User login
GOP health reform dead for now
Senate Republicans are scrambling to come up with another plan now that at least four member of their caucus have said that they would vote against moving forward with debate on the Better Care Reconciliation Act.
Support for the bill, which included dramatic Medicaid cuts and stripped many coverage provisions of the Affordable Care Act, was lacking after revisions were announced on July 13. At that time, conservative Sen. Ran Paul (R-Ky.) and moderate Susan Collins (R-Maine) voiced their opposition for different ideological reasons. They were joined by Sen. Mike Lee (R-Utah) and Sen. Jerry Moran (R-Kan.), who also declined to support the bill. Senate GOP leadership, with a slim 52-48 majority, could only afford to lose two votes (Vice President Mike Pence would have been the tie-breaking vote).
No new timeline has been revealed for the next steps.
“The health reform debate is by no means over,” David Barbe, MD, president of the American Medical Association, said in a statement. “Congress must begin a collaborative process that produces a bipartisan solution. ... Near-term action is needed to stabilize the individual/nongroup health insurance marketplace. In the long term, stakeholders and policymakers need to address the unsustainable trends in health care costs while achieving meaningful, affordable coverage for all Americans.”
AGA believes that, at a minimum, any replacement package must ensure patient access to and coverage of specialty care, ensure patient access to and coverage of evidence-based preventive screenings without cost-sharing, ensure that insurers cannot discriminate because of a pre-existing condition, ensure that insurers cannot discriminate based on gender, allow parents to keep their children on their plans until age 26, and there should be no annual or lifetime caps.
Senate Republicans are scrambling to come up with another plan now that at least four member of their caucus have said that they would vote against moving forward with debate on the Better Care Reconciliation Act.
Support for the bill, which included dramatic Medicaid cuts and stripped many coverage provisions of the Affordable Care Act, was lacking after revisions were announced on July 13. At that time, conservative Sen. Ran Paul (R-Ky.) and moderate Susan Collins (R-Maine) voiced their opposition for different ideological reasons. They were joined by Sen. Mike Lee (R-Utah) and Sen. Jerry Moran (R-Kan.), who also declined to support the bill. Senate GOP leadership, with a slim 52-48 majority, could only afford to lose two votes (Vice President Mike Pence would have been the tie-breaking vote).
No new timeline has been revealed for the next steps.
“The health reform debate is by no means over,” David Barbe, MD, president of the American Medical Association, said in a statement. “Congress must begin a collaborative process that produces a bipartisan solution. ... Near-term action is needed to stabilize the individual/nongroup health insurance marketplace. In the long term, stakeholders and policymakers need to address the unsustainable trends in health care costs while achieving meaningful, affordable coverage for all Americans.”
AGA believes that, at a minimum, any replacement package must ensure patient access to and coverage of specialty care, ensure patient access to and coverage of evidence-based preventive screenings without cost-sharing, ensure that insurers cannot discriminate because of a pre-existing condition, ensure that insurers cannot discriminate based on gender, allow parents to keep their children on their plans until age 26, and there should be no annual or lifetime caps.
Senate Republicans are scrambling to come up with another plan now that at least four member of their caucus have said that they would vote against moving forward with debate on the Better Care Reconciliation Act.
Support for the bill, which included dramatic Medicaid cuts and stripped many coverage provisions of the Affordable Care Act, was lacking after revisions were announced on July 13. At that time, conservative Sen. Ran Paul (R-Ky.) and moderate Susan Collins (R-Maine) voiced their opposition for different ideological reasons. They were joined by Sen. Mike Lee (R-Utah) and Sen. Jerry Moran (R-Kan.), who also declined to support the bill. Senate GOP leadership, with a slim 52-48 majority, could only afford to lose two votes (Vice President Mike Pence would have been the tie-breaking vote).
No new timeline has been revealed for the next steps.
“The health reform debate is by no means over,” David Barbe, MD, president of the American Medical Association, said in a statement. “Congress must begin a collaborative process that produces a bipartisan solution. ... Near-term action is needed to stabilize the individual/nongroup health insurance marketplace. In the long term, stakeholders and policymakers need to address the unsustainable trends in health care costs while achieving meaningful, affordable coverage for all Americans.”
AGA believes that, at a minimum, any replacement package must ensure patient access to and coverage of specialty care, ensure patient access to and coverage of evidence-based preventive screenings without cost-sharing, ensure that insurers cannot discriminate because of a pre-existing condition, ensure that insurers cannot discriminate based on gender, allow parents to keep their children on their plans until age 26, and there should be no annual or lifetime caps.
Prenatal SSRI exposure’s effect on development
Unfortunately, the bottom line for most of these important questions is that we really don’t know as much as we probably should.
Just when we’ve read a convincing finding from a reputable journal that establishes a link between prenatal SSRI use and an untoward outcome, we see it disputed the next month. Why is this always happening, and why can’t we really know anything with certainty? Much of the confusion can be attributed to research methods and the obvious difficulty of using randomized, controlled trials to control for potential confounding factors. While statistical techniques have become increasingly sophisticated in addressing these confounding factors, they remain imperfect. For example, one of the most difficult challenges that remains is separating any effects of a medication from any effects caused by the condition it was designed to treat. Comparing women with the same underlying condition, some of whom are treated with a medication and some of whom are not, is a step forward, but there may be important reasons that one group decides to seek treatment and the other doesn’t. One clever research design that was employed to look at congenital anomalies in the offspring of women taking SSRIs accounted for siblings of these children who were born when their mother was not taking an SSRI. This study demonstrated that these women were more likely to have children with congenital malformations even when they weren’t taking the SSRIs.1 Other factors that render this literature difficult to interpret include small sample sizes when looking at specific SSRIs (many studies cluster them all), dose effects, timing (which trimester), duration of treatment, and method of recording compliance.
The potential link between SSRIs and autism has received a fair amount of attention lately, especially after a very well-designed study in 2016 suggested a significantly increased risk.10 However, as with many of the findings, this study was quickly disputed by other high-quality, well-powered research that found no increased risk after controlling for maternal illness.11,12
ADHD generally has not been found to be related to maternal SSRI use, although one study did find a link between ADHD and tricyclic antidepressants.12,13
In terms of other neurodevelopmental outcomes, there have been many negative studies examining IQ, nonverbal communication, as well as speech and motor skills.14,15,16 However, as with so many other outcomes, some other studies contradict these negative results. According to a recent, large cohort study, there may be some concern regarding SSRI exposure prenatally and an increase in speech disorders by age 14 years, as well as lower language competence at age 3 years.17,18 Likewise, mild motor abnormalities have been observed, with maternal depression severity as an independent but contributing factor.19
Several studies demonstrate a connection between prenatal SSRI exposure and childhood internalizing symptoms, such as depression and anxiety, independent of maternal depression.12,20 These findings must be balanced with our knowledge of the serious mental health conditions in offspring that are associated with untreated maternal illness, including both internalizing and externalizing disorders.21,22
How does one come to any firm conclusions to guide a primary care clinician’s practice and recommendations? Hopefully, the evidence will become clearer over time as we adopt more sophisticated designs and accumulate observations. A larger number of observations would allow us to decrease heterogeneity by studying subgroups according to type of SSRI and duration of exposure. Enhanced understanding of the role of genetic factors also may shed some light on individual variation as the serotonin transporter gene has been suggested as a potential moderator of sensitivity.23
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont Robert Larner College of Medicine, both in Burlington. She works with children and adolescents as well as women in the perinatal period. She has no relevant financial disclosures.
References
1. BMJ. 2015 Apr 17;350:h1798.
2. Can J Clin Pharmacol. 2009 Winter;16(1):e66-7.
3. J Matern Fetal Neonatal Med. 2008 Oct;21(10):745-51.
4. PLoS ONE. 2014 Nov; 9(11): e111327.
5. Pediatr Res. 2017 Jun 30. doi: 10.1038/pr.2017.156. [Epub ahead of print].
6. J Clin Psychiatry. 2017 May;78(5):605-11.
7. Acta Psychiatr Scand. 2010 Jun;121(6):471-9.
8. Am J Psychiatry. 2016 Feb 1;173(2):147-57.
9. J Perinatol. 2011 Sep;31(9):615-20.
10. JAMA Pediatr. 2016 Feb;170(2):117-24.
11. JAMA. 2017 Apr 18;317(15):1544-52.
12. J Am Acad Child Adolesc Psychiatry. 2016 May;55(5):359-66.
13. Paediatr Perinat Epidemiol. 2017 Jul;31(4):363-73.
14. Acta Obstet Gynecol Scand. 2015 May;94(5):501-7.
15. J Psychopharmacol. 2017 Mar;31(3):346-55.
16. CNS Drugs. 2005;19(7):623-33.
17. JAMA Psychiatry. 2016 Nov 1;73(11):1163-70.
18. BJOG. 2014. doi: 10.1111/1471-0528.12821.
19. BJOG. 2016 Nov;123(12):1908-17.
20. Pediatr Res. 2015 Aug;78(2):174-80.
21. Neuroscience. 2017 Feb 7;342:154-66.
22. Depress Anxiety. 2014 Jan;31(1):9-18.
23. Neuroscience. 2017 Feb 7;342:212-31.
Unfortunately, the bottom line for most of these important questions is that we really don’t know as much as we probably should.
Just when we’ve read a convincing finding from a reputable journal that establishes a link between prenatal SSRI use and an untoward outcome, we see it disputed the next month. Why is this always happening, and why can’t we really know anything with certainty? Much of the confusion can be attributed to research methods and the obvious difficulty of using randomized, controlled trials to control for potential confounding factors. While statistical techniques have become increasingly sophisticated in addressing these confounding factors, they remain imperfect. For example, one of the most difficult challenges that remains is separating any effects of a medication from any effects caused by the condition it was designed to treat. Comparing women with the same underlying condition, some of whom are treated with a medication and some of whom are not, is a step forward, but there may be important reasons that one group decides to seek treatment and the other doesn’t. One clever research design that was employed to look at congenital anomalies in the offspring of women taking SSRIs accounted for siblings of these children who were born when their mother was not taking an SSRI. This study demonstrated that these women were more likely to have children with congenital malformations even when they weren’t taking the SSRIs.1 Other factors that render this literature difficult to interpret include small sample sizes when looking at specific SSRIs (many studies cluster them all), dose effects, timing (which trimester), duration of treatment, and method of recording compliance.
The potential link between SSRIs and autism has received a fair amount of attention lately, especially after a very well-designed study in 2016 suggested a significantly increased risk.10 However, as with many of the findings, this study was quickly disputed by other high-quality, well-powered research that found no increased risk after controlling for maternal illness.11,12
ADHD generally has not been found to be related to maternal SSRI use, although one study did find a link between ADHD and tricyclic antidepressants.12,13
In terms of other neurodevelopmental outcomes, there have been many negative studies examining IQ, nonverbal communication, as well as speech and motor skills.14,15,16 However, as with so many other outcomes, some other studies contradict these negative results. According to a recent, large cohort study, there may be some concern regarding SSRI exposure prenatally and an increase in speech disorders by age 14 years, as well as lower language competence at age 3 years.17,18 Likewise, mild motor abnormalities have been observed, with maternal depression severity as an independent but contributing factor.19
Several studies demonstrate a connection between prenatal SSRI exposure and childhood internalizing symptoms, such as depression and anxiety, independent of maternal depression.12,20 These findings must be balanced with our knowledge of the serious mental health conditions in offspring that are associated with untreated maternal illness, including both internalizing and externalizing disorders.21,22
How does one come to any firm conclusions to guide a primary care clinician’s practice and recommendations? Hopefully, the evidence will become clearer over time as we adopt more sophisticated designs and accumulate observations. A larger number of observations would allow us to decrease heterogeneity by studying subgroups according to type of SSRI and duration of exposure. Enhanced understanding of the role of genetic factors also may shed some light on individual variation as the serotonin transporter gene has been suggested as a potential moderator of sensitivity.23
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont Robert Larner College of Medicine, both in Burlington. She works with children and adolescents as well as women in the perinatal period. She has no relevant financial disclosures.
References
1. BMJ. 2015 Apr 17;350:h1798.
2. Can J Clin Pharmacol. 2009 Winter;16(1):e66-7.
3. J Matern Fetal Neonatal Med. 2008 Oct;21(10):745-51.
4. PLoS ONE. 2014 Nov; 9(11): e111327.
5. Pediatr Res. 2017 Jun 30. doi: 10.1038/pr.2017.156. [Epub ahead of print].
6. J Clin Psychiatry. 2017 May;78(5):605-11.
7. Acta Psychiatr Scand. 2010 Jun;121(6):471-9.
8. Am J Psychiatry. 2016 Feb 1;173(2):147-57.
9. J Perinatol. 2011 Sep;31(9):615-20.
10. JAMA Pediatr. 2016 Feb;170(2):117-24.
11. JAMA. 2017 Apr 18;317(15):1544-52.
12. J Am Acad Child Adolesc Psychiatry. 2016 May;55(5):359-66.
13. Paediatr Perinat Epidemiol. 2017 Jul;31(4):363-73.
14. Acta Obstet Gynecol Scand. 2015 May;94(5):501-7.
15. J Psychopharmacol. 2017 Mar;31(3):346-55.
16. CNS Drugs. 2005;19(7):623-33.
17. JAMA Psychiatry. 2016 Nov 1;73(11):1163-70.
18. BJOG. 2014. doi: 10.1111/1471-0528.12821.
19. BJOG. 2016 Nov;123(12):1908-17.
20. Pediatr Res. 2015 Aug;78(2):174-80.
21. Neuroscience. 2017 Feb 7;342:154-66.
22. Depress Anxiety. 2014 Jan;31(1):9-18.
23. Neuroscience. 2017 Feb 7;342:212-31.
Unfortunately, the bottom line for most of these important questions is that we really don’t know as much as we probably should.
Just when we’ve read a convincing finding from a reputable journal that establishes a link between prenatal SSRI use and an untoward outcome, we see it disputed the next month. Why is this always happening, and why can’t we really know anything with certainty? Much of the confusion can be attributed to research methods and the obvious difficulty of using randomized, controlled trials to control for potential confounding factors. While statistical techniques have become increasingly sophisticated in addressing these confounding factors, they remain imperfect. For example, one of the most difficult challenges that remains is separating any effects of a medication from any effects caused by the condition it was designed to treat. Comparing women with the same underlying condition, some of whom are treated with a medication and some of whom are not, is a step forward, but there may be important reasons that one group decides to seek treatment and the other doesn’t. One clever research design that was employed to look at congenital anomalies in the offspring of women taking SSRIs accounted for siblings of these children who were born when their mother was not taking an SSRI. This study demonstrated that these women were more likely to have children with congenital malformations even when they weren’t taking the SSRIs.1 Other factors that render this literature difficult to interpret include small sample sizes when looking at specific SSRIs (many studies cluster them all), dose effects, timing (which trimester), duration of treatment, and method of recording compliance.
The potential link between SSRIs and autism has received a fair amount of attention lately, especially after a very well-designed study in 2016 suggested a significantly increased risk.10 However, as with many of the findings, this study was quickly disputed by other high-quality, well-powered research that found no increased risk after controlling for maternal illness.11,12
ADHD generally has not been found to be related to maternal SSRI use, although one study did find a link between ADHD and tricyclic antidepressants.12,13
In terms of other neurodevelopmental outcomes, there have been many negative studies examining IQ, nonverbal communication, as well as speech and motor skills.14,15,16 However, as with so many other outcomes, some other studies contradict these negative results. According to a recent, large cohort study, there may be some concern regarding SSRI exposure prenatally and an increase in speech disorders by age 14 years, as well as lower language competence at age 3 years.17,18 Likewise, mild motor abnormalities have been observed, with maternal depression severity as an independent but contributing factor.19
Several studies demonstrate a connection between prenatal SSRI exposure and childhood internalizing symptoms, such as depression and anxiety, independent of maternal depression.12,20 These findings must be balanced with our knowledge of the serious mental health conditions in offspring that are associated with untreated maternal illness, including both internalizing and externalizing disorders.21,22
How does one come to any firm conclusions to guide a primary care clinician’s practice and recommendations? Hopefully, the evidence will become clearer over time as we adopt more sophisticated designs and accumulate observations. A larger number of observations would allow us to decrease heterogeneity by studying subgroups according to type of SSRI and duration of exposure. Enhanced understanding of the role of genetic factors also may shed some light on individual variation as the serotonin transporter gene has been suggested as a potential moderator of sensitivity.23
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont Robert Larner College of Medicine, both in Burlington. She works with children and adolescents as well as women in the perinatal period. She has no relevant financial disclosures.
References
1. BMJ. 2015 Apr 17;350:h1798.
2. Can J Clin Pharmacol. 2009 Winter;16(1):e66-7.
3. J Matern Fetal Neonatal Med. 2008 Oct;21(10):745-51.
4. PLoS ONE. 2014 Nov; 9(11): e111327.
5. Pediatr Res. 2017 Jun 30. doi: 10.1038/pr.2017.156. [Epub ahead of print].
6. J Clin Psychiatry. 2017 May;78(5):605-11.
7. Acta Psychiatr Scand. 2010 Jun;121(6):471-9.
8. Am J Psychiatry. 2016 Feb 1;173(2):147-57.
9. J Perinatol. 2011 Sep;31(9):615-20.
10. JAMA Pediatr. 2016 Feb;170(2):117-24.
11. JAMA. 2017 Apr 18;317(15):1544-52.
12. J Am Acad Child Adolesc Psychiatry. 2016 May;55(5):359-66.
13. Paediatr Perinat Epidemiol. 2017 Jul;31(4):363-73.
14. Acta Obstet Gynecol Scand. 2015 May;94(5):501-7.
15. J Psychopharmacol. 2017 Mar;31(3):346-55.
16. CNS Drugs. 2005;19(7):623-33.
17. JAMA Psychiatry. 2016 Nov 1;73(11):1163-70.
18. BJOG. 2014. doi: 10.1111/1471-0528.12821.
19. BJOG. 2016 Nov;123(12):1908-17.
20. Pediatr Res. 2015 Aug;78(2):174-80.
21. Neuroscience. 2017 Feb 7;342:154-66.
22. Depress Anxiety. 2014 Jan;31(1):9-18.
23. Neuroscience. 2017 Feb 7;342:212-31.
Corticosteroid therapy in Kawasaki disease
Clinical Question
What is the efficacy of corticosteroid therapy in Kawasaki disease?
Background
First described in 1967 in Japan, Kawasaki disease (KD), or mucocutaneous lymph node syndrome, is an acute systemic vasculitis of unclear etiology which primarily affects infants and children. Of significant clinical concern, 30%-50% of untreated patients develop acute coronary artery dilatation, and about one fourth progress to serious coronary artery abnormalities (CAA) such as aneurysm and ectasia.1,2 These patients have a higher risk of long-term complications, such as coronary artery thrombus, myocardial infarction, and sudden death.3 KD is typically treated with a combination of intravenous immunoglobulin (IVIG) and aspirin, which reduces the risk of CAA.1 However, more than 20% of cases are resistant to this conventional therapy and have higher risk of CAA than nonresistant patients.4 Corticosteroids have been suggested as therapy in KD, as the anti-inflammatory effect is useful for many other vasculitides, but studies to date have had conflicting results. This study was performed to comprehensively evaluate the effect of corticosteroids in KD as initial or rescue therapy (after failure to respond to IVIG).
Study design
Systematic review and meta-analysis.
Synopsis
The population of interest was children diagnosed with KD. The intervention of interest was treatment with adjunctive corticosteroids either as initial or rescue therapy. Comparisons were made between the corticosteroids group and the conventional therapy (IVIG) group. Outcome measurements included the incidence of CAA (primary outcome), duration until defervescence, and adverse events. IVIG resistance was defined as persistent or recurrent fever lasting (or relapsed within) 24-48 hours after the initial IVIG treatment.
A total of 681 articles were initially retrieved, and after exclusions, 16 comparative studies were enrolled for meta-analysis. In these studies, a total of 2,746 cases were involved, with 861 in the corticosteroid group and 1,885 in the IVIG group. Ten studies used corticosteroids as initial treatment (comparing this plus IVIG versus IVIG therapy alone), and six used steroids as rescue treatment after initial IVIG failure (comparing corticosteroids with additional IVIG therapy). Four studies enrolled patients with KD who were predicted to have high risk of IVIG resistance, based on published scoring systems. All patients in the studies received oral aspirin.
Overall, this meta-analysis found that adding corticosteroid therapy was associated with a relative risk reduction of 58% in CAA (odds ratio, 0.424; 95% confidence interval, 0.270-0.665; P less than .001). Further analysis showed that the longer the duration of illness prior to corticosteroids, the less of a treatment effect was noticed. The studies using steroids as initial adjunctive therapy had duration of illness 4.7 days prior to treatment, and showed an advantage, compared with IVIG alone, while studies using steroids as rescue therapy had a longer duration of illness prior to steroid therapy (7.2 days), and did not show significant benefit, compared with additional IVIG. In analyzing patients predicted to be at high risk of IVIG resistance at baseline, addition of corticosteroids with IVIG as initial therapy showed a significantly lower risk of CAA development (relative risk reduction of 76%) versus IVIG alone (OR, 0.240; 95% CI, 0.123-0.467; P less than .001). As a secondary outcome, the use of adjunctive corticosteroid therapy was associated with a quicker resolution of fever, compared with IVIG alone (0.66 days vs. 2.18 days). There was no significant difference in adverse events between the two groups.
Although this is the most comprehensive study of corticosteroids in KD, there are some limitations. High-risk patients were found to receive the greatest benefit, but the predictive ability of published scoring systems have not been optimized or generalized to all populations. Most of the studies included in this review were conducted in Japan, so it is uncertain if the results are applicable to other regions. Also, the selection of corticosteroids and treatment regimens were not consistent between studies.
Bottom line
This study suggests that corticosteroids combined with IVIG as initial therapy for KD showed a more protective effect against CAA, compared with conventional IVIG therapy, and the efficacy was more pronounced in the high-risk patient group.
Citation
Chen S, Dong Y, Kiuchi MG, et al. Coronary Artery Complication in Kawasaki Disease and the Importance of Early Intervention: A Systematic Review and Meta-analysis. JAMA Pediatr. 2016;170(12):1156-1163.
References
1. Newburger JW, Takahashi M, Gerber MA, et al. Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease. Council on Cardiovascular Disease in the Young; American Heart Association; American Academy of Pediatrics: diagnosis, treatment, and long-term management of Kawasaki disease. Circulation. 2004;110:2747-71.
2. Daniels LB, Tjajadi MS, Walford HH, et al. Prevalence of Kawasaki disease in young adults with suspected myocardial ischemia. Circulation. 2012;125(20):2447-53.
3. Gordon JB, Kahn AM, Burns JC. When children with Kawasaki disease grow up: myocardial and vascular complications in adulthood. J Am Coll Cardiol. 2009;54(21):1911-20.
4. Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr. 2008;153(1):117-21.
Dr. Galloway is a pediatric hospitalist at Sanford Children’s Hospital in Sioux Falls, S.D., assistant professor of pediatrics at the University of South Dakota Sanford School of Medicine, and vice chief of the division of hospital pediatrics at USD SSOM and Sanford Children’s Hospital.
Clinical Question
What is the efficacy of corticosteroid therapy in Kawasaki disease?
Background
First described in 1967 in Japan, Kawasaki disease (KD), or mucocutaneous lymph node syndrome, is an acute systemic vasculitis of unclear etiology which primarily affects infants and children. Of significant clinical concern, 30%-50% of untreated patients develop acute coronary artery dilatation, and about one fourth progress to serious coronary artery abnormalities (CAA) such as aneurysm and ectasia.1,2 These patients have a higher risk of long-term complications, such as coronary artery thrombus, myocardial infarction, and sudden death.3 KD is typically treated with a combination of intravenous immunoglobulin (IVIG) and aspirin, which reduces the risk of CAA.1 However, more than 20% of cases are resistant to this conventional therapy and have higher risk of CAA than nonresistant patients.4 Corticosteroids have been suggested as therapy in KD, as the anti-inflammatory effect is useful for many other vasculitides, but studies to date have had conflicting results. This study was performed to comprehensively evaluate the effect of corticosteroids in KD as initial or rescue therapy (after failure to respond to IVIG).
Study design
Systematic review and meta-analysis.
Synopsis
The population of interest was children diagnosed with KD. The intervention of interest was treatment with adjunctive corticosteroids either as initial or rescue therapy. Comparisons were made between the corticosteroids group and the conventional therapy (IVIG) group. Outcome measurements included the incidence of CAA (primary outcome), duration until defervescence, and adverse events. IVIG resistance was defined as persistent or recurrent fever lasting (or relapsed within) 24-48 hours after the initial IVIG treatment.
A total of 681 articles were initially retrieved, and after exclusions, 16 comparative studies were enrolled for meta-analysis. In these studies, a total of 2,746 cases were involved, with 861 in the corticosteroid group and 1,885 in the IVIG group. Ten studies used corticosteroids as initial treatment (comparing this plus IVIG versus IVIG therapy alone), and six used steroids as rescue treatment after initial IVIG failure (comparing corticosteroids with additional IVIG therapy). Four studies enrolled patients with KD who were predicted to have high risk of IVIG resistance, based on published scoring systems. All patients in the studies received oral aspirin.
Overall, this meta-analysis found that adding corticosteroid therapy was associated with a relative risk reduction of 58% in CAA (odds ratio, 0.424; 95% confidence interval, 0.270-0.665; P less than .001). Further analysis showed that the longer the duration of illness prior to corticosteroids, the less of a treatment effect was noticed. The studies using steroids as initial adjunctive therapy had duration of illness 4.7 days prior to treatment, and showed an advantage, compared with IVIG alone, while studies using steroids as rescue therapy had a longer duration of illness prior to steroid therapy (7.2 days), and did not show significant benefit, compared with additional IVIG. In analyzing patients predicted to be at high risk of IVIG resistance at baseline, addition of corticosteroids with IVIG as initial therapy showed a significantly lower risk of CAA development (relative risk reduction of 76%) versus IVIG alone (OR, 0.240; 95% CI, 0.123-0.467; P less than .001). As a secondary outcome, the use of adjunctive corticosteroid therapy was associated with a quicker resolution of fever, compared with IVIG alone (0.66 days vs. 2.18 days). There was no significant difference in adverse events between the two groups.
Although this is the most comprehensive study of corticosteroids in KD, there are some limitations. High-risk patients were found to receive the greatest benefit, but the predictive ability of published scoring systems have not been optimized or generalized to all populations. Most of the studies included in this review were conducted in Japan, so it is uncertain if the results are applicable to other regions. Also, the selection of corticosteroids and treatment regimens were not consistent between studies.
Bottom line
This study suggests that corticosteroids combined with IVIG as initial therapy for KD showed a more protective effect against CAA, compared with conventional IVIG therapy, and the efficacy was more pronounced in the high-risk patient group.
Citation
Chen S, Dong Y, Kiuchi MG, et al. Coronary Artery Complication in Kawasaki Disease and the Importance of Early Intervention: A Systematic Review and Meta-analysis. JAMA Pediatr. 2016;170(12):1156-1163.
References
1. Newburger JW, Takahashi M, Gerber MA, et al. Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease. Council on Cardiovascular Disease in the Young; American Heart Association; American Academy of Pediatrics: diagnosis, treatment, and long-term management of Kawasaki disease. Circulation. 2004;110:2747-71.
2. Daniels LB, Tjajadi MS, Walford HH, et al. Prevalence of Kawasaki disease in young adults with suspected myocardial ischemia. Circulation. 2012;125(20):2447-53.
3. Gordon JB, Kahn AM, Burns JC. When children with Kawasaki disease grow up: myocardial and vascular complications in adulthood. J Am Coll Cardiol. 2009;54(21):1911-20.
4. Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr. 2008;153(1):117-21.
Dr. Galloway is a pediatric hospitalist at Sanford Children’s Hospital in Sioux Falls, S.D., assistant professor of pediatrics at the University of South Dakota Sanford School of Medicine, and vice chief of the division of hospital pediatrics at USD SSOM and Sanford Children’s Hospital.
Clinical Question
What is the efficacy of corticosteroid therapy in Kawasaki disease?
Background
First described in 1967 in Japan, Kawasaki disease (KD), or mucocutaneous lymph node syndrome, is an acute systemic vasculitis of unclear etiology which primarily affects infants and children. Of significant clinical concern, 30%-50% of untreated patients develop acute coronary artery dilatation, and about one fourth progress to serious coronary artery abnormalities (CAA) such as aneurysm and ectasia.1,2 These patients have a higher risk of long-term complications, such as coronary artery thrombus, myocardial infarction, and sudden death.3 KD is typically treated with a combination of intravenous immunoglobulin (IVIG) and aspirin, which reduces the risk of CAA.1 However, more than 20% of cases are resistant to this conventional therapy and have higher risk of CAA than nonresistant patients.4 Corticosteroids have been suggested as therapy in KD, as the anti-inflammatory effect is useful for many other vasculitides, but studies to date have had conflicting results. This study was performed to comprehensively evaluate the effect of corticosteroids in KD as initial or rescue therapy (after failure to respond to IVIG).
Study design
Systematic review and meta-analysis.
Synopsis
The population of interest was children diagnosed with KD. The intervention of interest was treatment with adjunctive corticosteroids either as initial or rescue therapy. Comparisons were made between the corticosteroids group and the conventional therapy (IVIG) group. Outcome measurements included the incidence of CAA (primary outcome), duration until defervescence, and adverse events. IVIG resistance was defined as persistent or recurrent fever lasting (or relapsed within) 24-48 hours after the initial IVIG treatment.
A total of 681 articles were initially retrieved, and after exclusions, 16 comparative studies were enrolled for meta-analysis. In these studies, a total of 2,746 cases were involved, with 861 in the corticosteroid group and 1,885 in the IVIG group. Ten studies used corticosteroids as initial treatment (comparing this plus IVIG versus IVIG therapy alone), and six used steroids as rescue treatment after initial IVIG failure (comparing corticosteroids with additional IVIG therapy). Four studies enrolled patients with KD who were predicted to have high risk of IVIG resistance, based on published scoring systems. All patients in the studies received oral aspirin.
Overall, this meta-analysis found that adding corticosteroid therapy was associated with a relative risk reduction of 58% in CAA (odds ratio, 0.424; 95% confidence interval, 0.270-0.665; P less than .001). Further analysis showed that the longer the duration of illness prior to corticosteroids, the less of a treatment effect was noticed. The studies using steroids as initial adjunctive therapy had duration of illness 4.7 days prior to treatment, and showed an advantage, compared with IVIG alone, while studies using steroids as rescue therapy had a longer duration of illness prior to steroid therapy (7.2 days), and did not show significant benefit, compared with additional IVIG. In analyzing patients predicted to be at high risk of IVIG resistance at baseline, addition of corticosteroids with IVIG as initial therapy showed a significantly lower risk of CAA development (relative risk reduction of 76%) versus IVIG alone (OR, 0.240; 95% CI, 0.123-0.467; P less than .001). As a secondary outcome, the use of adjunctive corticosteroid therapy was associated with a quicker resolution of fever, compared with IVIG alone (0.66 days vs. 2.18 days). There was no significant difference in adverse events between the two groups.
Although this is the most comprehensive study of corticosteroids in KD, there are some limitations. High-risk patients were found to receive the greatest benefit, but the predictive ability of published scoring systems have not been optimized or generalized to all populations. Most of the studies included in this review were conducted in Japan, so it is uncertain if the results are applicable to other regions. Also, the selection of corticosteroids and treatment regimens were not consistent between studies.
Bottom line
This study suggests that corticosteroids combined with IVIG as initial therapy for KD showed a more protective effect against CAA, compared with conventional IVIG therapy, and the efficacy was more pronounced in the high-risk patient group.
Citation
Chen S, Dong Y, Kiuchi MG, et al. Coronary Artery Complication in Kawasaki Disease and the Importance of Early Intervention: A Systematic Review and Meta-analysis. JAMA Pediatr. 2016;170(12):1156-1163.
References
1. Newburger JW, Takahashi M, Gerber MA, et al. Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease. Council on Cardiovascular Disease in the Young; American Heart Association; American Academy of Pediatrics: diagnosis, treatment, and long-term management of Kawasaki disease. Circulation. 2004;110:2747-71.
2. Daniels LB, Tjajadi MS, Walford HH, et al. Prevalence of Kawasaki disease in young adults with suspected myocardial ischemia. Circulation. 2012;125(20):2447-53.
3. Gordon JB, Kahn AM, Burns JC. When children with Kawasaki disease grow up: myocardial and vascular complications in adulthood. J Am Coll Cardiol. 2009;54(21):1911-20.
4. Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr. 2008;153(1):117-21.
Dr. Galloway is a pediatric hospitalist at Sanford Children’s Hospital in Sioux Falls, S.D., assistant professor of pediatrics at the University of South Dakota Sanford School of Medicine, and vice chief of the division of hospital pediatrics at USD SSOM and Sanford Children’s Hospital.
Pembrolizumab takes on r/r PMBCL
LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.
Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.
“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.
Although standard cytotoxic chemotherapy regimens are curative in approximately 80% of patients with PMBCL, those with relapsed/refractory disease have a poor prognosis and limited treatment options. In the United States, about 200 patients are diagnosed with relapsed/refractory PMBCL each year, Dr. Zinzani noted.
The rationale for using a programmed death-1 (PD-1) inhibitor such as pembrolizumab is that PMBCL tumors frequently harbor amplifications and/or translocations in the 9p24.1 locus that lead to overexpression of PD ligand 1 (PD-L1) or PD-L2. Pembrolizumab blocks interactions between PD-1 and its ligands.
In the Keynote-013 PMBCL cohort, the objective response rate (ORR) was 48%, including 24% CR.
Keynote 170 investigators are enrolling adults with relapsed/refractory PMBCL who are either ineligible for ASCT following at least two prior lines of therapy, or who had a relapse following a transplant.
Patients receive pembrolizumab 200 mg every 3 weeks. Those who achieve a complete response are allowed to discontinue after a minimum of 24 weeks on study, those with partial response or stable disease are treated for 35 cycles or until disease progression or intolerable toxicities, and those with disease progression are discontinued, but are allowed to remain on study until progression is confirmed.
Responses are assessed by PET and CT scans according to 2007 International Working Group criteria.
Among the 29 patients assessable for efficacy at the time of Dr. Zinzani’s presentations, the best response by blinded central review was 41% (12 patients: 4 CR and 8 PR). Three patients had stable disease, and eight had disease progression. Six patients died or discontinued participation prior to the first assessment.
In all, 16 of 22 patients had reductions in target lesions, and all but one of these patients had reductions greater than 50%.
After a median follow-up of 6.6 months, 10 patients had ongoing responses. The median time to response was 2.9 months. The median duration of response has not been reached.
Of the 10 patients for whom ASCT had failed, three had a CR, and three had a PR. Among 19 ASCT-ineligible patients, one had a CR and five had a PR.
The interim safety analysis included 49 patients. Of this group, only one discontinued treatment because of adverse events. There were 26 treatment-related adverse events, but no treatment-related deaths.
The most frequent adverse events were neutropenia, asthenia, hypothyroidism, and pyrexia.
The study is supported by Merck. Dr Zinzani disclosed serving on advisory boards for several companies.
LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.
Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.
“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.
Although standard cytotoxic chemotherapy regimens are curative in approximately 80% of patients with PMBCL, those with relapsed/refractory disease have a poor prognosis and limited treatment options. In the United States, about 200 patients are diagnosed with relapsed/refractory PMBCL each year, Dr. Zinzani noted.
The rationale for using a programmed death-1 (PD-1) inhibitor such as pembrolizumab is that PMBCL tumors frequently harbor amplifications and/or translocations in the 9p24.1 locus that lead to overexpression of PD ligand 1 (PD-L1) or PD-L2. Pembrolizumab blocks interactions between PD-1 and its ligands.
In the Keynote-013 PMBCL cohort, the objective response rate (ORR) was 48%, including 24% CR.
Keynote 170 investigators are enrolling adults with relapsed/refractory PMBCL who are either ineligible for ASCT following at least two prior lines of therapy, or who had a relapse following a transplant.
Patients receive pembrolizumab 200 mg every 3 weeks. Those who achieve a complete response are allowed to discontinue after a minimum of 24 weeks on study, those with partial response or stable disease are treated for 35 cycles or until disease progression or intolerable toxicities, and those with disease progression are discontinued, but are allowed to remain on study until progression is confirmed.
Responses are assessed by PET and CT scans according to 2007 International Working Group criteria.
Among the 29 patients assessable for efficacy at the time of Dr. Zinzani’s presentations, the best response by blinded central review was 41% (12 patients: 4 CR and 8 PR). Three patients had stable disease, and eight had disease progression. Six patients died or discontinued participation prior to the first assessment.
In all, 16 of 22 patients had reductions in target lesions, and all but one of these patients had reductions greater than 50%.
After a median follow-up of 6.6 months, 10 patients had ongoing responses. The median time to response was 2.9 months. The median duration of response has not been reached.
Of the 10 patients for whom ASCT had failed, three had a CR, and three had a PR. Among 19 ASCT-ineligible patients, one had a CR and five had a PR.
The interim safety analysis included 49 patients. Of this group, only one discontinued treatment because of adverse events. There were 26 treatment-related adverse events, but no treatment-related deaths.
The most frequent adverse events were neutropenia, asthenia, hypothyroidism, and pyrexia.
The study is supported by Merck. Dr Zinzani disclosed serving on advisory boards for several companies.
LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.
Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.
“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.
Although standard cytotoxic chemotherapy regimens are curative in approximately 80% of patients with PMBCL, those with relapsed/refractory disease have a poor prognosis and limited treatment options. In the United States, about 200 patients are diagnosed with relapsed/refractory PMBCL each year, Dr. Zinzani noted.
The rationale for using a programmed death-1 (PD-1) inhibitor such as pembrolizumab is that PMBCL tumors frequently harbor amplifications and/or translocations in the 9p24.1 locus that lead to overexpression of PD ligand 1 (PD-L1) or PD-L2. Pembrolizumab blocks interactions between PD-1 and its ligands.
In the Keynote-013 PMBCL cohort, the objective response rate (ORR) was 48%, including 24% CR.
Keynote 170 investigators are enrolling adults with relapsed/refractory PMBCL who are either ineligible for ASCT following at least two prior lines of therapy, or who had a relapse following a transplant.
Patients receive pembrolizumab 200 mg every 3 weeks. Those who achieve a complete response are allowed to discontinue after a minimum of 24 weeks on study, those with partial response or stable disease are treated for 35 cycles or until disease progression or intolerable toxicities, and those with disease progression are discontinued, but are allowed to remain on study until progression is confirmed.
Responses are assessed by PET and CT scans according to 2007 International Working Group criteria.
Among the 29 patients assessable for efficacy at the time of Dr. Zinzani’s presentations, the best response by blinded central review was 41% (12 patients: 4 CR and 8 PR). Three patients had stable disease, and eight had disease progression. Six patients died or discontinued participation prior to the first assessment.
In all, 16 of 22 patients had reductions in target lesions, and all but one of these patients had reductions greater than 50%.
After a median follow-up of 6.6 months, 10 patients had ongoing responses. The median time to response was 2.9 months. The median duration of response has not been reached.
Of the 10 patients for whom ASCT had failed, three had a CR, and three had a PR. Among 19 ASCT-ineligible patients, one had a CR and five had a PR.
The interim safety analysis included 49 patients. Of this group, only one discontinued treatment because of adverse events. There were 26 treatment-related adverse events, but no treatment-related deaths.
The most frequent adverse events were neutropenia, asthenia, hypothyroidism, and pyrexia.
The study is supported by Merck. Dr Zinzani disclosed serving on advisory boards for several companies.
AT 14-ICML
Key clinical point: Poor-prognosis relapsed/refractory primary mediastinal large B-cell lymphoma may respond to PD-1 inhibition.
Major finding: The best response by blinded central review was 41% (12 patients: 4 complete and 8 partial responses).
Data source: Interim analysis from a phase 2 study with 29 patients evaluable for efficacy, 49 for safety.
Disclosures: Merck supports the study. Dr Zinzani disclosed serving on advisory boards for several companies.
Selim Benbadis, MD
Allele-matching in cord blood transplant yields better survival
Matching down to the allele level in umbilical cord blood transplantation between unrelated donors results in greater overall survival for those with nonmalignant diseases, such as aplastic anemia, researchers found in a retrospective study published in the Lancet Haematology.
The review (Lancet Haematol. 2017 Jul;4[7]:e325-33), the largest published on the topic, indicates that clinicians should change practice from the current standard of antigen-level matching, said Mary Eapen, MD, director of the Center for International Blood and Marrow Transplant Research (CIBMTR) in Wauwatosa, Wisconsin.
“Our findings,” Dr. Eapen wrote, “support a change in clinical practice to prioritization of units on allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1.”
Data were pulled from cases reported to the Center for International Blood and Marrow Transplant Research or the European Group for Blood and Marrow Transplant. Researchers looked at 1,199 donor-recipient matches of cord blood transplantation for diseases, such as severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency, inborn errors of metabolism, severe aplastic anemia, and Fanconi anemia. Recipients could be as old as age 16, but most were age 5 or younger.
After adjustment for factors, including cytomegalovirus serostatus, the intensity of the conditioning regimen, and the total nucleated cell dose, the 5-year overall survival was 79% for transplants that were matched at all eight alleles at HLA-A, HLA-B, HLA-C and HLA-DRB1. These results compare with 76% after transplants with one mismatch, 70% with two mismatches, 62% with three mismatches, and 49% with 4 or more mismatches.
Mortality risks were significantly higher for patients who received transplants with two (P = .018), three (P = .0001), and four or more mismatches (P less than .0001), compared with those whose transplants were fully matched. There was no difference statistically between full matches and one mismatch, but the findings suggest that the mortality risk might prove significant with a larger sample size.
Researchers cautioned that, because most patients were age 5 or younger, the results might not be generalizable to older children.
Although HLA typing is available at CIBMTR for most blood cord transplants for nonmalignant diseases, full allele matches or just one mismatch are not the norm, Dr. Eapen wrote. Researchers said that they suspect this is because of difficulties finding matches or because a high total nucleated cell count is prioritized above HLA matching. They suggest clinicians change their decision making in this regard.
Matching down to the allele level in umbilical cord blood transplantation between unrelated donors results in greater overall survival for those with nonmalignant diseases, such as aplastic anemia, researchers found in a retrospective study published in the Lancet Haematology.
The review (Lancet Haematol. 2017 Jul;4[7]:e325-33), the largest published on the topic, indicates that clinicians should change practice from the current standard of antigen-level matching, said Mary Eapen, MD, director of the Center for International Blood and Marrow Transplant Research (CIBMTR) in Wauwatosa, Wisconsin.
“Our findings,” Dr. Eapen wrote, “support a change in clinical practice to prioritization of units on allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1.”
Data were pulled from cases reported to the Center for International Blood and Marrow Transplant Research or the European Group for Blood and Marrow Transplant. Researchers looked at 1,199 donor-recipient matches of cord blood transplantation for diseases, such as severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency, inborn errors of metabolism, severe aplastic anemia, and Fanconi anemia. Recipients could be as old as age 16, but most were age 5 or younger.
After adjustment for factors, including cytomegalovirus serostatus, the intensity of the conditioning regimen, and the total nucleated cell dose, the 5-year overall survival was 79% for transplants that were matched at all eight alleles at HLA-A, HLA-B, HLA-C and HLA-DRB1. These results compare with 76% after transplants with one mismatch, 70% with two mismatches, 62% with three mismatches, and 49% with 4 or more mismatches.
Mortality risks were significantly higher for patients who received transplants with two (P = .018), three (P = .0001), and four or more mismatches (P less than .0001), compared with those whose transplants were fully matched. There was no difference statistically between full matches and one mismatch, but the findings suggest that the mortality risk might prove significant with a larger sample size.
Researchers cautioned that, because most patients were age 5 or younger, the results might not be generalizable to older children.
Although HLA typing is available at CIBMTR for most blood cord transplants for nonmalignant diseases, full allele matches or just one mismatch are not the norm, Dr. Eapen wrote. Researchers said that they suspect this is because of difficulties finding matches or because a high total nucleated cell count is prioritized above HLA matching. They suggest clinicians change their decision making in this regard.
Matching down to the allele level in umbilical cord blood transplantation between unrelated donors results in greater overall survival for those with nonmalignant diseases, such as aplastic anemia, researchers found in a retrospective study published in the Lancet Haematology.
The review (Lancet Haematol. 2017 Jul;4[7]:e325-33), the largest published on the topic, indicates that clinicians should change practice from the current standard of antigen-level matching, said Mary Eapen, MD, director of the Center for International Blood and Marrow Transplant Research (CIBMTR) in Wauwatosa, Wisconsin.
“Our findings,” Dr. Eapen wrote, “support a change in clinical practice to prioritization of units on allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1.”
Data were pulled from cases reported to the Center for International Blood and Marrow Transplant Research or the European Group for Blood and Marrow Transplant. Researchers looked at 1,199 donor-recipient matches of cord blood transplantation for diseases, such as severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency, inborn errors of metabolism, severe aplastic anemia, and Fanconi anemia. Recipients could be as old as age 16, but most were age 5 or younger.
After adjustment for factors, including cytomegalovirus serostatus, the intensity of the conditioning regimen, and the total nucleated cell dose, the 5-year overall survival was 79% for transplants that were matched at all eight alleles at HLA-A, HLA-B, HLA-C and HLA-DRB1. These results compare with 76% after transplants with one mismatch, 70% with two mismatches, 62% with three mismatches, and 49% with 4 or more mismatches.
Mortality risks were significantly higher for patients who received transplants with two (P = .018), three (P = .0001), and four or more mismatches (P less than .0001), compared with those whose transplants were fully matched. There was no difference statistically between full matches and one mismatch, but the findings suggest that the mortality risk might prove significant with a larger sample size.
Researchers cautioned that, because most patients were age 5 or younger, the results might not be generalizable to older children.
Although HLA typing is available at CIBMTR for most blood cord transplants for nonmalignant diseases, full allele matches or just one mismatch are not the norm, Dr. Eapen wrote. Researchers said that they suspect this is because of difficulties finding matches or because a high total nucleated cell count is prioritized above HLA matching. They suggest clinicians change their decision making in this regard.
FROM THE LANCET HAEMATOLOGY
Key clinical point: HLA matching at the allele-level produces better survival in umbilical cord blood transplantation for nonmalignant diseases.
Major finding: Mortality risks were significantly higher for patients who received transplants with two (P = .018), three (P = .0001), and four or more mismatches (P less than .0001), compared with those whose transplants were fully matched at all eight alleles at HLA-A, HLA-B, HLA-C and HLA-DRB1.
Data source: A retrospective review of 1,199 cases reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) or the European Group for Blood and Marrow Transplant (EGBMT).
Disclosures: The authors reported no conflicts of interest.
Avelumab induces response in Hodgkin lymphoma after failed allo-SCT
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
AT 14-ICML
Key clinical point: Avelumab showed efficacy in patients with classical Hodgkin lymphoma that relapsed following allogeneic stem cell transplant.
Major finding: The objective response rate among all patients in the study was 41.9%.
Data source: A phase 1 dose-finding and expansion study in 31 patients with relapsed/refractory classical Hodgkin lymphoma who were ineligible for SCT or experienced relapses following SCT.
Disclosures: The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
TKI dose de-escalation feasible in CML with stable MMR
Tyrosine kinase inhibitor de-escalation is generally safe and may lead to symptom improvement in patients with chronic myeloid leukemia who respond well to the therapy, according to an interim analysis of the nonrandomized phase 2 DESTINY trial.
The findings imply that some patients are unnecessarily overtreated, as responses were sometimes maintained with lower tyrosine kinase inhibitor (TKI) doses, according to Richard E. Clark, MD, of the University of Liverpool, England, and his colleagues (Lancet Haematol. 2017 May 26;4:e310-16).
Of 174 patients with chronic myeloid leukemia (CML) in first chronic phase who had received TKIs for at least 3 years and who were either in stable molecular response 4 logs below the standard arbitrary baseline (MR4, 125 patients) or stable major molecular response (MMR) but not MR4 (49 patients) for at least 12 months at the time of enrollment, 12 (7%) had molecular recurrence during 12 months of half-dose TKI therapy, and all patients who experienced molecular recurrence regained MMR within 4 months of being back on full-dose TKIs, the researchers noted.
The median time to recovery was 77 days.
The recurrence rate was significantly lower in the MR4 cohort than in the MMR cohort (2% vs. 19%; hazard ratio, 0.12), and time to relapse was significantly longer in the MR4 cohort (median, 8.7 vs. 4.4 months), the investigators said.
Recurrence was not associated with age, sex, weight, performance status, BCR-ABL1 transcript type, or duration of TKI therapy, which was a median of 6.9 years overall, they noted.
During the first 3 months of de-escalation, adverse events associated with treatment, including lethargy, diarrhea, rash, and nausea, all improved.
Adverse events during de-escalation occurred in 16 patients, and included one fatality due to worsening of peripheral arterial occlusive disease, but all were deemed unrelated to the TKI or underlying chronic CML, the investigators noted.
Study subjects were adults with positive BCR-ABL1 transcripts, with either e13a2, e14a2, or e19a2 fusion transcript. They were enrolled between December 2013 and April 2015 from 20 hospitals in the United Kingdom; 148 were receiving imatinib, 16 were receiving nilotinib, and 10 were receiving dasatinib. They received half of their standard dose of imatinib (200 mg daily), dasatinib (50 mg daily), or nilotinib (200 mg twice daily) for 12 months. Recurrence during de-escalation was defined as BCR-ABL1:ABL1 ratio greater than 0.1% on two consecutive measurements.
“Although several studies of TKI cessation have been reported, little is known about the feasibility of treatment de-escalation in patients with stable molecular responses,” the investigators wrote, adding that the current study shows that de-escalation is “clearly safe for patients in stable MR4 or deeper remission” and could be a “reasonable option.”
This “practice-changing view” is reinforced by the finding of general improvement of adverse events in both cohorts, they said.
Also of note, de-escalation in this study was associated with savings of almost half the expected TKI costs, they added.
The findings imply that many patients with stable responses might be able to maintain responses on lower TKI doses, they concluded, adding that studies of more ambitious de-escalation are warranted.
Newcastle University and Bloodwise funded the study. Dr. Clark received other grants from Bloodwise during the study, as well as grants and personal fees from Novartis, Bristol-Myers Squibb, and Pfizer, and personal fees from Ariad/Incyte.
The interim DESTINY trial findings indicate the feasibility of a dose reduction approach to minimize adverse events associated with TKI treatment and to improve quality of life, Elisabetta Abruzzese, MD, wrote in an editorial.
De-escalation also appears to provide important cost savings, she noted (Lancet Haematol. 2017 Jul;4:e304-5).
“For patients who are unable to stop therapy, adjustment of the treatment doses without jeopardizing the clinical outcome has important clinical implications. Combination of reduced dosage TKIs with newer (ABL001) or older approaches (immunomodulation) might represent a future answer to that,” she said.
Dr. Abruzzese is with Tor Vergata University, Rome. She reported receiving personal fees from Ariad/Incyte, and serving on the advisory board or as a consultant for Novartis, Pfizer, Ariad/Incyte, and Bristol-Myers Squibb.
The interim DESTINY trial findings indicate the feasibility of a dose reduction approach to minimize adverse events associated with TKI treatment and to improve quality of life, Elisabetta Abruzzese, MD, wrote in an editorial.
De-escalation also appears to provide important cost savings, she noted (Lancet Haematol. 2017 Jul;4:e304-5).
“For patients who are unable to stop therapy, adjustment of the treatment doses without jeopardizing the clinical outcome has important clinical implications. Combination of reduced dosage TKIs with newer (ABL001) or older approaches (immunomodulation) might represent a future answer to that,” she said.
Dr. Abruzzese is with Tor Vergata University, Rome. She reported receiving personal fees from Ariad/Incyte, and serving on the advisory board or as a consultant for Novartis, Pfizer, Ariad/Incyte, and Bristol-Myers Squibb.
The interim DESTINY trial findings indicate the feasibility of a dose reduction approach to minimize adverse events associated with TKI treatment and to improve quality of life, Elisabetta Abruzzese, MD, wrote in an editorial.
De-escalation also appears to provide important cost savings, she noted (Lancet Haematol. 2017 Jul;4:e304-5).
“For patients who are unable to stop therapy, adjustment of the treatment doses without jeopardizing the clinical outcome has important clinical implications. Combination of reduced dosage TKIs with newer (ABL001) or older approaches (immunomodulation) might represent a future answer to that,” she said.
Dr. Abruzzese is with Tor Vergata University, Rome. She reported receiving personal fees from Ariad/Incyte, and serving on the advisory board or as a consultant for Novartis, Pfizer, Ariad/Incyte, and Bristol-Myers Squibb.
Tyrosine kinase inhibitor de-escalation is generally safe and may lead to symptom improvement in patients with chronic myeloid leukemia who respond well to the therapy, according to an interim analysis of the nonrandomized phase 2 DESTINY trial.
The findings imply that some patients are unnecessarily overtreated, as responses were sometimes maintained with lower tyrosine kinase inhibitor (TKI) doses, according to Richard E. Clark, MD, of the University of Liverpool, England, and his colleagues (Lancet Haematol. 2017 May 26;4:e310-16).
Of 174 patients with chronic myeloid leukemia (CML) in first chronic phase who had received TKIs for at least 3 years and who were either in stable molecular response 4 logs below the standard arbitrary baseline (MR4, 125 patients) or stable major molecular response (MMR) but not MR4 (49 patients) for at least 12 months at the time of enrollment, 12 (7%) had molecular recurrence during 12 months of half-dose TKI therapy, and all patients who experienced molecular recurrence regained MMR within 4 months of being back on full-dose TKIs, the researchers noted.
The median time to recovery was 77 days.
The recurrence rate was significantly lower in the MR4 cohort than in the MMR cohort (2% vs. 19%; hazard ratio, 0.12), and time to relapse was significantly longer in the MR4 cohort (median, 8.7 vs. 4.4 months), the investigators said.
Recurrence was not associated with age, sex, weight, performance status, BCR-ABL1 transcript type, or duration of TKI therapy, which was a median of 6.9 years overall, they noted.
During the first 3 months of de-escalation, adverse events associated with treatment, including lethargy, diarrhea, rash, and nausea, all improved.
Adverse events during de-escalation occurred in 16 patients, and included one fatality due to worsening of peripheral arterial occlusive disease, but all were deemed unrelated to the TKI or underlying chronic CML, the investigators noted.
Study subjects were adults with positive BCR-ABL1 transcripts, with either e13a2, e14a2, or e19a2 fusion transcript. They were enrolled between December 2013 and April 2015 from 20 hospitals in the United Kingdom; 148 were receiving imatinib, 16 were receiving nilotinib, and 10 were receiving dasatinib. They received half of their standard dose of imatinib (200 mg daily), dasatinib (50 mg daily), or nilotinib (200 mg twice daily) for 12 months. Recurrence during de-escalation was defined as BCR-ABL1:ABL1 ratio greater than 0.1% on two consecutive measurements.
“Although several studies of TKI cessation have been reported, little is known about the feasibility of treatment de-escalation in patients with stable molecular responses,” the investigators wrote, adding that the current study shows that de-escalation is “clearly safe for patients in stable MR4 or deeper remission” and could be a “reasonable option.”
This “practice-changing view” is reinforced by the finding of general improvement of adverse events in both cohorts, they said.
Also of note, de-escalation in this study was associated with savings of almost half the expected TKI costs, they added.
The findings imply that many patients with stable responses might be able to maintain responses on lower TKI doses, they concluded, adding that studies of more ambitious de-escalation are warranted.
Newcastle University and Bloodwise funded the study. Dr. Clark received other grants from Bloodwise during the study, as well as grants and personal fees from Novartis, Bristol-Myers Squibb, and Pfizer, and personal fees from Ariad/Incyte.
Tyrosine kinase inhibitor de-escalation is generally safe and may lead to symptom improvement in patients with chronic myeloid leukemia who respond well to the therapy, according to an interim analysis of the nonrandomized phase 2 DESTINY trial.
The findings imply that some patients are unnecessarily overtreated, as responses were sometimes maintained with lower tyrosine kinase inhibitor (TKI) doses, according to Richard E. Clark, MD, of the University of Liverpool, England, and his colleagues (Lancet Haematol. 2017 May 26;4:e310-16).
Of 174 patients with chronic myeloid leukemia (CML) in first chronic phase who had received TKIs for at least 3 years and who were either in stable molecular response 4 logs below the standard arbitrary baseline (MR4, 125 patients) or stable major molecular response (MMR) but not MR4 (49 patients) for at least 12 months at the time of enrollment, 12 (7%) had molecular recurrence during 12 months of half-dose TKI therapy, and all patients who experienced molecular recurrence regained MMR within 4 months of being back on full-dose TKIs, the researchers noted.
The median time to recovery was 77 days.
The recurrence rate was significantly lower in the MR4 cohort than in the MMR cohort (2% vs. 19%; hazard ratio, 0.12), and time to relapse was significantly longer in the MR4 cohort (median, 8.7 vs. 4.4 months), the investigators said.
Recurrence was not associated with age, sex, weight, performance status, BCR-ABL1 transcript type, or duration of TKI therapy, which was a median of 6.9 years overall, they noted.
During the first 3 months of de-escalation, adverse events associated with treatment, including lethargy, diarrhea, rash, and nausea, all improved.
Adverse events during de-escalation occurred in 16 patients, and included one fatality due to worsening of peripheral arterial occlusive disease, but all were deemed unrelated to the TKI or underlying chronic CML, the investigators noted.
Study subjects were adults with positive BCR-ABL1 transcripts, with either e13a2, e14a2, or e19a2 fusion transcript. They were enrolled between December 2013 and April 2015 from 20 hospitals in the United Kingdom; 148 were receiving imatinib, 16 were receiving nilotinib, and 10 were receiving dasatinib. They received half of their standard dose of imatinib (200 mg daily), dasatinib (50 mg daily), or nilotinib (200 mg twice daily) for 12 months. Recurrence during de-escalation was defined as BCR-ABL1:ABL1 ratio greater than 0.1% on two consecutive measurements.
“Although several studies of TKI cessation have been reported, little is known about the feasibility of treatment de-escalation in patients with stable molecular responses,” the investigators wrote, adding that the current study shows that de-escalation is “clearly safe for patients in stable MR4 or deeper remission” and could be a “reasonable option.”
This “practice-changing view” is reinforced by the finding of general improvement of adverse events in both cohorts, they said.
Also of note, de-escalation in this study was associated with savings of almost half the expected TKI costs, they added.
The findings imply that many patients with stable responses might be able to maintain responses on lower TKI doses, they concluded, adding that studies of more ambitious de-escalation are warranted.
Newcastle University and Bloodwise funded the study. Dr. Clark received other grants from Bloodwise during the study, as well as grants and personal fees from Novartis, Bristol-Myers Squibb, and Pfizer, and personal fees from Ariad/Incyte.
FROM LANCET HAEMATOLOGY
Key clinical point:
Major finding: Only 12 of 174 CML patients had molecular recurrence during 12 months of half-dose TKI therapy, and all regained MMR within 4 months of being back on full-dose TKIs.
Data source: The nonrandomized phase 2 DESTINY study of 174 adults with CML.
Disclosures: Newcastle University and Bloodwise funded the study. Dr. Clark received other grants from Bloodwise during the study, as well as grants and personal fees from Novartis, Bristol-Myers Squibb, and Pfizer, and personal fees from Ariad/Incyte.
Enhanced antimicrobial prophylaxis cuts advanced HIV mortality
An enhanced antimicrobial prophylaxis regimen administered to patients with advanced HIV infection who were starting antiretroviral therapy for the first time led to significantly reduced mortality after 24 weeks, compared with patients who received standard antimicrobial prophylaxis, in a randomized, multicenter trial with 1,805 patients.
The enhanced prophylaxis regimen tested “is relatively inexpensive, has a low pill burden and an acceptable side effect profile, and would be easy to implement at primary health centers,” according to James Hakim, MD, and his associates. The report was published July 20 (N Engl J Med. 2017 July 20;377[3]:233-45).
The researchers who ran the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial enrolled HIV-infected patients who were at least 5 years old who had not previously received antiretroviral therapy and had a CD4+ T cell count of fewer than 100 cells/mm3 at the time of entry. Enrollment occurred during June 2013–April 2015 at eight centers in Kenya, Malawi, Uganda, or Zimbabwe. All patients started treatment with two nucleoside and one non-nucleoside reverse-transcriptase inhibitors.
After randomization, 906 patients entered the subgroup that received enhanced prophylaxis with a single dose of albendazole, 5 days of azithromycin, 12 weeks of fluconazole, and open-ended prophylaxis with trimethoprim-sulfamethoxazole, isoniazid, and pyridoxine (use of isoniazid and pyridoxine beyond 12 weeks depended on national guidelines in each country). Another 899 patients entered the subgroup that received standard antimicrobial prophylaxis with trimethoprim-sulfamethoxazole and isoniazid only.
All-cause mortality at 24 weeks after entry was the primary endpoint. This occurred in about 9% of patients on enhanced prophylaxis and about 12% of those on standard prophylaxis, which calculated to a statistically significant relative risk reduction of 27% with enhanced prophylaxis, and a number needed to treat of 30 patients with enhanced prophylaxis to prevent one additional death. At 48 weeks after entry, the relative risk reduction for all-cause mortality with enhanced prophylaxis was a statistically significant 24% lower with enhanced prophylaxis.
Enhanced prophylaxis also led to significant gains in life years and quality-adjusted life years. Based on actual drug costs, enhanced prophylaxis cost $613 per life year gained and $761 per quality-adjusted life year gained.
The REALITY trial received no commercial support. Dr. Hakim has been an adviser to Mylan and a consultant to Gilead and Johnson & Johnson.
[email protected]
On Twitter @mitchelzoler
A substantial number of HIV patients, when first diagnosed, continue to have advanced infection, defined by the World Health Organization as a CD4+ T cell count of fewer than 200 cell/mm3. In the REALITY trial, nearly half the patients with a CD4+ T cell count of fewer than 100 cells/mm3 at the time of their initial HIV diagnosis had mild or no symptoms. This finding highlights the limitations of relying on clinical assessment alone to identify people infected with HIV and needing testing and treatment.
In addition to showing the efficacy of enhanced antimicrobial prophylaxis compared with standard prophylaxis in the types of patients studied in REALITY, the results showed that the enhanced prophylaxis regimen had an acceptable side-effect profile, a high level of patient adherence to prophylaxis treatment, and no discernible effect on adherence to antiretroviral therapy. Nevertheless, the regimen used raises some concerns that warrant careful assessment: What is the risk posed by the enhanced regimen tested to producing microbial resistance to fluconazole or azithromycin? And is blanket use of this prophylaxis cost effective in locations where diagnostic testing for microbial infections is available?
The relatively consistent proportion of HIV-infected patients who newly present with a low CD4+ T cell count, as well as the seriously ill patients who return for care after an interruption in their HIV treatment, both call for renewed focus on the needs of patients with advanced HIV infection who have a high risk for illness and death.
Nathan Ford, PhD, and Meg Doherty, MD , are in the department of HIV/AIDS at the World Health Organization in Geneva. They had no disclosures. Their comments appeared in an editorial that accompanied the REALITY trial report ( N Engl J Med. 2017 Jul 20;377[3]:283-4 ).
A substantial number of HIV patients, when first diagnosed, continue to have advanced infection, defined by the World Health Organization as a CD4+ T cell count of fewer than 200 cell/mm3. In the REALITY trial, nearly half the patients with a CD4+ T cell count of fewer than 100 cells/mm3 at the time of their initial HIV diagnosis had mild or no symptoms. This finding highlights the limitations of relying on clinical assessment alone to identify people infected with HIV and needing testing and treatment.
In addition to showing the efficacy of enhanced antimicrobial prophylaxis compared with standard prophylaxis in the types of patients studied in REALITY, the results showed that the enhanced prophylaxis regimen had an acceptable side-effect profile, a high level of patient adherence to prophylaxis treatment, and no discernible effect on adherence to antiretroviral therapy. Nevertheless, the regimen used raises some concerns that warrant careful assessment: What is the risk posed by the enhanced regimen tested to producing microbial resistance to fluconazole or azithromycin? And is blanket use of this prophylaxis cost effective in locations where diagnostic testing for microbial infections is available?
The relatively consistent proportion of HIV-infected patients who newly present with a low CD4+ T cell count, as well as the seriously ill patients who return for care after an interruption in their HIV treatment, both call for renewed focus on the needs of patients with advanced HIV infection who have a high risk for illness and death.
Nathan Ford, PhD, and Meg Doherty, MD , are in the department of HIV/AIDS at the World Health Organization in Geneva. They had no disclosures. Their comments appeared in an editorial that accompanied the REALITY trial report ( N Engl J Med. 2017 Jul 20;377[3]:283-4 ).
A substantial number of HIV patients, when first diagnosed, continue to have advanced infection, defined by the World Health Organization as a CD4+ T cell count of fewer than 200 cell/mm3. In the REALITY trial, nearly half the patients with a CD4+ T cell count of fewer than 100 cells/mm3 at the time of their initial HIV diagnosis had mild or no symptoms. This finding highlights the limitations of relying on clinical assessment alone to identify people infected with HIV and needing testing and treatment.
In addition to showing the efficacy of enhanced antimicrobial prophylaxis compared with standard prophylaxis in the types of patients studied in REALITY, the results showed that the enhanced prophylaxis regimen had an acceptable side-effect profile, a high level of patient adherence to prophylaxis treatment, and no discernible effect on adherence to antiretroviral therapy. Nevertheless, the regimen used raises some concerns that warrant careful assessment: What is the risk posed by the enhanced regimen tested to producing microbial resistance to fluconazole or azithromycin? And is blanket use of this prophylaxis cost effective in locations where diagnostic testing for microbial infections is available?
The relatively consistent proportion of HIV-infected patients who newly present with a low CD4+ T cell count, as well as the seriously ill patients who return for care after an interruption in their HIV treatment, both call for renewed focus on the needs of patients with advanced HIV infection who have a high risk for illness and death.
Nathan Ford, PhD, and Meg Doherty, MD , are in the department of HIV/AIDS at the World Health Organization in Geneva. They had no disclosures. Their comments appeared in an editorial that accompanied the REALITY trial report ( N Engl J Med. 2017 Jul 20;377[3]:283-4 ).
An enhanced antimicrobial prophylaxis regimen administered to patients with advanced HIV infection who were starting antiretroviral therapy for the first time led to significantly reduced mortality after 24 weeks, compared with patients who received standard antimicrobial prophylaxis, in a randomized, multicenter trial with 1,805 patients.
The enhanced prophylaxis regimen tested “is relatively inexpensive, has a low pill burden and an acceptable side effect profile, and would be easy to implement at primary health centers,” according to James Hakim, MD, and his associates. The report was published July 20 (N Engl J Med. 2017 July 20;377[3]:233-45).
The researchers who ran the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial enrolled HIV-infected patients who were at least 5 years old who had not previously received antiretroviral therapy and had a CD4+ T cell count of fewer than 100 cells/mm3 at the time of entry. Enrollment occurred during June 2013–April 2015 at eight centers in Kenya, Malawi, Uganda, or Zimbabwe. All patients started treatment with two nucleoside and one non-nucleoside reverse-transcriptase inhibitors.
After randomization, 906 patients entered the subgroup that received enhanced prophylaxis with a single dose of albendazole, 5 days of azithromycin, 12 weeks of fluconazole, and open-ended prophylaxis with trimethoprim-sulfamethoxazole, isoniazid, and pyridoxine (use of isoniazid and pyridoxine beyond 12 weeks depended on national guidelines in each country). Another 899 patients entered the subgroup that received standard antimicrobial prophylaxis with trimethoprim-sulfamethoxazole and isoniazid only.
All-cause mortality at 24 weeks after entry was the primary endpoint. This occurred in about 9% of patients on enhanced prophylaxis and about 12% of those on standard prophylaxis, which calculated to a statistically significant relative risk reduction of 27% with enhanced prophylaxis, and a number needed to treat of 30 patients with enhanced prophylaxis to prevent one additional death. At 48 weeks after entry, the relative risk reduction for all-cause mortality with enhanced prophylaxis was a statistically significant 24% lower with enhanced prophylaxis.
Enhanced prophylaxis also led to significant gains in life years and quality-adjusted life years. Based on actual drug costs, enhanced prophylaxis cost $613 per life year gained and $761 per quality-adjusted life year gained.
The REALITY trial received no commercial support. Dr. Hakim has been an adviser to Mylan and a consultant to Gilead and Johnson & Johnson.
[email protected]
On Twitter @mitchelzoler
An enhanced antimicrobial prophylaxis regimen administered to patients with advanced HIV infection who were starting antiretroviral therapy for the first time led to significantly reduced mortality after 24 weeks, compared with patients who received standard antimicrobial prophylaxis, in a randomized, multicenter trial with 1,805 patients.
The enhanced prophylaxis regimen tested “is relatively inexpensive, has a low pill burden and an acceptable side effect profile, and would be easy to implement at primary health centers,” according to James Hakim, MD, and his associates. The report was published July 20 (N Engl J Med. 2017 July 20;377[3]:233-45).
The researchers who ran the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial enrolled HIV-infected patients who were at least 5 years old who had not previously received antiretroviral therapy and had a CD4+ T cell count of fewer than 100 cells/mm3 at the time of entry. Enrollment occurred during June 2013–April 2015 at eight centers in Kenya, Malawi, Uganda, or Zimbabwe. All patients started treatment with two nucleoside and one non-nucleoside reverse-transcriptase inhibitors.
After randomization, 906 patients entered the subgroup that received enhanced prophylaxis with a single dose of albendazole, 5 days of azithromycin, 12 weeks of fluconazole, and open-ended prophylaxis with trimethoprim-sulfamethoxazole, isoniazid, and pyridoxine (use of isoniazid and pyridoxine beyond 12 weeks depended on national guidelines in each country). Another 899 patients entered the subgroup that received standard antimicrobial prophylaxis with trimethoprim-sulfamethoxazole and isoniazid only.
All-cause mortality at 24 weeks after entry was the primary endpoint. This occurred in about 9% of patients on enhanced prophylaxis and about 12% of those on standard prophylaxis, which calculated to a statistically significant relative risk reduction of 27% with enhanced prophylaxis, and a number needed to treat of 30 patients with enhanced prophylaxis to prevent one additional death. At 48 weeks after entry, the relative risk reduction for all-cause mortality with enhanced prophylaxis was a statistically significant 24% lower with enhanced prophylaxis.
Enhanced prophylaxis also led to significant gains in life years and quality-adjusted life years. Based on actual drug costs, enhanced prophylaxis cost $613 per life year gained and $761 per quality-adjusted life year gained.
The REALITY trial received no commercial support. Dr. Hakim has been an adviser to Mylan and a consultant to Gilead and Johnson & Johnson.
[email protected]
On Twitter @mitchelzoler
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Enhanced prophylaxis cut mortality by a relative 27% compared with standard prophylaxis after 24 weeks.
Data source: REALITY, a multicenter randomized trial with 1,805 patients.
Disclosures: REALITY received no commercial support. Dr. Hakim has been an adviser to Mylan and a consultant to Gilead and Johnson & Johnson.
Lower Limb Morel-Lavallée Lesion Treated With Short-Stretch Compression Bandaging
Take-Home Points
- Have a high-index of suspicion for MLLs and initiate treatment early.
- Compression needs to occur through short-stretch bandaging over a conventional Ace wrap in order to be successful.
- Apply the short-stretch compression with care to avoid shearing underlying tissue.
- Nonoperative treatment modalities require high patient compliance.
- MLLs need close monitoring until final healing occurs.
Morel-Lavallée lesions (MLLs) are traumatic degloving injuries resulting from separation of subcutaneous fat from underlying fascia. MLLs occur in association with acetabular fractures and are also associated with low-velocity crush injuries.1,2 Shearing creates a “false” space that is filled with hemorrhaged blood, fat, and lymphatic tissue.3 Disruption of the lymphatics leads to cavity formation and, eventually, a fibrotic pseudocapsule.4The pseudocapsule prevents resorption, leading to a chronic fluid collection, which potentiates the risk of infection or tissue necrosis.3,5,6 Skin necrosis may occur through direct-pressure compromise of the dermal vascular plexus.4 Necrotic skin may require multiple débridements, negative-pressure wound therapy or soft-tissue coverage, and may ultimately result in infection. MLLs classically occur in the greater trochanteric region, lateral thigh, buttocks, and back but also appear in the prepatellar region.1,3 Patients present with soft-tissue swelling, bruising, bulging, decreased cutaneous sensation over the region, and a palpable, fluctuant subcutaneous fluid collection with mobile skin.2,4,7 The mechanism of injury may cause a concomitant fracture. Magnetic resonance imaging (MRI), the preferred imaging modality, shows a discrete fluid collection between subcutaneous fat and underlying fascia. Ultrasonography may reveal a thickened capsule surrounding either a hypoechoic area or an anechoic area but its accuracy is user-dependent.7
Large MLLs may be treated with open serial débridement and healing by secondary intention; infection rates, however, are high. Authors have described several other treatment modalities, including percutaneous débridement with a brush followed by use of a large-bore drain and antibiotics; open débridement with meticulous dead-space closure; elastic compression bandaging; aspiration; and doxycycline sclerodesis.1,5,6,8,9 Modifications of short-stretch compression bandaging were recently described in edema control for hindfoot trauma, ankle trauma, and total ankle arthroplasty, but not for MLLs.10,11 Nickerson and colleagues4 retrospectively reviewed 87 MLLs, found that fluid aspirate of >50 mL predicted recurrence and failure with conservative measures, and recommended operative intervention for any MLL with >50 mL of fluid aspirated.
We report the case of an MLL that occurred in an unusual anatomical region, and we describe a novel application of a conservative treatment, which was selected on the basis of its success in lymphedema management. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 66-year-old man was injured when a parked vehicle began moving, pulled him under, and ran over his lower right leg. In the emergency department, no fractures or major injuries were noted (Figures 1A, 1B), and the patient was discharged.
About 10 days after injury, profuse ecchymosis and swelling were noted running from the distal medial thigh to the proximal medial calf (Figures 2A-2C).
Given the size of the MLL, the fluid collection reaccumulated. The patient was evaluated by an orthopedic traumatologist 3 days after the aspiration (17 days after injury).
Another orthopedic traumatologist confirmed the low likelihood that compression would resolve the MLL, given its size (Figures 4A, 4B). 
After the second orthopedic consultation, the patient saw a physical therapist trained in complete decongestive therapy. The therapist suggested placing short-stretch bandage wraps over the conventional long-stretch Ace bandage currently being used—a treatment common in lymphedema. The patient was wrapped from toe to groin without an initial layer of padding (Figures 6A, 6B), and the response was immediate. 
Nine weeks after injury, the leg was significantly improved, and clinical signs resolved (Figure 7). 
Discussion
Short-stretch bandaging has been performed mainly in lymphedema and ulcer management. 
Compression bandaging reduces volume in lymphedematous limbs by reducing capillary filtration, shifting fluid into noncompressed parts of the body, increasing lymphatic reabsorption and lymphatic transport stimulation, improving venous pumping, and breaking down fibrosclerotic tissue.15 We think containment, improved venous flow, and enhanced muscle contraction contributed to the effectiveness of short-stretch bandaging as treatment for our patient’s MLL. Because MLLs also contain disrupted lymphatics, lymphedema management strategies (eg, short-stretch bandages) can be used. Our patient rapidly improved after conversion to short-stretch bandages.
These bandages are applied with 50% overlap to ensure even pressures throughout.16 Multiple layers are applied using a combination of spiral and figure-of-8 techniques, first clockwise and then counterclockwise, to avoid shearing underlying tissue.17 This method is very important in MLL treatment, given the degloving involved and the highly mobile skin and subcutaneous fat.
In standard lymphedema management, a foam padding layer is applied before the short-stretch bandage in order to reshape the limb and avoid proximal constrictions.13 In our patient’s case, the short-stretch wrap was applied without padding. Because his condition was acute, and the limb contour was preserved, limb reshaping and thus padding were not necessary.
Given the rapid, high-volume reduction that occurs within the first 1 to 2 weeks, bandages are reapplied daily to effectively adjust for the decreased swelling and altered limb shape.17 Most improvement is expected within the first few weeks—consistent with our patient’s case. Bandages usually are applied to the entire limb. For partial cases, the bandaging must extend past the area of swelling and incorporate the knee to prevent displacement of fluid into the joint.17 Feet and ankles are bandaged in dorsiflexion.17Several factors must be considered with short-stretch wraps. For example, pressure may need to be adjusted in patients with peripheral vascular disease. In patients with ankle-brachial indexes >0.5, it is safe to apply pressure up to 40 mm Hg.12 Reduced pressure is recommended for patients with arterial disease, sensory disturbance, lipoedema, poor mobility, frailty, or palliative needs.13The unusual location of our patient’s MLL accounts for the delay in diagnosis. To our knowledge, no other authors have reported such a large MLL in this location. A few series and case reports have listed MLLs in the calf near the gastrocnemius muscle, in the ankle, in the prepatellar area, and in the suprapatellar region, including the thigh,1,3,18-20 but there are no reports of MLLs running from medial thigh to proximal calf. MLLs of this size classically are treated surgically, but our patient selected nonoperative management.
To our knowledge, there are no earlier reports of using this nonoperative technique to treat MLLs. Conservative treatment with compression has been discussed, but no case involved short-stretch bandages. Large MLLs are thought to require surgery plus some type of drainage. The success of using short-stretch bandages in our patient’s case should prompt further investigation of use in adherent patients—which could ultimately result in reduced surgical needs, improved wound care (surgery is avoided), and a maintained low risk of infection. Although more work is needed to come to a more definitive verdict on this treatment method, it is a promising option that warrants consideration.
Am J Orthop. 2017;46(4):E213-E218. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
1. Tejwani SG, Cohen SB, Bradley JP. Management of Morel-Lavallee lesion of the knee: twenty-seven cases in the National Football League. Am J Sports Med. 2007;35(7):1162-1167.
2. Tsur A, Galin A, Kogan L, Loberant N. Morel-Lavallee syndrome after crush injury [in Hebrew]. Harefuah. 2006;145(2):111-113.
3. Ciaschini M, Sundaram M. Radiologic case study. Prepatellar Morel-Lavallée lesion. Orthopedics. 2008;31(7):626, 719-721.
4. Nickerson TP, Zielinski MD, Jenkins DH, Schiller HJ. The Mayo Clinic experience with Morel-Lavallée lesions: establishment of a practice management guideline. J Trauma Acute Care Surg. 2014;76(2):493-497.
5. Bansal A, Bhatia N, Singh A, Singh AK. Doxycycline sclerodesis as a treatment option for persistent Morel-Lavallée lesions. Injury. 2013;44(1):66-69.
6. Carlson DA, Simmons J, Sando W, Weber T, Clements B. Morel-Lavalée lesions treated with debridement and meticulous dead space closure: surgical technique. J Orthop Trauma. 2007;21(2):140-144.
7. Miller J, Daggett J, Ambay R, Payne WG. Morel-Lavallée lesion. Eplasty. 2014;14:ic12.
8. Tseng S, Tornetta P 3rd. Percutaneous management of Morel-Lavallee lesions. J Bone Joint Surg Am. 2006;88(1):92-96.
9. Harma A, Inan M, Ertem K. The Morel-Lavallée lesion: a conservative approach to closed degloving injuries [in Turkish]. Acta Orthop Traumatol Turc. 2004;38(4):270-273.
10. Hsu A, Franceschina D, Haddad SL. A novel method of postoperative wound care following total ankle arthroplasty. Foot Ankle Int. 2014;35(7):719-724.
11. Rohner-Spengler M, Frotzler A, Honigmann P, Babst R. Effective treatment of posttraumatic and postoperative edema in patients with ankle and hindfoot fractures: a randomized controlled trial comparing multilayer compression therapy and intermittent impulse compression with the standard treatment with ice. J Bone Joint Surg Am. 2014;96(15):1263-1271.
12. Bjork R. The long and short of it: understanding compression bandaging. Wound Care Advisor. 2013;2(6):12-15.
13. Partsch H. Assessing the effectiveness of multilayer inelastic bandaging. J Lymphoedema. 2007;2(2):55-61.
14. Hafner J, Botonakis I, Burg G. A comparison of multilayer bandage systems during rest, exercise, and over 2 days of wear time. Arch Dermatol. 2000;136(7):857-863.
15. Földi E, Jünger M, Partsch H. The science of lymphoedema bandaging. In: Lymphoedema Bandaging in Practice [European Wound Management Association focus document]. London, England: Medical Education Partnership; 2005:2-4.
16. King TI, Droessler JL. Physical properties of short-stretch compression bandages used to treat lymphedema. Am J Occup Ther. 2001;55(5):573-576.
17. Williams AF, Keller M. Practical guidance on lymphoedema bandaging of the upper and lower limbs. In: Lymphoedema Bandaging in Practice [European Wound Management Association focus document]. London, England: Medical Education Partnership; 2005:10-14.
18. Moriarty JM, Borrero CG, Kavanagh EC. A rare cause of calf swelling: the Morel-Lavallee lesion. Ir J Med Sci. 2011;180(1):265-268.
19. Anakwenze OA, Trivedi V, Goodman AM, Ganley TJ. Knee Morel-Lavallee lesion after a football injury in an 11-year-old boy: case report and review of the literature. Univ Pa Orthop J. 2011;21:56-58.
20. Hudson DA, Knottenbelt JD, Krige JE. Closed degloving injuries: results following conservative surgery. Plast Reconstr Surg. 1992;89(5):853-855.
Take-Home Points
- Have a high-index of suspicion for MLLs and initiate treatment early.
- Compression needs to occur through short-stretch bandaging over a conventional Ace wrap in order to be successful.
- Apply the short-stretch compression with care to avoid shearing underlying tissue.
- Nonoperative treatment modalities require high patient compliance.
- MLLs need close monitoring until final healing occurs.
Morel-Lavallée lesions (MLLs) are traumatic degloving injuries resulting from separation of subcutaneous fat from underlying fascia. MLLs occur in association with acetabular fractures and are also associated with low-velocity crush injuries.1,2 Shearing creates a “false” space that is filled with hemorrhaged blood, fat, and lymphatic tissue.3 Disruption of the lymphatics leads to cavity formation and, eventually, a fibrotic pseudocapsule.4The pseudocapsule prevents resorption, leading to a chronic fluid collection, which potentiates the risk of infection or tissue necrosis.3,5,6 Skin necrosis may occur through direct-pressure compromise of the dermal vascular plexus.4 Necrotic skin may require multiple débridements, negative-pressure wound therapy or soft-tissue coverage, and may ultimately result in infection. MLLs classically occur in the greater trochanteric region, lateral thigh, buttocks, and back but also appear in the prepatellar region.1,3 Patients present with soft-tissue swelling, bruising, bulging, decreased cutaneous sensation over the region, and a palpable, fluctuant subcutaneous fluid collection with mobile skin.2,4,7 The mechanism of injury may cause a concomitant fracture. Magnetic resonance imaging (MRI), the preferred imaging modality, shows a discrete fluid collection between subcutaneous fat and underlying fascia. Ultrasonography may reveal a thickened capsule surrounding either a hypoechoic area or an anechoic area but its accuracy is user-dependent.7
Large MLLs may be treated with open serial débridement and healing by secondary intention; infection rates, however, are high. Authors have described several other treatment modalities, including percutaneous débridement with a brush followed by use of a large-bore drain and antibiotics; open débridement with meticulous dead-space closure; elastic compression bandaging; aspiration; and doxycycline sclerodesis.1,5,6,8,9 Modifications of short-stretch compression bandaging were recently described in edema control for hindfoot trauma, ankle trauma, and total ankle arthroplasty, but not for MLLs.10,11 Nickerson and colleagues4 retrospectively reviewed 87 MLLs, found that fluid aspirate of >50 mL predicted recurrence and failure with conservative measures, and recommended operative intervention for any MLL with >50 mL of fluid aspirated.
We report the case of an MLL that occurred in an unusual anatomical region, and we describe a novel application of a conservative treatment, which was selected on the basis of its success in lymphedema management. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 66-year-old man was injured when a parked vehicle began moving, pulled him under, and ran over his lower right leg. In the emergency department, no fractures or major injuries were noted (Figures 1A, 1B), and the patient was discharged.
About 10 days after injury, profuse ecchymosis and swelling were noted running from the distal medial thigh to the proximal medial calf (Figures 2A-2C).
Given the size of the MLL, the fluid collection reaccumulated. The patient was evaluated by an orthopedic traumatologist 3 days after the aspiration (17 days after injury).
Another orthopedic traumatologist confirmed the low likelihood that compression would resolve the MLL, given its size (Figures 4A, 4B).
After the second orthopedic consultation, the patient saw a physical therapist trained in complete decongestive therapy. The therapist suggested placing short-stretch bandage wraps over the conventional long-stretch Ace bandage currently being used—a treatment common in lymphedema. The patient was wrapped from toe to groin without an initial layer of padding (Figures 6A, 6B), and the response was immediate.
Nine weeks after injury, the leg was significantly improved, and clinical signs resolved (Figure 7).
Discussion
Short-stretch bandaging has been performed mainly in lymphedema and ulcer management.
Compression bandaging reduces volume in lymphedematous limbs by reducing capillary filtration, shifting fluid into noncompressed parts of the body, increasing lymphatic reabsorption and lymphatic transport stimulation, improving venous pumping, and breaking down fibrosclerotic tissue.15 We think containment, improved venous flow, and enhanced muscle contraction contributed to the effectiveness of short-stretch bandaging as treatment for our patient’s MLL. Because MLLs also contain disrupted lymphatics, lymphedema management strategies (eg, short-stretch bandages) can be used. Our patient rapidly improved after conversion to short-stretch bandages.
These bandages are applied with 50% overlap to ensure even pressures throughout.16 Multiple layers are applied using a combination of spiral and figure-of-8 techniques, first clockwise and then counterclockwise, to avoid shearing underlying tissue.17 This method is very important in MLL treatment, given the degloving involved and the highly mobile skin and subcutaneous fat.
In standard lymphedema management, a foam padding layer is applied before the short-stretch bandage in order to reshape the limb and avoid proximal constrictions.13 In our patient’s case, the short-stretch wrap was applied without padding. Because his condition was acute, and the limb contour was preserved, limb reshaping and thus padding were not necessary.
Given the rapid, high-volume reduction that occurs within the first 1 to 2 weeks, bandages are reapplied daily to effectively adjust for the decreased swelling and altered limb shape.17 Most improvement is expected within the first few weeks—consistent with our patient’s case. Bandages usually are applied to the entire limb. For partial cases, the bandaging must extend past the area of swelling and incorporate the knee to prevent displacement of fluid into the joint.17 Feet and ankles are bandaged in dorsiflexion.17Several factors must be considered with short-stretch wraps. For example, pressure may need to be adjusted in patients with peripheral vascular disease. In patients with ankle-brachial indexes >0.5, it is safe to apply pressure up to 40 mm Hg.12 Reduced pressure is recommended for patients with arterial disease, sensory disturbance, lipoedema, poor mobility, frailty, or palliative needs.13The unusual location of our patient’s MLL accounts for the delay in diagnosis. To our knowledge, no other authors have reported such a large MLL in this location. A few series and case reports have listed MLLs in the calf near the gastrocnemius muscle, in the ankle, in the prepatellar area, and in the suprapatellar region, including the thigh,1,3,18-20 but there are no reports of MLLs running from medial thigh to proximal calf. MLLs of this size classically are treated surgically, but our patient selected nonoperative management.
To our knowledge, there are no earlier reports of using this nonoperative technique to treat MLLs. Conservative treatment with compression has been discussed, but no case involved short-stretch bandages. Large MLLs are thought to require surgery plus some type of drainage. The success of using short-stretch bandages in our patient’s case should prompt further investigation of use in adherent patients—which could ultimately result in reduced surgical needs, improved wound care (surgery is avoided), and a maintained low risk of infection. Although more work is needed to come to a more definitive verdict on this treatment method, it is a promising option that warrants consideration.
Am J Orthop. 2017;46(4):E213-E218. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
Take-Home Points
- Have a high-index of suspicion for MLLs and initiate treatment early.
- Compression needs to occur through short-stretch bandaging over a conventional Ace wrap in order to be successful.
- Apply the short-stretch compression with care to avoid shearing underlying tissue.
- Nonoperative treatment modalities require high patient compliance.
- MLLs need close monitoring until final healing occurs.
Morel-Lavallée lesions (MLLs) are traumatic degloving injuries resulting from separation of subcutaneous fat from underlying fascia. MLLs occur in association with acetabular fractures and are also associated with low-velocity crush injuries.1,2 Shearing creates a “false” space that is filled with hemorrhaged blood, fat, and lymphatic tissue.3 Disruption of the lymphatics leads to cavity formation and, eventually, a fibrotic pseudocapsule.4The pseudocapsule prevents resorption, leading to a chronic fluid collection, which potentiates the risk of infection or tissue necrosis.3,5,6 Skin necrosis may occur through direct-pressure compromise of the dermal vascular plexus.4 Necrotic skin may require multiple débridements, negative-pressure wound therapy or soft-tissue coverage, and may ultimately result in infection. MLLs classically occur in the greater trochanteric region, lateral thigh, buttocks, and back but also appear in the prepatellar region.1,3 Patients present with soft-tissue swelling, bruising, bulging, decreased cutaneous sensation over the region, and a palpable, fluctuant subcutaneous fluid collection with mobile skin.2,4,7 The mechanism of injury may cause a concomitant fracture. Magnetic resonance imaging (MRI), the preferred imaging modality, shows a discrete fluid collection between subcutaneous fat and underlying fascia. Ultrasonography may reveal a thickened capsule surrounding either a hypoechoic area or an anechoic area but its accuracy is user-dependent.7
Large MLLs may be treated with open serial débridement and healing by secondary intention; infection rates, however, are high. Authors have described several other treatment modalities, including percutaneous débridement with a brush followed by use of a large-bore drain and antibiotics; open débridement with meticulous dead-space closure; elastic compression bandaging; aspiration; and doxycycline sclerodesis.1,5,6,8,9 Modifications of short-stretch compression bandaging were recently described in edema control for hindfoot trauma, ankle trauma, and total ankle arthroplasty, but not for MLLs.10,11 Nickerson and colleagues4 retrospectively reviewed 87 MLLs, found that fluid aspirate of >50 mL predicted recurrence and failure with conservative measures, and recommended operative intervention for any MLL with >50 mL of fluid aspirated.
We report the case of an MLL that occurred in an unusual anatomical region, and we describe a novel application of a conservative treatment, which was selected on the basis of its success in lymphedema management. The patient provided written informed consent for print and electronic publication of this case report.
Case Report
A 66-year-old man was injured when a parked vehicle began moving, pulled him under, and ran over his lower right leg. In the emergency department, no fractures or major injuries were noted (Figures 1A, 1B), and the patient was discharged.
About 10 days after injury, profuse ecchymosis and swelling were noted running from the distal medial thigh to the proximal medial calf (Figures 2A-2C).
Given the size of the MLL, the fluid collection reaccumulated. The patient was evaluated by an orthopedic traumatologist 3 days after the aspiration (17 days after injury).
Another orthopedic traumatologist confirmed the low likelihood that compression would resolve the MLL, given its size (Figures 4A, 4B).
After the second orthopedic consultation, the patient saw a physical therapist trained in complete decongestive therapy. The therapist suggested placing short-stretch bandage wraps over the conventional long-stretch Ace bandage currently being used—a treatment common in lymphedema. The patient was wrapped from toe to groin without an initial layer of padding (Figures 6A, 6B), and the response was immediate.
Nine weeks after injury, the leg was significantly improved, and clinical signs resolved (Figure 7).
Discussion
Short-stretch bandaging has been performed mainly in lymphedema and ulcer management.
Compression bandaging reduces volume in lymphedematous limbs by reducing capillary filtration, shifting fluid into noncompressed parts of the body, increasing lymphatic reabsorption and lymphatic transport stimulation, improving venous pumping, and breaking down fibrosclerotic tissue.15 We think containment, improved venous flow, and enhanced muscle contraction contributed to the effectiveness of short-stretch bandaging as treatment for our patient’s MLL. Because MLLs also contain disrupted lymphatics, lymphedema management strategies (eg, short-stretch bandages) can be used. Our patient rapidly improved after conversion to short-stretch bandages.
These bandages are applied with 50% overlap to ensure even pressures throughout.16 Multiple layers are applied using a combination of spiral and figure-of-8 techniques, first clockwise and then counterclockwise, to avoid shearing underlying tissue.17 This method is very important in MLL treatment, given the degloving involved and the highly mobile skin and subcutaneous fat.
In standard lymphedema management, a foam padding layer is applied before the short-stretch bandage in order to reshape the limb and avoid proximal constrictions.13 In our patient’s case, the short-stretch wrap was applied without padding. Because his condition was acute, and the limb contour was preserved, limb reshaping and thus padding were not necessary.
Given the rapid, high-volume reduction that occurs within the first 1 to 2 weeks, bandages are reapplied daily to effectively adjust for the decreased swelling and altered limb shape.17 Most improvement is expected within the first few weeks—consistent with our patient’s case. Bandages usually are applied to the entire limb. For partial cases, the bandaging must extend past the area of swelling and incorporate the knee to prevent displacement of fluid into the joint.17 Feet and ankles are bandaged in dorsiflexion.17Several factors must be considered with short-stretch wraps. For example, pressure may need to be adjusted in patients with peripheral vascular disease. In patients with ankle-brachial indexes >0.5, it is safe to apply pressure up to 40 mm Hg.12 Reduced pressure is recommended for patients with arterial disease, sensory disturbance, lipoedema, poor mobility, frailty, or palliative needs.13The unusual location of our patient’s MLL accounts for the delay in diagnosis. To our knowledge, no other authors have reported such a large MLL in this location. A few series and case reports have listed MLLs in the calf near the gastrocnemius muscle, in the ankle, in the prepatellar area, and in the suprapatellar region, including the thigh,1,3,18-20 but there are no reports of MLLs running from medial thigh to proximal calf. MLLs of this size classically are treated surgically, but our patient selected nonoperative management.
To our knowledge, there are no earlier reports of using this nonoperative technique to treat MLLs. Conservative treatment with compression has been discussed, but no case involved short-stretch bandages. Large MLLs are thought to require surgery plus some type of drainage. The success of using short-stretch bandages in our patient’s case should prompt further investigation of use in adherent patients—which could ultimately result in reduced surgical needs, improved wound care (surgery is avoided), and a maintained low risk of infection. Although more work is needed to come to a more definitive verdict on this treatment method, it is a promising option that warrants consideration.
Am J Orthop. 2017;46(4):E213-E218. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
1. Tejwani SG, Cohen SB, Bradley JP. Management of Morel-Lavallee lesion of the knee: twenty-seven cases in the National Football League. Am J Sports Med. 2007;35(7):1162-1167.
2. Tsur A, Galin A, Kogan L, Loberant N. Morel-Lavallee syndrome after crush injury [in Hebrew]. Harefuah. 2006;145(2):111-113.
3. Ciaschini M, Sundaram M. Radiologic case study. Prepatellar Morel-Lavallée lesion. Orthopedics. 2008;31(7):626, 719-721.
4. Nickerson TP, Zielinski MD, Jenkins DH, Schiller HJ. The Mayo Clinic experience with Morel-Lavallée lesions: establishment of a practice management guideline. J Trauma Acute Care Surg. 2014;76(2):493-497.
5. Bansal A, Bhatia N, Singh A, Singh AK. Doxycycline sclerodesis as a treatment option for persistent Morel-Lavallée lesions. Injury. 2013;44(1):66-69.
6. Carlson DA, Simmons J, Sando W, Weber T, Clements B. Morel-Lavalée lesions treated with debridement and meticulous dead space closure: surgical technique. J Orthop Trauma. 2007;21(2):140-144.
7. Miller J, Daggett J, Ambay R, Payne WG. Morel-Lavallée lesion. Eplasty. 2014;14:ic12.
8. Tseng S, Tornetta P 3rd. Percutaneous management of Morel-Lavallee lesions. J Bone Joint Surg Am. 2006;88(1):92-96.
9. Harma A, Inan M, Ertem K. The Morel-Lavallée lesion: a conservative approach to closed degloving injuries [in Turkish]. Acta Orthop Traumatol Turc. 2004;38(4):270-273.
10. Hsu A, Franceschina D, Haddad SL. A novel method of postoperative wound care following total ankle arthroplasty. Foot Ankle Int. 2014;35(7):719-724.
11. Rohner-Spengler M, Frotzler A, Honigmann P, Babst R. Effective treatment of posttraumatic and postoperative edema in patients with ankle and hindfoot fractures: a randomized controlled trial comparing multilayer compression therapy and intermittent impulse compression with the standard treatment with ice. J Bone Joint Surg Am. 2014;96(15):1263-1271.
12. Bjork R. The long and short of it: understanding compression bandaging. Wound Care Advisor. 2013;2(6):12-15.
13. Partsch H. Assessing the effectiveness of multilayer inelastic bandaging. J Lymphoedema. 2007;2(2):55-61.
14. Hafner J, Botonakis I, Burg G. A comparison of multilayer bandage systems during rest, exercise, and over 2 days of wear time. Arch Dermatol. 2000;136(7):857-863.
15. Földi E, Jünger M, Partsch H. The science of lymphoedema bandaging. In: Lymphoedema Bandaging in Practice [European Wound Management Association focus document]. London, England: Medical Education Partnership; 2005:2-4.
16. King TI, Droessler JL. Physical properties of short-stretch compression bandages used to treat lymphedema. Am J Occup Ther. 2001;55(5):573-576.
17. Williams AF, Keller M. Practical guidance on lymphoedema bandaging of the upper and lower limbs. In: Lymphoedema Bandaging in Practice [European Wound Management Association focus document]. London, England: Medical Education Partnership; 2005:10-14.
18. Moriarty JM, Borrero CG, Kavanagh EC. A rare cause of calf swelling: the Morel-Lavallee lesion. Ir J Med Sci. 2011;180(1):265-268.
19. Anakwenze OA, Trivedi V, Goodman AM, Ganley TJ. Knee Morel-Lavallee lesion after a football injury in an 11-year-old boy: case report and review of the literature. Univ Pa Orthop J. 2011;21:56-58.
20. Hudson DA, Knottenbelt JD, Krige JE. Closed degloving injuries: results following conservative surgery. Plast Reconstr Surg. 1992;89(5):853-855.
1. Tejwani SG, Cohen SB, Bradley JP. Management of Morel-Lavallee lesion of the knee: twenty-seven cases in the National Football League. Am J Sports Med. 2007;35(7):1162-1167.
2. Tsur A, Galin A, Kogan L, Loberant N. Morel-Lavallee syndrome after crush injury [in Hebrew]. Harefuah. 2006;145(2):111-113.
3. Ciaschini M, Sundaram M. Radiologic case study. Prepatellar Morel-Lavallée lesion. Orthopedics. 2008;31(7):626, 719-721.
4. Nickerson TP, Zielinski MD, Jenkins DH, Schiller HJ. The Mayo Clinic experience with Morel-Lavallée lesions: establishment of a practice management guideline. J Trauma Acute Care Surg. 2014;76(2):493-497.
5. Bansal A, Bhatia N, Singh A, Singh AK. Doxycycline sclerodesis as a treatment option for persistent Morel-Lavallée lesions. Injury. 2013;44(1):66-69.
6. Carlson DA, Simmons J, Sando W, Weber T, Clements B. Morel-Lavalée lesions treated with debridement and meticulous dead space closure: surgical technique. J Orthop Trauma. 2007;21(2):140-144.
7. Miller J, Daggett J, Ambay R, Payne WG. Morel-Lavallée lesion. Eplasty. 2014;14:ic12.
8. Tseng S, Tornetta P 3rd. Percutaneous management of Morel-Lavallee lesions. J Bone Joint Surg Am. 2006;88(1):92-96.
9. Harma A, Inan M, Ertem K. The Morel-Lavallée lesion: a conservative approach to closed degloving injuries [in Turkish]. Acta Orthop Traumatol Turc. 2004;38(4):270-273.
10. Hsu A, Franceschina D, Haddad SL. A novel method of postoperative wound care following total ankle arthroplasty. Foot Ankle Int. 2014;35(7):719-724.
11. Rohner-Spengler M, Frotzler A, Honigmann P, Babst R. Effective treatment of posttraumatic and postoperative edema in patients with ankle and hindfoot fractures: a randomized controlled trial comparing multilayer compression therapy and intermittent impulse compression with the standard treatment with ice. J Bone Joint Surg Am. 2014;96(15):1263-1271.
12. Bjork R. The long and short of it: understanding compression bandaging. Wound Care Advisor. 2013;2(6):12-15.
13. Partsch H. Assessing the effectiveness of multilayer inelastic bandaging. J Lymphoedema. 2007;2(2):55-61.
14. Hafner J, Botonakis I, Burg G. A comparison of multilayer bandage systems during rest, exercise, and over 2 days of wear time. Arch Dermatol. 2000;136(7):857-863.
15. Földi E, Jünger M, Partsch H. The science of lymphoedema bandaging. In: Lymphoedema Bandaging in Practice [European Wound Management Association focus document]. London, England: Medical Education Partnership; 2005:2-4.
16. King TI, Droessler JL. Physical properties of short-stretch compression bandages used to treat lymphedema. Am J Occup Ther. 2001;55(5):573-576.
17. Williams AF, Keller M. Practical guidance on lymphoedema bandaging of the upper and lower limbs. In: Lymphoedema Bandaging in Practice [European Wound Management Association focus document]. London, England: Medical Education Partnership; 2005:10-14.
18. Moriarty JM, Borrero CG, Kavanagh EC. A rare cause of calf swelling: the Morel-Lavallee lesion. Ir J Med Sci. 2011;180(1):265-268.
19. Anakwenze OA, Trivedi V, Goodman AM, Ganley TJ. Knee Morel-Lavallee lesion after a football injury in an 11-year-old boy: case report and review of the literature. Univ Pa Orthop J. 2011;21:56-58.
20. Hudson DA, Knottenbelt JD, Krige JE. Closed degloving injuries: results following conservative surgery. Plast Reconstr Surg. 1992;89(5):853-855.
