical point. Bowel preparation with low-volume polyethylene glycol (PEG) led to hypokalemia in at-risk patients.
Major finding: In all, 24% of patients who were normokalemic before bowel cleansing developed hypokalemia afterward. Diuretic use was a significant risk factor for hypokalemia (odds ratio, 2.3; P = .004).
Data source: A prospective study of 1,822 colonoscopy patients considered at high risk of hypokalemia.
Disclosures: The investigators reported having no funding sources and no competing interests.
Methotrexate prolonged efficacy of steroid injections in oligoarticular JIA
Oral methotrexate prolonged and slightly boosted the efficacy of intra-articular corticosteroid injections in children with oligoarticular juvenile idiopathic arthritis without causing serious adverse effects, based on the results of a first-in-kind multicenter, randomized, open-label trial.
“This combination could be considered as reference treatment in everyday clinical practice for pediatricians, particularly in children with higher erythrocyte sedimentation rate,” Angelo Ravelli, MD, of Istituto Giannini Gaslini, Genoa, Italy, and his associates wrote in The Lancet. The regimen also could take center stage in treat-to-target strategies for children with chronic arthritis, they said (Lancet. 2017 Feb 2. doi: 10.1016/S0140-6736[17]30065-X).
For the study, they randomly assigned 207 children and adolescents with oligoarticular juvenile idiopathic arthritis to receive intra-articular injections with triamcinolone hexacetonide or methylprednisolone acetate, either alone or with 15 mg/m2 oral methotrexate at a maximum dose of 20 mg. The primary endpoint was the proportion of patients with remission of all injected joints at 12 months.
Methotrexate missed this endpoint – 12-month remission rates were 34% in the injection-only group and 39% in the dual therapy group (P = .48). However, methotrexate seemed to prolong the time to arthritis flare. The median time to flare was 10.1 months (95% confidence interval, 7.6 to more than 16 months) when patients received injections plus methotrexate, and only 6 months (95% CI, 4.6-8.2 months) when they received injections only (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .03).
Consequently, the dual therapy group had a higher rate of remission at 6 months (67%; 95% CI, 56%-75%) than did the injection-only group (49%; 95% CI, 39%-58%). Cumulative remission rates at 12 months also were higher for dual therapy (46%), compared with injections only (35%).
Erythrocyte sedimentation rate predicted arthritis flare, but did not seem to affect the chances of methotrexate being effective, the researchers said. After controlling for erythrocyte sedimentation rate, methotrexate decreased the 12-month risk of flare by 47%, “although the statistical effect was marginal,” they noted (adjusted odds ratio, 0.53; 95% CI, 0.27-1.01; P = .05).
These findings support those of noncontrolled studies and can inform strategies for initial treatment of oligoarticular juvenile idiopathic arthritis because study participants had short disease durations, the researchers said. But they emphasized that the cohort excluded patients with monoarthritis of the knee, for whom they use only local injections, adding methotrexate if patients relapse soon after the knee is injected or if arthritis spreads to other joints within 6-12 months.
Rates of new-onset uveitis were less than 10% and did not significantly differ between arms. Methotrexate most frequently caused nausea, vomiting, or constipation, but eight patients developed elevated liver enzymes. One patient stopped methotrexate as a result, and five interrupted treatment or had dose reductions. Another patient stopped treatment because of gastrointestinal discomfort, but no there were no serious adverse effects of any type, the researchers said. They will follow the cohort for up to 2 years to evaluate longer-term safety, they added.
The Italian Agency of Drug Evaluation funded the study. Dr. Ravelli disclosed personal fees from AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Johnson & Johnson. Several coinvestigators also disclosed ties to a number of pharmaceutical companies.
These outcomes [of adding methotrexate to intra-articular corticosteroids] seem of substantial benefit for the individual patient [with juvenile idiopathic arthritis]. However, we need to know more about the pathogenesis of this disease and to develop more robust and validated biomarkers to predict an individual’s disease course and response to therapy. Both oral and subcutaneous methotrexate are associated with nausea or intolerance symptoms in up to 40% of patients, which often causes noncompliance in children and adolescents. Therefore, knowledge of who will benefit most from early methotrexate therapy is important.
Nico M. Wulffraat, MD, is with the department of pediatric rheumatology at University Medical Center Utrecht (the Netherlands). He disclosed unrestricted grants from AbbVie, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi, and Sobi. These comments are from his editorial accompanying Dr. Ravelli and his colleagues’ report (Lancet. 2017 Feb 2. doi: 10.1016/S0140-6736[17]30180-0).
These outcomes [of adding methotrexate to intra-articular corticosteroids] seem of substantial benefit for the individual patient [with juvenile idiopathic arthritis]. However, we need to know more about the pathogenesis of this disease and to develop more robust and validated biomarkers to predict an individual’s disease course and response to therapy. Both oral and subcutaneous methotrexate are associated with nausea or intolerance symptoms in up to 40% of patients, which often causes noncompliance in children and adolescents. Therefore, knowledge of who will benefit most from early methotrexate therapy is important.
Nico M. Wulffraat, MD, is with the department of pediatric rheumatology at University Medical Center Utrecht (the Netherlands). He disclosed unrestricted grants from AbbVie, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi, and Sobi. These comments are from his editorial accompanying Dr. Ravelli and his colleagues’ report (Lancet. 2017 Feb 2. doi: 10.1016/S0140-6736[17]30180-0).
These outcomes [of adding methotrexate to intra-articular corticosteroids] seem of substantial benefit for the individual patient [with juvenile idiopathic arthritis]. However, we need to know more about the pathogenesis of this disease and to develop more robust and validated biomarkers to predict an individual’s disease course and response to therapy. Both oral and subcutaneous methotrexate are associated with nausea or intolerance symptoms in up to 40% of patients, which often causes noncompliance in children and adolescents. Therefore, knowledge of who will benefit most from early methotrexate therapy is important.
Nico M. Wulffraat, MD, is with the department of pediatric rheumatology at University Medical Center Utrecht (the Netherlands). He disclosed unrestricted grants from AbbVie, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi, and Sobi. These comments are from his editorial accompanying Dr. Ravelli and his colleagues’ report (Lancet. 2017 Feb 2. doi: 10.1016/S0140-6736[17]30180-0).
Oral methotrexate prolonged and slightly boosted the efficacy of intra-articular corticosteroid injections in children with oligoarticular juvenile idiopathic arthritis without causing serious adverse effects, based on the results of a first-in-kind multicenter, randomized, open-label trial.
“This combination could be considered as reference treatment in everyday clinical practice for pediatricians, particularly in children with higher erythrocyte sedimentation rate,” Angelo Ravelli, MD, of Istituto Giannini Gaslini, Genoa, Italy, and his associates wrote in The Lancet. The regimen also could take center stage in treat-to-target strategies for children with chronic arthritis, they said (Lancet. 2017 Feb 2. doi: 10.1016/S0140-6736[17]30065-X).
For the study, they randomly assigned 207 children and adolescents with oligoarticular juvenile idiopathic arthritis to receive intra-articular injections with triamcinolone hexacetonide or methylprednisolone acetate, either alone or with 15 mg/m2 oral methotrexate at a maximum dose of 20 mg. The primary endpoint was the proportion of patients with remission of all injected joints at 12 months.
Methotrexate missed this endpoint – 12-month remission rates were 34% in the injection-only group and 39% in the dual therapy group (P = .48). However, methotrexate seemed to prolong the time to arthritis flare. The median time to flare was 10.1 months (95% confidence interval, 7.6 to more than 16 months) when patients received injections plus methotrexate, and only 6 months (95% CI, 4.6-8.2 months) when they received injections only (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .03).
Consequently, the dual therapy group had a higher rate of remission at 6 months (67%; 95% CI, 56%-75%) than did the injection-only group (49%; 95% CI, 39%-58%). Cumulative remission rates at 12 months also were higher for dual therapy (46%), compared with injections only (35%).
Erythrocyte sedimentation rate predicted arthritis flare, but did not seem to affect the chances of methotrexate being effective, the researchers said. After controlling for erythrocyte sedimentation rate, methotrexate decreased the 12-month risk of flare by 47%, “although the statistical effect was marginal,” they noted (adjusted odds ratio, 0.53; 95% CI, 0.27-1.01; P = .05).
These findings support those of noncontrolled studies and can inform strategies for initial treatment of oligoarticular juvenile idiopathic arthritis because study participants had short disease durations, the researchers said. But they emphasized that the cohort excluded patients with monoarthritis of the knee, for whom they use only local injections, adding methotrexate if patients relapse soon after the knee is injected or if arthritis spreads to other joints within 6-12 months.
Rates of new-onset uveitis were less than 10% and did not significantly differ between arms. Methotrexate most frequently caused nausea, vomiting, or constipation, but eight patients developed elevated liver enzymes. One patient stopped methotrexate as a result, and five interrupted treatment or had dose reductions. Another patient stopped treatment because of gastrointestinal discomfort, but no there were no serious adverse effects of any type, the researchers said. They will follow the cohort for up to 2 years to evaluate longer-term safety, they added.
The Italian Agency of Drug Evaluation funded the study. Dr. Ravelli disclosed personal fees from AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Johnson & Johnson. Several coinvestigators also disclosed ties to a number of pharmaceutical companies.
Oral methotrexate prolonged and slightly boosted the efficacy of intra-articular corticosteroid injections in children with oligoarticular juvenile idiopathic arthritis without causing serious adverse effects, based on the results of a first-in-kind multicenter, randomized, open-label trial.
“This combination could be considered as reference treatment in everyday clinical practice for pediatricians, particularly in children with higher erythrocyte sedimentation rate,” Angelo Ravelli, MD, of Istituto Giannini Gaslini, Genoa, Italy, and his associates wrote in The Lancet. The regimen also could take center stage in treat-to-target strategies for children with chronic arthritis, they said (Lancet. 2017 Feb 2. doi: 10.1016/S0140-6736[17]30065-X).
For the study, they randomly assigned 207 children and adolescents with oligoarticular juvenile idiopathic arthritis to receive intra-articular injections with triamcinolone hexacetonide or methylprednisolone acetate, either alone or with 15 mg/m2 oral methotrexate at a maximum dose of 20 mg. The primary endpoint was the proportion of patients with remission of all injected joints at 12 months.
Methotrexate missed this endpoint – 12-month remission rates were 34% in the injection-only group and 39% in the dual therapy group (P = .48). However, methotrexate seemed to prolong the time to arthritis flare. The median time to flare was 10.1 months (95% confidence interval, 7.6 to more than 16 months) when patients received injections plus methotrexate, and only 6 months (95% CI, 4.6-8.2 months) when they received injections only (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .03).
Consequently, the dual therapy group had a higher rate of remission at 6 months (67%; 95% CI, 56%-75%) than did the injection-only group (49%; 95% CI, 39%-58%). Cumulative remission rates at 12 months also were higher for dual therapy (46%), compared with injections only (35%).
Erythrocyte sedimentation rate predicted arthritis flare, but did not seem to affect the chances of methotrexate being effective, the researchers said. After controlling for erythrocyte sedimentation rate, methotrexate decreased the 12-month risk of flare by 47%, “although the statistical effect was marginal,” they noted (adjusted odds ratio, 0.53; 95% CI, 0.27-1.01; P = .05).
These findings support those of noncontrolled studies and can inform strategies for initial treatment of oligoarticular juvenile idiopathic arthritis because study participants had short disease durations, the researchers said. But they emphasized that the cohort excluded patients with monoarthritis of the knee, for whom they use only local injections, adding methotrexate if patients relapse soon after the knee is injected or if arthritis spreads to other joints within 6-12 months.
Rates of new-onset uveitis were less than 10% and did not significantly differ between arms. Methotrexate most frequently caused nausea, vomiting, or constipation, but eight patients developed elevated liver enzymes. One patient stopped methotrexate as a result, and five interrupted treatment or had dose reductions. Another patient stopped treatment because of gastrointestinal discomfort, but no there were no serious adverse effects of any type, the researchers said. They will follow the cohort for up to 2 years to evaluate longer-term safety, they added.
The Italian Agency of Drug Evaluation funded the study. Dr. Ravelli disclosed personal fees from AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Johnson & Johnson. Several coinvestigators also disclosed ties to a number of pharmaceutical companies.
FROM THE LANCET
Key clinical point:
Major finding: The primary endpoint, remission of arthritis in all injected joints at 12 months, occurred in 34% of patients who received intra-articular corticosteroids only and in 39% of those who also received oral methotrexate (P = .48). Median time to arthritis flare was 10.1 months with dual therapy and 6 months with injections only (HR, 0.67; P = .03).
Data source: A multicenter, open-label, randomized trial of 207 children younger than 18 years with oligoarticular juvenile idiopathic arthritis.
Disclosures: The Italian Agency of Drug Evaluation funded the study. Dr. Ravelli disclosed personal fees from AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Johnson & Johnson. Several coinvestigators also disclosed ties to a number of pharmaceutical companies.
In CLL, specific mutation is key to ibrutinib resistance
Acquired BTKC481S and PLCG2 mutations led to ibrutinib resistance in chronic lymphocytic leukemia (CLL), investigators reported online in the Journal of Clinical Oncology.
These mutations preceded 85% of clinical relapses, appearing a median of 9.3 months beforehand, Jennifer A. Woyach, MD, and her associates from the Ohio State University, Columbus, concluded from a retrospective study of 308 patients. In a separate prospective study of 112 patients, acquired BTKC481S mutation and clonal expansion preceded all eight cases of relapse, they said. “Relapse of CLL after ibrutinib is an issue of increasing clinical significance,” they concluded. “We show that mutations in Bruton tyrosine kinase (BTK) and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.”
Ibrutinib has transformed the CLL treatment landscape, but patients face poor outcomes if they relapse with Richter transformation or develop progressive disease. Past work has linked ibrutinib resistance to acquired mutations in BTK at the binding site of ibrutinib and in PLCG2 located just downstream. But the scope of ibrutinib resistance in CLL and key mutational players were unknown (J Clin Oncol. 2017. doi: 10.1200/JCO.2016.70.2282).
To fill that gap, the researchers retrospectively analyzed data from four sequential ibrutinib CLL trials at the Ohio State University. The separate prospective analysis involved analyzing the entire BTK and PLCG2 coding regions every 3 months.
In the retrospective study, patients had received a median of 3 and up to 16 prior therapies. Given the median follow-up period of 3.4 years, about 19% of patients experienced clinical relapse within 4 years of starting ibrutinib, the researchers estimated (95% confidence interval, 14%-24%). Deep sequencing by Ion Torrent (Life Technologies) identified mutations in BTKC481S and/or PLCG2, in 40 of 47 (85%) relapses. In 31 cases, BTKC481S was the sole mutation. Mutational burdens varied among patients, but generally correlated with CLL progression in peripheral blood versus primarily nodal relapse.
At baseline, 172 (58%) of retrospective study participants had complex cytogenetics, 52% had del(13q), 40% had del(17p), and 21% had MYC abnormality. Median age was 65 years (range, 26-91 years) and 70% of patients were female. Multivariable analyses linked transformation to complex karyotype (hazard ratio, 5.0; 95% CI, 1.5-16.5) and MYC abnormality (HR, 2.5; 95% CI, 1.0-4.7), and linked progressive CLL to age younger than 65 years, complex karyotype, and del(17)(p13.1).
Richter transformation usually occurred within 2 years of starting ibrutinib and had a cumulative 4-year incidence of 10%, the investigators also reported. Patients survived a median of only 3.9 months after stopping ibrutinib because of transformation. The cumulative rate of progressive CLL was higher (19.1%), but early progression was rare, and patients who stopped ibrutinib because of progression survived longer (median, 22.7 months).
In the prospective study, all eight patients with BTKC481S who had not yet clinically relapsed nonetheless had increasing frequency of this mutation over time, the investigators reported. Together, the findings confirm BTK and PLCG2 mutations as the key players in CLL resistance to ibrutinib, they stated. Perhaps most importantly, they reveal “a prolonged period of asymptomatic clonal expression” in CLL that precedes clinical relapse and provides a window of opportunity to target these cells with novel therapies in clinical trials, they wrote.
Given that ibrutinib was approved for use in relapsed CLL only 2 years ago, “We are likely just starting to see the first emergence of relapse in the community setting,” the researchers concluded. “Enhanced knowledge of both the molecular and clinical mechanisms of relapse may allow for strategic alterations in monitoring and management that could change the natural history of ibrutinib resistance.”
Funding sources included the D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, the Four Winds Foundation, the Leukemia and Lymphoma Society, Pelotonia, and the National Cancer Institute. Pharmacyclics also provided partial support. Dr. Woyach disclosed ties to Janssen, Acerta Pharma, Karyopharm Therapeutics, and MorphoSys, and a provisional patent related to C481S detection.
Acquired BTKC481S and PLCG2 mutations led to ibrutinib resistance in chronic lymphocytic leukemia (CLL), investigators reported online in the Journal of Clinical Oncology.
These mutations preceded 85% of clinical relapses, appearing a median of 9.3 months beforehand, Jennifer A. Woyach, MD, and her associates from the Ohio State University, Columbus, concluded from a retrospective study of 308 patients. In a separate prospective study of 112 patients, acquired BTKC481S mutation and clonal expansion preceded all eight cases of relapse, they said. “Relapse of CLL after ibrutinib is an issue of increasing clinical significance,” they concluded. “We show that mutations in Bruton tyrosine kinase (BTK) and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.”
Ibrutinib has transformed the CLL treatment landscape, but patients face poor outcomes if they relapse with Richter transformation or develop progressive disease. Past work has linked ibrutinib resistance to acquired mutations in BTK at the binding site of ibrutinib and in PLCG2 located just downstream. But the scope of ibrutinib resistance in CLL and key mutational players were unknown (J Clin Oncol. 2017. doi: 10.1200/JCO.2016.70.2282).
To fill that gap, the researchers retrospectively analyzed data from four sequential ibrutinib CLL trials at the Ohio State University. The separate prospective analysis involved analyzing the entire BTK and PLCG2 coding regions every 3 months.
In the retrospective study, patients had received a median of 3 and up to 16 prior therapies. Given the median follow-up period of 3.4 years, about 19% of patients experienced clinical relapse within 4 years of starting ibrutinib, the researchers estimated (95% confidence interval, 14%-24%). Deep sequencing by Ion Torrent (Life Technologies) identified mutations in BTKC481S and/or PLCG2, in 40 of 47 (85%) relapses. In 31 cases, BTKC481S was the sole mutation. Mutational burdens varied among patients, but generally correlated with CLL progression in peripheral blood versus primarily nodal relapse.
At baseline, 172 (58%) of retrospective study participants had complex cytogenetics, 52% had del(13q), 40% had del(17p), and 21% had MYC abnormality. Median age was 65 years (range, 26-91 years) and 70% of patients were female. Multivariable analyses linked transformation to complex karyotype (hazard ratio, 5.0; 95% CI, 1.5-16.5) and MYC abnormality (HR, 2.5; 95% CI, 1.0-4.7), and linked progressive CLL to age younger than 65 years, complex karyotype, and del(17)(p13.1).
Richter transformation usually occurred within 2 years of starting ibrutinib and had a cumulative 4-year incidence of 10%, the investigators also reported. Patients survived a median of only 3.9 months after stopping ibrutinib because of transformation. The cumulative rate of progressive CLL was higher (19.1%), but early progression was rare, and patients who stopped ibrutinib because of progression survived longer (median, 22.7 months).
In the prospective study, all eight patients with BTKC481S who had not yet clinically relapsed nonetheless had increasing frequency of this mutation over time, the investigators reported. Together, the findings confirm BTK and PLCG2 mutations as the key players in CLL resistance to ibrutinib, they stated. Perhaps most importantly, they reveal “a prolonged period of asymptomatic clonal expression” in CLL that precedes clinical relapse and provides a window of opportunity to target these cells with novel therapies in clinical trials, they wrote.
Given that ibrutinib was approved for use in relapsed CLL only 2 years ago, “We are likely just starting to see the first emergence of relapse in the community setting,” the researchers concluded. “Enhanced knowledge of both the molecular and clinical mechanisms of relapse may allow for strategic alterations in monitoring and management that could change the natural history of ibrutinib resistance.”
Funding sources included the D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, the Four Winds Foundation, the Leukemia and Lymphoma Society, Pelotonia, and the National Cancer Institute. Pharmacyclics also provided partial support. Dr. Woyach disclosed ties to Janssen, Acerta Pharma, Karyopharm Therapeutics, and MorphoSys, and a provisional patent related to C481S detection.
Acquired BTKC481S and PLCG2 mutations led to ibrutinib resistance in chronic lymphocytic leukemia (CLL), investigators reported online in the Journal of Clinical Oncology.
These mutations preceded 85% of clinical relapses, appearing a median of 9.3 months beforehand, Jennifer A. Woyach, MD, and her associates from the Ohio State University, Columbus, concluded from a retrospective study of 308 patients. In a separate prospective study of 112 patients, acquired BTKC481S mutation and clonal expansion preceded all eight cases of relapse, they said. “Relapse of CLL after ibrutinib is an issue of increasing clinical significance,” they concluded. “We show that mutations in Bruton tyrosine kinase (BTK) and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.”
Ibrutinib has transformed the CLL treatment landscape, but patients face poor outcomes if they relapse with Richter transformation or develop progressive disease. Past work has linked ibrutinib resistance to acquired mutations in BTK at the binding site of ibrutinib and in PLCG2 located just downstream. But the scope of ibrutinib resistance in CLL and key mutational players were unknown (J Clin Oncol. 2017. doi: 10.1200/JCO.2016.70.2282).
To fill that gap, the researchers retrospectively analyzed data from four sequential ibrutinib CLL trials at the Ohio State University. The separate prospective analysis involved analyzing the entire BTK and PLCG2 coding regions every 3 months.
In the retrospective study, patients had received a median of 3 and up to 16 prior therapies. Given the median follow-up period of 3.4 years, about 19% of patients experienced clinical relapse within 4 years of starting ibrutinib, the researchers estimated (95% confidence interval, 14%-24%). Deep sequencing by Ion Torrent (Life Technologies) identified mutations in BTKC481S and/or PLCG2, in 40 of 47 (85%) relapses. In 31 cases, BTKC481S was the sole mutation. Mutational burdens varied among patients, but generally correlated with CLL progression in peripheral blood versus primarily nodal relapse.
At baseline, 172 (58%) of retrospective study participants had complex cytogenetics, 52% had del(13q), 40% had del(17p), and 21% had MYC abnormality. Median age was 65 years (range, 26-91 years) and 70% of patients were female. Multivariable analyses linked transformation to complex karyotype (hazard ratio, 5.0; 95% CI, 1.5-16.5) and MYC abnormality (HR, 2.5; 95% CI, 1.0-4.7), and linked progressive CLL to age younger than 65 years, complex karyotype, and del(17)(p13.1).
Richter transformation usually occurred within 2 years of starting ibrutinib and had a cumulative 4-year incidence of 10%, the investigators also reported. Patients survived a median of only 3.9 months after stopping ibrutinib because of transformation. The cumulative rate of progressive CLL was higher (19.1%), but early progression was rare, and patients who stopped ibrutinib because of progression survived longer (median, 22.7 months).
In the prospective study, all eight patients with BTKC481S who had not yet clinically relapsed nonetheless had increasing frequency of this mutation over time, the investigators reported. Together, the findings confirm BTK and PLCG2 mutations as the key players in CLL resistance to ibrutinib, they stated. Perhaps most importantly, they reveal “a prolonged period of asymptomatic clonal expression” in CLL that precedes clinical relapse and provides a window of opportunity to target these cells with novel therapies in clinical trials, they wrote.
Given that ibrutinib was approved for use in relapsed CLL only 2 years ago, “We are likely just starting to see the first emergence of relapse in the community setting,” the researchers concluded. “Enhanced knowledge of both the molecular and clinical mechanisms of relapse may allow for strategic alterations in monitoring and management that could change the natural history of ibrutinib resistance.”
Funding sources included the D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, the Four Winds Foundation, the Leukemia and Lymphoma Society, Pelotonia, and the National Cancer Institute. Pharmacyclics also provided partial support. Dr. Woyach disclosed ties to Janssen, Acerta Pharma, Karyopharm Therapeutics, and MorphoSys, and a provisional patent related to C481S detection.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Acquired mutations in BTKC481S and PLCG2 predict ibrutinib resistance in chronic lymphocytic leukemia.
Major finding: These mutations appeared a median of 9.3 months before clinical relapse in 85% of cases. In a separate study, all eight CLL patients who relapsed on ibrutinib had previously developed the BTKC481S mutation with clonal expansion.
Data source: A retrospective analysis of 308 CLL patients from four ibrutinib trials, and a separate prospective study of 118 CLL patients.
Disclosures: Funding sources included the D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, the Four Winds Foundation, the Leukemia and Lymphoma Society, Pelotonia, and the National Cancer Institute. Pharmacyclics also provided partial support. Dr. Woyach disclosed ties to Janssen, Acerta Pharma, Karyopharm Therapeutics, and MorphoSys, and a provisional patent related to C481S detection.
Guideline: Prioritize nondrug therapies for low back pain
Clinicians and patients should prioritize nonpharmacologic therapies for low back pain of any duration, according to an updated guideline from the American College of Physicians.
For acute and subacute low back pain, first-line choices include heat, massage, acupuncture, and spinal manipulation, Amir Qaseem, MD, PhD, and his associates wrote in the Annals of Internal Medicine. Patients with chronic low back pain have many nondrug options, ranging from exercise and tai chi to mindfulness-based stress reduction and spinal manipulation, the authors add (Ann Intern Med. 2017 Feb 14. doi: 10.7326/M16-2367).
The updated therapeutic recommendations focus on clinical presentations. They define acute low back pain as lasting less than 4 weeks, subacute low back pain as lasting 4-12 weeks, and chronic low back pain as lasting more than 12 weeks. For acute and subacute low back pain, low to moderate quality evidence supports the efficacy of acupuncture, massage, spinal manipulation, superficial heat, lumbar supports, and low-level laser therapy, the guideline authors conclude.
They recommend considering nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants for patients who want medications for acute or subacute low back pain. There is moderate-quality evidence that NSAIDs confer a small analgesic benefit, compared with placebo, but their renal and gastrointestinal risks call for careful patient selection and use of the lowest possible doses and treatment durations, the authors emphasized.
Likewise, moderate-quality evidence supports the use of skeletal muscle relaxants for short-term pain relief, but patients should know that these drugs can lead to sedation and other adverse effects on the central nervous system, they stated.
Acetaminophen is no longer recommended for low back pain, having failed to shorten time to recovery, compared with placebo, in a large, multicenter, randomized trial (Lancet. 2014 Nov 1;384[9954]:1586-96).
Likewise, short-term oral or intramuscular corticosteroids have been found ineffective for acute low back pain, while benzodiazepines are ineffective for radiculopathy, the experts noted.
“Evidence was insufficient to determine effectiveness of antidepressants, benzodiazepines, antiseizure medications, or opioids, versus placebo, in patients with acute or subacute low back pain,” they added.
The guideline authors also noted insufficient evidence for many nondrug therapies for acute and subacute low back pain, including transcutaneous electrical nerve stimulation, electrical muscle stimulation, inferential therapy, short-wave diathermy, traction, superficial cold, motor control exercise, Pilates, tai chi, yoga, psychological therapies, multidisciplinary rehabilitation, ultrasound, and taping.
For chronic low back pain, the guideline strongly recommends starting with nondrug therapies, including exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction, tai chi, yoga, motor control exercise, progressive relaxation, electromyography biofeedback, low-level laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation.
Despite low-quality evidence for these modalities, “fewer harms are associated with these types of therapies than with pharmacologic options,” the authors wrote.
If nonpharmacologic interventions fail to improve chronic low back pain, the experts recommended NSAIDs in the first line, followed by second-line therapy with tramadol or duloxetine (Cymbalta). Recent evidence suggests that NSAIDs are less effective for low back pain than previously thought, while the trials that reported a modest analgesic benefit of duloxetine over placebo were industry funded, the authors note.
Opioids should only be considered for chronic low back pain that fails both nondrug and nonopioid therapies, “and only if the potential benefits outweigh the risks for individual patients, and after a discussion of known risks and realistic benefits,” the guideline authors emphasized.
This update does not cover topical therapies or epidural injections. Epidural steroid injections decreased pain associated with radiculopathy in the short term but did not confer long-term benefits, according to a recent separate review (Ann Intern Med. 2015 Sep 1;163[5]:373-81).
The Agency for Healthcare Research and Quality funded the work. One coauthor disclosed personal fees from Takeda Pharmaceuticals outside the submitted work, and membership in the American College of Physicians Clinical Guidelines Committee and the American College of Rheumatology Quality of Care Committee. The other authors had no conflicts. Two members of the ACP Clinical Guidelines Committee disclosed ties to Healthwise and UpToDate outside the submitted work.
Despite the considerable effort invested in these systematic reviews and in providing clinicians with rational recommendations for care, doubts exist as to whether simply publishing this work will be sufficient to drive guideline-concordant care.
Systematic reviews and recommendations from governmental organizations and professional societies are not new and predate large increases in diagnostic and therapeutic services.
For example, the lack of evidence supporting opiates for low back pain did not prevent their dramatic increase in use. Moreover, these updated reviews and recommendations do not focus on diagnostic tests, such as magnetic resonance imaging, and invasive therapies, such as injections and surgery, which are major drivers of health care spending for low back pain.
If clinicians and their professional societies cannot demonstrate that their recommendations are improving the delivery of high-value services, what are the alternatives?
Likely what is needed is an “all of the above” approach: more pragmatic trials to evaluate proven therapies and their combinations in real-world settings; efforts to reduce the use of low-value services, such as payer coverage policies based on guideline recommendations; patient engagement through shared decision making; and pressure on insurers to cover nonpharmacologic, noninvasive therapies that have shown benefit.
Steven J. Atlas, MD, MPH, is at Massachusetts General Hospital in Boston. He disclosed royalties from UpToDate and personal fees from Healthwise. These comments are from his editorial (Ann Intern Med. 2017 Feb 14. doi: 10.7326/M17-0923).
Despite the considerable effort invested in these systematic reviews and in providing clinicians with rational recommendations for care, doubts exist as to whether simply publishing this work will be sufficient to drive guideline-concordant care.
Systematic reviews and recommendations from governmental organizations and professional societies are not new and predate large increases in diagnostic and therapeutic services.
For example, the lack of evidence supporting opiates for low back pain did not prevent their dramatic increase in use. Moreover, these updated reviews and recommendations do not focus on diagnostic tests, such as magnetic resonance imaging, and invasive therapies, such as injections and surgery, which are major drivers of health care spending for low back pain.
If clinicians and their professional societies cannot demonstrate that their recommendations are improving the delivery of high-value services, what are the alternatives?
Likely what is needed is an “all of the above” approach: more pragmatic trials to evaluate proven therapies and their combinations in real-world settings; efforts to reduce the use of low-value services, such as payer coverage policies based on guideline recommendations; patient engagement through shared decision making; and pressure on insurers to cover nonpharmacologic, noninvasive therapies that have shown benefit.
Steven J. Atlas, MD, MPH, is at Massachusetts General Hospital in Boston. He disclosed royalties from UpToDate and personal fees from Healthwise. These comments are from his editorial (Ann Intern Med. 2017 Feb 14. doi: 10.7326/M17-0923).
Despite the considerable effort invested in these systematic reviews and in providing clinicians with rational recommendations for care, doubts exist as to whether simply publishing this work will be sufficient to drive guideline-concordant care.
Systematic reviews and recommendations from governmental organizations and professional societies are not new and predate large increases in diagnostic and therapeutic services.
For example, the lack of evidence supporting opiates for low back pain did not prevent their dramatic increase in use. Moreover, these updated reviews and recommendations do not focus on diagnostic tests, such as magnetic resonance imaging, and invasive therapies, such as injections and surgery, which are major drivers of health care spending for low back pain.
If clinicians and their professional societies cannot demonstrate that their recommendations are improving the delivery of high-value services, what are the alternatives?
Likely what is needed is an “all of the above” approach: more pragmatic trials to evaluate proven therapies and their combinations in real-world settings; efforts to reduce the use of low-value services, such as payer coverage policies based on guideline recommendations; patient engagement through shared decision making; and pressure on insurers to cover nonpharmacologic, noninvasive therapies that have shown benefit.
Steven J. Atlas, MD, MPH, is at Massachusetts General Hospital in Boston. He disclosed royalties from UpToDate and personal fees from Healthwise. These comments are from his editorial (Ann Intern Med. 2017 Feb 14. doi: 10.7326/M17-0923).
Clinicians and patients should prioritize nonpharmacologic therapies for low back pain of any duration, according to an updated guideline from the American College of Physicians.
For acute and subacute low back pain, first-line choices include heat, massage, acupuncture, and spinal manipulation, Amir Qaseem, MD, PhD, and his associates wrote in the Annals of Internal Medicine. Patients with chronic low back pain have many nondrug options, ranging from exercise and tai chi to mindfulness-based stress reduction and spinal manipulation, the authors add (Ann Intern Med. 2017 Feb 14. doi: 10.7326/M16-2367).
The updated therapeutic recommendations focus on clinical presentations. They define acute low back pain as lasting less than 4 weeks, subacute low back pain as lasting 4-12 weeks, and chronic low back pain as lasting more than 12 weeks. For acute and subacute low back pain, low to moderate quality evidence supports the efficacy of acupuncture, massage, spinal manipulation, superficial heat, lumbar supports, and low-level laser therapy, the guideline authors conclude.
They recommend considering nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants for patients who want medications for acute or subacute low back pain. There is moderate-quality evidence that NSAIDs confer a small analgesic benefit, compared with placebo, but their renal and gastrointestinal risks call for careful patient selection and use of the lowest possible doses and treatment durations, the authors emphasized.
Likewise, moderate-quality evidence supports the use of skeletal muscle relaxants for short-term pain relief, but patients should know that these drugs can lead to sedation and other adverse effects on the central nervous system, they stated.
Acetaminophen is no longer recommended for low back pain, having failed to shorten time to recovery, compared with placebo, in a large, multicenter, randomized trial (Lancet. 2014 Nov 1;384[9954]:1586-96).
Likewise, short-term oral or intramuscular corticosteroids have been found ineffective for acute low back pain, while benzodiazepines are ineffective for radiculopathy, the experts noted.
“Evidence was insufficient to determine effectiveness of antidepressants, benzodiazepines, antiseizure medications, or opioids, versus placebo, in patients with acute or subacute low back pain,” they added.
The guideline authors also noted insufficient evidence for many nondrug therapies for acute and subacute low back pain, including transcutaneous electrical nerve stimulation, electrical muscle stimulation, inferential therapy, short-wave diathermy, traction, superficial cold, motor control exercise, Pilates, tai chi, yoga, psychological therapies, multidisciplinary rehabilitation, ultrasound, and taping.
For chronic low back pain, the guideline strongly recommends starting with nondrug therapies, including exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction, tai chi, yoga, motor control exercise, progressive relaxation, electromyography biofeedback, low-level laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation.
Despite low-quality evidence for these modalities, “fewer harms are associated with these types of therapies than with pharmacologic options,” the authors wrote.
If nonpharmacologic interventions fail to improve chronic low back pain, the experts recommended NSAIDs in the first line, followed by second-line therapy with tramadol or duloxetine (Cymbalta). Recent evidence suggests that NSAIDs are less effective for low back pain than previously thought, while the trials that reported a modest analgesic benefit of duloxetine over placebo were industry funded, the authors note.
Opioids should only be considered for chronic low back pain that fails both nondrug and nonopioid therapies, “and only if the potential benefits outweigh the risks for individual patients, and after a discussion of known risks and realistic benefits,” the guideline authors emphasized.
This update does not cover topical therapies or epidural injections. Epidural steroid injections decreased pain associated with radiculopathy in the short term but did not confer long-term benefits, according to a recent separate review (Ann Intern Med. 2015 Sep 1;163[5]:373-81).
The Agency for Healthcare Research and Quality funded the work. One coauthor disclosed personal fees from Takeda Pharmaceuticals outside the submitted work, and membership in the American College of Physicians Clinical Guidelines Committee and the American College of Rheumatology Quality of Care Committee. The other authors had no conflicts. Two members of the ACP Clinical Guidelines Committee disclosed ties to Healthwise and UpToDate outside the submitted work.
Clinicians and patients should prioritize nonpharmacologic therapies for low back pain of any duration, according to an updated guideline from the American College of Physicians.
For acute and subacute low back pain, first-line choices include heat, massage, acupuncture, and spinal manipulation, Amir Qaseem, MD, PhD, and his associates wrote in the Annals of Internal Medicine. Patients with chronic low back pain have many nondrug options, ranging from exercise and tai chi to mindfulness-based stress reduction and spinal manipulation, the authors add (Ann Intern Med. 2017 Feb 14. doi: 10.7326/M16-2367).
The updated therapeutic recommendations focus on clinical presentations. They define acute low back pain as lasting less than 4 weeks, subacute low back pain as lasting 4-12 weeks, and chronic low back pain as lasting more than 12 weeks. For acute and subacute low back pain, low to moderate quality evidence supports the efficacy of acupuncture, massage, spinal manipulation, superficial heat, lumbar supports, and low-level laser therapy, the guideline authors conclude.
They recommend considering nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants for patients who want medications for acute or subacute low back pain. There is moderate-quality evidence that NSAIDs confer a small analgesic benefit, compared with placebo, but their renal and gastrointestinal risks call for careful patient selection and use of the lowest possible doses and treatment durations, the authors emphasized.
Likewise, moderate-quality evidence supports the use of skeletal muscle relaxants for short-term pain relief, but patients should know that these drugs can lead to sedation and other adverse effects on the central nervous system, they stated.
Acetaminophen is no longer recommended for low back pain, having failed to shorten time to recovery, compared with placebo, in a large, multicenter, randomized trial (Lancet. 2014 Nov 1;384[9954]:1586-96).
Likewise, short-term oral or intramuscular corticosteroids have been found ineffective for acute low back pain, while benzodiazepines are ineffective for radiculopathy, the experts noted.
“Evidence was insufficient to determine effectiveness of antidepressants, benzodiazepines, antiseizure medications, or opioids, versus placebo, in patients with acute or subacute low back pain,” they added.
The guideline authors also noted insufficient evidence for many nondrug therapies for acute and subacute low back pain, including transcutaneous electrical nerve stimulation, electrical muscle stimulation, inferential therapy, short-wave diathermy, traction, superficial cold, motor control exercise, Pilates, tai chi, yoga, psychological therapies, multidisciplinary rehabilitation, ultrasound, and taping.
For chronic low back pain, the guideline strongly recommends starting with nondrug therapies, including exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction, tai chi, yoga, motor control exercise, progressive relaxation, electromyography biofeedback, low-level laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation.
Despite low-quality evidence for these modalities, “fewer harms are associated with these types of therapies than with pharmacologic options,” the authors wrote.
If nonpharmacologic interventions fail to improve chronic low back pain, the experts recommended NSAIDs in the first line, followed by second-line therapy with tramadol or duloxetine (Cymbalta). Recent evidence suggests that NSAIDs are less effective for low back pain than previously thought, while the trials that reported a modest analgesic benefit of duloxetine over placebo were industry funded, the authors note.
Opioids should only be considered for chronic low back pain that fails both nondrug and nonopioid therapies, “and only if the potential benefits outweigh the risks for individual patients, and after a discussion of known risks and realistic benefits,” the guideline authors emphasized.
This update does not cover topical therapies or epidural injections. Epidural steroid injections decreased pain associated with radiculopathy in the short term but did not confer long-term benefits, according to a recent separate review (Ann Intern Med. 2015 Sep 1;163[5]:373-81).
The Agency for Healthcare Research and Quality funded the work. One coauthor disclosed personal fees from Takeda Pharmaceuticals outside the submitted work, and membership in the American College of Physicians Clinical Guidelines Committee and the American College of Rheumatology Quality of Care Committee. The other authors had no conflicts. Two members of the ACP Clinical Guidelines Committee disclosed ties to Healthwise and UpToDate outside the submitted work.
FROM ANNALS OF INTERNAL MEDICINE
Eradicate HCV in patients with HIV, regardless of fibrosis stage
Eradicating hepatitis C virus in HIV-coinfected patients was associated with a significantly lower risk of diabetes mellitus and possibly chronic renal failure, along with lower rates of deaths, HIV progression, and liver-related events, according to an observational study of 1,625 patients.
“These findings argue for the prescription of HCV therapy regardless of liver fibrosis stage in coinfected patients,” Juan Berenguer, MD, PhD, and his associates at Hospital General Universitario Gregario Marañón, Madrid. Extrahepatic manifestations of HCV infection are numerous and contribute substantially to morbidity and mortality. “To the best of our knowledge, the effect of eradication of HCV on extrahepatic manifestations of HCV has not been systematically studied in HIV/HCV-coinfected patients,” the researchers wrote in Hepatology (Hepatology 2017 Jan 21:doi:10.1002/hep.29071 [Epub ahead of print]).
After a median of 5 years of follow-up, SVR was associated with a 43% decrease in the likelihood of developing diabetes, even after controlling for a host of potential confounders, including Fibrosis-4 score (using 3.25 as the cutoff value), age, sex, history of AIDS, HIV-transmission category, nadir CD4+ T-cell count, antiretroviral therapy, HIV-RNA, HCV genotype, and exposure to specific anti-HIV drugs (adjusted hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.93; P = .02). Sustained viral response also was associated with a lower likelihood of chronic renal failure with borderline statistical significance (aHR, 0.43; 95% CI, 0.17 to 1.09; P = .075).
“In agreement with previous reports from this cohort, we found that treatment response was associated with a decreased hazard of overall and liver-related death, all types of liver-related events, and new AIDS-related conditions,” the researchers noted. These findings underscore the vital importance of HCV therapy for HIV-coinfected patients, regardless of liver fibrosis stage, they emphasized.
The study was funded by Spanish Health Research Funds and AIDS Research Network. The investigators reported having no relevant conflicts of interest.
Eradicating hepatitis C virus in HIV-coinfected patients was associated with a significantly lower risk of diabetes mellitus and possibly chronic renal failure, along with lower rates of deaths, HIV progression, and liver-related events, according to an observational study of 1,625 patients.
“These findings argue for the prescription of HCV therapy regardless of liver fibrosis stage in coinfected patients,” Juan Berenguer, MD, PhD, and his associates at Hospital General Universitario Gregario Marañón, Madrid. Extrahepatic manifestations of HCV infection are numerous and contribute substantially to morbidity and mortality. “To the best of our knowledge, the effect of eradication of HCV on extrahepatic manifestations of HCV has not been systematically studied in HIV/HCV-coinfected patients,” the researchers wrote in Hepatology (Hepatology 2017 Jan 21:doi:10.1002/hep.29071 [Epub ahead of print]).
After a median of 5 years of follow-up, SVR was associated with a 43% decrease in the likelihood of developing diabetes, even after controlling for a host of potential confounders, including Fibrosis-4 score (using 3.25 as the cutoff value), age, sex, history of AIDS, HIV-transmission category, nadir CD4+ T-cell count, antiretroviral therapy, HIV-RNA, HCV genotype, and exposure to specific anti-HIV drugs (adjusted hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.93; P = .02). Sustained viral response also was associated with a lower likelihood of chronic renal failure with borderline statistical significance (aHR, 0.43; 95% CI, 0.17 to 1.09; P = .075).
“In agreement with previous reports from this cohort, we found that treatment response was associated with a decreased hazard of overall and liver-related death, all types of liver-related events, and new AIDS-related conditions,” the researchers noted. These findings underscore the vital importance of HCV therapy for HIV-coinfected patients, regardless of liver fibrosis stage, they emphasized.
The study was funded by Spanish Health Research Funds and AIDS Research Network. The investigators reported having no relevant conflicts of interest.
Eradicating hepatitis C virus in HIV-coinfected patients was associated with a significantly lower risk of diabetes mellitus and possibly chronic renal failure, along with lower rates of deaths, HIV progression, and liver-related events, according to an observational study of 1,625 patients.
“These findings argue for the prescription of HCV therapy regardless of liver fibrosis stage in coinfected patients,” Juan Berenguer, MD, PhD, and his associates at Hospital General Universitario Gregario Marañón, Madrid. Extrahepatic manifestations of HCV infection are numerous and contribute substantially to morbidity and mortality. “To the best of our knowledge, the effect of eradication of HCV on extrahepatic manifestations of HCV has not been systematically studied in HIV/HCV-coinfected patients,” the researchers wrote in Hepatology (Hepatology 2017 Jan 21:doi:10.1002/hep.29071 [Epub ahead of print]).
After a median of 5 years of follow-up, SVR was associated with a 43% decrease in the likelihood of developing diabetes, even after controlling for a host of potential confounders, including Fibrosis-4 score (using 3.25 as the cutoff value), age, sex, history of AIDS, HIV-transmission category, nadir CD4+ T-cell count, antiretroviral therapy, HIV-RNA, HCV genotype, and exposure to specific anti-HIV drugs (adjusted hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.93; P = .02). Sustained viral response also was associated with a lower likelihood of chronic renal failure with borderline statistical significance (aHR, 0.43; 95% CI, 0.17 to 1.09; P = .075).
“In agreement with previous reports from this cohort, we found that treatment response was associated with a decreased hazard of overall and liver-related death, all types of liver-related events, and new AIDS-related conditions,” the researchers noted. These findings underscore the vital importance of HCV therapy for HIV-coinfected patients, regardless of liver fibrosis stage, they emphasized.
The study was funded by Spanish Health Research Funds and AIDS Research Network. The investigators reported having no relevant conflicts of interest.
FROM HEPATOLOGY
Key clinical point. Eradicating hepatitis C virus infection in HIV-coinfected patients is crucial, regardless of fibrosis stage.
Major finding: After a median of 5 years of follow-up, sustained viral response to HCV treatment was associated with a 43% decrease in the likelihood of developing diabetes, even after controlling for fibrosis stage and other potential confounders. Reaching SVR also was associated with decreased rates of renal failure, HIV progression, and mortality.
Data source: An observational study of 1,625 patients with HIV and hepatitis C virus coinfection.
Disclosures: The study was funded by Spanish Health Research Funds and AIDS Research Network. The investigators reported having no relevant conflicts of interest.
Worse outcomes with video laryngoscopy in ICU
When used in intensive care units, video laryngoscopy did not improve the chances of successful intubation on the first try, compared with direct laryngoscopy, and was associated with a significantly higher risk of severe life-threatening complications, researchers reported.
In a multicenter, randomized trial of 371 patients, first-pass intubation rates did not differ significantly whether video or direct laryngoscopy was used, at 67.7% and 70.3%, respectively, Jean Baptiste Lascarrou, MD, of District Hospital Centre, La Roche-sur-Yon, France, and his associates wrote. Meanwhile, the combined rate of death, cardiac arrest, severe cardiovascular collapse, and hypoxemia was 9.5% with video laryngoscopy and just 2.8% with direct laryngoscopy, a significant difference (JAMA. 2017 Jan 24;317[5]:483-93).
“Improved glottis visualization with video laryngoscopy did not translate into a higher success rate for first-pass intubation, because tracheal catheterization under indirect vision was more difficult, in keeping with earlier data,” the researchers concluded. “Further studies are needed to assess the comparative effectiveness of these two strategies in different clinical settings and among operators with diverse skill levels.”
Intubation in the ICU carries an inherently high risk because patients are often acutely unstable, and the intubating clinician is usually a nonexpert, the investigators noted. At the same time, the procedure must be done quickly to prevent aspiration because patients usually have not fasted. Care bundles and training on simulators have improved safety, but ICU intubations remain riskier than those done in the operating room.
Observational studies and smaller trials in ICUs seemed to support video laryngoscopy over the Macintosh laryngoscope, but raised questions about intubation time and mortality, the investigators noted. To help resolve these issues, they randomly assigned adults needing orotracheal intubation at seven ICUs in France to either video or direct Macintosh laryngoscopy, and followed them for 28 days. Patients averaged 63 years of age, and 37% were women.
For both arms, residents performed the initial intubation attempt in about 80% of cases, and successful intubation usually took 3 minutes. Video laryngoscopy did not significantly increase the combined risk of esophageal intubation, aspiration, arrhythmia, or dental injury (5.4% versus 7.7% for direct laryngoscopy). But the only death in the study occurred after video laryngoscopy, and there were four cardiac arrests after video laryngoscopy and none after direct laryngoscopy, the researchers said. Furthermore, the rate of severe hypoxemia was nearly six times higher after video laryngoscopy than with direct laryngoscopy, and the rate of hypotension was twice as high.
The researchers did not identify predictors of life-threatening complications with video laryngoscopy, but hypothesized that being able to clearly visualize the glottis might create “a false impression of safety,” especially among nonexperts. “In addition, poorer alignment of the pharyngeal axis, laryngeal axis, and mouth opening despite good glottis visualization by video laryngoscopy can lead to mechanical upper airway obstruction and faster progression to hypoxemia,” they wrote.
Centre Hospitalier Département de la Vendée sponsored the study. Dr. Lascarrou reported having no relevant conflicts of interest. Four coinvestigators disclosed ties to Fisher & Paykel, LFB, Merck Sharp & Dohme, Astellas, Basilea Pharmaceutica. Gilead, Alexion, and Cubist. The remaining coinvestigators had no disclosures.
The results of this trial illustrate the fundamental problem with video laryngoscopy: It generates excellent views of the larynx but may not facilitate tracheal intubation.
The use of video laryngoscopy can lead to the creation of blind spots, both visual and cognitive. Because the lens of the laryngoscope is located at the tip of the device, the pharynx and hypopharynx are not visualized during video laryngoscopy. Manipulating the endotracheal tube into view therefore occurs within this blind spot, and this can be difficult depending on the patient’s pharyngeal anatomy. This phenomenon has been linked to higher rates of pharyngeal soft tissue injury and longer intubation times in patients undergoing video laryngoscopy as compared with direct laryngoscopy.
The view during video laryngoscopy can also create a cognitive blind spot: laryngoscopists may fail to abort a laryngoscopy attempt in a timely manner because they have such a clear view of the larynx.
Brian O’Gara, MD, and Daniel Talmor, MD, of Harvard University, Boston, and Samuel Brown, MD, MS, of the University of Utah School, Murray, Utah, made these comments in an accompanying editorial (JAMA. 2017 Feb 7; doi: 10.1001/jama.2016.21036) . None of the authors had relevant financial disclosures.
The results of this trial illustrate the fundamental problem with video laryngoscopy: It generates excellent views of the larynx but may not facilitate tracheal intubation.
The use of video laryngoscopy can lead to the creation of blind spots, both visual and cognitive. Because the lens of the laryngoscope is located at the tip of the device, the pharynx and hypopharynx are not visualized during video laryngoscopy. Manipulating the endotracheal tube into view therefore occurs within this blind spot, and this can be difficult depending on the patient’s pharyngeal anatomy. This phenomenon has been linked to higher rates of pharyngeal soft tissue injury and longer intubation times in patients undergoing video laryngoscopy as compared with direct laryngoscopy.
The view during video laryngoscopy can also create a cognitive blind spot: laryngoscopists may fail to abort a laryngoscopy attempt in a timely manner because they have such a clear view of the larynx.
Brian O’Gara, MD, and Daniel Talmor, MD, of Harvard University, Boston, and Samuel Brown, MD, MS, of the University of Utah School, Murray, Utah, made these comments in an accompanying editorial (JAMA. 2017 Feb 7; doi: 10.1001/jama.2016.21036) . None of the authors had relevant financial disclosures.
The results of this trial illustrate the fundamental problem with video laryngoscopy: It generates excellent views of the larynx but may not facilitate tracheal intubation.
The use of video laryngoscopy can lead to the creation of blind spots, both visual and cognitive. Because the lens of the laryngoscope is located at the tip of the device, the pharynx and hypopharynx are not visualized during video laryngoscopy. Manipulating the endotracheal tube into view therefore occurs within this blind spot, and this can be difficult depending on the patient’s pharyngeal anatomy. This phenomenon has been linked to higher rates of pharyngeal soft tissue injury and longer intubation times in patients undergoing video laryngoscopy as compared with direct laryngoscopy.
The view during video laryngoscopy can also create a cognitive blind spot: laryngoscopists may fail to abort a laryngoscopy attempt in a timely manner because they have such a clear view of the larynx.
Brian O’Gara, MD, and Daniel Talmor, MD, of Harvard University, Boston, and Samuel Brown, MD, MS, of the University of Utah School, Murray, Utah, made these comments in an accompanying editorial (JAMA. 2017 Feb 7; doi: 10.1001/jama.2016.21036) . None of the authors had relevant financial disclosures.
When used in intensive care units, video laryngoscopy did not improve the chances of successful intubation on the first try, compared with direct laryngoscopy, and was associated with a significantly higher risk of severe life-threatening complications, researchers reported.
In a multicenter, randomized trial of 371 patients, first-pass intubation rates did not differ significantly whether video or direct laryngoscopy was used, at 67.7% and 70.3%, respectively, Jean Baptiste Lascarrou, MD, of District Hospital Centre, La Roche-sur-Yon, France, and his associates wrote. Meanwhile, the combined rate of death, cardiac arrest, severe cardiovascular collapse, and hypoxemia was 9.5% with video laryngoscopy and just 2.8% with direct laryngoscopy, a significant difference (JAMA. 2017 Jan 24;317[5]:483-93).
“Improved glottis visualization with video laryngoscopy did not translate into a higher success rate for first-pass intubation, because tracheal catheterization under indirect vision was more difficult, in keeping with earlier data,” the researchers concluded. “Further studies are needed to assess the comparative effectiveness of these two strategies in different clinical settings and among operators with diverse skill levels.”
Intubation in the ICU carries an inherently high risk because patients are often acutely unstable, and the intubating clinician is usually a nonexpert, the investigators noted. At the same time, the procedure must be done quickly to prevent aspiration because patients usually have not fasted. Care bundles and training on simulators have improved safety, but ICU intubations remain riskier than those done in the operating room.
Observational studies and smaller trials in ICUs seemed to support video laryngoscopy over the Macintosh laryngoscope, but raised questions about intubation time and mortality, the investigators noted. To help resolve these issues, they randomly assigned adults needing orotracheal intubation at seven ICUs in France to either video or direct Macintosh laryngoscopy, and followed them for 28 days. Patients averaged 63 years of age, and 37% were women.
For both arms, residents performed the initial intubation attempt in about 80% of cases, and successful intubation usually took 3 minutes. Video laryngoscopy did not significantly increase the combined risk of esophageal intubation, aspiration, arrhythmia, or dental injury (5.4% versus 7.7% for direct laryngoscopy). But the only death in the study occurred after video laryngoscopy, and there were four cardiac arrests after video laryngoscopy and none after direct laryngoscopy, the researchers said. Furthermore, the rate of severe hypoxemia was nearly six times higher after video laryngoscopy than with direct laryngoscopy, and the rate of hypotension was twice as high.
The researchers did not identify predictors of life-threatening complications with video laryngoscopy, but hypothesized that being able to clearly visualize the glottis might create “a false impression of safety,” especially among nonexperts. “In addition, poorer alignment of the pharyngeal axis, laryngeal axis, and mouth opening despite good glottis visualization by video laryngoscopy can lead to mechanical upper airway obstruction and faster progression to hypoxemia,” they wrote.
Centre Hospitalier Département de la Vendée sponsored the study. Dr. Lascarrou reported having no relevant conflicts of interest. Four coinvestigators disclosed ties to Fisher & Paykel, LFB, Merck Sharp & Dohme, Astellas, Basilea Pharmaceutica. Gilead, Alexion, and Cubist. The remaining coinvestigators had no disclosures.
When used in intensive care units, video laryngoscopy did not improve the chances of successful intubation on the first try, compared with direct laryngoscopy, and was associated with a significantly higher risk of severe life-threatening complications, researchers reported.
In a multicenter, randomized trial of 371 patients, first-pass intubation rates did not differ significantly whether video or direct laryngoscopy was used, at 67.7% and 70.3%, respectively, Jean Baptiste Lascarrou, MD, of District Hospital Centre, La Roche-sur-Yon, France, and his associates wrote. Meanwhile, the combined rate of death, cardiac arrest, severe cardiovascular collapse, and hypoxemia was 9.5% with video laryngoscopy and just 2.8% with direct laryngoscopy, a significant difference (JAMA. 2017 Jan 24;317[5]:483-93).
“Improved glottis visualization with video laryngoscopy did not translate into a higher success rate for first-pass intubation, because tracheal catheterization under indirect vision was more difficult, in keeping with earlier data,” the researchers concluded. “Further studies are needed to assess the comparative effectiveness of these two strategies in different clinical settings and among operators with diverse skill levels.”
Intubation in the ICU carries an inherently high risk because patients are often acutely unstable, and the intubating clinician is usually a nonexpert, the investigators noted. At the same time, the procedure must be done quickly to prevent aspiration because patients usually have not fasted. Care bundles and training on simulators have improved safety, but ICU intubations remain riskier than those done in the operating room.
Observational studies and smaller trials in ICUs seemed to support video laryngoscopy over the Macintosh laryngoscope, but raised questions about intubation time and mortality, the investigators noted. To help resolve these issues, they randomly assigned adults needing orotracheal intubation at seven ICUs in France to either video or direct Macintosh laryngoscopy, and followed them for 28 days. Patients averaged 63 years of age, and 37% were women.
For both arms, residents performed the initial intubation attempt in about 80% of cases, and successful intubation usually took 3 minutes. Video laryngoscopy did not significantly increase the combined risk of esophageal intubation, aspiration, arrhythmia, or dental injury (5.4% versus 7.7% for direct laryngoscopy). But the only death in the study occurred after video laryngoscopy, and there were four cardiac arrests after video laryngoscopy and none after direct laryngoscopy, the researchers said. Furthermore, the rate of severe hypoxemia was nearly six times higher after video laryngoscopy than with direct laryngoscopy, and the rate of hypotension was twice as high.
The researchers did not identify predictors of life-threatening complications with video laryngoscopy, but hypothesized that being able to clearly visualize the glottis might create “a false impression of safety,” especially among nonexperts. “In addition, poorer alignment of the pharyngeal axis, laryngeal axis, and mouth opening despite good glottis visualization by video laryngoscopy can lead to mechanical upper airway obstruction and faster progression to hypoxemia,” they wrote.
Centre Hospitalier Département de la Vendée sponsored the study. Dr. Lascarrou reported having no relevant conflicts of interest. Four coinvestigators disclosed ties to Fisher & Paykel, LFB, Merck Sharp & Dohme, Astellas, Basilea Pharmaceutica. Gilead, Alexion, and Cubist. The remaining coinvestigators had no disclosures.
FROM JAMA
Key clinical point: Among patients in intensive care units, video laryngoscopy did not improve the chances of successful intubation on the first try, when compared with standard Macintosh laryngoscopy, and was associated with a significantly higher risk of severe life-threatening events.
Major finding: Rates of first-pass intubation were 67.7% for video laryngoscopy and 70.3% for direct laryngoscopy (P = .6). The combined rate of death, cardiac arrest, severe cardiovascular collapse, and hypoxemia was 9.5% with video laryngoscopy and 2.8% with direct laryngoscopy (P = .01).
Data source: A multicenter randomized trial of 371 ICU patients.
Disclosures: Centre Hospitalier Département de la Vendée sponsored the study. Dr. Lascarrou reported having no relevant conflicts of interest. Four coinvestigators disclosed ties to Fisher & Paykel, LFB, Merck Sharp & Dohme, Astellas, Basilea Pharmaceutica. Gilead, Alexion, and Cubist. The remaining coinvestigators had no disclosures.
Ibrutinib, palbociclib yield durable complete responses in pretreated mantle cell lymphoma
SAN DIEGO – A “mechanism-based” combination of ibrutinib and palbociclib was reasonably well tolerated and induced complete responses in 44% of patients with previously treated mantle cell lymphoma, Peter Martin, MD, reported at the annual meeting of the American Society of Hematology.
Fully 67% of patients remained alive and progression-free after a median of 11 months of follow-up, and no responders progressed during this phase I trial, added Dr. Martin of Weill Cornell Medical College in New York. These rates “appear better than those reported in studies of single-agent ibrutinib, although the number of patients was very small,” he acknowledged. Most patients tolerated therapy, although 25% developed dose-limiting toxicities or stopped treatment because of adverse effects. Based on these results, the investigators are studying biomarkers for resistance and are planning a phase II, multicenter trial to evaluate time to progression.
Single-agent ibrutinib (Imbruvica) has shown promise in mantle cell lymphoma, but treatment failure affects about half of patients within 1 year, Dr. Martin noted. The CDK4/6 inhibitor palbociclib (Ibrance) induces prolonged arrest early in the G1 phase of the cell cycle, which overcame ibrutinib resistance in mantle cell lymphoma cell lines in a prior study (Cancer Discov. 2014;4[9]:1022-35).
To test the maximum tolerated dose of combination therapy, Dr. Martin and his associates enrolled 20 adults with previously treated mantle cell lymphoma who were naive to ibrutinib and CD4/6 inhibitors. The patients had received a median of one and up to five prior lines of therapy, and six (30%) were refractory to their most recent therapy. They received ibrutinib daily and palbociclib on the first 21 days of each 28-day treatment cycle. Dosing began at one of five levels, ranging from 280 mg ibrutinib/75 mg palbociclib to 560 mg ibrutinib/125 mg palbociclib. Doses were escalated based on a standard phase I 3+3 design.
Among 18 patients evaluated, 12 (67%) responded to treatment, and 8 (44%) had a complete response. Median time to complete response was three cycles. The most common grade 1-2 adverse events were diarrhea, fatigue, rash, and bruising. Three patients (15%) developed dose-limiting toxicities. These included one case of grade 4 thrombocytopenia at 420 mg ibrutinib/100 mg palbociclib and two cases of grade 3 rash at 560 mg ibrutinib/125 mg palbociclib. The grade 3 rashes led to dose reductions, and six patients needed dose interruptions. Also, four patients stopped treatment because of disease progression, two did so because of elevated liver enzymes or prolonged cytopenia, and one did so to undergo allogeneic stem cell transplantation.
The National Cancer Institute sponsored the study. Dr. Martin disclosed ties to Janssen, which makes ibrutinib, and to Celgene, Gilead, Novartis, Acerta, and Teva. Senior author John P. Leonard, MD, and one of 10 coinvestigators disclosed ties to several pharmaceutical companies.
SAN DIEGO – A “mechanism-based” combination of ibrutinib and palbociclib was reasonably well tolerated and induced complete responses in 44% of patients with previously treated mantle cell lymphoma, Peter Martin, MD, reported at the annual meeting of the American Society of Hematology.
Fully 67% of patients remained alive and progression-free after a median of 11 months of follow-up, and no responders progressed during this phase I trial, added Dr. Martin of Weill Cornell Medical College in New York. These rates “appear better than those reported in studies of single-agent ibrutinib, although the number of patients was very small,” he acknowledged. Most patients tolerated therapy, although 25% developed dose-limiting toxicities or stopped treatment because of adverse effects. Based on these results, the investigators are studying biomarkers for resistance and are planning a phase II, multicenter trial to evaluate time to progression.
Single-agent ibrutinib (Imbruvica) has shown promise in mantle cell lymphoma, but treatment failure affects about half of patients within 1 year, Dr. Martin noted. The CDK4/6 inhibitor palbociclib (Ibrance) induces prolonged arrest early in the G1 phase of the cell cycle, which overcame ibrutinib resistance in mantle cell lymphoma cell lines in a prior study (Cancer Discov. 2014;4[9]:1022-35).
To test the maximum tolerated dose of combination therapy, Dr. Martin and his associates enrolled 20 adults with previously treated mantle cell lymphoma who were naive to ibrutinib and CD4/6 inhibitors. The patients had received a median of one and up to five prior lines of therapy, and six (30%) were refractory to their most recent therapy. They received ibrutinib daily and palbociclib on the first 21 days of each 28-day treatment cycle. Dosing began at one of five levels, ranging from 280 mg ibrutinib/75 mg palbociclib to 560 mg ibrutinib/125 mg palbociclib. Doses were escalated based on a standard phase I 3+3 design.
Among 18 patients evaluated, 12 (67%) responded to treatment, and 8 (44%) had a complete response. Median time to complete response was three cycles. The most common grade 1-2 adverse events were diarrhea, fatigue, rash, and bruising. Three patients (15%) developed dose-limiting toxicities. These included one case of grade 4 thrombocytopenia at 420 mg ibrutinib/100 mg palbociclib and two cases of grade 3 rash at 560 mg ibrutinib/125 mg palbociclib. The grade 3 rashes led to dose reductions, and six patients needed dose interruptions. Also, four patients stopped treatment because of disease progression, two did so because of elevated liver enzymes or prolonged cytopenia, and one did so to undergo allogeneic stem cell transplantation.
The National Cancer Institute sponsored the study. Dr. Martin disclosed ties to Janssen, which makes ibrutinib, and to Celgene, Gilead, Novartis, Acerta, and Teva. Senior author John P. Leonard, MD, and one of 10 coinvestigators disclosed ties to several pharmaceutical companies.
SAN DIEGO – A “mechanism-based” combination of ibrutinib and palbociclib was reasonably well tolerated and induced complete responses in 44% of patients with previously treated mantle cell lymphoma, Peter Martin, MD, reported at the annual meeting of the American Society of Hematology.
Fully 67% of patients remained alive and progression-free after a median of 11 months of follow-up, and no responders progressed during this phase I trial, added Dr. Martin of Weill Cornell Medical College in New York. These rates “appear better than those reported in studies of single-agent ibrutinib, although the number of patients was very small,” he acknowledged. Most patients tolerated therapy, although 25% developed dose-limiting toxicities or stopped treatment because of adverse effects. Based on these results, the investigators are studying biomarkers for resistance and are planning a phase II, multicenter trial to evaluate time to progression.
Single-agent ibrutinib (Imbruvica) has shown promise in mantle cell lymphoma, but treatment failure affects about half of patients within 1 year, Dr. Martin noted. The CDK4/6 inhibitor palbociclib (Ibrance) induces prolonged arrest early in the G1 phase of the cell cycle, which overcame ibrutinib resistance in mantle cell lymphoma cell lines in a prior study (Cancer Discov. 2014;4[9]:1022-35).
To test the maximum tolerated dose of combination therapy, Dr. Martin and his associates enrolled 20 adults with previously treated mantle cell lymphoma who were naive to ibrutinib and CD4/6 inhibitors. The patients had received a median of one and up to five prior lines of therapy, and six (30%) were refractory to their most recent therapy. They received ibrutinib daily and palbociclib on the first 21 days of each 28-day treatment cycle. Dosing began at one of five levels, ranging from 280 mg ibrutinib/75 mg palbociclib to 560 mg ibrutinib/125 mg palbociclib. Doses were escalated based on a standard phase I 3+3 design.
Among 18 patients evaluated, 12 (67%) responded to treatment, and 8 (44%) had a complete response. Median time to complete response was three cycles. The most common grade 1-2 adverse events were diarrhea, fatigue, rash, and bruising. Three patients (15%) developed dose-limiting toxicities. These included one case of grade 4 thrombocytopenia at 420 mg ibrutinib/100 mg palbociclib and two cases of grade 3 rash at 560 mg ibrutinib/125 mg palbociclib. The grade 3 rashes led to dose reductions, and six patients needed dose interruptions. Also, four patients stopped treatment because of disease progression, two did so because of elevated liver enzymes or prolonged cytopenia, and one did so to undergo allogeneic stem cell transplantation.
The National Cancer Institute sponsored the study. Dr. Martin disclosed ties to Janssen, which makes ibrutinib, and to Celgene, Gilead, Novartis, Acerta, and Teva. Senior author John P. Leonard, MD, and one of 10 coinvestigators disclosed ties to several pharmaceutical companies.
AT ASH 2016
Key clinical point: Combination therapy with ibrutinib and palbociclib was generally well tolerated and induced complete responses in patients with pretreated mantle cell lymphoma.
Major finding: A total of 44% of patients had complete responses, and 67% remained alive and progression-free after a median of 11 months of follow-up. Severe rashes occurred at the highest dose studied (420 mg ibrutinib/100 mg palbociclib).
Data source: A phase I trial of 20 patients with previously treated mantle cell lymphoma.
Disclosures: The National Cancer Institute sponsored the study. Dr. Martin disclosed ties to Janssen, which makes ibrutinib, and to Celgene, Gilead, Novartis, Acerta, and Teva. Senior author John P. Leonard, MD, and one of 10 coinvestigators disclosed ties to several pharmaceutical companies.
Early mild cognitive impairment in Parkinson’s leads to dementia in more than 40%
Developing persistent mild cognitive impairment soon after being diagnosed with Parkinson’s disease significantly increased the risk of subsequent dementia, according to a cohort study that examined the natural history of mild cognitive impairment in 178 patients over 5 years.
After the researchers controlled for age, sex, and education, patients who had persistent mild cognitive impairment (MCI) by 1 year after their Parkinson’s disease (PD) diagnosis had a 16.6-fold greater odds of subsequent dementia, compared with those who were cognitively normal (95% confidence interval, 5.1-54.7; P less than .001). Notably, early MCI significantly predicted dementia even if patients reverted to normal cognition with dopaminergic treatment, reported Kenn F. Pedersen, MD, PhD, of the Norwegian Centre for Movement Disorders at Stavanger (Norway) University Hospital, and his associates. “Early PD-MCI, regardless of persistence or reversion to normal cognition, has prognostic value for predicting dementia in patients with PD,” they concluded.
At baseline, 20% of patients had MCI. Among those who did not, cumulative incidence rates of MCI were 10% at year 1, 23% at year 3, and 29% by the end of the study after 5 years of follow-up. In all, 59% of patients with persistent MCI by year 1 developed dementia, compared with 7% of patients who retained normal cognition at 1 year. About one in four patients with MCI reverted to normal cognition by the end of the study, but they still faced a 10.7-fold greater odds of dementia at the 5-year follow-up, compared with cognitively normal patients (95% CI, 1.5-78.5; P = .02).
The Research Council of Norway, the Western Norway Regional Health Authority, and the Norwegian Parkinson’s Disease Association funded the study. Dr. Pedersen had no disclosures. One coauthor reported serving on advisory boards for Lundbeck and GlaxoSmithKline and receiving payment for lecturing from Orion Pharma and GlaxoSmithKline.
Developing persistent mild cognitive impairment soon after being diagnosed with Parkinson’s disease significantly increased the risk of subsequent dementia, according to a cohort study that examined the natural history of mild cognitive impairment in 178 patients over 5 years.
After the researchers controlled for age, sex, and education, patients who had persistent mild cognitive impairment (MCI) by 1 year after their Parkinson’s disease (PD) diagnosis had a 16.6-fold greater odds of subsequent dementia, compared with those who were cognitively normal (95% confidence interval, 5.1-54.7; P less than .001). Notably, early MCI significantly predicted dementia even if patients reverted to normal cognition with dopaminergic treatment, reported Kenn F. Pedersen, MD, PhD, of the Norwegian Centre for Movement Disorders at Stavanger (Norway) University Hospital, and his associates. “Early PD-MCI, regardless of persistence or reversion to normal cognition, has prognostic value for predicting dementia in patients with PD,” they concluded.
At baseline, 20% of patients had MCI. Among those who did not, cumulative incidence rates of MCI were 10% at year 1, 23% at year 3, and 29% by the end of the study after 5 years of follow-up. In all, 59% of patients with persistent MCI by year 1 developed dementia, compared with 7% of patients who retained normal cognition at 1 year. About one in four patients with MCI reverted to normal cognition by the end of the study, but they still faced a 10.7-fold greater odds of dementia at the 5-year follow-up, compared with cognitively normal patients (95% CI, 1.5-78.5; P = .02).
The Research Council of Norway, the Western Norway Regional Health Authority, and the Norwegian Parkinson’s Disease Association funded the study. Dr. Pedersen had no disclosures. One coauthor reported serving on advisory boards for Lundbeck and GlaxoSmithKline and receiving payment for lecturing from Orion Pharma and GlaxoSmithKline.
Developing persistent mild cognitive impairment soon after being diagnosed with Parkinson’s disease significantly increased the risk of subsequent dementia, according to a cohort study that examined the natural history of mild cognitive impairment in 178 patients over 5 years.
After the researchers controlled for age, sex, and education, patients who had persistent mild cognitive impairment (MCI) by 1 year after their Parkinson’s disease (PD) diagnosis had a 16.6-fold greater odds of subsequent dementia, compared with those who were cognitively normal (95% confidence interval, 5.1-54.7; P less than .001). Notably, early MCI significantly predicted dementia even if patients reverted to normal cognition with dopaminergic treatment, reported Kenn F. Pedersen, MD, PhD, of the Norwegian Centre for Movement Disorders at Stavanger (Norway) University Hospital, and his associates. “Early PD-MCI, regardless of persistence or reversion to normal cognition, has prognostic value for predicting dementia in patients with PD,” they concluded.
At baseline, 20% of patients had MCI. Among those who did not, cumulative incidence rates of MCI were 10% at year 1, 23% at year 3, and 29% by the end of the study after 5 years of follow-up. In all, 59% of patients with persistent MCI by year 1 developed dementia, compared with 7% of patients who retained normal cognition at 1 year. About one in four patients with MCI reverted to normal cognition by the end of the study, but they still faced a 10.7-fold greater odds of dementia at the 5-year follow-up, compared with cognitively normal patients (95% CI, 1.5-78.5; P = .02).
The Research Council of Norway, the Western Norway Regional Health Authority, and the Norwegian Parkinson’s Disease Association funded the study. Dr. Pedersen had no disclosures. One coauthor reported serving on advisory boards for Lundbeck and GlaxoSmithKline and receiving payment for lecturing from Orion Pharma and GlaxoSmithKline.
FROM NEUROLOGY
Key clinical point: Developing mild cognitive impairment early in the course of Parkinson’s disease significantly increases the risk of subsequent dementia.
Major finding: In all, 59% of patients with persistent mild cognitive impairment at 1 year and 7% of those with normal cognition later developed dementia (odds ratio, 16.6; P less than .001).
Data source: A population-based cohort study of 178 patients with newly diagnosed Parkinson’s disease.
Disclosures: The Research Council of Norway, the Western Norway Regional Health Authority, and the Norwegian Parkinson’s Disease Association funded the study. Dr. Pederson had no disclosures. One coauthor reported serving on advisory boards for Lundbeck and GlaxoSmithKline and receiving payment for lecturing from Orion Pharma and GlaxoSmithKline.
Bortezomib-based regimen led to durable remissions in mantle cell lymphoma
SAN DIEGO – For adults with mantle cell lymphoma, adding bortezomib to a modified hyper-CVAD (VcR-CVAD) regimen followed by rituximab maintenance induced durable remissions at rates resembling those seen with more intensive chemotherapy followed by autologous hematopoietic stem cell transplantation, according to long-term results from a multicenter phase II trial.
Two-thirds of patients were alive and 50% remained in remission after a median follow-up period of 7.8 years, said Julie E. Chang, MD, who reported the results of the study at the annual meeting of the American Society of Hematology. “VcR-CVAD is a moderate-intensity chemotherapy regimen that is tolerable for many older and less fit adult patients as first-line therapy of mantle cell lymphoma,” she emphasized.
Mantle cell lymphoma lacks a clear standard first-line therapy, noted Dr. Chang of the University of Wisconsin in Madison. “We hypothesized that the addition of bortezomib would improve the complete response rate, and maintenance rituximab would improve the remission duration,” she said.
To test that idea, she and her associates enrolled 30 adults with histologically confirmed mantle cell lymphoma who had received either no treatment or just one cycle of CHOP or CHOP-like chemotherapy.
Patients received six 21-day cycles of VcR-CVAD induction chemotherapy. This regimen consisted of rituximab (375 mg/m2 IV) on day 1; bortezomib (1.3 mg/m2 IV) on days 1 and 4; cyclophosphamide (300 mg/m2 IV every 12 hours) on days 1 through 3; doxorubicin (50 mg/m2 IV given as a continuous infusion) on days 1 and 2; vincristine (1 mg IV) on day 3; and dexamethasone (40 mg orally) on days 1 through 4.
Patients were permitted all supportive care measures, including prophylaxis for tumor lysis syndrome, transfusions, and antibiotics. Those with at least a partial response received rituximab consolidation (375 mg/m2 IV per week for 4 weeks) followed by rituximab maintenance (375 mg/m2 IV every 12 weeks for 5 years).
Median age was 61 years (range, 48-74 years), 80% of patients were male, all had advanced-stage disease, 60% were mantle cell lymphoma international prognostic index (MIPI) medium or high risk, and six had blastic morphology, the researchers noted.
Estimated 6-year rates of progression-free and overall survival were 53% (95% confidence interval, 38%-75%) and 70% (95% CI, 55%-84%), respectively. Neither age nor MIPI score significantly affected the chances of progression-free or overall survival, but there was a trend toward worse survival among MIPI high-risk patients.
The 10 deaths included 5 from progressive disease, 3 from complications after allogeneic transplant, and 2 from unrelated causes. No patients who remained progression free for 5 years subsequently relapsed, nor were there late toxicities related to treatment.
A recent phase III trial (N Engl J Med. 2015 Mar 5;372[10]:944-53) confirmed the benefits of adding bortezomib to standard immunochemotherapy in mantle cell lymphoma, Dr. Chang noted. “VcR-CVAD remains an effective therapy choice for initial treatment of MCL, both in younger and older MCL populations,” she concluded.
Dr. Chang had no relevant disclosures. Senior author Brad S. Kahl, MD, disclosed ties to Celgene, Gilead, Infinity, Juno, Pharmacyclics, and Seattle Genetics.
SAN DIEGO – For adults with mantle cell lymphoma, adding bortezomib to a modified hyper-CVAD (VcR-CVAD) regimen followed by rituximab maintenance induced durable remissions at rates resembling those seen with more intensive chemotherapy followed by autologous hematopoietic stem cell transplantation, according to long-term results from a multicenter phase II trial.
Two-thirds of patients were alive and 50% remained in remission after a median follow-up period of 7.8 years, said Julie E. Chang, MD, who reported the results of the study at the annual meeting of the American Society of Hematology. “VcR-CVAD is a moderate-intensity chemotherapy regimen that is tolerable for many older and less fit adult patients as first-line therapy of mantle cell lymphoma,” she emphasized.
Mantle cell lymphoma lacks a clear standard first-line therapy, noted Dr. Chang of the University of Wisconsin in Madison. “We hypothesized that the addition of bortezomib would improve the complete response rate, and maintenance rituximab would improve the remission duration,” she said.
To test that idea, she and her associates enrolled 30 adults with histologically confirmed mantle cell lymphoma who had received either no treatment or just one cycle of CHOP or CHOP-like chemotherapy.
Patients received six 21-day cycles of VcR-CVAD induction chemotherapy. This regimen consisted of rituximab (375 mg/m2 IV) on day 1; bortezomib (1.3 mg/m2 IV) on days 1 and 4; cyclophosphamide (300 mg/m2 IV every 12 hours) on days 1 through 3; doxorubicin (50 mg/m2 IV given as a continuous infusion) on days 1 and 2; vincristine (1 mg IV) on day 3; and dexamethasone (40 mg orally) on days 1 through 4.
Patients were permitted all supportive care measures, including prophylaxis for tumor lysis syndrome, transfusions, and antibiotics. Those with at least a partial response received rituximab consolidation (375 mg/m2 IV per week for 4 weeks) followed by rituximab maintenance (375 mg/m2 IV every 12 weeks for 5 years).
Median age was 61 years (range, 48-74 years), 80% of patients were male, all had advanced-stage disease, 60% were mantle cell lymphoma international prognostic index (MIPI) medium or high risk, and six had blastic morphology, the researchers noted.
Estimated 6-year rates of progression-free and overall survival were 53% (95% confidence interval, 38%-75%) and 70% (95% CI, 55%-84%), respectively. Neither age nor MIPI score significantly affected the chances of progression-free or overall survival, but there was a trend toward worse survival among MIPI high-risk patients.
The 10 deaths included 5 from progressive disease, 3 from complications after allogeneic transplant, and 2 from unrelated causes. No patients who remained progression free for 5 years subsequently relapsed, nor were there late toxicities related to treatment.
A recent phase III trial (N Engl J Med. 2015 Mar 5;372[10]:944-53) confirmed the benefits of adding bortezomib to standard immunochemotherapy in mantle cell lymphoma, Dr. Chang noted. “VcR-CVAD remains an effective therapy choice for initial treatment of MCL, both in younger and older MCL populations,” she concluded.
Dr. Chang had no relevant disclosures. Senior author Brad S. Kahl, MD, disclosed ties to Celgene, Gilead, Infinity, Juno, Pharmacyclics, and Seattle Genetics.
SAN DIEGO – For adults with mantle cell lymphoma, adding bortezomib to a modified hyper-CVAD (VcR-CVAD) regimen followed by rituximab maintenance induced durable remissions at rates resembling those seen with more intensive chemotherapy followed by autologous hematopoietic stem cell transplantation, according to long-term results from a multicenter phase II trial.
Two-thirds of patients were alive and 50% remained in remission after a median follow-up period of 7.8 years, said Julie E. Chang, MD, who reported the results of the study at the annual meeting of the American Society of Hematology. “VcR-CVAD is a moderate-intensity chemotherapy regimen that is tolerable for many older and less fit adult patients as first-line therapy of mantle cell lymphoma,” she emphasized.
Mantle cell lymphoma lacks a clear standard first-line therapy, noted Dr. Chang of the University of Wisconsin in Madison. “We hypothesized that the addition of bortezomib would improve the complete response rate, and maintenance rituximab would improve the remission duration,” she said.
To test that idea, she and her associates enrolled 30 adults with histologically confirmed mantle cell lymphoma who had received either no treatment or just one cycle of CHOP or CHOP-like chemotherapy.
Patients received six 21-day cycles of VcR-CVAD induction chemotherapy. This regimen consisted of rituximab (375 mg/m2 IV) on day 1; bortezomib (1.3 mg/m2 IV) on days 1 and 4; cyclophosphamide (300 mg/m2 IV every 12 hours) on days 1 through 3; doxorubicin (50 mg/m2 IV given as a continuous infusion) on days 1 and 2; vincristine (1 mg IV) on day 3; and dexamethasone (40 mg orally) on days 1 through 4.
Patients were permitted all supportive care measures, including prophylaxis for tumor lysis syndrome, transfusions, and antibiotics. Those with at least a partial response received rituximab consolidation (375 mg/m2 IV per week for 4 weeks) followed by rituximab maintenance (375 mg/m2 IV every 12 weeks for 5 years).
Median age was 61 years (range, 48-74 years), 80% of patients were male, all had advanced-stage disease, 60% were mantle cell lymphoma international prognostic index (MIPI) medium or high risk, and six had blastic morphology, the researchers noted.
Estimated 6-year rates of progression-free and overall survival were 53% (95% confidence interval, 38%-75%) and 70% (95% CI, 55%-84%), respectively. Neither age nor MIPI score significantly affected the chances of progression-free or overall survival, but there was a trend toward worse survival among MIPI high-risk patients.
The 10 deaths included 5 from progressive disease, 3 from complications after allogeneic transplant, and 2 from unrelated causes. No patients who remained progression free for 5 years subsequently relapsed, nor were there late toxicities related to treatment.
A recent phase III trial (N Engl J Med. 2015 Mar 5;372[10]:944-53) confirmed the benefits of adding bortezomib to standard immunochemotherapy in mantle cell lymphoma, Dr. Chang noted. “VcR-CVAD remains an effective therapy choice for initial treatment of MCL, both in younger and older MCL populations,” she concluded.
Dr. Chang had no relevant disclosures. Senior author Brad S. Kahl, MD, disclosed ties to Celgene, Gilead, Infinity, Juno, Pharmacyclics, and Seattle Genetics.
Key clinical point: First-line therapy with bortezomib plus modified hyper-CVAD followed by rituximab maintenance induced durable remissions in mantle cell lymphoma.
Major finding: Two-thirds of patients were alive and 50% remained in remission after a median follow-up period of 7.8 years.
Data source: A multicenter phase II trial of 30 adults with mantle cell lymphoma who were treatment-naïve or had received only one cycle of CHOP or CHOP-like chemotherapy.
Disclosures: Dr. Chang had no relevant disclosures. Senior author Brad S. Kahl, MD, disclosed ties to Celgene, Gilead, Infinity, Juno, Pharmacyclics, and Seattle Genetics.