Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma, based on the results of a pilot study of 27 patients.

Of study participants whose multiple myeloma at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001), reported Anna Oberle of University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and her associates. The findings were published in Haematologica.

“Taken together, our pilot study gives valuable biological insights into the circulating cellular and cell-free compartments explorable by ‘liquid biopsy’ in multiple myeloma,” the investigators wrote. Levels of V(D)J-positive circulating myeloma cells and cell-free DNA might decline faster in response to effective therapy than the “relatively inert M-protein,” and might therefore be a better way to immediately estimate treatment efficacy or predict minimum residual disease negativity, they added (Haematologica. 2017 Feb 9. doi: 10.3324/haematol.2016.161414).

Novel multiple myeloma therapies are inducing deeper, longer responses, which highlights the need for minimum residual disease monitoring, the researchers said. Next-generation sequencing of the clonotypic V(D)J immunoglobulin rearrangement has shown promise but requires painful bone marrow sampling. A minimally invasive alternative is to monitor for circulating myeloma cells (cmc) or cell-free myeloma (cfm). To investigate the feasibility of this technique, the researchers used next-generation sequencing to define the myeloma V(D)J rearrangement in bone marrow and to track sequential peripheral blood samples from multiple myeloma patients before and during treatment. Next-generation sequencing was performed with an Illumina MiSeq sequencer with 500 or 600 cycle single-indexed, paired-end runs.

After treatment initiation, 47% of follow-up peripheral blood samples were positive for cmc-V(D)J, cfm-V(D)J, or both, the researchers said. They found a clear link between poor remission status assessed by M-protein based IMWG criteria and positive cmc-V(D)J sampling, with a regression coefficient of 1.60 (95% CI, 0.68 to 2.50; P = .002). Poor remission status was also associated with evidence of cfm-V(D)J (regression coefficient 1.49; 95% CI, 0.70 to 2.27; P = .001).

“About half of partial responders showed complete clearance of circulating myeloma cells-/cell-free myeloma DNA -V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover, and therefore decline more rapidly after initiation of effective treatment,” the researchers emphasized. Also, in 30% of cases, patients were positive for only one of the two V(D)J measures, suggesting that cfm-V(D)J might reflect overall tumor burden, not just circulating tumor cells, they added. “Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma,” they concluded.

Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.

Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma, based on the results of a pilot study of 27 patients.

Of study participants whose multiple myeloma at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001), reported Anna Oberle of University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and her associates. The findings were published in Haematologica.

“Taken together, our pilot study gives valuable biological insights into the circulating cellular and cell-free compartments explorable by ‘liquid biopsy’ in multiple myeloma,” the investigators wrote. Levels of V(D)J-positive circulating myeloma cells and cell-free DNA might decline faster in response to effective therapy than the “relatively inert M-protein,” and might therefore be a better way to immediately estimate treatment efficacy or predict minimum residual disease negativity, they added (Haematologica. 2017 Feb 9. doi: 10.3324/haematol.2016.161414).

Novel multiple myeloma therapies are inducing deeper, longer responses, which highlights the need for minimum residual disease monitoring, the researchers said. Next-generation sequencing of the clonotypic V(D)J immunoglobulin rearrangement has shown promise but requires painful bone marrow sampling. A minimally invasive alternative is to monitor for circulating myeloma cells (cmc) or cell-free myeloma (cfm). To investigate the feasibility of this technique, the researchers used next-generation sequencing to define the myeloma V(D)J rearrangement in bone marrow and to track sequential peripheral blood samples from multiple myeloma patients before and during treatment. Next-generation sequencing was performed with an Illumina MiSeq sequencer with 500 or 600 cycle single-indexed, paired-end runs.

After treatment initiation, 47% of follow-up peripheral blood samples were positive for cmc-V(D)J, cfm-V(D)J, or both, the researchers said. They found a clear link between poor remission status assessed by M-protein based IMWG criteria and positive cmc-V(D)J sampling, with a regression coefficient of 1.60 (95% CI, 0.68 to 2.50; P = .002). Poor remission status was also associated with evidence of cfm-V(D)J (regression coefficient 1.49; 95% CI, 0.70 to 2.27; P = .001).

“About half of partial responders showed complete clearance of circulating myeloma cells-/cell-free myeloma DNA -V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover, and therefore decline more rapidly after initiation of effective treatment,” the researchers emphasized. Also, in 30% of cases, patients were positive for only one of the two V(D)J measures, suggesting that cfm-V(D)J might reflect overall tumor burden, not just circulating tumor cells, they added. “Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma,” they concluded.

Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.

Next-generation sequencing might be useful to monitor for minimum residual disease in multiple myeloma, based on the results of a pilot study of 27 patients.

Of study participants whose multiple myeloma at least partially remitted on therapy, 41% showed evidence of persistent circulating myeloma cells or cell-free myeloma DNA based on next-generation sequencing of the clonotypic V(D)J rearrangement, compared with 91% of nonresponders or progressors (P less than .001), reported Anna Oberle of University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and her associates. The findings were published in Haematologica.

“Taken together, our pilot study gives valuable biological insights into the circulating cellular and cell-free compartments explorable by ‘liquid biopsy’ in multiple myeloma,” the investigators wrote. Levels of V(D)J-positive circulating myeloma cells and cell-free DNA might decline faster in response to effective therapy than the “relatively inert M-protein,” and might therefore be a better way to immediately estimate treatment efficacy or predict minimum residual disease negativity, they added (Haematologica. 2017 Feb 9. doi: 10.3324/haematol.2016.161414).

Novel multiple myeloma therapies are inducing deeper, longer responses, which highlights the need for minimum residual disease monitoring, the researchers said. Next-generation sequencing of the clonotypic V(D)J immunoglobulin rearrangement has shown promise but requires painful bone marrow sampling. A minimally invasive alternative is to monitor for circulating myeloma cells (cmc) or cell-free myeloma (cfm). To investigate the feasibility of this technique, the researchers used next-generation sequencing to define the myeloma V(D)J rearrangement in bone marrow and to track sequential peripheral blood samples from multiple myeloma patients before and during treatment. Next-generation sequencing was performed with an Illumina MiSeq sequencer with 500 or 600 cycle single-indexed, paired-end runs.

After treatment initiation, 47% of follow-up peripheral blood samples were positive for cmc-V(D)J, cfm-V(D)J, or both, the researchers said. They found a clear link between poor remission status assessed by M-protein based IMWG criteria and positive cmc-V(D)J sampling, with a regression coefficient of 1.60 (95% CI, 0.68 to 2.50; P = .002). Poor remission status was also associated with evidence of cfm-V(D)J (regression coefficient 1.49; 95% CI, 0.70 to 2.27; P = .001).

“About half of partial responders showed complete clearance of circulating myeloma cells-/cell-free myeloma DNA -V(D)J despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover, and therefore decline more rapidly after initiation of effective treatment,” the researchers emphasized. Also, in 30% of cases, patients were positive for only one of the two V(D)J measures, suggesting that cfm-V(D)J might reflect overall tumor burden, not just circulating tumor cells, they added. “Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma,” they concluded.

Eppendorfer Krebs- und Leukämiehilfe e.V. and the Deutsche Krebshilfe funded the study. The researchers disclosed no conflicts of interest.

The small interfering RNA molecule inclisiran has achieved significant reductions in LDL-cholesterol levels in patients at high cardiovascular risk, according to data presented at the annual meeting of the American College of Cardiology and published simultaneously in the New England Journal of Medicine.

Inclisiran is an investigational, chemically synthesized, small interfering RNA molecule that targets the liver-derived serine protease proprotein convertase subtilisin-kexin type 9 (PCSK9), which promotes degradation of the LDL-receptor.

An earlier phase I trial of inclisiran in healthy volunteers showed sustained reductions in LDL-C levels. In this phase II randomized, placebo-controlled trial, researchers tested a single dose (200, 300, or 500 mg) or double dose (100, 200, or 300 mg on day 1 and day 90) subcutaneous injection, compared with placebo in 501 patients with elevated LDL-C who were at high risk for cardiovascular disease.

By day 30 after the first injection, mean reductions in LDL-C ranged from 44.5% to 50.5% below baseline levels across all dosages of inclisiran (N Engl J Med. 2017 Mar 17. doi: 10.1056/NEJMoa1615758).

By day 180, the mean reductions in LDL-C were 27.9%-41.9% in patients who received a single dose and 35.5%-52.6% in those who received a double dose. By comparison, patients who received placebo showed a 2.1% mean increase in LDL-C.

All patients who received two 300-mg doses of inclisiran showed reductions in LDL-C by day 180, with a mean absolute change of –64.2 ± 20.7 mg/dL. More than half of this group (54%) achieved LDL-C reductions of 50% or more below baseline.

In this same dosage group, 5% of patients achieved LDL-C levels below 25 mg/dL, 48% achieved levels below 50 mg/dL, and 66% achieved levels below 70 mg/dL by day 180 after the first dose.

Researchers observed a nadir in patients’ response at around day 60 for the single-dose group and day 140 for the double-dose group.

“Maintaining consistent and effective reductions in LDL-cholesterol levels in the long term through the use of statins is, in part, hindered by adherence,” wrote Kausik K. Ray, MD, of Imperial College London, and his coauthors. “Hence, approaches that not only lower LDL-cholesterol levels safely but also can maintain reduction consistently over time, when applied either in lieu of or simultaneously with statin therapy, are being sought.”

However, they also clarified that it was still unknown as to whether these LDL-C reductions would translate into reductions in cardiovascular events.

Researchers also saw significant declines in PCSK9 levels from baseline in all patients who received inclisiran. Among those who received a single dose, mean reductions in PCSK9 at 180 days ranged from 47.9% to 59.3%, while those who received a double dose showed mean reductions ranging from 53.2% to 69.1%.

The overall rate of adverse events was similar between the inclisiran and placebo groups (76% vs. 79%, respectively), while the rate of serious adverse events was 11% in the inclisiran group and 8% in the placebo group.

One patient in the inclisiran group and one in the placebo group showed increased levels of hepatic aspartate aminotransferase, and three patients in the inclisiran group had elevated alanine aminotransferase. No increases in bilirubin levels were observed.

“Symptoms of immune activation, which is often a concern with therapies targeting RNA, were rare in association with inclisiran: There were few instances of flu-like symptoms and no observed elevations in C-reactive protein,” the authors wrote.

Injection-site reactions were also relatively uncommon, occurring in 4% of patients treated with one dose of inclisiran, 7% of those treated with two doses, and none of the placebo group.

The authors, however, said that, given the small size and relatively short duration of the trial, they could not rule out the possibility of other infrequent serious side effects. A long-term open-label study also is being conducted.

The study was funded by the Medicines Company. Several authors declared receiving personal fees from pharmaceutical companies outside the submitted work and 10 also declared receiving personal fees from the Medicines Company, 6 involving the submitted work. One author was an employee of the Medicines Company with stock options.

The small interfering RNA molecule inclisiran has achieved significant reductions in LDL-cholesterol levels in patients at high cardiovascular risk, according to data presented at the annual meeting of the American College of Cardiology and published simultaneously in the New England Journal of Medicine.

Inclisiran is an investigational, chemically synthesized, small interfering RNA molecule that targets the liver-derived serine protease proprotein convertase subtilisin-kexin type 9 (PCSK9), which promotes degradation of the LDL-receptor.

An earlier phase I trial of inclisiran in healthy volunteers showed sustained reductions in LDL-C levels. In this phase II randomized, placebo-controlled trial, researchers tested a single dose (200, 300, or 500 mg) or double dose (100, 200, or 300 mg on day 1 and day 90) subcutaneous injection, compared with placebo in 501 patients with elevated LDL-C who were at high risk for cardiovascular disease.

By day 30 after the first injection, mean reductions in LDL-C ranged from 44.5% to 50.5% below baseline levels across all dosages of inclisiran (N Engl J Med. 2017 Mar 17. doi: 10.1056/NEJMoa1615758).

By day 180, the mean reductions in LDL-C were 27.9%-41.9% in patients who received a single dose and 35.5%-52.6% in those who received a double dose. By comparison, patients who received placebo showed a 2.1% mean increase in LDL-C.

All patients who received two 300-mg doses of inclisiran showed reductions in LDL-C by day 180, with a mean absolute change of –64.2 ± 20.7 mg/dL. More than half of this group (54%) achieved LDL-C reductions of 50% or more below baseline.

In this same dosage group, 5% of patients achieved LDL-C levels below 25 mg/dL, 48% achieved levels below 50 mg/dL, and 66% achieved levels below 70 mg/dL by day 180 after the first dose.

Researchers observed a nadir in patients’ response at around day 60 for the single-dose group and day 140 for the double-dose group.

“Maintaining consistent and effective reductions in LDL-cholesterol levels in the long term through the use of statins is, in part, hindered by adherence,” wrote Kausik K. Ray, MD, of Imperial College London, and his coauthors. “Hence, approaches that not only lower LDL-cholesterol levels safely but also can maintain reduction consistently over time, when applied either in lieu of or simultaneously with statin therapy, are being sought.”

However, they also clarified that it was still unknown as to whether these LDL-C reductions would translate into reductions in cardiovascular events.

Researchers also saw significant declines in PCSK9 levels from baseline in all patients who received inclisiran. Among those who received a single dose, mean reductions in PCSK9 at 180 days ranged from 47.9% to 59.3%, while those who received a double dose showed mean reductions ranging from 53.2% to 69.1%.

The overall rate of adverse events was similar between the inclisiran and placebo groups (76% vs. 79%, respectively), while the rate of serious adverse events was 11% in the inclisiran group and 8% in the placebo group.

One patient in the inclisiran group and one in the placebo group showed increased levels of hepatic aspartate aminotransferase, and three patients in the inclisiran group had elevated alanine aminotransferase. No increases in bilirubin levels were observed.

“Symptoms of immune activation, which is often a concern with therapies targeting RNA, were rare in association with inclisiran: There were few instances of flu-like symptoms and no observed elevations in C-reactive protein,” the authors wrote.

Injection-site reactions were also relatively uncommon, occurring in 4% of patients treated with one dose of inclisiran, 7% of those treated with two doses, and none of the placebo group.

The authors, however, said that, given the small size and relatively short duration of the trial, they could not rule out the possibility of other infrequent serious side effects. A long-term open-label study also is being conducted.

The study was funded by the Medicines Company. Several authors declared receiving personal fees from pharmaceutical companies outside the submitted work and 10 also declared receiving personal fees from the Medicines Company, 6 involving the submitted work. One author was an employee of the Medicines Company with stock options.

The small interfering RNA molecule inclisiran has achieved significant reductions in LDL-cholesterol levels in patients at high cardiovascular risk, according to data presented at the annual meeting of the American College of Cardiology and published simultaneously in the New England Journal of Medicine.

Inclisiran is an investigational, chemically synthesized, small interfering RNA molecule that targets the liver-derived serine protease proprotein convertase subtilisin-kexin type 9 (PCSK9), which promotes degradation of the LDL-receptor.

An earlier phase I trial of inclisiran in healthy volunteers showed sustained reductions in LDL-C levels. In this phase II randomized, placebo-controlled trial, researchers tested a single dose (200, 300, or 500 mg) or double dose (100, 200, or 300 mg on day 1 and day 90) subcutaneous injection, compared with placebo in 501 patients with elevated LDL-C who were at high risk for cardiovascular disease.

By day 30 after the first injection, mean reductions in LDL-C ranged from 44.5% to 50.5% below baseline levels across all dosages of inclisiran (N Engl J Med. 2017 Mar 17. doi: 10.1056/NEJMoa1615758).

By day 180, the mean reductions in LDL-C were 27.9%-41.9% in patients who received a single dose and 35.5%-52.6% in those who received a double dose. By comparison, patients who received placebo showed a 2.1% mean increase in LDL-C.

All patients who received two 300-mg doses of inclisiran showed reductions in LDL-C by day 180, with a mean absolute change of –64.2 ± 20.7 mg/dL. More than half of this group (54%) achieved LDL-C reductions of 50% or more below baseline.

In this same dosage group, 5% of patients achieved LDL-C levels below 25 mg/dL, 48% achieved levels below 50 mg/dL, and 66% achieved levels below 70 mg/dL by day 180 after the first dose.

Researchers observed a nadir in patients’ response at around day 60 for the single-dose group and day 140 for the double-dose group.

“Maintaining consistent and effective reductions in LDL-cholesterol levels in the long term through the use of statins is, in part, hindered by adherence,” wrote Kausik K. Ray, MD, of Imperial College London, and his coauthors. “Hence, approaches that not only lower LDL-cholesterol levels safely but also can maintain reduction consistently over time, when applied either in lieu of or simultaneously with statin therapy, are being sought.”

However, they also clarified that it was still unknown as to whether these LDL-C reductions would translate into reductions in cardiovascular events.

Researchers also saw significant declines in PCSK9 levels from baseline in all patients who received inclisiran. Among those who received a single dose, mean reductions in PCSK9 at 180 days ranged from 47.9% to 59.3%, while those who received a double dose showed mean reductions ranging from 53.2% to 69.1%.

The overall rate of adverse events was similar between the inclisiran and placebo groups (76% vs. 79%, respectively), while the rate of serious adverse events was 11% in the inclisiran group and 8% in the placebo group.

One patient in the inclisiran group and one in the placebo group showed increased levels of hepatic aspartate aminotransferase, and three patients in the inclisiran group had elevated alanine aminotransferase. No increases in bilirubin levels were observed.

“Symptoms of immune activation, which is often a concern with therapies targeting RNA, were rare in association with inclisiran: There were few instances of flu-like symptoms and no observed elevations in C-reactive protein,” the authors wrote.

Injection-site reactions were also relatively uncommon, occurring in 4% of patients treated with one dose of inclisiran, 7% of those treated with two doses, and none of the placebo group.

The authors, however, said that, given the small size and relatively short duration of the trial, they could not rule out the possibility of other infrequent serious side effects. A long-term open-label study also is being conducted.

The study was funded by the Medicines Company. Several authors declared receiving personal fees from pharmaceutical companies outside the submitted work and 10 also declared receiving personal fees from the Medicines Company, 6 involving the submitted work. One author was an employee of the Medicines Company with stock options.

More than 40% of women are unaware that endometriosis may cause dyspareunia, and less than a quarter of physicians and nurse practitioners ask about it, according to the findings of a recent survey.

The survey, conducted by HealthyWomen with support from drug-maker AbbVie, highlights some of the knowledge gaps surrounding endometriosis. They surveyed 1,211 adult women in the United States and 352 health care providers, including ob.gyns, primary care physicians, reproductive endocrinologists, gynecologic specialists, and nurse practitioners.

[email protected]

On Twitter @maryellenny

More than 40% of women are unaware that endometriosis may cause dyspareunia, and less than a quarter of physicians and nurse practitioners ask about it, according to the findings of a recent survey.

The survey, conducted by HealthyWomen with support from drug-maker AbbVie, highlights some of the knowledge gaps surrounding endometriosis. They surveyed 1,211 adult women in the United States and 352 health care providers, including ob.gyns, primary care physicians, reproductive endocrinologists, gynecologic specialists, and nurse practitioners.

[email protected]

On Twitter @maryellenny

More than 40% of women are unaware that endometriosis may cause dyspareunia, and less than a quarter of physicians and nurse practitioners ask about it, according to the findings of a recent survey.

The survey, conducted by HealthyWomen with support from drug-maker AbbVie, highlights some of the knowledge gaps surrounding endometriosis. They surveyed 1,211 adult women in the United States and 352 health care providers, including ob.gyns, primary care physicians, reproductive endocrinologists, gynecologic specialists, and nurse practitioners.

[email protected]

On Twitter @maryellenny

A genetic variant associated with a poorer therapeutic response in patients with asthma may also be linked to more severe chronic obstructive pulmonary disease, researchers have found.

The polymorphisms at codons 16 and 27 of the beta-2-adrenoreceptor (ADRB2) gene are responsible for enhanced down-regulation of the beta-2-adrenoreceptor, and research suggests that Arg/Arg homozygosity at position 16 is associated with worse control of disease in patients with bronchial asthma.

However, the results of studies exploring the impact of this variant “on the clinical response to the administration of the beta-2-adrenoreceptor agonists in COPD patients are “parse and inconclusive,” according to Justyna Emeryk-Maksymiuk and colleagues at the Medical University of Lublin in Poland.

In a study published in the April issue of Pulmonary Pharmacology & Therapeutics, the researchers looked for variants of the ADRB2 gene in blood samples taken from 92 patients with stable grade COPD.

They collected data on each patient’s disease course during the previous 12 months, including the frequency of exacerbations requiring hospitalization, and antibiotic and systemic corticosteroid use.

They found significant differences between patients with either the Arg/Arg (n = 18), Arg/Gly (n = 61) and Gly/Gly (n = 13) polymorphism at codon 16 of the ADRB2 gene (Pulm Pharmacol Ther. 2017. doi: 10.1016/j.pupt.2017.01.005).

Those who were Arg/Arg homozygotes were significantly more likely to require two or more courses of antibiotic therapy: 33% of this group required two courses of antibiotics compared to 16.4% of those with the Arg/Gly polymorphism and none of those with the Gly/Gly polymorphism.

Those with the Arg/Arg polymorphism also required significantly more corticosteroid therapy; 16.7% needed three or more courses of systemic corticosteroid therapy, compared to none of the patients with the other polymorphisms.

However there were no significant differences between the three groups in the number of hospitalizations over the prior 12 months.

The researchers did not see any significant effects on hospitalizations, courses of corticosteroids or antibiotics from polymorphisms at codon 27 of the ADRB2 gene.

“The majority of researchers focus on the bronchodilator effect brought by the activation of the beta-2-adrenoreceptors, with less emphasis on the facts that these receptors are also involved in the inhibition of mast cell degranulation, chemotaxis, adhesion and activation of leukocytes, as well as in the improvement of mucociliary clearance of respiratory epithelium,” the authors wrote.

“The results of these studies confirmed that the Arg/Arg genotype at codon 16 predisposes patients to clinically more severe manifestation of obstructive respiratory disorders.”

The authors noted that the differences in the effect of genetic polymorphisms in the ADRB2 gene could also be the result of differences in the use of inhaled glucocorticoids, as these can prevent the desensitization of the beta-2-adrenoreceptor.

Previous research has found that nonusage of inhaled glucocorticoids in asthma patients with the Arg/Arg phenotype is associated with a twofold greater odds of uncontrolled asthma, when compared with patients with the Gly/Gly phenotype.

While patients with asthma are recommended to have inhaled glucocorticoids in conjunction with beta-2-mimetics, a considerable fraction of patients with COPD would not be administered glucocorticoids.

“Therefore, it cannot be excluded that a more severe course of asthma and COPD in patients with [the] Arg/Arg genotype of [the] ADRB2 gene at codon 16 does not result solely from the polymorphism itself, but also from the lack of [inhaled glucocorticoids].”

The Ministry of Science and Education supported the study. No conflicts of interest were declared.

A genetic variant associated with a poorer therapeutic response in patients with asthma may also be linked to more severe chronic obstructive pulmonary disease, researchers have found.

The polymorphisms at codons 16 and 27 of the beta-2-adrenoreceptor (ADRB2) gene are responsible for enhanced down-regulation of the beta-2-adrenoreceptor, and research suggests that Arg/Arg homozygosity at position 16 is associated with worse control of disease in patients with bronchial asthma.

However, the results of studies exploring the impact of this variant “on the clinical response to the administration of the beta-2-adrenoreceptor agonists in COPD patients are “parse and inconclusive,” according to Justyna Emeryk-Maksymiuk and colleagues at the Medical University of Lublin in Poland.

In a study published in the April issue of Pulmonary Pharmacology & Therapeutics, the researchers looked for variants of the ADRB2 gene in blood samples taken from 92 patients with stable grade COPD.

They collected data on each patient’s disease course during the previous 12 months, including the frequency of exacerbations requiring hospitalization, and antibiotic and systemic corticosteroid use.

They found significant differences between patients with either the Arg/Arg (n = 18), Arg/Gly (n = 61) and Gly/Gly (n = 13) polymorphism at codon 16 of the ADRB2 gene (Pulm Pharmacol Ther. 2017. doi: 10.1016/j.pupt.2017.01.005).

Those who were Arg/Arg homozygotes were significantly more likely to require two or more courses of antibiotic therapy: 33% of this group required two courses of antibiotics compared to 16.4% of those with the Arg/Gly polymorphism and none of those with the Gly/Gly polymorphism.

Those with the Arg/Arg polymorphism also required significantly more corticosteroid therapy; 16.7% needed three or more courses of systemic corticosteroid therapy, compared to none of the patients with the other polymorphisms.

However there were no significant differences between the three groups in the number of hospitalizations over the prior 12 months.

The researchers did not see any significant effects on hospitalizations, courses of corticosteroids or antibiotics from polymorphisms at codon 27 of the ADRB2 gene.

“The majority of researchers focus on the bronchodilator effect brought by the activation of the beta-2-adrenoreceptors, with less emphasis on the facts that these receptors are also involved in the inhibition of mast cell degranulation, chemotaxis, adhesion and activation of leukocytes, as well as in the improvement of mucociliary clearance of respiratory epithelium,” the authors wrote.

“The results of these studies confirmed that the Arg/Arg genotype at codon 16 predisposes patients to clinically more severe manifestation of obstructive respiratory disorders.”

The authors noted that the differences in the effect of genetic polymorphisms in the ADRB2 gene could also be the result of differences in the use of inhaled glucocorticoids, as these can prevent the desensitization of the beta-2-adrenoreceptor.

Previous research has found that nonusage of inhaled glucocorticoids in asthma patients with the Arg/Arg phenotype is associated with a twofold greater odds of uncontrolled asthma, when compared with patients with the Gly/Gly phenotype.

While patients with asthma are recommended to have inhaled glucocorticoids in conjunction with beta-2-mimetics, a considerable fraction of patients with COPD would not be administered glucocorticoids.

“Therefore, it cannot be excluded that a more severe course of asthma and COPD in patients with [the] Arg/Arg genotype of [the] ADRB2 gene at codon 16 does not result solely from the polymorphism itself, but also from the lack of [inhaled glucocorticoids].”

The Ministry of Science and Education supported the study. No conflicts of interest were declared.

A genetic variant associated with a poorer therapeutic response in patients with asthma may also be linked to more severe chronic obstructive pulmonary disease, researchers have found.

The polymorphisms at codons 16 and 27 of the beta-2-adrenoreceptor (ADRB2) gene are responsible for enhanced down-regulation of the beta-2-adrenoreceptor, and research suggests that Arg/Arg homozygosity at position 16 is associated with worse control of disease in patients with bronchial asthma.

However, the results of studies exploring the impact of this variant “on the clinical response to the administration of the beta-2-adrenoreceptor agonists in COPD patients are “parse and inconclusive,” according to Justyna Emeryk-Maksymiuk and colleagues at the Medical University of Lublin in Poland.

In a study published in the April issue of Pulmonary Pharmacology & Therapeutics, the researchers looked for variants of the ADRB2 gene in blood samples taken from 92 patients with stable grade COPD.

They collected data on each patient’s disease course during the previous 12 months, including the frequency of exacerbations requiring hospitalization, and antibiotic and systemic corticosteroid use.

They found significant differences between patients with either the Arg/Arg (n = 18), Arg/Gly (n = 61) and Gly/Gly (n = 13) polymorphism at codon 16 of the ADRB2 gene (Pulm Pharmacol Ther. 2017. doi: 10.1016/j.pupt.2017.01.005).

Those who were Arg/Arg homozygotes were significantly more likely to require two or more courses of antibiotic therapy: 33% of this group required two courses of antibiotics compared to 16.4% of those with the Arg/Gly polymorphism and none of those with the Gly/Gly polymorphism.

Those with the Arg/Arg polymorphism also required significantly more corticosteroid therapy; 16.7% needed three or more courses of systemic corticosteroid therapy, compared to none of the patients with the other polymorphisms.

However there were no significant differences between the three groups in the number of hospitalizations over the prior 12 months.

The researchers did not see any significant effects on hospitalizations, courses of corticosteroids or antibiotics from polymorphisms at codon 27 of the ADRB2 gene.

“The majority of researchers focus on the bronchodilator effect brought by the activation of the beta-2-adrenoreceptors, with less emphasis on the facts that these receptors are also involved in the inhibition of mast cell degranulation, chemotaxis, adhesion and activation of leukocytes, as well as in the improvement of mucociliary clearance of respiratory epithelium,” the authors wrote.

“The results of these studies confirmed that the Arg/Arg genotype at codon 16 predisposes patients to clinically more severe manifestation of obstructive respiratory disorders.”

The authors noted that the differences in the effect of genetic polymorphisms in the ADRB2 gene could also be the result of differences in the use of inhaled glucocorticoids, as these can prevent the desensitization of the beta-2-adrenoreceptor.

Previous research has found that nonusage of inhaled glucocorticoids in asthma patients with the Arg/Arg phenotype is associated with a twofold greater odds of uncontrolled asthma, when compared with patients with the Gly/Gly phenotype.

While patients with asthma are recommended to have inhaled glucocorticoids in conjunction with beta-2-mimetics, a considerable fraction of patients with COPD would not be administered glucocorticoids.

“Therefore, it cannot be excluded that a more severe course of asthma and COPD in patients with [the] Arg/Arg genotype of [the] ADRB2 gene at codon 16 does not result solely from the polymorphism itself, but also from the lack of [inhaled glucocorticoids].”

The Ministry of Science and Education supported the study. No conflicts of interest were declared.

As more and more physicians, both young and experienced, choose to merge with larger practices or join multispecialty groups, I am getting numerous questions about the contracts they are being asked to sign. Obviously, every circumstance will be unique; but some common issues and avoidable mistakes are worth mentioning.

The most common error I see is failing to retain an attorney in a timely manner. Incredibly, many physicians try to do their own negotiating, and call a lawyer only when unpleasant discoveries are made after the contract has been signed. You will need counsel from the very beginning – and not your brother-in-law, or a family friend. Get referrals from colleagues who have gone through the process and are happy with their contracts.

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

As more and more physicians, both young and experienced, choose to merge with larger practices or join multispecialty groups, I am getting numerous questions about the contracts they are being asked to sign. Obviously, every circumstance will be unique; but some common issues and avoidable mistakes are worth mentioning.

The most common error I see is failing to retain an attorney in a timely manner. Incredibly, many physicians try to do their own negotiating, and call a lawyer only when unpleasant discoveries are made after the contract has been signed. You will need counsel from the very beginning – and not your brother-in-law, or a family friend. Get referrals from colleagues who have gone through the process and are happy with their contracts.

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

As more and more physicians, both young and experienced, choose to merge with larger practices or join multispecialty groups, I am getting numerous questions about the contracts they are being asked to sign. Obviously, every circumstance will be unique; but some common issues and avoidable mistakes are worth mentioning.

The most common error I see is failing to retain an attorney in a timely manner. Incredibly, many physicians try to do their own negotiating, and call a lawyer only when unpleasant discoveries are made after the contract has been signed. You will need counsel from the very beginning – and not your brother-in-law, or a family friend. Get referrals from colleagues who have gone through the process and are happy with their contracts.

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

Generalized vaccinia (GV) is a rare, self-limiting complication of the smallpox vaccination that is caused by the systemic spread of the virus from the inoculation site. The incidence of GV became rare after routine vaccination was discontinued in the U.S. in 1971 and globally in the 1980s after the disease was eradicated.^1,2 However in 2002, heightened concerns for the deliberate release of the smallpox virus as a bioweapon led the U.S. military to restart its smallpox vaccination program for soldiers and public health workers.^3,4 Here, the authors describe a patient with concomitant GV and mononucleosis.

Case Report

A 19-year-old active-duty marine presented to his battalion aid station with concern for a spreading vesicular rash 9 days after a primary inoculation with the smallpox vaccine. The rash was limited to the inoculation site on his left shoulder (Figure 1). He had no medical history of eczema, atopic dermatitis, or other rashes and reported no systemic symptoms. His vitals also were within normal limits. A clinical diagnosis of inadvertent inoculation (also termed accidental infection) with satellite lesions was made, and he was discharged with counseling on wound care and close follow-up. Two days later, on postvaccination day 11, he presented with new symptoms of a headache, fever, chills, diffuse myalgia, sore throat, and spreading erythematous macules, papules, and vesicles on his arms, chest, abdomen, back, legs, and face (Figures 2A-2D). His vital signs were remarkable for tachycardia with heart rate of 100 bpm and a fever of 103º F (39.4º C). He was sent to the emergency department with a presumed GV diagnosis.

A complete blood count, liver function tests, and basic metabolic panel were unremarkable. Given his symptom of pharyngitis, a rapid strep test was performed. The test was negative, and a throat culture showed no growth. A mononucleosis screen also was performed and was positive. The patient was diagnosed with mononucleosis and GV. His condition improved, and his vital signs stabilized with conservative treatment without the need for vaccine immune globulin (VIG). He convalesced for 72 hours and was referred to dermatology on the following day. Quarantining him in a single occupancy barracks room until all lesions crusted over addressed the concern for spread of the virus to nonimmunized marines or family members.

On postvaccination day 12, the patient continued to be clinically well, and he remained afebrile. The dermatologist obtained a skin biopsy from a lesion on the patient’s right shin. The biopsy demonstrated marked epidermal necrosis with peripheral keratinocytes showing ballooning degeneration and viral cytopathic changes consistent with GV. Antibody titers showing high levels of Epstein-Barr virus (EBV) capsid IgM and IgG present confirmed mononucleosis infection within the past 6 months. The patient remained clinically well and was released from quarantine on postvaccination day 22 when all lesions crusted over (Figures 3A-3D).

Discussion

The CDC current definition for GV is “the spread of lesions to other parts of the body that are benign in appearance and occur as a result of viremia.”⁵ Although the exact mechanisms of viral spread are unknown, it may be due to a subtle immunologic defect, specifically in the B-cell line.^6,7 Epstein-Barr virus affects the B-cell line, and concurrent infection may depress humoral immunity and allow for systemic spread of the virus.^8,9

This case illustrates the potential for a severe reaction after smallpox vaccination in a patient with a concomitant EBV infection. Service members primarily receive the smallpox vaccination early in their career when the risk of mononucleosis is at its highest incidence among young adults, 11 to 48 per 1,000.^10-13 Although the potential for disseminated vaccinia following vaccination is rare, clinicians need to remain cognizant of the risk, which may be enhanced by recent or subsequent infection with EBV. However, regular screening for EBV would be of questionable value given the large number of tests needed to prevent a single case of GV.

Generalized vaccinia is a rare complication after smallpox vaccination. Despite its dire appearance, GV typically resolves spontaneously with limited adverse effects (AEs).¹⁴ The pre-eradication reported incidence was 17.7 per 1,000,000 recipients in a national survey.¹⁵ Posteradication the incidence of GV was 3 times as high with 2 reported cases in 2003 after administration of 38,440 vaccinations.¹⁶ Inflammatory reactions can be common; however, these reactions are not due to systemic viral spread.⁵ When dealing with a vaccinia-specific AE, it is important to distinguish the benign inadvertent inoculations and GV from the more serious reactions of eczema vaccinatum (EV) or progressive vaccinia (PV). ⁵

Inadvertent inoculations and GV are usually benign and self-limited—requiring only prevention of secondary transmission and nosocomial infection. Eczema vaccinatum occurs among persons with atopic dermatitis or eczema.⁵ The rash that is indicative of EV has similar characteristics to GV, it can occur anywhere but favors areas of previous atopic dermatitis lesions. Unlike patients experiencing GV, patients with EV often are systemically ill and usually require VIG treatment.^5,17 A progressive enlarging necrosis at the primary vaccination site characterizes PV, also known as vaccinia necrosum and vaccinia gangrenosa; unlike GV there are no viral metastases to distant sites.^5,18 Progressive vaccinia is confined to immune-compromised individuals with defective cellular immunity.^18,19 Due to high mortality rates associated with PV, the CDC advocates aggressive therapy with VIG, intensive monitoring, and tertiary-level supportive care.⁵

Conclusion

The smallpox vaccination is unique among vaccinations. It is the only vaccine that is administered via inoculation with a bifurcated needle, requires regular follow-up care, and can be spread to casual contacts.⁵

It is important for any practitioner administering the smallpox vaccine to be aware of associated AEs. A greater knowledge of the unique challenges with the smallpox vaccine allows for better patient selection that eliminates those with conditions that impair their immune system and improves patient education.

Generalized vaccinia (GV) is a rare, self-limiting complication of the smallpox vaccination that is caused by the systemic spread of the virus from the inoculation site. The incidence of GV became rare after routine vaccination was discontinued in the U.S. in 1971 and globally in the 1980s after the disease was eradicated.^1,2 However in 2002, heightened concerns for the deliberate release of the smallpox virus as a bioweapon led the U.S. military to restart its smallpox vaccination program for soldiers and public health workers.^3,4 Here, the authors describe a patient with concomitant GV and mononucleosis.

Case Report

A 19-year-old active-duty marine presented to his battalion aid station with concern for a spreading vesicular rash 9 days after a primary inoculation with the smallpox vaccine. The rash was limited to the inoculation site on his left shoulder (Figure 1). He had no medical history of eczema, atopic dermatitis, or other rashes and reported no systemic symptoms. His vitals also were within normal limits. A clinical diagnosis of inadvertent inoculation (also termed accidental infection) with satellite lesions was made, and he was discharged with counseling on wound care and close follow-up. Two days later, on postvaccination day 11, he presented with new symptoms of a headache, fever, chills, diffuse myalgia, sore throat, and spreading erythematous macules, papules, and vesicles on his arms, chest, abdomen, back, legs, and face (Figures 2A-2D). His vital signs were remarkable for tachycardia with heart rate of 100 bpm and a fever of 103º F (39.4º C). He was sent to the emergency department with a presumed GV diagnosis.

A complete blood count, liver function tests, and basic metabolic panel were unremarkable. Given his symptom of pharyngitis, a rapid strep test was performed. The test was negative, and a throat culture showed no growth. A mononucleosis screen also was performed and was positive. The patient was diagnosed with mononucleosis and GV. His condition improved, and his vital signs stabilized with conservative treatment without the need for vaccine immune globulin (VIG). He convalesced for 72 hours and was referred to dermatology on the following day. Quarantining him in a single occupancy barracks room until all lesions crusted over addressed the concern for spread of the virus to nonimmunized marines or family members.

On postvaccination day 12, the patient continued to be clinically well, and he remained afebrile. The dermatologist obtained a skin biopsy from a lesion on the patient’s right shin. The biopsy demonstrated marked epidermal necrosis with peripheral keratinocytes showing ballooning degeneration and viral cytopathic changes consistent with GV. Antibody titers showing high levels of Epstein-Barr virus (EBV) capsid IgM and IgG present confirmed mononucleosis infection within the past 6 months. The patient remained clinically well and was released from quarantine on postvaccination day 22 when all lesions crusted over (Figures 3A-3D).

Discussion

The CDC current definition for GV is “the spread of lesions to other parts of the body that are benign in appearance and occur as a result of viremia.”⁵ Although the exact mechanisms of viral spread are unknown, it may be due to a subtle immunologic defect, specifically in the B-cell line.^6,7 Epstein-Barr virus affects the B-cell line, and concurrent infection may depress humoral immunity and allow for systemic spread of the virus.^8,9

This case illustrates the potential for a severe reaction after smallpox vaccination in a patient with a concomitant EBV infection. Service members primarily receive the smallpox vaccination early in their career when the risk of mononucleosis is at its highest incidence among young adults, 11 to 48 per 1,000.^10-13 Although the potential for disseminated vaccinia following vaccination is rare, clinicians need to remain cognizant of the risk, which may be enhanced by recent or subsequent infection with EBV. However, regular screening for EBV would be of questionable value given the large number of tests needed to prevent a single case of GV.

Generalized vaccinia is a rare complication after smallpox vaccination. Despite its dire appearance, GV typically resolves spontaneously with limited adverse effects (AEs).¹⁴ The pre-eradication reported incidence was 17.7 per 1,000,000 recipients in a national survey.¹⁵ Posteradication the incidence of GV was 3 times as high with 2 reported cases in 2003 after administration of 38,440 vaccinations.¹⁶ Inflammatory reactions can be common; however, these reactions are not due to systemic viral spread.⁵ When dealing with a vaccinia-specific AE, it is important to distinguish the benign inadvertent inoculations and GV from the more serious reactions of eczema vaccinatum (EV) or progressive vaccinia (PV). ⁵

Inadvertent inoculations and GV are usually benign and self-limited—requiring only prevention of secondary transmission and nosocomial infection. Eczema vaccinatum occurs among persons with atopic dermatitis or eczema.⁵ The rash that is indicative of EV has similar characteristics to GV, it can occur anywhere but favors areas of previous atopic dermatitis lesions. Unlike patients experiencing GV, patients with EV often are systemically ill and usually require VIG treatment.^5,17 A progressive enlarging necrosis at the primary vaccination site characterizes PV, also known as vaccinia necrosum and vaccinia gangrenosa; unlike GV there are no viral metastases to distant sites.^5,18 Progressive vaccinia is confined to immune-compromised individuals with defective cellular immunity.^18,19 Due to high mortality rates associated with PV, the CDC advocates aggressive therapy with VIG, intensive monitoring, and tertiary-level supportive care.⁵

Conclusion

The smallpox vaccination is unique among vaccinations. It is the only vaccine that is administered via inoculation with a bifurcated needle, requires regular follow-up care, and can be spread to casual contacts.⁵

It is important for any practitioner administering the smallpox vaccine to be aware of associated AEs. A greater knowledge of the unique challenges with the smallpox vaccine allows for better patient selection that eliminates those with conditions that impair their immune system and improves patient education.

Generalized vaccinia (GV) is a rare, self-limiting complication of the smallpox vaccination that is caused by the systemic spread of the virus from the inoculation site. The incidence of GV became rare after routine vaccination was discontinued in the U.S. in 1971 and globally in the 1980s after the disease was eradicated.^1,2 However in 2002, heightened concerns for the deliberate release of the smallpox virus as a bioweapon led the U.S. military to restart its smallpox vaccination program for soldiers and public health workers.^3,4 Here, the authors describe a patient with concomitant GV and mononucleosis.

Case Report

A 19-year-old active-duty marine presented to his battalion aid station with concern for a spreading vesicular rash 9 days after a primary inoculation with the smallpox vaccine. The rash was limited to the inoculation site on his left shoulder (Figure 1). He had no medical history of eczema, atopic dermatitis, or other rashes and reported no systemic symptoms. His vitals also were within normal limits. A clinical diagnosis of inadvertent inoculation (also termed accidental infection) with satellite lesions was made, and he was discharged with counseling on wound care and close follow-up. Two days later, on postvaccination day 11, he presented with new symptoms of a headache, fever, chills, diffuse myalgia, sore throat, and spreading erythematous macules, papules, and vesicles on his arms, chest, abdomen, back, legs, and face (Figures 2A-2D). His vital signs were remarkable for tachycardia with heart rate of 100 bpm and a fever of 103º F (39.4º C). He was sent to the emergency department with a presumed GV diagnosis.

A complete blood count, liver function tests, and basic metabolic panel were unremarkable. Given his symptom of pharyngitis, a rapid strep test was performed. The test was negative, and a throat culture showed no growth. A mononucleosis screen also was performed and was positive. The patient was diagnosed with mononucleosis and GV. His condition improved, and his vital signs stabilized with conservative treatment without the need for vaccine immune globulin (VIG). He convalesced for 72 hours and was referred to dermatology on the following day. Quarantining him in a single occupancy barracks room until all lesions crusted over addressed the concern for spread of the virus to nonimmunized marines or family members.

On postvaccination day 12, the patient continued to be clinically well, and he remained afebrile. The dermatologist obtained a skin biopsy from a lesion on the patient’s right shin. The biopsy demonstrated marked epidermal necrosis with peripheral keratinocytes showing ballooning degeneration and viral cytopathic changes consistent with GV. Antibody titers showing high levels of Epstein-Barr virus (EBV) capsid IgM and IgG present confirmed mononucleosis infection within the past 6 months. The patient remained clinically well and was released from quarantine on postvaccination day 22 when all lesions crusted over (Figures 3A-3D).

Discussion

The CDC current definition for GV is “the spread of lesions to other parts of the body that are benign in appearance and occur as a result of viremia.”⁵ Although the exact mechanisms of viral spread are unknown, it may be due to a subtle immunologic defect, specifically in the B-cell line.^6,7 Epstein-Barr virus affects the B-cell line, and concurrent infection may depress humoral immunity and allow for systemic spread of the virus.^8,9

This case illustrates the potential for a severe reaction after smallpox vaccination in a patient with a concomitant EBV infection. Service members primarily receive the smallpox vaccination early in their career when the risk of mononucleosis is at its highest incidence among young adults, 11 to 48 per 1,000.^10-13 Although the potential for disseminated vaccinia following vaccination is rare, clinicians need to remain cognizant of the risk, which may be enhanced by recent or subsequent infection with EBV. However, regular screening for EBV would be of questionable value given the large number of tests needed to prevent a single case of GV.

Generalized vaccinia is a rare complication after smallpox vaccination. Despite its dire appearance, GV typically resolves spontaneously with limited adverse effects (AEs).¹⁴ The pre-eradication reported incidence was 17.7 per 1,000,000 recipients in a national survey.¹⁵ Posteradication the incidence of GV was 3 times as high with 2 reported cases in 2003 after administration of 38,440 vaccinations.¹⁶ Inflammatory reactions can be common; however, these reactions are not due to systemic viral spread.⁵ When dealing with a vaccinia-specific AE, it is important to distinguish the benign inadvertent inoculations and GV from the more serious reactions of eczema vaccinatum (EV) or progressive vaccinia (PV). ⁵

Inadvertent inoculations and GV are usually benign and self-limited—requiring only prevention of secondary transmission and nosocomial infection. Eczema vaccinatum occurs among persons with atopic dermatitis or eczema.⁵ The rash that is indicative of EV has similar characteristics to GV, it can occur anywhere but favors areas of previous atopic dermatitis lesions. Unlike patients experiencing GV, patients with EV often are systemically ill and usually require VIG treatment.^5,17 A progressive enlarging necrosis at the primary vaccination site characterizes PV, also known as vaccinia necrosum and vaccinia gangrenosa; unlike GV there are no viral metastases to distant sites.^5,18 Progressive vaccinia is confined to immune-compromised individuals with defective cellular immunity.^18,19 Due to high mortality rates associated with PV, the CDC advocates aggressive therapy with VIG, intensive monitoring, and tertiary-level supportive care.⁵

Conclusion

The smallpox vaccination is unique among vaccinations. It is the only vaccine that is administered via inoculation with a bifurcated needle, requires regular follow-up care, and can be spread to casual contacts.⁵

It is important for any practitioner administering the smallpox vaccine to be aware of associated AEs. A greater knowledge of the unique challenges with the smallpox vaccine allows for better patient selection that eliminates those with conditions that impair their immune system and improves patient education.

Micrograph showing diffuse large B-cell lymphoma

When given after low-dose chemotherapy, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy can produce durable complete responses (CRs) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to research published in the Journal of Clinical Oncology.

In this phase 1 study, the overall response rate was 73%, and 50% of patients had an ongoing CR at last follow-up.

Fifty-five percent of patients experienced grade 3/4 neurologic toxicities, though these events eventually resolved.

This research was conducted under a cooperative research and development agreement between the National Cancer Institute and Kite Pharma, Inc.

Kite is developing the CAR T-cell therapy axicabtagene ciloleucel (formerly known as KTE-C19), and the therapy tested in this trial has the same CAR construct as axicabtagene ciloleucel.

Results from this study (NCT00924326) were previously published in the Journal of Clinical Oncology in 2014.

The current report included 22 patients with relapsed/refractory NHL. Seventeen patients had diffuse large B-cell lymphoma (DLBCL), 2 had primary mediastinal B-cell lymphoma (PMBCL), 2 had follicular lymphoma (FL), and 1 had mantle cell lymphoma (MCL).

Patients received a single dose of CAR T cells 2 days after a low-dose chemotherapy conditioning regimen consisting of cyclophosphamide and fludarabine.

Response

The overall response rate was 73% (16/22), with a CR rate of 55% (n=12) and a partial response (PR) rate of 18% (n=4).

Among patients with DLBCL, there were 9 CRs, 4 PRs, 1 patient with stable disease, and 3 patients with progressive disease.

Both FL patients achieved a CR, as did the patient with MCL. One patient with PMBCL had stable disease, and the other progressed.

Eleven of the 12 CRs are ongoing, with durations ranging from more than 7 months to more than 24 months. The median duration of CR is 12.5 months.

The researchers found that serum IL-15 levels and CAR T-cell expansion correlated with treatment response (CR or PR).

The median peak blood CAR+ cell level was 98/μL in patients who achieved a response and 15/μL in those who did not (P=0.027).

High serum IL-15 levels were significantly associated with high peak blood CAR+ cell levels (P=0.001) and response (P<0.001).

Toxicity

Fifty-five percent of patients had grade 3 or 4 neurologic toxicities, the most common of which were dysphasia (n=9) and confusion (n=8).

The researchers said all acute toxicities resolved completely, and none of the patients died as a result of toxicity.

One patient experienced vision loss 3 months after receiving CAR T-cell therapy. The researchers said they could not confirm the cause of the vision loss, but it is consistent with fludarabine toxicity.

One patient developed myelodysplastic syndrome, which was thought to be related to prior therapy.

The researchers noted that patients who experienced grade 3/4 neurologic toxicity had significantly higher levels of blood CAR+ cells than patients who had neurologic toxicities of a lower grade (P=0.003).

In addition, peak levels of serum IL-10 and IL-15 were higher in patients with grade 3/4 neurologic toxicities (P=0.006 and 0.014, respectively).

Micrograph showing diffuse large B-cell lymphoma

When given after low-dose chemotherapy, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy can produce durable complete responses (CRs) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to research published in the Journal of Clinical Oncology.

In this phase 1 study, the overall response rate was 73%, and 50% of patients had an ongoing CR at last follow-up.

Fifty-five percent of patients experienced grade 3/4 neurologic toxicities, though these events eventually resolved.

This research was conducted under a cooperative research and development agreement between the National Cancer Institute and Kite Pharma, Inc.

Kite is developing the CAR T-cell therapy axicabtagene ciloleucel (formerly known as KTE-C19), and the therapy tested in this trial has the same CAR construct as axicabtagene ciloleucel.

Results from this study (NCT00924326) were previously published in the Journal of Clinical Oncology in 2014.

The current report included 22 patients with relapsed/refractory NHL. Seventeen patients had diffuse large B-cell lymphoma (DLBCL), 2 had primary mediastinal B-cell lymphoma (PMBCL), 2 had follicular lymphoma (FL), and 1 had mantle cell lymphoma (MCL).

Patients received a single dose of CAR T cells 2 days after a low-dose chemotherapy conditioning regimen consisting of cyclophosphamide and fludarabine.

Response

The overall response rate was 73% (16/22), with a CR rate of 55% (n=12) and a partial response (PR) rate of 18% (n=4).

Among patients with DLBCL, there were 9 CRs, 4 PRs, 1 patient with stable disease, and 3 patients with progressive disease.

Both FL patients achieved a CR, as did the patient with MCL. One patient with PMBCL had stable disease, and the other progressed.

Eleven of the 12 CRs are ongoing, with durations ranging from more than 7 months to more than 24 months. The median duration of CR is 12.5 months.

The researchers found that serum IL-15 levels and CAR T-cell expansion correlated with treatment response (CR or PR).

The median peak blood CAR+ cell level was 98/μL in patients who achieved a response and 15/μL in those who did not (P=0.027).

High serum IL-15 levels were significantly associated with high peak blood CAR+ cell levels (P=0.001) and response (P<0.001).

Toxicity

Fifty-five percent of patients had grade 3 or 4 neurologic toxicities, the most common of which were dysphasia (n=9) and confusion (n=8).

The researchers said all acute toxicities resolved completely, and none of the patients died as a result of toxicity.

One patient experienced vision loss 3 months after receiving CAR T-cell therapy. The researchers said they could not confirm the cause of the vision loss, but it is consistent with fludarabine toxicity.

One patient developed myelodysplastic syndrome, which was thought to be related to prior therapy.

The researchers noted that patients who experienced grade 3/4 neurologic toxicity had significantly higher levels of blood CAR+ cells than patients who had neurologic toxicities of a lower grade (P=0.003).

In addition, peak levels of serum IL-10 and IL-15 were higher in patients with grade 3/4 neurologic toxicities (P=0.006 and 0.014, respectively).

Micrograph showing diffuse large B-cell lymphoma

When given after low-dose chemotherapy, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy can produce durable complete responses (CRs) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to research published in the Journal of Clinical Oncology.

In this phase 1 study, the overall response rate was 73%, and 50% of patients had an ongoing CR at last follow-up.

Fifty-five percent of patients experienced grade 3/4 neurologic toxicities, though these events eventually resolved.

This research was conducted under a cooperative research and development agreement between the National Cancer Institute and Kite Pharma, Inc.

Kite is developing the CAR T-cell therapy axicabtagene ciloleucel (formerly known as KTE-C19), and the therapy tested in this trial has the same CAR construct as axicabtagene ciloleucel.

Results from this study (NCT00924326) were previously published in the Journal of Clinical Oncology in 2014.

The current report included 22 patients with relapsed/refractory NHL. Seventeen patients had diffuse large B-cell lymphoma (DLBCL), 2 had primary mediastinal B-cell lymphoma (PMBCL), 2 had follicular lymphoma (FL), and 1 had mantle cell lymphoma (MCL).

Patients received a single dose of CAR T cells 2 days after a low-dose chemotherapy conditioning regimen consisting of cyclophosphamide and fludarabine.

Response

The overall response rate was 73% (16/22), with a CR rate of 55% (n=12) and a partial response (PR) rate of 18% (n=4).

Among patients with DLBCL, there were 9 CRs, 4 PRs, 1 patient with stable disease, and 3 patients with progressive disease.

Both FL patients achieved a CR, as did the patient with MCL. One patient with PMBCL had stable disease, and the other progressed.

Eleven of the 12 CRs are ongoing, with durations ranging from more than 7 months to more than 24 months. The median duration of CR is 12.5 months.

The researchers found that serum IL-15 levels and CAR T-cell expansion correlated with treatment response (CR or PR).

The median peak blood CAR+ cell level was 98/μL in patients who achieved a response and 15/μL in those who did not (P=0.027).

High serum IL-15 levels were significantly associated with high peak blood CAR+ cell levels (P=0.001) and response (P<0.001).

Toxicity

Fifty-five percent of patients had grade 3 or 4 neurologic toxicities, the most common of which were dysphasia (n=9) and confusion (n=8).

The researchers said all acute toxicities resolved completely, and none of the patients died as a result of toxicity.

One patient experienced vision loss 3 months after receiving CAR T-cell therapy. The researchers said they could not confirm the cause of the vision loss, but it is consistent with fludarabine toxicity.

One patient developed myelodysplastic syndrome, which was thought to be related to prior therapy.

The researchers noted that patients who experienced grade 3/4 neurologic toxicity had significantly higher levels of blood CAR+ cells than patients who had neurologic toxicities of a lower grade (P=0.003).

In addition, peak levels of serum IL-10 and IL-15 were higher in patients with grade 3/4 neurologic toxicities (P=0.006 and 0.014, respectively).

The Scripps Research Institute

A class of antibody-drug conjugates (ADCs) have shown promise for treating hematologic and solid tumor malignancies, according to research published in Cell Chemical Biology.

The ADCs, known as selenomab-drug conjugates, demonstrated in vitro activity against breast cancer and multiple myeloma (MM).

The ADCs also inhibited tumor growth and prolonged survival in mouse models of both malignancies.

“We’ve been working on this technology for some time,” said study author Christoph Rader, PhD, of The Scripps Research Institute (TSRI) in Jupiter, Florida.

“It’s based on the rarely used natural amino acid selenocysteine, which we insert into our antibodies. We refer to these engineered antibodies as selenomabs.”

He then explained that selenomab-drug conjugates are ADCs that “utilize the unique reactivity of selenocysteine for drug attachment.”

For this study, Dr Rader and his colleagues generated selective selenomab-drug conjugates and tested them in vitro and in vivo.

The team found that CD138-targeting selenomab-drug conjugates were effective against MM cell lines (U266 and H929), and HER2-targeting selenomab-drug conjugates were effective against breast cancer cell lines.

Both types of ADCs demonstrated efficacy in mouse models as well.

One of the CD138-targeting selenomab-drug conjugates, known as CN29, was tested in a mouse model of MM.

One group of mice received CN29 at 3 mg/kg every 4 days for a total of 4 cycles, another group received unconjugated selenomab, and a third received vehicle control.

CN29 significantly inhibited tumor growth (P=0.000085) and extended survival time (P=0.0083) in the mice.

Based on these results, Dr Rader said selenomab-drug conjugates “promise broad utility for cancer therapy.”

The Scripps Research Institute

A class of antibody-drug conjugates (ADCs) have shown promise for treating hematologic and solid tumor malignancies, according to research published in Cell Chemical Biology.

The ADCs, known as selenomab-drug conjugates, demonstrated in vitro activity against breast cancer and multiple myeloma (MM).

The ADCs also inhibited tumor growth and prolonged survival in mouse models of both malignancies.

“We’ve been working on this technology for some time,” said study author Christoph Rader, PhD, of The Scripps Research Institute (TSRI) in Jupiter, Florida.

“It’s based on the rarely used natural amino acid selenocysteine, which we insert into our antibodies. We refer to these engineered antibodies as selenomabs.”

He then explained that selenomab-drug conjugates are ADCs that “utilize the unique reactivity of selenocysteine for drug attachment.”

For this study, Dr Rader and his colleagues generated selective selenomab-drug conjugates and tested them in vitro and in vivo.

The team found that CD138-targeting selenomab-drug conjugates were effective against MM cell lines (U266 and H929), and HER2-targeting selenomab-drug conjugates were effective against breast cancer cell lines.

Both types of ADCs demonstrated efficacy in mouse models as well.

One of the CD138-targeting selenomab-drug conjugates, known as CN29, was tested in a mouse model of MM.

One group of mice received CN29 at 3 mg/kg every 4 days for a total of 4 cycles, another group received unconjugated selenomab, and a third received vehicle control.

CN29 significantly inhibited tumor growth (P=0.000085) and extended survival time (P=0.0083) in the mice.

Based on these results, Dr Rader said selenomab-drug conjugates “promise broad utility for cancer therapy.”

The Scripps Research Institute

A class of antibody-drug conjugates (ADCs) have shown promise for treating hematologic and solid tumor malignancies, according to research published in Cell Chemical Biology.

The ADCs, known as selenomab-drug conjugates, demonstrated in vitro activity against breast cancer and multiple myeloma (MM).

The ADCs also inhibited tumor growth and prolonged survival in mouse models of both malignancies.

“We’ve been working on this technology for some time,” said study author Christoph Rader, PhD, of The Scripps Research Institute (TSRI) in Jupiter, Florida.

“It’s based on the rarely used natural amino acid selenocysteine, which we insert into our antibodies. We refer to these engineered antibodies as selenomabs.”

He then explained that selenomab-drug conjugates are ADCs that “utilize the unique reactivity of selenocysteine for drug attachment.”

For this study, Dr Rader and his colleagues generated selective selenomab-drug conjugates and tested them in vitro and in vivo.

The team found that CD138-targeting selenomab-drug conjugates were effective against MM cell lines (U266 and H929), and HER2-targeting selenomab-drug conjugates were effective against breast cancer cell lines.

Both types of ADCs demonstrated efficacy in mouse models as well.

One of the CD138-targeting selenomab-drug conjugates, known as CN29, was tested in a mouse model of MM.

One group of mice received CN29 at 3 mg/kg every 4 days for a total of 4 cycles, another group received unconjugated selenomab, and a third received vehicle control.

CN29 significantly inhibited tumor growth (P=0.000085) and extended survival time (P=0.0083) in the mice.

Based on these results, Dr Rader said selenomab-drug conjugates “promise broad utility for cancer therapy.”

Photo by Rhoda Baer

A study published in The Lancet suggests agencies that distribute public funds for research could do more to reduce waste.

Investigators evaluated 11 agencies from various countries and found the agencies aren’t always transparent about what they are doing to prevent waste in research.

The investigators also found evidence to suggest that some agencies are not taking certain steps that could reduce waste, and the governments responsible for the public money these agencies distribute are not holding them to account.

“Our investigation has shown that, on the whole, information about the policies and processes used by national funding agencies across the funding landscape are not transparent or readily available,” said Mona Nasser, DDS, of Plymouth University in the UK.

“It would appear that governments around the world often do not hold these agencies accountable for adding value to research and reducing research waste. This is not a call for governments to reduce spending on medical research, but, rather, as public funds become increasingly squeezed, there is no better time for funding agencies and governments to work together to ensure that we will all get the best ‘bang for the buck.’”

For this study, Dr Nasser and her colleagues investigated how research funders monitor and take steps to reduce waste in the research they support. The team also examined how funders support methodology research and the development of research infrastructures to reduce waste.

The investigators looked through the websites of 11 national research funders that distribute public funds in the US, UK, Australia, Canada, Germany, France, The Netherlands, Denmark, and Norway.

The team looked for information on how the agencies decide what to fund and how they ensure what they fund is not wasteful. The investigators also contacted these agencies to verify their findings.

The team found that approaches vary among the funders, but there are weaknesses that are applicable across all funding bodies.

One weakness is that grant committees tend to be dominated by academics and clinicians, which is a problem because patients’ interests may be overlooked.

The funders with the “most extensive” involvement of the general public are the National Institute of Health Research (NIHR) in the UK and ZonMW in The Netherlands.

Another weakness is the fact that practice and policy decisions are often made without the systematic assessment of existing research evidence.

The only funder to require reference to relevant systematic reviews in all funding applications is NIHR.

Yet another weakness is that only 6 of the 11 funding agencies require the publication of full reports of the research they have funded. And none of the funders have a comprehensive strategy to make data from all research projects freely available.

Based on these results, Dr Nasser and her colleagues concluded that more should be done to ensure transparency and accountability.

“In simple terms, there is a 2-pronged requirement for medical research funding bodies which distribute public funds,” Dr Nasser said. “The first is that they need to be fully responsible for how and why those funds are distributed because they are ultimately answerable to every tax payer in their home countries.”

“The second is that they need to ensure that public funds are not only invested wisely in research projects which represent both good value and waste-limited practice, but also to ensure that the results of these studies are made available in a usable format to the people who need them.”

Photo by Rhoda Baer

A study published in The Lancet suggests agencies that distribute public funds for research could do more to reduce waste.

Investigators evaluated 11 agencies from various countries and found the agencies aren’t always transparent about what they are doing to prevent waste in research.

The investigators also found evidence to suggest that some agencies are not taking certain steps that could reduce waste, and the governments responsible for the public money these agencies distribute are not holding them to account.

“Our investigation has shown that, on the whole, information about the policies and processes used by national funding agencies across the funding landscape are not transparent or readily available,” said Mona Nasser, DDS, of Plymouth University in the UK.

“It would appear that governments around the world often do not hold these agencies accountable for adding value to research and reducing research waste. This is not a call for governments to reduce spending on medical research, but, rather, as public funds become increasingly squeezed, there is no better time for funding agencies and governments to work together to ensure that we will all get the best ‘bang for the buck.’”

For this study, Dr Nasser and her colleagues investigated how research funders monitor and take steps to reduce waste in the research they support. The team also examined how funders support methodology research and the development of research infrastructures to reduce waste.

The investigators looked through the websites of 11 national research funders that distribute public funds in the US, UK, Australia, Canada, Germany, France, The Netherlands, Denmark, and Norway.

The team looked for information on how the agencies decide what to fund and how they ensure what they fund is not wasteful. The investigators also contacted these agencies to verify their findings.

The team found that approaches vary among the funders, but there are weaknesses that are applicable across all funding bodies.

One weakness is that grant committees tend to be dominated by academics and clinicians, which is a problem because patients’ interests may be overlooked.

The funders with the “most extensive” involvement of the general public are the National Institute of Health Research (NIHR) in the UK and ZonMW in The Netherlands.

Another weakness is the fact that practice and policy decisions are often made without the systematic assessment of existing research evidence.

The only funder to require reference to relevant systematic reviews in all funding applications is NIHR.

Yet another weakness is that only 6 of the 11 funding agencies require the publication of full reports of the research they have funded. And none of the funders have a comprehensive strategy to make data from all research projects freely available.

Based on these results, Dr Nasser and her colleagues concluded that more should be done to ensure transparency and accountability.

“In simple terms, there is a 2-pronged requirement for medical research funding bodies which distribute public funds,” Dr Nasser said. “The first is that they need to be fully responsible for how and why those funds are distributed because they are ultimately answerable to every tax payer in their home countries.”

“The second is that they need to ensure that public funds are not only invested wisely in research projects which represent both good value and waste-limited practice, but also to ensure that the results of these studies are made available in a usable format to the people who need them.”

Photo by Rhoda Baer

A study published in The Lancet suggests agencies that distribute public funds for research could do more to reduce waste.

Investigators evaluated 11 agencies from various countries and found the agencies aren’t always transparent about what they are doing to prevent waste in research.

The investigators also found evidence to suggest that some agencies are not taking certain steps that could reduce waste, and the governments responsible for the public money these agencies distribute are not holding them to account.

“Our investigation has shown that, on the whole, information about the policies and processes used by national funding agencies across the funding landscape are not transparent or readily available,” said Mona Nasser, DDS, of Plymouth University in the UK.

“It would appear that governments around the world often do not hold these agencies accountable for adding value to research and reducing research waste. This is not a call for governments to reduce spending on medical research, but, rather, as public funds become increasingly squeezed, there is no better time for funding agencies and governments to work together to ensure that we will all get the best ‘bang for the buck.’”

For this study, Dr Nasser and her colleagues investigated how research funders monitor and take steps to reduce waste in the research they support. The team also examined how funders support methodology research and the development of research infrastructures to reduce waste.

The investigators looked through the websites of 11 national research funders that distribute public funds in the US, UK, Australia, Canada, Germany, France, The Netherlands, Denmark, and Norway.

The team looked for information on how the agencies decide what to fund and how they ensure what they fund is not wasteful. The investigators also contacted these agencies to verify their findings.

The team found that approaches vary among the funders, but there are weaknesses that are applicable across all funding bodies.

One weakness is that grant committees tend to be dominated by academics and clinicians, which is a problem because patients’ interests may be overlooked.

The funders with the “most extensive” involvement of the general public are the National Institute of Health Research (NIHR) in the UK and ZonMW in The Netherlands.

Another weakness is the fact that practice and policy decisions are often made without the systematic assessment of existing research evidence.

The only funder to require reference to relevant systematic reviews in all funding applications is NIHR.

Yet another weakness is that only 6 of the 11 funding agencies require the publication of full reports of the research they have funded. And none of the funders have a comprehensive strategy to make data from all research projects freely available.

Based on these results, Dr Nasser and her colleagues concluded that more should be done to ensure transparency and accountability.

“In simple terms, there is a 2-pronged requirement for medical research funding bodies which distribute public funds,” Dr Nasser said. “The first is that they need to be fully responsible for how and why those funds are distributed because they are ultimately answerable to every tax payer in their home countries.”

“The second is that they need to ensure that public funds are not only invested wisely in research projects which represent both good value and waste-limited practice, but also to ensure that the results of these studies are made available in a usable format to the people who need them.”

Case

A 19-year-old female with a history of sickle cell anemia and hemoglobin SS, presents with a 2-day history of worsening lower back pain and dyspnea. Physical exam reveals oxygen saturation of 87% on room air, a temperature of 39.2° C, respiratory rate of 24 breaths per minute, and right-sided rales. Her hemoglobin is 5.3 g/dL (baseline hemoglobin of 7.8 g/dL). Chest radiograph reveals a right upper lobe pneumonia, and she is diagnosed with acute chest syndrome.

What are indications and complications of acute transfusion in sickle cell anemia?
 

Background

Chronic hemolytic anemia is a trademark of sickle cell anemia (SCA) or hemoglobin (Hb) SS as is acute anemia during illness or vaso-occlusive crises. Blood transfusions were the first therapy used in sickle cell disease, long before the pathophysiology was understood. Transfusion of red blood cells (RBC) increases the percentage of circulating normal Hb A, thereby decreasing the percentage of abnormal, sickled cells. This increases the oxygen-carrying capacity of the patient’s RBCs, improves organ perfusion, prevents organ damage, and can be life saving. SCA patients are the largest users of the United States rare donor blood bank registry.¹

Unfortunately, transfusion comes with many risks including infection, transfusion reactions, alloimmunization, iron overload, hyperviscosity, and volume overload.

As SCA is a low-prevalence disease in a minority population, very few studies have been performed. Currently, the guidance available regarding blood transfusion is primarily based on expert opinion.
 

What to transfuse

Spencer Grant/Science Source

Leukoreduced and intensive phenotypically matched RBC are not possible in many medical centers. Previous studies have noted decreased incidence of febrile nonhemolytic anemia transfusion reactions, cytomegalovirus transmission, and human leukocyte antigen alloimmunization in leukoreduced blood transfusions, however, these studies did not include SCA patients.²

Complications from transfusion

Complications from blood transfusions include febrile nonhemolytic transfusion reaction, acute hemolytic transfusion reaction (ABO incompatibility), transfusion-associated lung injury (TRALI), transfusion-associated circulatory overload (TACO), infections, and anaphylaxis. The National Heart, Lung, and Blood Institute guidelines specifically highlight the complications of delayed hemolytic transfusion reaction, iron overload, and hyperviscosity in SCA.Approximately 30% of SCA patients have alloantibodies.² SCA patients may also develop autoimmunization, an immune response to their own RBC, particularly if the patient has multiple autoantibodies.

Infection is a risk for all individuals receiving transfusion. Screening for hepatitis B, hepatitis C, HIV, human T-cell lymphotropic virus, syphilis, West Nile virus, Trympanosoma, and bacteria are routinely performed but not 100% conclusive. Other diseases not routinely screened for include Creutzfeldt-Jakob disease, Babesia, human herpesvirus-8, dengue fever, malaria, and newer concerns such as Zika virus. ^2,3

Febrile nonhemolytic transfusion reactions present as an increase in body temperature of more than 1° C during or shortly after receiving a blood transfusion in the absence of other pyrexic stimulus. Febrile nonhemolytic transfusion reaction occurs more frequently in patients with a previous history of transfusions. The use of leukoreduced RBCs reduces the occurrence to less than 1%.²

TRALI presents with the acute onset of hypoxemia and noncardiogenic pulmonary edema within 6 hours of a blood transfusion in the absence of other etiologies. The mechanism of TRALI is caused by an inflammatory response causing injury to the alveolar capillary membrane and the development of pulmonary edema.¹

TACO presents with cardiogenic pulmonary edema not from another etiology. This is usually seen after transfusion of excessive volumes of blood or after excessively rapid rates of transfusion.¹

Delayed hemolytic transfusion reaction (DHTR) may be a life-threatening immune response to donor cell antigens. The reaction is identified by a drop in the patient’s hemoglobin below the pretransfusion level, reticulocytopenia, a positive direct Coombs test, and occasionally jaundice on physical exam.² Patients may have an unexpectedly high hemoglobin S% after transfusion from the hemolysis of donor cells. The pathognomonic feature is development of a new alloantibody. DHTR occurs more often in individuals who have received recurrent transfusions and has been reported in 4%-11% of transfused SCA patients.³ Donor and native cells hemolyze intra- and extravascularly 5-20 days after receiving a transfusion.² DHTR is likely underestimated in SCA as it may be confused for a vaso-occlusive crisis.

Iron overload from recurrent transfusions is a slow, chronic process resulting in end organ damage of the heart, liver, and pancreas. It is associated with more frequent hospitalizations and higher mortality in SCA.³ The average person has 4-5 g of iron with no process to remove the excess. One unit of packed red blood cells adds 250-300 mg of iron.² Ferritin somewhat correlates to iron overload but is not a reliable method because it is an acute-phase reactant. Liver biopsy is the current diagnostic gold standard, however, noninvasive MRI is gaining diagnostic credibility.

Hb SS blood has up to 10 times higher viscosity than does non–sickle cell blood at the same hemoglobin level. RBC transfusion increases the already hyperviscous state of SCA resulting in slow blood flow through vessels. The slow flow through small vessels from hyperviscosity may result in additional sickling and trigger or worsen a vaso-occlusive crisis. Avascular necrosis is theorized to be a result of hyperviscosity as it occurs more commonly in sickle cell patients with higher hemoglobin. It is important not to transfuse to baseline or above a hemoglobin of 10 g/dL to avoid worsening hyperviscosity.²

When to consider transfusion

Unfortunately, there are no strong randomized controlled trials to definitively dictate when simple transfusions or exchange transfusions are indicated. Acute simple transfusions should be considered in certain circumstances including acute chest syndrome, acute stroke, aplastic anemia, preoperative transfusion, splenic sequestration plus severe anemia, acute hepatic sequestration, and severe acute intrahepatic cholestasis.²

When not to transfuse

• Do not transfuse for simple vaso-occlusive crisis in the absence of symptoms attributable to acute anemia.^1-3
• Do not transfuse for priapism.²
• Do not transfuse for acute renal failure unless there is MSOF.²

Back to the case

The patient was admitted for vaso-occlusive crisis and was started on patient-controlled analgesia with hydromorphone and IV fluids. Azithromycin and ceftriaxone were initiated empirically for community-acquired pneumonia. She was given one unit of phenotypically matched, leukoreduced RBCs for acute chest syndrome. Her hemoglobin increased to 6.1 g/dL. Her fever resolved on day 2, and her dyspnea improved on day 3 of hospitalization. She was weaned off of her patient-controlled analgesia on day 4 and discharged home on day 5 with moxifloxacin to complete 7 days of antibiotics.

Bottom line

Acute simple transfusions and exchange transfusions are indicated for multiple serious and life-threatening complications in SCA. However, transfusion has many serious and life-threatening potential adverse effects. It is essential to conduct a thorough risk-benefit analysis for each individual SCA patient. Whenever possible, intensive phenotypically matched and leukoreduced RBCs should be used. TH
 

References

1. American Red Cross. A Compendium of Transfusion Practice Guidelines. Second Edition, April 2013.

2. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute. Evidence-Based Management of Sickle Cell Disease, Expert Panel Report, 2014.

3. Smith-Whitely, K and Thompson, AA. Indications and complications of transfusions in sickle cell disease. Pediatr Blood Cancer. 2012;59(2):358-64.

• SCA patients are at risk for serious transfusion complications including iron overload, delayed hemolytic transfusion reaction, and hyperviscosity in addition to the usual transfusion risks.
• Do not transfuse an uncomplicated vaso-occlusive crisis without symptomatic anemia.^1-3
• Repeated transfusions create alloimmunization in SCA patients increasing risk for life-threatening transfusion reactions and difficulty locating phenotypically matched RBCs.
• Transfusion should be considered in SCA patients experiencing acute chest syndrome, aplastic anemia, splenic sequestration with acute anemia, acute hepatic sequestration, and severe intrahepatic cholestasis.^1,2
• If available, exchange transfusion should be considered for SCA patients experiencing multisystem organ failure, acute stroke, and severe acute chest syndrome.^1,2

• American Red Cross. A Compendium of Transfusion Practice Guidelines. Second Edition, April 2013.

Case

A 19-year-old female with a history of sickle cell anemia and hemoglobin SS, presents with a 2-day history of worsening lower back pain and dyspnea. Physical exam reveals oxygen saturation of 87% on room air, a temperature of 39.2° C, respiratory rate of 24 breaths per minute, and right-sided rales. Her hemoglobin is 5.3 g/dL (baseline hemoglobin of 7.8 g/dL). Chest radiograph reveals a right upper lobe pneumonia, and she is diagnosed with acute chest syndrome.

What are indications and complications of acute transfusion in sickle cell anemia?
 

Background

Chronic hemolytic anemia is a trademark of sickle cell anemia (SCA) or hemoglobin (Hb) SS as is acute anemia during illness or vaso-occlusive crises. Blood transfusions were the first therapy used in sickle cell disease, long before the pathophysiology was understood. Transfusion of red blood cells (RBC) increases the percentage of circulating normal Hb A, thereby decreasing the percentage of abnormal, sickled cells. This increases the oxygen-carrying capacity of the patient’s RBCs, improves organ perfusion, prevents organ damage, and can be life saving. SCA patients are the largest users of the United States rare donor blood bank registry.¹

Unfortunately, transfusion comes with many risks including infection, transfusion reactions, alloimmunization, iron overload, hyperviscosity, and volume overload.

As SCA is a low-prevalence disease in a minority population, very few studies have been performed. Currently, the guidance available regarding blood transfusion is primarily based on expert opinion.
 

What to transfuse

Spencer Grant/Science Source

Leukoreduced and intensive phenotypically matched RBC are not possible in many medical centers. Previous studies have noted decreased incidence of febrile nonhemolytic anemia transfusion reactions, cytomegalovirus transmission, and human leukocyte antigen alloimmunization in leukoreduced blood transfusions, however, these studies did not include SCA patients.²

Complications from transfusion

Complications from blood transfusions include febrile nonhemolytic transfusion reaction, acute hemolytic transfusion reaction (ABO incompatibility), transfusion-associated lung injury (TRALI), transfusion-associated circulatory overload (TACO), infections, and anaphylaxis. The National Heart, Lung, and Blood Institute guidelines specifically highlight the complications of delayed hemolytic transfusion reaction, iron overload, and hyperviscosity in SCA.Approximately 30% of SCA patients have alloantibodies.² SCA patients may also develop autoimmunization, an immune response to their own RBC, particularly if the patient has multiple autoantibodies.

Infection is a risk for all individuals receiving transfusion. Screening for hepatitis B, hepatitis C, HIV, human T-cell lymphotropic virus, syphilis, West Nile virus, Trympanosoma, and bacteria are routinely performed but not 100% conclusive. Other diseases not routinely screened for include Creutzfeldt-Jakob disease, Babesia, human herpesvirus-8, dengue fever, malaria, and newer concerns such as Zika virus. ^2,3

Febrile nonhemolytic transfusion reactions present as an increase in body temperature of more than 1° C during or shortly after receiving a blood transfusion in the absence of other pyrexic stimulus. Febrile nonhemolytic transfusion reaction occurs more frequently in patients with a previous history of transfusions. The use of leukoreduced RBCs reduces the occurrence to less than 1%.²

TRALI presents with the acute onset of hypoxemia and noncardiogenic pulmonary edema within 6 hours of a blood transfusion in the absence of other etiologies. The mechanism of TRALI is caused by an inflammatory response causing injury to the alveolar capillary membrane and the development of pulmonary edema.¹

TACO presents with cardiogenic pulmonary edema not from another etiology. This is usually seen after transfusion of excessive volumes of blood or after excessively rapid rates of transfusion.¹

Delayed hemolytic transfusion reaction (DHTR) may be a life-threatening immune response to donor cell antigens. The reaction is identified by a drop in the patient’s hemoglobin below the pretransfusion level, reticulocytopenia, a positive direct Coombs test, and occasionally jaundice on physical exam.² Patients may have an unexpectedly high hemoglobin S% after transfusion from the hemolysis of donor cells. The pathognomonic feature is development of a new alloantibody. DHTR occurs more often in individuals who have received recurrent transfusions and has been reported in 4%-11% of transfused SCA patients.³ Donor and native cells hemolyze intra- and extravascularly 5-20 days after receiving a transfusion.² DHTR is likely underestimated in SCA as it may be confused for a vaso-occlusive crisis.

Iron overload from recurrent transfusions is a slow, chronic process resulting in end organ damage of the heart, liver, and pancreas. It is associated with more frequent hospitalizations and higher mortality in SCA.³ The average person has 4-5 g of iron with no process to remove the excess. One unit of packed red blood cells adds 250-300 mg of iron.² Ferritin somewhat correlates to iron overload but is not a reliable method because it is an acute-phase reactant. Liver biopsy is the current diagnostic gold standard, however, noninvasive MRI is gaining diagnostic credibility.

Hb SS blood has up to 10 times higher viscosity than does non–sickle cell blood at the same hemoglobin level. RBC transfusion increases the already hyperviscous state of SCA resulting in slow blood flow through vessels. The slow flow through small vessels from hyperviscosity may result in additional sickling and trigger or worsen a vaso-occlusive crisis. Avascular necrosis is theorized to be a result of hyperviscosity as it occurs more commonly in sickle cell patients with higher hemoglobin. It is important not to transfuse to baseline or above a hemoglobin of 10 g/dL to avoid worsening hyperviscosity.²

When to consider transfusion

Unfortunately, there are no strong randomized controlled trials to definitively dictate when simple transfusions or exchange transfusions are indicated. Acute simple transfusions should be considered in certain circumstances including acute chest syndrome, acute stroke, aplastic anemia, preoperative transfusion, splenic sequestration plus severe anemia, acute hepatic sequestration, and severe acute intrahepatic cholestasis.²

When not to transfuse

• Do not transfuse for simple vaso-occlusive crisis in the absence of symptoms attributable to acute anemia.^1-3
• Do not transfuse for priapism.²
• Do not transfuse for acute renal failure unless there is MSOF.²

Back to the case

The patient was admitted for vaso-occlusive crisis and was started on patient-controlled analgesia with hydromorphone and IV fluids. Azithromycin and ceftriaxone were initiated empirically for community-acquired pneumonia. She was given one unit of phenotypically matched, leukoreduced RBCs for acute chest syndrome. Her hemoglobin increased to 6.1 g/dL. Her fever resolved on day 2, and her dyspnea improved on day 3 of hospitalization. She was weaned off of her patient-controlled analgesia on day 4 and discharged home on day 5 with moxifloxacin to complete 7 days of antibiotics.

Bottom line

Acute simple transfusions and exchange transfusions are indicated for multiple serious and life-threatening complications in SCA. However, transfusion has many serious and life-threatening potential adverse effects. It is essential to conduct a thorough risk-benefit analysis for each individual SCA patient. Whenever possible, intensive phenotypically matched and leukoreduced RBCs should be used. TH
 

References

1. American Red Cross. A Compendium of Transfusion Practice Guidelines. Second Edition, April 2013.

2. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute. Evidence-Based Management of Sickle Cell Disease, Expert Panel Report, 2014.

3. Smith-Whitely, K and Thompson, AA. Indications and complications of transfusions in sickle cell disease. Pediatr Blood Cancer. 2012;59(2):358-64.

• SCA patients are at risk for serious transfusion complications including iron overload, delayed hemolytic transfusion reaction, and hyperviscosity in addition to the usual transfusion risks.
• Do not transfuse an uncomplicated vaso-occlusive crisis without symptomatic anemia.^1-3
• Repeated transfusions create alloimmunization in SCA patients increasing risk for life-threatening transfusion reactions and difficulty locating phenotypically matched RBCs.
• Transfusion should be considered in SCA patients experiencing acute chest syndrome, aplastic anemia, splenic sequestration with acute anemia, acute hepatic sequestration, and severe intrahepatic cholestasis.^1,2
• If available, exchange transfusion should be considered for SCA patients experiencing multisystem organ failure, acute stroke, and severe acute chest syndrome.^1,2

• American Red Cross. A Compendium of Transfusion Practice Guidelines. Second Edition, April 2013.

Case

A 19-year-old female with a history of sickle cell anemia and hemoglobin SS, presents with a 2-day history of worsening lower back pain and dyspnea. Physical exam reveals oxygen saturation of 87% on room air, a temperature of 39.2° C, respiratory rate of 24 breaths per minute, and right-sided rales. Her hemoglobin is 5.3 g/dL (baseline hemoglobin of 7.8 g/dL). Chest radiograph reveals a right upper lobe pneumonia, and she is diagnosed with acute chest syndrome.

What are indications and complications of acute transfusion in sickle cell anemia?
 

Background

Chronic hemolytic anemia is a trademark of sickle cell anemia (SCA) or hemoglobin (Hb) SS as is acute anemia during illness or vaso-occlusive crises. Blood transfusions were the first therapy used in sickle cell disease, long before the pathophysiology was understood. Transfusion of red blood cells (RBC) increases the percentage of circulating normal Hb A, thereby decreasing the percentage of abnormal, sickled cells. This increases the oxygen-carrying capacity of the patient’s RBCs, improves organ perfusion, prevents organ damage, and can be life saving. SCA patients are the largest users of the United States rare donor blood bank registry.¹

Unfortunately, transfusion comes with many risks including infection, transfusion reactions, alloimmunization, iron overload, hyperviscosity, and volume overload.

As SCA is a low-prevalence disease in a minority population, very few studies have been performed. Currently, the guidance available regarding blood transfusion is primarily based on expert opinion.
 

What to transfuse

Spencer Grant/Science Source

Leukoreduced and intensive phenotypically matched RBC are not possible in many medical centers. Previous studies have noted decreased incidence of febrile nonhemolytic anemia transfusion reactions, cytomegalovirus transmission, and human leukocyte antigen alloimmunization in leukoreduced blood transfusions, however, these studies did not include SCA patients.²

Complications from transfusion

Complications from blood transfusions include febrile nonhemolytic transfusion reaction, acute hemolytic transfusion reaction (ABO incompatibility), transfusion-associated lung injury (TRALI), transfusion-associated circulatory overload (TACO), infections, and anaphylaxis. The National Heart, Lung, and Blood Institute guidelines specifically highlight the complications of delayed hemolytic transfusion reaction, iron overload, and hyperviscosity in SCA.Approximately 30% of SCA patients have alloantibodies.² SCA patients may also develop autoimmunization, an immune response to their own RBC, particularly if the patient has multiple autoantibodies.

Infection is a risk for all individuals receiving transfusion. Screening for hepatitis B, hepatitis C, HIV, human T-cell lymphotropic virus, syphilis, West Nile virus, Trympanosoma, and bacteria are routinely performed but not 100% conclusive. Other diseases not routinely screened for include Creutzfeldt-Jakob disease, Babesia, human herpesvirus-8, dengue fever, malaria, and newer concerns such as Zika virus. ^2,3

Febrile nonhemolytic transfusion reactions present as an increase in body temperature of more than 1° C during or shortly after receiving a blood transfusion in the absence of other pyrexic stimulus. Febrile nonhemolytic transfusion reaction occurs more frequently in patients with a previous history of transfusions. The use of leukoreduced RBCs reduces the occurrence to less than 1%.²

TRALI presents with the acute onset of hypoxemia and noncardiogenic pulmonary edema within 6 hours of a blood transfusion in the absence of other etiologies. The mechanism of TRALI is caused by an inflammatory response causing injury to the alveolar capillary membrane and the development of pulmonary edema.¹

TACO presents with cardiogenic pulmonary edema not from another etiology. This is usually seen after transfusion of excessive volumes of blood or after excessively rapid rates of transfusion.¹

Delayed hemolytic transfusion reaction (DHTR) may be a life-threatening immune response to donor cell antigens. The reaction is identified by a drop in the patient’s hemoglobin below the pretransfusion level, reticulocytopenia, a positive direct Coombs test, and occasionally jaundice on physical exam.² Patients may have an unexpectedly high hemoglobin S% after transfusion from the hemolysis of donor cells. The pathognomonic feature is development of a new alloantibody. DHTR occurs more often in individuals who have received recurrent transfusions and has been reported in 4%-11% of transfused SCA patients.³ Donor and native cells hemolyze intra- and extravascularly 5-20 days after receiving a transfusion.² DHTR is likely underestimated in SCA as it may be confused for a vaso-occlusive crisis.

Iron overload from recurrent transfusions is a slow, chronic process resulting in end organ damage of the heart, liver, and pancreas. It is associated with more frequent hospitalizations and higher mortality in SCA.³ The average person has 4-5 g of iron with no process to remove the excess. One unit of packed red blood cells adds 250-300 mg of iron.² Ferritin somewhat correlates to iron overload but is not a reliable method because it is an acute-phase reactant. Liver biopsy is the current diagnostic gold standard, however, noninvasive MRI is gaining diagnostic credibility.

Hb SS blood has up to 10 times higher viscosity than does non–sickle cell blood at the same hemoglobin level. RBC transfusion increases the already hyperviscous state of SCA resulting in slow blood flow through vessels. The slow flow through small vessels from hyperviscosity may result in additional sickling and trigger or worsen a vaso-occlusive crisis. Avascular necrosis is theorized to be a result of hyperviscosity as it occurs more commonly in sickle cell patients with higher hemoglobin. It is important not to transfuse to baseline or above a hemoglobin of 10 g/dL to avoid worsening hyperviscosity.²

When to consider transfusion

Unfortunately, there are no strong randomized controlled trials to definitively dictate when simple transfusions or exchange transfusions are indicated. Acute simple transfusions should be considered in certain circumstances including acute chest syndrome, acute stroke, aplastic anemia, preoperative transfusion, splenic sequestration plus severe anemia, acute hepatic sequestration, and severe acute intrahepatic cholestasis.²

When not to transfuse

• Do not transfuse for simple vaso-occlusive crisis in the absence of symptoms attributable to acute anemia.^1-3
• Do not transfuse for priapism.²
• Do not transfuse for acute renal failure unless there is MSOF.²

Back to the case

The patient was admitted for vaso-occlusive crisis and was started on patient-controlled analgesia with hydromorphone and IV fluids. Azithromycin and ceftriaxone were initiated empirically for community-acquired pneumonia. She was given one unit of phenotypically matched, leukoreduced RBCs for acute chest syndrome. Her hemoglobin increased to 6.1 g/dL. Her fever resolved on day 2, and her dyspnea improved on day 3 of hospitalization. She was weaned off of her patient-controlled analgesia on day 4 and discharged home on day 5 with moxifloxacin to complete 7 days of antibiotics.

Bottom line

Acute simple transfusions and exchange transfusions are indicated for multiple serious and life-threatening complications in SCA. However, transfusion has many serious and life-threatening potential adverse effects. It is essential to conduct a thorough risk-benefit analysis for each individual SCA patient. Whenever possible, intensive phenotypically matched and leukoreduced RBCs should be used. TH
 

References

1. American Red Cross. A Compendium of Transfusion Practice Guidelines. Second Edition, April 2013.

2. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute. Evidence-Based Management of Sickle Cell Disease, Expert Panel Report, 2014.

3. Smith-Whitely, K and Thompson, AA. Indications and complications of transfusions in sickle cell disease. Pediatr Blood Cancer. 2012;59(2):358-64.

• SCA patients are at risk for serious transfusion complications including iron overload, delayed hemolytic transfusion reaction, and hyperviscosity in addition to the usual transfusion risks.
• Do not transfuse an uncomplicated vaso-occlusive crisis without symptomatic anemia.^1-3
• Repeated transfusions create alloimmunization in SCA patients increasing risk for life-threatening transfusion reactions and difficulty locating phenotypically matched RBCs.
• Transfusion should be considered in SCA patients experiencing acute chest syndrome, aplastic anemia, splenic sequestration with acute anemia, acute hepatic sequestration, and severe intrahepatic cholestasis.^1,2
• If available, exchange transfusion should be considered for SCA patients experiencing multisystem organ failure, acute stroke, and severe acute chest syndrome.^1,2

• American Red Cross. A Compendium of Transfusion Practice Guidelines. Second Edition, April 2013.