User login
Letter to the Editor
We appreciate Dr. Antonios' comments regarding our article[1] and agree with his view that there is a need for both a recovery auditor and observation reform. The House of Representatives recently unanimously passed the NOTICE Act (H.R. 876), which would require hospitals to provide verbal and written notification to patients hospitalized as observation for more than 24 hours and obtain a signed record that the patient has received this information.[2] Also, the law to repeal the Medicare Sustainable Growth Rate (SGR) (Medicare Access and CHIP Reauthorization Act of 2105, P.L. 114‐10), signed into law by President Obama in April, 2015, included a provision to delay recovery auditor activity for an additional 6 months, through September 30, 2015.[3] Although both of these bills demonstrate that congress is informed about problems with recovery auditors and observation policy, neither beneficiary notification of observation nor a 6‐month auditing delay does anything to reform the fundamental problems with observation and the recovery audit program that have resulted in the appeals backlog described by Dr. Antionios.
While we agree that hospitalized beneficiaries should be notified of their visit status, notification alone of outpatient status with observation services, without any enhanced ability of beneficiaries to appeal this determination, or adequate beneficiary education that status determinations are made by clinicians based on Centers for Medicare and Medicaid Services (CMS) regulations, may result in even more confusion and frustration for beneficiaries and clinicians. We hope that Congress will move forward with improvements in actual observation policy, such as counting observation midnights toward the 3‐midnight stay requirement for skilled nursing facility coverage.[4]
Furthermore, as Dr. Antonios points out, the March 2015 victory in a federal circuit court by CGI Federal, Inc., an RAC contractor, over CMS's new payment terms for recovery audit contracts, which reversed a previous decision and remanded the case to the Court of Federal Claims, will delay CMS' awarding of the new RAC contracts. This makes the actual effect of the 6‐month RAC auditing delay in the SGR bill unclear at this time.[5] We hope that these current legislative efforts are revisited and will be the beginning, and not the end, of legislative and regulatory reform efforts on these important issues.
- , , , , , . Changes to inpatient versus outpatient hospitalization: Medicare's 2‐midnight rule. J Hosp Med. 2015;10:194–201.
- NOTICE Act, H.R. 876, Section 2. Medicare requirement for hospital notifications of observation status. Available at: https://www.govtrack.us/congress/bills/114/hr876/text. Accessed March 27, 2015.
- Medicare Access and CHIP Reauthorization Act of 2105, H.R. 2, Section 521. Extension of two‐midnight PAMA rules on certain medical review activities. Available at: https://www.congress.gov/bill/114th‐congress/house‐bill/2/text. Accessed on April 29, 2015.
- Improving Access to Medicare Coverage Act, H.R. 1571 and S. 843. Available at: https://www.congress.gov/bill/114th‐congress/house‐bill/1571. Accessed March 31, 2015.
- United States Court of Appeals for the Federal Circuit, CGI FEDERAL INC., Plaintiff‐Appellant v. UNITED STATES, Defendant‐Appellee, 2014–5143. http://www.cafc.uscourts.gov/images/stories/opinions‐orders/14–5143.Opinion.3–6‐2015.1.PDF. Accessed March 30, 2015.
We appreciate Dr. Antonios' comments regarding our article[1] and agree with his view that there is a need for both a recovery auditor and observation reform. The House of Representatives recently unanimously passed the NOTICE Act (H.R. 876), which would require hospitals to provide verbal and written notification to patients hospitalized as observation for more than 24 hours and obtain a signed record that the patient has received this information.[2] Also, the law to repeal the Medicare Sustainable Growth Rate (SGR) (Medicare Access and CHIP Reauthorization Act of 2105, P.L. 114‐10), signed into law by President Obama in April, 2015, included a provision to delay recovery auditor activity for an additional 6 months, through September 30, 2015.[3] Although both of these bills demonstrate that congress is informed about problems with recovery auditors and observation policy, neither beneficiary notification of observation nor a 6‐month auditing delay does anything to reform the fundamental problems with observation and the recovery audit program that have resulted in the appeals backlog described by Dr. Antionios.
While we agree that hospitalized beneficiaries should be notified of their visit status, notification alone of outpatient status with observation services, without any enhanced ability of beneficiaries to appeal this determination, or adequate beneficiary education that status determinations are made by clinicians based on Centers for Medicare and Medicaid Services (CMS) regulations, may result in even more confusion and frustration for beneficiaries and clinicians. We hope that Congress will move forward with improvements in actual observation policy, such as counting observation midnights toward the 3‐midnight stay requirement for skilled nursing facility coverage.[4]
Furthermore, as Dr. Antonios points out, the March 2015 victory in a federal circuit court by CGI Federal, Inc., an RAC contractor, over CMS's new payment terms for recovery audit contracts, which reversed a previous decision and remanded the case to the Court of Federal Claims, will delay CMS' awarding of the new RAC contracts. This makes the actual effect of the 6‐month RAC auditing delay in the SGR bill unclear at this time.[5] We hope that these current legislative efforts are revisited and will be the beginning, and not the end, of legislative and regulatory reform efforts on these important issues.
We appreciate Dr. Antonios' comments regarding our article[1] and agree with his view that there is a need for both a recovery auditor and observation reform. The House of Representatives recently unanimously passed the NOTICE Act (H.R. 876), which would require hospitals to provide verbal and written notification to patients hospitalized as observation for more than 24 hours and obtain a signed record that the patient has received this information.[2] Also, the law to repeal the Medicare Sustainable Growth Rate (SGR) (Medicare Access and CHIP Reauthorization Act of 2105, P.L. 114‐10), signed into law by President Obama in April, 2015, included a provision to delay recovery auditor activity for an additional 6 months, through September 30, 2015.[3] Although both of these bills demonstrate that congress is informed about problems with recovery auditors and observation policy, neither beneficiary notification of observation nor a 6‐month auditing delay does anything to reform the fundamental problems with observation and the recovery audit program that have resulted in the appeals backlog described by Dr. Antionios.
While we agree that hospitalized beneficiaries should be notified of their visit status, notification alone of outpatient status with observation services, without any enhanced ability of beneficiaries to appeal this determination, or adequate beneficiary education that status determinations are made by clinicians based on Centers for Medicare and Medicaid Services (CMS) regulations, may result in even more confusion and frustration for beneficiaries and clinicians. We hope that Congress will move forward with improvements in actual observation policy, such as counting observation midnights toward the 3‐midnight stay requirement for skilled nursing facility coverage.[4]
Furthermore, as Dr. Antonios points out, the March 2015 victory in a federal circuit court by CGI Federal, Inc., an RAC contractor, over CMS's new payment terms for recovery audit contracts, which reversed a previous decision and remanded the case to the Court of Federal Claims, will delay CMS' awarding of the new RAC contracts. This makes the actual effect of the 6‐month RAC auditing delay in the SGR bill unclear at this time.[5] We hope that these current legislative efforts are revisited and will be the beginning, and not the end, of legislative and regulatory reform efforts on these important issues.
- , , , , , . Changes to inpatient versus outpatient hospitalization: Medicare's 2‐midnight rule. J Hosp Med. 2015;10:194–201.
- NOTICE Act, H.R. 876, Section 2. Medicare requirement for hospital notifications of observation status. Available at: https://www.govtrack.us/congress/bills/114/hr876/text. Accessed March 27, 2015.
- Medicare Access and CHIP Reauthorization Act of 2105, H.R. 2, Section 521. Extension of two‐midnight PAMA rules on certain medical review activities. Available at: https://www.congress.gov/bill/114th‐congress/house‐bill/2/text. Accessed on April 29, 2015.
- Improving Access to Medicare Coverage Act, H.R. 1571 and S. 843. Available at: https://www.congress.gov/bill/114th‐congress/house‐bill/1571. Accessed March 31, 2015.
- United States Court of Appeals for the Federal Circuit, CGI FEDERAL INC., Plaintiff‐Appellant v. UNITED STATES, Defendant‐Appellee, 2014–5143. http://www.cafc.uscourts.gov/images/stories/opinions‐orders/14–5143.Opinion.3–6‐2015.1.PDF. Accessed March 30, 2015.
- , , , , , . Changes to inpatient versus outpatient hospitalization: Medicare's 2‐midnight rule. J Hosp Med. 2015;10:194–201.
- NOTICE Act, H.R. 876, Section 2. Medicare requirement for hospital notifications of observation status. Available at: https://www.govtrack.us/congress/bills/114/hr876/text. Accessed March 27, 2015.
- Medicare Access and CHIP Reauthorization Act of 2105, H.R. 2, Section 521. Extension of two‐midnight PAMA rules on certain medical review activities. Available at: https://www.congress.gov/bill/114th‐congress/house‐bill/2/text. Accessed on April 29, 2015.
- Improving Access to Medicare Coverage Act, H.R. 1571 and S. 843. Available at: https://www.congress.gov/bill/114th‐congress/house‐bill/1571. Accessed March 31, 2015.
- United States Court of Appeals for the Federal Circuit, CGI FEDERAL INC., Plaintiff‐Appellant v. UNITED STATES, Defendant‐Appellee, 2014–5143. http://www.cafc.uscourts.gov/images/stories/opinions‐orders/14–5143.Opinion.3–6‐2015.1.PDF. Accessed March 30, 2015.
Perfect is the enemy of good
Urban legends never seem to die. They haunt those who chase the truth because most legends have a kernel of truth. Reflux nephropathy is one of those legends.
In the 1970s, neurosurgeons began treating children with spina bifida rather than allowing them to die shortly after birth. As these children entered their second and third decade of life, episodes of renal failure were noted. The reflux and recurring urinary tract infections (UTIs) from neurogenic bladders damaged kidneys. Self-catheter programs were invented and were effective. Surgical correction of anatomic urinary obstructions and severe reflux yielded similar benefits. By the 1990s, this paradigm had been extrapolated to all children with vesicoureteral reflux (VUR) and codified in the 1999 practice parameter. The unproven hope was that aggressive antibiotic prophylaxis to protect young, growing kidneys from infections would reduce the incidence of renal failure and hypertension in adults.
This is a common methodology for quality improvement at a Mortality and Morbidity conference. A problem is identified. A solution is developed to prevent the bad outcome. The solution is implemented without fully proving that the obvious, customized intervention truly works. No one ever assesses whether the remedy causes more mischief than benefit.
VUR has a pyramid shaped spectrum. Few children have the severe grade V reflux which responds to surgical intervention. At the base of the pyramid are a much larger group of children with mild reflux that usually resolves spontaneously by age 5 years. This pyramid is a setup for overdiagnosis and overtreatment of mild disease. Pediatricians soon recognized that the small portion of the 1999 practice parameter addressing reflux nephropathy was overly aggressive and based on unsound science. However, that same lack of clear evidence delayed creating a new consensus until 2011.
The recent efforts to prove the benefit of prophylaxis used exemplary evidence-based medicine. The RIVUR study over 4 years assessed 10,000 children in a multicenter study involving 19 locations. It enrolled 600 children in a prospective, double-blind, randomized, controlled trial with a placebo control. It followed the children for 2 years. Even by modern standards, this was a huge, prolonged and well-designed trial. It did demonstrate a benefit. About 20% of children on placebo had a recurrent UTI in that 2-year time frame. There was a 50% reduction in the number of UTIs in the children treated with antibiotic prophylaxis. Phrased that way, it was a success. But the numbers can be spun differently. The article duly noted a number needed to treat of eight. Eight children treated for 2 years at 365 days per year and one dose per day, means that 6,000 doses of antibiotics were necessary to prevent one UTI. There was no demonstrated benefit in renal scarring, renal failure, or other long-term outcomes. There was a downside. The rate of antibiotic-resistant organisms in the breakthrough UTIs tripled from 19% of the placebo group to 63% of the prophylaxis group. As large as this study was, it wasn’t able to measure the rate of other known adverse outcomes, such as Stevens-Johnson syndrome from the use of sulfa medications or the impact on resistant infections elsewhere in the body.
With the 2011 practice parameter, pediatricians became less aggressive at working up first UTIs. Urologists disagreed. The May 2015 issue of AAP News had a full page article by Dr. Saul Greenfield, who is the chairperson-elect for the Executive Committee of the American Academy of Pediatrics Section on Urology, a urologist in Buffalo, N.Y., and one of the RIVUR trial’s investigators (AAP News 2015;36:13). He rehashed the RIVUR study results emphasizing the reduction in UTIs, but offered no quantitative assessment of the risks, costs, and harms of prophylaxis.
A June 2015 article in Pediatrics gives the results of the CUTIE study, which ran in parallel with the RIVUR study (Pediatrics 2015 [doi:10.1542/peds.2015-0409]). The conclusions: “VUR and BBD [bladder and bowel dysfunction] are risk factors for recurrent UTI, especially when they appear in combination. Strategies for preventing recurrent UTI include antimicrobial prophylaxis and treatment of BBD.”
The article concludes with, “Therefore, clinicians must help families decide whether the benefits of prophylaxis outweigh the risks and inconvenience. … Additional research is needed to validate the risk factors and profiles that we identified.”
But six pages of discussing renal scarring (which is only a proxy for a small risk of future renal failure or hypertension), followed by a couple paragraphs, without numbers, about the risks of prophylaxis, does not provide the balanced presentation clinicians need to help families make wise decisions. In the new era of Choosing Wisely, scientific articles making clinical recommendations should not be published without an accompanying risk-benefit analysis, either in the article or in an editorial. The maxim in surgery, channeling Voltaire, is that “perfect is the enemy of good.”
There is mounting evidence that giving any antibiotics to young infants is harmful. Even 2 days of antibiotics before 1 month of age leads to measurable changes in the gut microbiota 6 months later. Antibiotics in infancy are associated with obesity at 24 months and at 48 months of age. All medical treatments introduce a substantial risk of harm. As Shakespeare wrote 400 years ago, “Striving to better, oft we mar what’s well.” I don’t doubt the conclusion that prophylaxis reduces UTIs, but giving 6,000 doses to prevent one UTI?! Even Kaley Cuoco can’t sell that.
Ultimately, this choice is not up to the hospitalist, the emergency department doctor, or the urologist. The decision belongs to the parents guided by a primary care doctor they trust. Our professional duty, ethically and legally, is to communicate the risks and benefits to the parents in a manner which they can understand and to provide them the support and counseling necessary to make a wise choice for their child. By focusing on the child and that duty, medical professionals can defuse any clashes of egos, departmental power struggles, or autocratic hierarchy that might interfere. Doctors educate and recommend, but the parent decides what is best for his or her child.
Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures or conflicts of interest. E-mail him at [email protected].
Urban legends never seem to die. They haunt those who chase the truth because most legends have a kernel of truth. Reflux nephropathy is one of those legends.
In the 1970s, neurosurgeons began treating children with spina bifida rather than allowing them to die shortly after birth. As these children entered their second and third decade of life, episodes of renal failure were noted. The reflux and recurring urinary tract infections (UTIs) from neurogenic bladders damaged kidneys. Self-catheter programs were invented and were effective. Surgical correction of anatomic urinary obstructions and severe reflux yielded similar benefits. By the 1990s, this paradigm had been extrapolated to all children with vesicoureteral reflux (VUR) and codified in the 1999 practice parameter. The unproven hope was that aggressive antibiotic prophylaxis to protect young, growing kidneys from infections would reduce the incidence of renal failure and hypertension in adults.
This is a common methodology for quality improvement at a Mortality and Morbidity conference. A problem is identified. A solution is developed to prevent the bad outcome. The solution is implemented without fully proving that the obvious, customized intervention truly works. No one ever assesses whether the remedy causes more mischief than benefit.
VUR has a pyramid shaped spectrum. Few children have the severe grade V reflux which responds to surgical intervention. At the base of the pyramid are a much larger group of children with mild reflux that usually resolves spontaneously by age 5 years. This pyramid is a setup for overdiagnosis and overtreatment of mild disease. Pediatricians soon recognized that the small portion of the 1999 practice parameter addressing reflux nephropathy was overly aggressive and based on unsound science. However, that same lack of clear evidence delayed creating a new consensus until 2011.
The recent efforts to prove the benefit of prophylaxis used exemplary evidence-based medicine. The RIVUR study over 4 years assessed 10,000 children in a multicenter study involving 19 locations. It enrolled 600 children in a prospective, double-blind, randomized, controlled trial with a placebo control. It followed the children for 2 years. Even by modern standards, this was a huge, prolonged and well-designed trial. It did demonstrate a benefit. About 20% of children on placebo had a recurrent UTI in that 2-year time frame. There was a 50% reduction in the number of UTIs in the children treated with antibiotic prophylaxis. Phrased that way, it was a success. But the numbers can be spun differently. The article duly noted a number needed to treat of eight. Eight children treated for 2 years at 365 days per year and one dose per day, means that 6,000 doses of antibiotics were necessary to prevent one UTI. There was no demonstrated benefit in renal scarring, renal failure, or other long-term outcomes. There was a downside. The rate of antibiotic-resistant organisms in the breakthrough UTIs tripled from 19% of the placebo group to 63% of the prophylaxis group. As large as this study was, it wasn’t able to measure the rate of other known adverse outcomes, such as Stevens-Johnson syndrome from the use of sulfa medications or the impact on resistant infections elsewhere in the body.
With the 2011 practice parameter, pediatricians became less aggressive at working up first UTIs. Urologists disagreed. The May 2015 issue of AAP News had a full page article by Dr. Saul Greenfield, who is the chairperson-elect for the Executive Committee of the American Academy of Pediatrics Section on Urology, a urologist in Buffalo, N.Y., and one of the RIVUR trial’s investigators (AAP News 2015;36:13). He rehashed the RIVUR study results emphasizing the reduction in UTIs, but offered no quantitative assessment of the risks, costs, and harms of prophylaxis.
A June 2015 article in Pediatrics gives the results of the CUTIE study, which ran in parallel with the RIVUR study (Pediatrics 2015 [doi:10.1542/peds.2015-0409]). The conclusions: “VUR and BBD [bladder and bowel dysfunction] are risk factors for recurrent UTI, especially when they appear in combination. Strategies for preventing recurrent UTI include antimicrobial prophylaxis and treatment of BBD.”
The article concludes with, “Therefore, clinicians must help families decide whether the benefits of prophylaxis outweigh the risks and inconvenience. … Additional research is needed to validate the risk factors and profiles that we identified.”
But six pages of discussing renal scarring (which is only a proxy for a small risk of future renal failure or hypertension), followed by a couple paragraphs, without numbers, about the risks of prophylaxis, does not provide the balanced presentation clinicians need to help families make wise decisions. In the new era of Choosing Wisely, scientific articles making clinical recommendations should not be published without an accompanying risk-benefit analysis, either in the article or in an editorial. The maxim in surgery, channeling Voltaire, is that “perfect is the enemy of good.”
There is mounting evidence that giving any antibiotics to young infants is harmful. Even 2 days of antibiotics before 1 month of age leads to measurable changes in the gut microbiota 6 months later. Antibiotics in infancy are associated with obesity at 24 months and at 48 months of age. All medical treatments introduce a substantial risk of harm. As Shakespeare wrote 400 years ago, “Striving to better, oft we mar what’s well.” I don’t doubt the conclusion that prophylaxis reduces UTIs, but giving 6,000 doses to prevent one UTI?! Even Kaley Cuoco can’t sell that.
Ultimately, this choice is not up to the hospitalist, the emergency department doctor, or the urologist. The decision belongs to the parents guided by a primary care doctor they trust. Our professional duty, ethically and legally, is to communicate the risks and benefits to the parents in a manner which they can understand and to provide them the support and counseling necessary to make a wise choice for their child. By focusing on the child and that duty, medical professionals can defuse any clashes of egos, departmental power struggles, or autocratic hierarchy that might interfere. Doctors educate and recommend, but the parent decides what is best for his or her child.
Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures or conflicts of interest. E-mail him at [email protected].
Urban legends never seem to die. They haunt those who chase the truth because most legends have a kernel of truth. Reflux nephropathy is one of those legends.
In the 1970s, neurosurgeons began treating children with spina bifida rather than allowing them to die shortly after birth. As these children entered their second and third decade of life, episodes of renal failure were noted. The reflux and recurring urinary tract infections (UTIs) from neurogenic bladders damaged kidneys. Self-catheter programs were invented and were effective. Surgical correction of anatomic urinary obstructions and severe reflux yielded similar benefits. By the 1990s, this paradigm had been extrapolated to all children with vesicoureteral reflux (VUR) and codified in the 1999 practice parameter. The unproven hope was that aggressive antibiotic prophylaxis to protect young, growing kidneys from infections would reduce the incidence of renal failure and hypertension in adults.
This is a common methodology for quality improvement at a Mortality and Morbidity conference. A problem is identified. A solution is developed to prevent the bad outcome. The solution is implemented without fully proving that the obvious, customized intervention truly works. No one ever assesses whether the remedy causes more mischief than benefit.
VUR has a pyramid shaped spectrum. Few children have the severe grade V reflux which responds to surgical intervention. At the base of the pyramid are a much larger group of children with mild reflux that usually resolves spontaneously by age 5 years. This pyramid is a setup for overdiagnosis and overtreatment of mild disease. Pediatricians soon recognized that the small portion of the 1999 practice parameter addressing reflux nephropathy was overly aggressive and based on unsound science. However, that same lack of clear evidence delayed creating a new consensus until 2011.
The recent efforts to prove the benefit of prophylaxis used exemplary evidence-based medicine. The RIVUR study over 4 years assessed 10,000 children in a multicenter study involving 19 locations. It enrolled 600 children in a prospective, double-blind, randomized, controlled trial with a placebo control. It followed the children for 2 years. Even by modern standards, this was a huge, prolonged and well-designed trial. It did demonstrate a benefit. About 20% of children on placebo had a recurrent UTI in that 2-year time frame. There was a 50% reduction in the number of UTIs in the children treated with antibiotic prophylaxis. Phrased that way, it was a success. But the numbers can be spun differently. The article duly noted a number needed to treat of eight. Eight children treated for 2 years at 365 days per year and one dose per day, means that 6,000 doses of antibiotics were necessary to prevent one UTI. There was no demonstrated benefit in renal scarring, renal failure, or other long-term outcomes. There was a downside. The rate of antibiotic-resistant organisms in the breakthrough UTIs tripled from 19% of the placebo group to 63% of the prophylaxis group. As large as this study was, it wasn’t able to measure the rate of other known adverse outcomes, such as Stevens-Johnson syndrome from the use of sulfa medications or the impact on resistant infections elsewhere in the body.
With the 2011 practice parameter, pediatricians became less aggressive at working up first UTIs. Urologists disagreed. The May 2015 issue of AAP News had a full page article by Dr. Saul Greenfield, who is the chairperson-elect for the Executive Committee of the American Academy of Pediatrics Section on Urology, a urologist in Buffalo, N.Y., and one of the RIVUR trial’s investigators (AAP News 2015;36:13). He rehashed the RIVUR study results emphasizing the reduction in UTIs, but offered no quantitative assessment of the risks, costs, and harms of prophylaxis.
A June 2015 article in Pediatrics gives the results of the CUTIE study, which ran in parallel with the RIVUR study (Pediatrics 2015 [doi:10.1542/peds.2015-0409]). The conclusions: “VUR and BBD [bladder and bowel dysfunction] are risk factors for recurrent UTI, especially when they appear in combination. Strategies for preventing recurrent UTI include antimicrobial prophylaxis and treatment of BBD.”
The article concludes with, “Therefore, clinicians must help families decide whether the benefits of prophylaxis outweigh the risks and inconvenience. … Additional research is needed to validate the risk factors and profiles that we identified.”
But six pages of discussing renal scarring (which is only a proxy for a small risk of future renal failure or hypertension), followed by a couple paragraphs, without numbers, about the risks of prophylaxis, does not provide the balanced presentation clinicians need to help families make wise decisions. In the new era of Choosing Wisely, scientific articles making clinical recommendations should not be published without an accompanying risk-benefit analysis, either in the article or in an editorial. The maxim in surgery, channeling Voltaire, is that “perfect is the enemy of good.”
There is mounting evidence that giving any antibiotics to young infants is harmful. Even 2 days of antibiotics before 1 month of age leads to measurable changes in the gut microbiota 6 months later. Antibiotics in infancy are associated with obesity at 24 months and at 48 months of age. All medical treatments introduce a substantial risk of harm. As Shakespeare wrote 400 years ago, “Striving to better, oft we mar what’s well.” I don’t doubt the conclusion that prophylaxis reduces UTIs, but giving 6,000 doses to prevent one UTI?! Even Kaley Cuoco can’t sell that.
Ultimately, this choice is not up to the hospitalist, the emergency department doctor, or the urologist. The decision belongs to the parents guided by a primary care doctor they trust. Our professional duty, ethically and legally, is to communicate the risks and benefits to the parents in a manner which they can understand and to provide them the support and counseling necessary to make a wise choice for their child. By focusing on the child and that duty, medical professionals can defuse any clashes of egos, departmental power struggles, or autocratic hierarchy that might interfere. Doctors educate and recommend, but the parent decides what is best for his or her child.
Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures or conflicts of interest. E-mail him at [email protected].
Increased VTE Prophylaxis Shows Little Benefit following Colorectal Surgery
NEW YORK—Although venous thromboembolism (VTE) rates are low in hospitalized patients following colorectal surgery, the increasing use of prophylaxis seems to have little impact, according to Washington state-based researchers.
Dr. Scott R. Steele, of Madigan Army Medical Center, Tacoma, and colleagues in JAMA Surgery note that although VTE is an important complication of such surgery its incidence in the current era of prophylaxis is unclear. To investigate further, the team examined Washington state data on more than 16,000 patients who underwent colorectal surgery between 2006 and 2011. Over the study period, the use of perioperative VTE chemoprophylaxis increased significantly from 31.6% to 86.4%. In-hospital VTE chemoprophylaxis rose from 59.6% to 91.4%. A total of 10.6% were discharged on VTE prophylaxis.
VTE within 90 days was seen in 360 patients (2.2%) overall. Patients undergoing abdominal operations had higher rates than those having pelvic operations (2.5% versus 1.8%, p=0.001). Rates were similar, but nonsignificant, in patients having an operation for cancer or for nonmalignant processes (2.1% versus 2.3%).
On adjusted analysis, being older, non-elective surgery, a history of VTE, and operations for inflammatory disease were associated with increased risk of 90-day VTE. However, despite the steady increase in chemoprophylaxis use in the perioperative and in-hospital settings, the annual VTE incidence remained low and largely unchanged, the researchers say. For example, the rate was 2.6% in 2007 and 3.0% in 2011.
In fact, the investigators say, "If nonselective perioperative and in-hospital prophylaxis is not successful in reducing rates of in-hospital VTE over time, are we placing patients at undue risk without significant benefit? With almost 40% of VTE events occurring after discharge, this may represent an area for quality improvement implementation."
As Dr. Steele told Reuters Health by email, "Despite our best practices, a small percentage of patients may still develop a VTE."
Prophylaxis efforts have improved greatly in the preoperative and perioperative in-hospital settings, but "in the post-discharge setting, we likely need a much larger randomized prospective study involving patients with similar risk profiles evaluating extended prophylaxis versus none to demonstrate whether or not this is a benefit." TH
—Reuters Health
NEW YORK—Although venous thromboembolism (VTE) rates are low in hospitalized patients following colorectal surgery, the increasing use of prophylaxis seems to have little impact, according to Washington state-based researchers.
Dr. Scott R. Steele, of Madigan Army Medical Center, Tacoma, and colleagues in JAMA Surgery note that although VTE is an important complication of such surgery its incidence in the current era of prophylaxis is unclear. To investigate further, the team examined Washington state data on more than 16,000 patients who underwent colorectal surgery between 2006 and 2011. Over the study period, the use of perioperative VTE chemoprophylaxis increased significantly from 31.6% to 86.4%. In-hospital VTE chemoprophylaxis rose from 59.6% to 91.4%. A total of 10.6% were discharged on VTE prophylaxis.
VTE within 90 days was seen in 360 patients (2.2%) overall. Patients undergoing abdominal operations had higher rates than those having pelvic operations (2.5% versus 1.8%, p=0.001). Rates were similar, but nonsignificant, in patients having an operation for cancer or for nonmalignant processes (2.1% versus 2.3%).
On adjusted analysis, being older, non-elective surgery, a history of VTE, and operations for inflammatory disease were associated with increased risk of 90-day VTE. However, despite the steady increase in chemoprophylaxis use in the perioperative and in-hospital settings, the annual VTE incidence remained low and largely unchanged, the researchers say. For example, the rate was 2.6% in 2007 and 3.0% in 2011.
In fact, the investigators say, "If nonselective perioperative and in-hospital prophylaxis is not successful in reducing rates of in-hospital VTE over time, are we placing patients at undue risk without significant benefit? With almost 40% of VTE events occurring after discharge, this may represent an area for quality improvement implementation."
As Dr. Steele told Reuters Health by email, "Despite our best practices, a small percentage of patients may still develop a VTE."
Prophylaxis efforts have improved greatly in the preoperative and perioperative in-hospital settings, but "in the post-discharge setting, we likely need a much larger randomized prospective study involving patients with similar risk profiles evaluating extended prophylaxis versus none to demonstrate whether or not this is a benefit." TH
—Reuters Health
NEW YORK—Although venous thromboembolism (VTE) rates are low in hospitalized patients following colorectal surgery, the increasing use of prophylaxis seems to have little impact, according to Washington state-based researchers.
Dr. Scott R. Steele, of Madigan Army Medical Center, Tacoma, and colleagues in JAMA Surgery note that although VTE is an important complication of such surgery its incidence in the current era of prophylaxis is unclear. To investigate further, the team examined Washington state data on more than 16,000 patients who underwent colorectal surgery between 2006 and 2011. Over the study period, the use of perioperative VTE chemoprophylaxis increased significantly from 31.6% to 86.4%. In-hospital VTE chemoprophylaxis rose from 59.6% to 91.4%. A total of 10.6% were discharged on VTE prophylaxis.
VTE within 90 days was seen in 360 patients (2.2%) overall. Patients undergoing abdominal operations had higher rates than those having pelvic operations (2.5% versus 1.8%, p=0.001). Rates were similar, but nonsignificant, in patients having an operation for cancer or for nonmalignant processes (2.1% versus 2.3%).
On adjusted analysis, being older, non-elective surgery, a history of VTE, and operations for inflammatory disease were associated with increased risk of 90-day VTE. However, despite the steady increase in chemoprophylaxis use in the perioperative and in-hospital settings, the annual VTE incidence remained low and largely unchanged, the researchers say. For example, the rate was 2.6% in 2007 and 3.0% in 2011.
In fact, the investigators say, "If nonselective perioperative and in-hospital prophylaxis is not successful in reducing rates of in-hospital VTE over time, are we placing patients at undue risk without significant benefit? With almost 40% of VTE events occurring after discharge, this may represent an area for quality improvement implementation."
As Dr. Steele told Reuters Health by email, "Despite our best practices, a small percentage of patients may still develop a VTE."
Prophylaxis efforts have improved greatly in the preoperative and perioperative in-hospital settings, but "in the post-discharge setting, we likely need a much larger randomized prospective study involving patients with similar risk profiles evaluating extended prophylaxis versus none to demonstrate whether or not this is a benefit." TH
—Reuters Health
Wife Says Husband Needs to Use Moisturizer
A 72-year-old man self-refers to dermatology at the insistence of his wife, who wants confirmation of her assertion that he needs to use a moisturizer on his arms. “They’re just so dry!” she says. “They’d look so much better if he’d use moisturizer every day, like I do.”
Her husband says he tried it and it didn’t help, so he stopped. “Besides, I can’t stand the greasy feeling it leaves behind!”
The patient claims to be in decent health aside from mild arthritis. He is retired from his job with the local power company, which kept him outdoors for many years. His employer required workers to wear long-sleeved khaki shirts, but, like all his fellow employees, the patient rolled up the sleeves in hot weather, exposing his forearms.
EXAMINATION
The patient has type II skin, blue eyes, and light brown hair. The skin on the dorsa of both arms is flecked with innumerable tan to orange macules from the mid forearms to (and including) the hands. Many old scars are seen in these same areas.
Closer examination reveals that the skin in these areas is quite thin and dry. Fine telangiectasias and focal scaling are also noted. The effect is much less pronounced from about the elbow up and is totally absent on both volar forearms.
What is the diagnosis?
DISCUSSION
The patient’s admittedly dry skin is not his primary problem, and all the moisturizers in the world will not make much difference. The term we use for his problem is dermatoheliosis , literally “sun condition,” which includes predictable indicators of past overexposure to UV sources. Specific lesions include solar lentigines, the tan to orange freckles that are commonly called “age spots” or “liver spots.” (Given enough sun exposure, a 25-year-old can develop solar lentigines, so age is not the cause. Likewise, the liver is not involved at all.)
Chronic overexposure to the sun thins the skin (solar atrophy), making it more susceptible to minor trauma and resultant scarring and also making the tortuous red blood vessels (telangiectasias) visible. Other indications of sun damage include actinic keratoses (flaky white papules), solar elastosis (creamy yellow to white “chicken skin”), and solar purpura. The combination of these superimposed colors (white, red, tan, orange, pink) in the context of dermatoheliosis is sometimes termed poikilodermatous change.
Although dermatoheliosis is a problem in terms of the potential for skin cancer and for cosmetic reasons, it will not be helped much by moisturizers. Sunscreen, too, will have minimal impact so long after the damage has been done. Laser resurfacing could erase most of these skin changes, but it would also knock out all the normal skin pigment, making the area contrast sharply with the rest of the patient’s skin.
A combination of fade cream (4% hydroquinone, applied bid) and sunscreen could reduce the brown discoloration to a degree. Twice-daily application of 5-fluorouracil cream for two weeks would erase much of the redness, but only for a few months. Various other methods have been tried with modest success.
The main outcome of this patient’s visit was to establish the need for periodic examination. His wife’s opinion notwithstanding, the utility of moisturizers is dubious.
TAKE-HOME LEARNING POINTS
• Dermatoheliosis is the collective term for skin changes associated with chronic overexposure to the sun.
• The white, red, pink, and yellow discoloration seen on this kind of sun-damaged skin is known as poikilodermatous change.
• In addition to poikiloderma, patients with advanced dermatoheliosis also have solar atrophy, multiple scars, telangiectasias, actinic keratoses, dry skin, and often solar purpura.
• Moisturizers play a minimal role in treating dermatoheliosis (providing skin-smoothing effects, if anything).
• Such patients need to be examined periodically for skin cancer.
• Younger patients with dermatoheliosis are well advised to use better sun protection.
A 72-year-old man self-refers to dermatology at the insistence of his wife, who wants confirmation of her assertion that he needs to use a moisturizer on his arms. “They’re just so dry!” she says. “They’d look so much better if he’d use moisturizer every day, like I do.”
Her husband says he tried it and it didn’t help, so he stopped. “Besides, I can’t stand the greasy feeling it leaves behind!”
The patient claims to be in decent health aside from mild arthritis. He is retired from his job with the local power company, which kept him outdoors for many years. His employer required workers to wear long-sleeved khaki shirts, but, like all his fellow employees, the patient rolled up the sleeves in hot weather, exposing his forearms.
EXAMINATION
The patient has type II skin, blue eyes, and light brown hair. The skin on the dorsa of both arms is flecked with innumerable tan to orange macules from the mid forearms to (and including) the hands. Many old scars are seen in these same areas.
Closer examination reveals that the skin in these areas is quite thin and dry. Fine telangiectasias and focal scaling are also noted. The effect is much less pronounced from about the elbow up and is totally absent on both volar forearms.
What is the diagnosis?
DISCUSSION
The patient’s admittedly dry skin is not his primary problem, and all the moisturizers in the world will not make much difference. The term we use for his problem is dermatoheliosis , literally “sun condition,” which includes predictable indicators of past overexposure to UV sources. Specific lesions include solar lentigines, the tan to orange freckles that are commonly called “age spots” or “liver spots.” (Given enough sun exposure, a 25-year-old can develop solar lentigines, so age is not the cause. Likewise, the liver is not involved at all.)
Chronic overexposure to the sun thins the skin (solar atrophy), making it more susceptible to minor trauma and resultant scarring and also making the tortuous red blood vessels (telangiectasias) visible. Other indications of sun damage include actinic keratoses (flaky white papules), solar elastosis (creamy yellow to white “chicken skin”), and solar purpura. The combination of these superimposed colors (white, red, tan, orange, pink) in the context of dermatoheliosis is sometimes termed poikilodermatous change.
Although dermatoheliosis is a problem in terms of the potential for skin cancer and for cosmetic reasons, it will not be helped much by moisturizers. Sunscreen, too, will have minimal impact so long after the damage has been done. Laser resurfacing could erase most of these skin changes, but it would also knock out all the normal skin pigment, making the area contrast sharply with the rest of the patient’s skin.
A combination of fade cream (4% hydroquinone, applied bid) and sunscreen could reduce the brown discoloration to a degree. Twice-daily application of 5-fluorouracil cream for two weeks would erase much of the redness, but only for a few months. Various other methods have been tried with modest success.
The main outcome of this patient’s visit was to establish the need for periodic examination. His wife’s opinion notwithstanding, the utility of moisturizers is dubious.
TAKE-HOME LEARNING POINTS
• Dermatoheliosis is the collective term for skin changes associated with chronic overexposure to the sun.
• The white, red, pink, and yellow discoloration seen on this kind of sun-damaged skin is known as poikilodermatous change.
• In addition to poikiloderma, patients with advanced dermatoheliosis also have solar atrophy, multiple scars, telangiectasias, actinic keratoses, dry skin, and often solar purpura.
• Moisturizers play a minimal role in treating dermatoheliosis (providing skin-smoothing effects, if anything).
• Such patients need to be examined periodically for skin cancer.
• Younger patients with dermatoheliosis are well advised to use better sun protection.
A 72-year-old man self-refers to dermatology at the insistence of his wife, who wants confirmation of her assertion that he needs to use a moisturizer on his arms. “They’re just so dry!” she says. “They’d look so much better if he’d use moisturizer every day, like I do.”
Her husband says he tried it and it didn’t help, so he stopped. “Besides, I can’t stand the greasy feeling it leaves behind!”
The patient claims to be in decent health aside from mild arthritis. He is retired from his job with the local power company, which kept him outdoors for many years. His employer required workers to wear long-sleeved khaki shirts, but, like all his fellow employees, the patient rolled up the sleeves in hot weather, exposing his forearms.
EXAMINATION
The patient has type II skin, blue eyes, and light brown hair. The skin on the dorsa of both arms is flecked with innumerable tan to orange macules from the mid forearms to (and including) the hands. Many old scars are seen in these same areas.
Closer examination reveals that the skin in these areas is quite thin and dry. Fine telangiectasias and focal scaling are also noted. The effect is much less pronounced from about the elbow up and is totally absent on both volar forearms.
What is the diagnosis?
DISCUSSION
The patient’s admittedly dry skin is not his primary problem, and all the moisturizers in the world will not make much difference. The term we use for his problem is dermatoheliosis , literally “sun condition,” which includes predictable indicators of past overexposure to UV sources. Specific lesions include solar lentigines, the tan to orange freckles that are commonly called “age spots” or “liver spots.” (Given enough sun exposure, a 25-year-old can develop solar lentigines, so age is not the cause. Likewise, the liver is not involved at all.)
Chronic overexposure to the sun thins the skin (solar atrophy), making it more susceptible to minor trauma and resultant scarring and also making the tortuous red blood vessels (telangiectasias) visible. Other indications of sun damage include actinic keratoses (flaky white papules), solar elastosis (creamy yellow to white “chicken skin”), and solar purpura. The combination of these superimposed colors (white, red, tan, orange, pink) in the context of dermatoheliosis is sometimes termed poikilodermatous change.
Although dermatoheliosis is a problem in terms of the potential for skin cancer and for cosmetic reasons, it will not be helped much by moisturizers. Sunscreen, too, will have minimal impact so long after the damage has been done. Laser resurfacing could erase most of these skin changes, but it would also knock out all the normal skin pigment, making the area contrast sharply with the rest of the patient’s skin.
A combination of fade cream (4% hydroquinone, applied bid) and sunscreen could reduce the brown discoloration to a degree. Twice-daily application of 5-fluorouracil cream for two weeks would erase much of the redness, but only for a few months. Various other methods have been tried with modest success.
The main outcome of this patient’s visit was to establish the need for periodic examination. His wife’s opinion notwithstanding, the utility of moisturizers is dubious.
TAKE-HOME LEARNING POINTS
• Dermatoheliosis is the collective term for skin changes associated with chronic overexposure to the sun.
• The white, red, pink, and yellow discoloration seen on this kind of sun-damaged skin is known as poikilodermatous change.
• In addition to poikiloderma, patients with advanced dermatoheliosis also have solar atrophy, multiple scars, telangiectasias, actinic keratoses, dry skin, and often solar purpura.
• Moisturizers play a minimal role in treating dermatoheliosis (providing skin-smoothing effects, if anything).
• Such patients need to be examined periodically for skin cancer.
• Younger patients with dermatoheliosis are well advised to use better sun protection.
Bullying: What we can do
For decades, bullying has been viewed as an unpleasant but generally benign rite of passage that many children experience and overcome without significant consequences. Some high-profile examples of youth suicide coupled with several stunning research studies demonstrating major negative effects of bullying that rival the impact of things like child abuse and out-of-home placement on future physical and mental health, however, have caused many clinicians across specialties to stop and take notice (Lancet Psychiatry 2015;2:524-31). The result has been concerted antibullying efforts from varied sources including the federal government, such as stopbullying.gov, and many professional organizations. Pediatricians are in a prime position both to help individual children and families and to serve as community advocates against this significant public health concern.
Case summary
Jeremy is an 11-year-old boy who has been followed by his pediatrician since birth. He has had few health concerns over the years other than some low levels of anxiety and being somewhat overweight. At an annual checkup, his mother reports that Jeremy has missed much more school this year, often making somewhat vague physical complaints. He also has told his mother that a couple of peers at school are particularly “mean” to him. He doesn’t elaborate and doesn’t want his parents to make “a big deal” about it for fear of causing further embarrassment at school.
Discussion
At least moderate levels of bullying are estimated to occur in about 30% of school-age children, resulting in approximately160,000 lost days of school. Bullying behavior can include anything from name calling to outright physical assault. Online bullying in the form of texts, e-mails, and social media also is increasingly common. School grounds remain the most common site for bullying, and physical appearance is the most common target of bullying behavior. What is thought to separate bullying from other forms of peer conflict is that there exists some sort of power differential between the bully and the victim in terms of physical size, social status, or other features. Some interesting data also suggest some sex differences regarding bullying with boys being more likely to bully children outside of their core group of friends, and girls being more likely to bully individuals within the network of individuals with whom they typically interact.
A key element of helping bullied children involves getting them to talk about the experience with a parent, teacher, physician, or counselor. Some tips that can help get kids to talk include reassurance that the child has control over what will happen with the information (within legal limits) and that no action will be taken without their knowledge and agreement, and having adults relate stories about their own past experience with bullying. Pediatricians also may want to consider opening up the conversation more broadly by asking if bullying is a problem “at your school” rather than in a particular child’s life.
In making an appropriate intervention, parents and physicians may want to differentiate lower levels of bullying (name calling, teasing) from higher levels (overt threats, physical violence, and intimidation), keeping in mind that all forms can be potentially harmful.
For lower-level bullying, the following tips can be helpful to keep in mind in working with kids directly and in helping parents help their children:
1. Don’t underestimate the power of sympathetic listening. Overt expressions to a child that he or she doesn’t deserve this, and that such behaviors are really hurtful can be very important to many kids. Positive experiences with friends and families also can go a long way to counteract a negative encounter with a bully.
2. Coach bully victims about how to respond. The old adage of telling a bully that he or she is hurting your feelings has been replaced with advice to react emotionally as little as possible. Some children also can be helped by rehearsing specific responses or learning to join groups during higher-risk activities.
3. If the bullying is occurring online, encourage kids to save the texts or social media posts if needed as evidence.
4. Consider the option of an anonymous report to a school principal or guidance counselor. While school personnel will be unable to make a direct response, they might be able, for example, to provide more monitoring in high-risk areas such as bathrooms, school buses, or locker rooms.
For higher levels of bullying, it often is important to have more direct involvement with school staff or even the police. Many states now have mandatory bullying prevention and intervention policies. While parents of bullying victims may have strong and natural urges to confront directly the parents of the alleged bully, this step often does not help the situation and often can makes things worse.
Finally, if there is evidence that bullying is having a strong negative impact on the child, a more in-depth evaluation to rule out anxiety disorders, depression, and the presence of any suicidal or homicidal thinking should be strongly considered (JAMA 2001;285:2094-100).
Case follow-up
After reassuring Jeremy that action would not be taken without his consent, the pediatrician was able to elicit more information. She learned that two older boys have been teasing Jeremy in the cafeteria and once took away part of his lunch while telling him he was too fat to need it. After some discussion, the pediatrician agreed to call the school principal to inform the school anonymously about bullying in the cafeteria. The mother, now aware of the situation, was able to offer some support and suggestions such as having lunch in a larger group and sitting at a table that is closer to adult supervision. They agreed to meet again to make sure improvements were occurring.
Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. E-mail him at [email protected].
For decades, bullying has been viewed as an unpleasant but generally benign rite of passage that many children experience and overcome without significant consequences. Some high-profile examples of youth suicide coupled with several stunning research studies demonstrating major negative effects of bullying that rival the impact of things like child abuse and out-of-home placement on future physical and mental health, however, have caused many clinicians across specialties to stop and take notice (Lancet Psychiatry 2015;2:524-31). The result has been concerted antibullying efforts from varied sources including the federal government, such as stopbullying.gov, and many professional organizations. Pediatricians are in a prime position both to help individual children and families and to serve as community advocates against this significant public health concern.
Case summary
Jeremy is an 11-year-old boy who has been followed by his pediatrician since birth. He has had few health concerns over the years other than some low levels of anxiety and being somewhat overweight. At an annual checkup, his mother reports that Jeremy has missed much more school this year, often making somewhat vague physical complaints. He also has told his mother that a couple of peers at school are particularly “mean” to him. He doesn’t elaborate and doesn’t want his parents to make “a big deal” about it for fear of causing further embarrassment at school.
Discussion
At least moderate levels of bullying are estimated to occur in about 30% of school-age children, resulting in approximately160,000 lost days of school. Bullying behavior can include anything from name calling to outright physical assault. Online bullying in the form of texts, e-mails, and social media also is increasingly common. School grounds remain the most common site for bullying, and physical appearance is the most common target of bullying behavior. What is thought to separate bullying from other forms of peer conflict is that there exists some sort of power differential between the bully and the victim in terms of physical size, social status, or other features. Some interesting data also suggest some sex differences regarding bullying with boys being more likely to bully children outside of their core group of friends, and girls being more likely to bully individuals within the network of individuals with whom they typically interact.
A key element of helping bullied children involves getting them to talk about the experience with a parent, teacher, physician, or counselor. Some tips that can help get kids to talk include reassurance that the child has control over what will happen with the information (within legal limits) and that no action will be taken without their knowledge and agreement, and having adults relate stories about their own past experience with bullying. Pediatricians also may want to consider opening up the conversation more broadly by asking if bullying is a problem “at your school” rather than in a particular child’s life.
In making an appropriate intervention, parents and physicians may want to differentiate lower levels of bullying (name calling, teasing) from higher levels (overt threats, physical violence, and intimidation), keeping in mind that all forms can be potentially harmful.
For lower-level bullying, the following tips can be helpful to keep in mind in working with kids directly and in helping parents help their children:
1. Don’t underestimate the power of sympathetic listening. Overt expressions to a child that he or she doesn’t deserve this, and that such behaviors are really hurtful can be very important to many kids. Positive experiences with friends and families also can go a long way to counteract a negative encounter with a bully.
2. Coach bully victims about how to respond. The old adage of telling a bully that he or she is hurting your feelings has been replaced with advice to react emotionally as little as possible. Some children also can be helped by rehearsing specific responses or learning to join groups during higher-risk activities.
3. If the bullying is occurring online, encourage kids to save the texts or social media posts if needed as evidence.
4. Consider the option of an anonymous report to a school principal or guidance counselor. While school personnel will be unable to make a direct response, they might be able, for example, to provide more monitoring in high-risk areas such as bathrooms, school buses, or locker rooms.
For higher levels of bullying, it often is important to have more direct involvement with school staff or even the police. Many states now have mandatory bullying prevention and intervention policies. While parents of bullying victims may have strong and natural urges to confront directly the parents of the alleged bully, this step often does not help the situation and often can makes things worse.
Finally, if there is evidence that bullying is having a strong negative impact on the child, a more in-depth evaluation to rule out anxiety disorders, depression, and the presence of any suicidal or homicidal thinking should be strongly considered (JAMA 2001;285:2094-100).
Case follow-up
After reassuring Jeremy that action would not be taken without his consent, the pediatrician was able to elicit more information. She learned that two older boys have been teasing Jeremy in the cafeteria and once took away part of his lunch while telling him he was too fat to need it. After some discussion, the pediatrician agreed to call the school principal to inform the school anonymously about bullying in the cafeteria. The mother, now aware of the situation, was able to offer some support and suggestions such as having lunch in a larger group and sitting at a table that is closer to adult supervision. They agreed to meet again to make sure improvements were occurring.
Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. E-mail him at [email protected].
For decades, bullying has been viewed as an unpleasant but generally benign rite of passage that many children experience and overcome without significant consequences. Some high-profile examples of youth suicide coupled with several stunning research studies demonstrating major negative effects of bullying that rival the impact of things like child abuse and out-of-home placement on future physical and mental health, however, have caused many clinicians across specialties to stop and take notice (Lancet Psychiatry 2015;2:524-31). The result has been concerted antibullying efforts from varied sources including the federal government, such as stopbullying.gov, and many professional organizations. Pediatricians are in a prime position both to help individual children and families and to serve as community advocates against this significant public health concern.
Case summary
Jeremy is an 11-year-old boy who has been followed by his pediatrician since birth. He has had few health concerns over the years other than some low levels of anxiety and being somewhat overweight. At an annual checkup, his mother reports that Jeremy has missed much more school this year, often making somewhat vague physical complaints. He also has told his mother that a couple of peers at school are particularly “mean” to him. He doesn’t elaborate and doesn’t want his parents to make “a big deal” about it for fear of causing further embarrassment at school.
Discussion
At least moderate levels of bullying are estimated to occur in about 30% of school-age children, resulting in approximately160,000 lost days of school. Bullying behavior can include anything from name calling to outright physical assault. Online bullying in the form of texts, e-mails, and social media also is increasingly common. School grounds remain the most common site for bullying, and physical appearance is the most common target of bullying behavior. What is thought to separate bullying from other forms of peer conflict is that there exists some sort of power differential between the bully and the victim in terms of physical size, social status, or other features. Some interesting data also suggest some sex differences regarding bullying with boys being more likely to bully children outside of their core group of friends, and girls being more likely to bully individuals within the network of individuals with whom they typically interact.
A key element of helping bullied children involves getting them to talk about the experience with a parent, teacher, physician, or counselor. Some tips that can help get kids to talk include reassurance that the child has control over what will happen with the information (within legal limits) and that no action will be taken without their knowledge and agreement, and having adults relate stories about their own past experience with bullying. Pediatricians also may want to consider opening up the conversation more broadly by asking if bullying is a problem “at your school” rather than in a particular child’s life.
In making an appropriate intervention, parents and physicians may want to differentiate lower levels of bullying (name calling, teasing) from higher levels (overt threats, physical violence, and intimidation), keeping in mind that all forms can be potentially harmful.
For lower-level bullying, the following tips can be helpful to keep in mind in working with kids directly and in helping parents help their children:
1. Don’t underestimate the power of sympathetic listening. Overt expressions to a child that he or she doesn’t deserve this, and that such behaviors are really hurtful can be very important to many kids. Positive experiences with friends and families also can go a long way to counteract a negative encounter with a bully.
2. Coach bully victims about how to respond. The old adage of telling a bully that he or she is hurting your feelings has been replaced with advice to react emotionally as little as possible. Some children also can be helped by rehearsing specific responses or learning to join groups during higher-risk activities.
3. If the bullying is occurring online, encourage kids to save the texts or social media posts if needed as evidence.
4. Consider the option of an anonymous report to a school principal or guidance counselor. While school personnel will be unable to make a direct response, they might be able, for example, to provide more monitoring in high-risk areas such as bathrooms, school buses, or locker rooms.
For higher levels of bullying, it often is important to have more direct involvement with school staff or even the police. Many states now have mandatory bullying prevention and intervention policies. While parents of bullying victims may have strong and natural urges to confront directly the parents of the alleged bully, this step often does not help the situation and often can makes things worse.
Finally, if there is evidence that bullying is having a strong negative impact on the child, a more in-depth evaluation to rule out anxiety disorders, depression, and the presence of any suicidal or homicidal thinking should be strongly considered (JAMA 2001;285:2094-100).
Case follow-up
After reassuring Jeremy that action would not be taken without his consent, the pediatrician was able to elicit more information. She learned that two older boys have been teasing Jeremy in the cafeteria and once took away part of his lunch while telling him he was too fat to need it. After some discussion, the pediatrician agreed to call the school principal to inform the school anonymously about bullying in the cafeteria. The mother, now aware of the situation, was able to offer some support and suggestions such as having lunch in a larger group and sitting at a table that is closer to adult supervision. They agreed to meet again to make sure improvements were occurring.
Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. Follow him on Twitter @pedipsych. E-mail him at [email protected].
New Tool Improves Harm Detection for Pediatric Inpatients
The newly developed Pediatric All-Cause Harm Measurement Tool (PACHMT) improved detection of harms in pediatric inpatients in a recent pilot study.
Using the tool, researchers found a rate of 40 harms per 100 patients admitted, and at least one harm in nearly a quarter of the children in the study. Close to half of the events were potentially or definitely preventable.
"Safety is measured inconsistently in health care, and the only way to make progress to improving these rates of harm is to understand how our patients are impacted by the care they receive," says Dr. David C. Stockwell, of George Washington University and Children's National Medical Center in Washington, D.C. "Therefore, we would like to see wider adoption of active surveillance of safety events with an approach like the PACHMT.
“While not replacing voluntarily reported events, it would greatly augment the understanding of all-cause harm." TH
—Reuters Health
The newly developed Pediatric All-Cause Harm Measurement Tool (PACHMT) improved detection of harms in pediatric inpatients in a recent pilot study.
Using the tool, researchers found a rate of 40 harms per 100 patients admitted, and at least one harm in nearly a quarter of the children in the study. Close to half of the events were potentially or definitely preventable.
"Safety is measured inconsistently in health care, and the only way to make progress to improving these rates of harm is to understand how our patients are impacted by the care they receive," says Dr. David C. Stockwell, of George Washington University and Children's National Medical Center in Washington, D.C. "Therefore, we would like to see wider adoption of active surveillance of safety events with an approach like the PACHMT.
“While not replacing voluntarily reported events, it would greatly augment the understanding of all-cause harm." TH
—Reuters Health
The newly developed Pediatric All-Cause Harm Measurement Tool (PACHMT) improved detection of harms in pediatric inpatients in a recent pilot study.
Using the tool, researchers found a rate of 40 harms per 100 patients admitted, and at least one harm in nearly a quarter of the children in the study. Close to half of the events were potentially or definitely preventable.
"Safety is measured inconsistently in health care, and the only way to make progress to improving these rates of harm is to understand how our patients are impacted by the care they receive," says Dr. David C. Stockwell, of George Washington University and Children's National Medical Center in Washington, D.C. "Therefore, we would like to see wider adoption of active surveillance of safety events with an approach like the PACHMT.
“While not replacing voluntarily reported events, it would greatly augment the understanding of all-cause harm." TH
—Reuters Health
Dose reductions make ponatinib safer for CP-CML
VIENNA—Administering ponatinib at lower doses can reduce the risk of arterial occlusive events (AOE) without hindering responses in patients with chronic-phase chronic myeloid leukemia (CP-CML), data from the PACE trial suggest.
When earlier results of this phase 2 study showed that ponatinib can cause AOEs, trials of the drug were put on partial clinical hold. Enrollment was stalled temporarily, and investigators began reducing ponatinib doses.
Now, updated data from the PACE trial suggest ponatinib can be administered safely and effectively in certain patients with CP-CML.
At a median follow-up of about 3.5 years, 95% of CP-CML patients who underwent dose reductions maintained a major cytogenetic response (MCyR). And AOEs occurred in 7% of patients who underwent dose reductions, compared to 13% of patients who did not.
“These continued responses . . . in such a heavily pretreated patient population are very encouraging,” said study investigator Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“Careful assessment of the benefit and risk of initiating ponatinib therapy, particularly in patients who may be at increased risk for arterial occlusive events, can help identify patients with refractory, Ph+ leukemias who can benefit most from this treatment.”
Dr Cortes and his colleagues presented data from the PACE trial at the 20th Congress of the European Hematology Association as abstract P234*. The study was sponsored by Ariad Pharmaceuticals, the company developing ponatinib.
Updated results
The trial included patients with resistant or intolerant CML or Philadelphia chromosome-positive acute lymphoblastic leukemia. A total of 449 patients received ponatinib at a starting dose of 45 mg/day.
Ninety-three percent of patients had previously received 2 or more approved tyrosine kinase inhibitors (TKI), and 55% had previously received 3 or more approved TKIs.
Dr Cortes and his colleagues presented data on 270 CP-CML patients. At a median follow-up of 42.3 months (data as of February 2, 2015), 114 patients (42%) continue to receive ponatinib.
Eighteen percent of patients discontinued treatment due to adverse events (AEs), 10% due to disease progression, 3% due to death, and 27% for other reasons.
Fifty-nine percent of CP-CML patients achieved an MCyR at any time during the study, and 83% of responders are estimated to remain in MCyR at 3 years. Thirty-nine percent of patients achieved a major molecular response (MMR).
The estimated progression-free survival at 3 years is 60%, and the estimated overall survival is 81%.
Twenty-three percent of CP-CML patients experienced an AOE designated a serious AE, and 28% experienced any AOE. The median time to onset for AOEs was 14.1 months (range, 0.3–44.0).
Four percent of CP-CML patients experienced a venous thromboembolism (VTE) that was considered an serious AE, and 5% experienced any VTE.
The most common all-grade, treatment-emergent AEs occurring in at least 40% of CP-CML patients were abdominal pain (46%), rash (46%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (41%).
Outcomes after dose reductions
On October 10, 2013, Ariad provided dose-reduction recommendations to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:
- CP-CML patients who already achieved an MCyR should have their ponatinib dose reduced to 15 mg/day
- CP-CML patients who had not already achieved an MCyR should have their dose reduced to 30 mg/day
- Advanced-phase patients should have their dose reduced to 30 mg/day.
As of February 2015, with 1.3 years (16 months) of follow-up after these recommendations, 95% of CP-CML patients maintained their response, whether or not they underwent prospective dose reductions.
Of the patients who were in MCyR as of October 10, 2013, and had a prospective dose reduction, 95% (61/64) maintained their response at 1.3 years. Of the patients who were in MMR as of October 10, 2013, and had a prospective dose reduction, 94% (44/47) maintained their response at 1.3 years.
Forty-two patients in MCyR did not undergo prospective dose reductions (the majority of which were already at a reduced dose of 30 mg or 15 mg as of October 10, 2013). Of these patients, 93% (n=39) maintained an MCyR after 1.3 more years of ponatinib treatment.
Twenty-four patients in MMR did not undergo prospective dose reductions, and 96% of these patients (n=22) maintained their response at 1.3 years.
Seven percent (5/71) of patients without prior AOEs who underwent dose reductions had a new AOE during the 1.3-year interval after dose reduction.
Thirteen percent (9/67) of patients without prior AOEs who did not undergo dose reductions had a new AOE in the same time interval. 
*Information in the abstract differs from that presented at the meeting.
VIENNA—Administering ponatinib at lower doses can reduce the risk of arterial occlusive events (AOE) without hindering responses in patients with chronic-phase chronic myeloid leukemia (CP-CML), data from the PACE trial suggest.
When earlier results of this phase 2 study showed that ponatinib can cause AOEs, trials of the drug were put on partial clinical hold. Enrollment was stalled temporarily, and investigators began reducing ponatinib doses.
Now, updated data from the PACE trial suggest ponatinib can be administered safely and effectively in certain patients with CP-CML.
At a median follow-up of about 3.5 years, 95% of CP-CML patients who underwent dose reductions maintained a major cytogenetic response (MCyR). And AOEs occurred in 7% of patients who underwent dose reductions, compared to 13% of patients who did not.
“These continued responses . . . in such a heavily pretreated patient population are very encouraging,” said study investigator Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“Careful assessment of the benefit and risk of initiating ponatinib therapy, particularly in patients who may be at increased risk for arterial occlusive events, can help identify patients with refractory, Ph+ leukemias who can benefit most from this treatment.”
Dr Cortes and his colleagues presented data from the PACE trial at the 20th Congress of the European Hematology Association as abstract P234*. The study was sponsored by Ariad Pharmaceuticals, the company developing ponatinib.
Updated results
The trial included patients with resistant or intolerant CML or Philadelphia chromosome-positive acute lymphoblastic leukemia. A total of 449 patients received ponatinib at a starting dose of 45 mg/day.
Ninety-three percent of patients had previously received 2 or more approved tyrosine kinase inhibitors (TKI), and 55% had previously received 3 or more approved TKIs.
Dr Cortes and his colleagues presented data on 270 CP-CML patients. At a median follow-up of 42.3 months (data as of February 2, 2015), 114 patients (42%) continue to receive ponatinib.
Eighteen percent of patients discontinued treatment due to adverse events (AEs), 10% due to disease progression, 3% due to death, and 27% for other reasons.
Fifty-nine percent of CP-CML patients achieved an MCyR at any time during the study, and 83% of responders are estimated to remain in MCyR at 3 years. Thirty-nine percent of patients achieved a major molecular response (MMR).
The estimated progression-free survival at 3 years is 60%, and the estimated overall survival is 81%.
Twenty-three percent of CP-CML patients experienced an AOE designated a serious AE, and 28% experienced any AOE. The median time to onset for AOEs was 14.1 months (range, 0.3–44.0).
Four percent of CP-CML patients experienced a venous thromboembolism (VTE) that was considered an serious AE, and 5% experienced any VTE.
The most common all-grade, treatment-emergent AEs occurring in at least 40% of CP-CML patients were abdominal pain (46%), rash (46%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (41%).
Outcomes after dose reductions
On October 10, 2013, Ariad provided dose-reduction recommendations to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:
- CP-CML patients who already achieved an MCyR should have their ponatinib dose reduced to 15 mg/day
- CP-CML patients who had not already achieved an MCyR should have their dose reduced to 30 mg/day
- Advanced-phase patients should have their dose reduced to 30 mg/day.
As of February 2015, with 1.3 years (16 months) of follow-up after these recommendations, 95% of CP-CML patients maintained their response, whether or not they underwent prospective dose reductions.
Of the patients who were in MCyR as of October 10, 2013, and had a prospective dose reduction, 95% (61/64) maintained their response at 1.3 years. Of the patients who were in MMR as of October 10, 2013, and had a prospective dose reduction, 94% (44/47) maintained their response at 1.3 years.
Forty-two patients in MCyR did not undergo prospective dose reductions (the majority of which were already at a reduced dose of 30 mg or 15 mg as of October 10, 2013). Of these patients, 93% (n=39) maintained an MCyR after 1.3 more years of ponatinib treatment.
Twenty-four patients in MMR did not undergo prospective dose reductions, and 96% of these patients (n=22) maintained their response at 1.3 years.
Seven percent (5/71) of patients without prior AOEs who underwent dose reductions had a new AOE during the 1.3-year interval after dose reduction.
Thirteen percent (9/67) of patients without prior AOEs who did not undergo dose reductions had a new AOE in the same time interval.
*Information in the abstract differs from that presented at the meeting.
VIENNA—Administering ponatinib at lower doses can reduce the risk of arterial occlusive events (AOE) without hindering responses in patients with chronic-phase chronic myeloid leukemia (CP-CML), data from the PACE trial suggest.
When earlier results of this phase 2 study showed that ponatinib can cause AOEs, trials of the drug were put on partial clinical hold. Enrollment was stalled temporarily, and investigators began reducing ponatinib doses.
Now, updated data from the PACE trial suggest ponatinib can be administered safely and effectively in certain patients with CP-CML.
At a median follow-up of about 3.5 years, 95% of CP-CML patients who underwent dose reductions maintained a major cytogenetic response (MCyR). And AOEs occurred in 7% of patients who underwent dose reductions, compared to 13% of patients who did not.
“These continued responses . . . in such a heavily pretreated patient population are very encouraging,” said study investigator Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.
“Careful assessment of the benefit and risk of initiating ponatinib therapy, particularly in patients who may be at increased risk for arterial occlusive events, can help identify patients with refractory, Ph+ leukemias who can benefit most from this treatment.”
Dr Cortes and his colleagues presented data from the PACE trial at the 20th Congress of the European Hematology Association as abstract P234*. The study was sponsored by Ariad Pharmaceuticals, the company developing ponatinib.
Updated results
The trial included patients with resistant or intolerant CML or Philadelphia chromosome-positive acute lymphoblastic leukemia. A total of 449 patients received ponatinib at a starting dose of 45 mg/day.
Ninety-three percent of patients had previously received 2 or more approved tyrosine kinase inhibitors (TKI), and 55% had previously received 3 or more approved TKIs.
Dr Cortes and his colleagues presented data on 270 CP-CML patients. At a median follow-up of 42.3 months (data as of February 2, 2015), 114 patients (42%) continue to receive ponatinib.
Eighteen percent of patients discontinued treatment due to adverse events (AEs), 10% due to disease progression, 3% due to death, and 27% for other reasons.
Fifty-nine percent of CP-CML patients achieved an MCyR at any time during the study, and 83% of responders are estimated to remain in MCyR at 3 years. Thirty-nine percent of patients achieved a major molecular response (MMR).
The estimated progression-free survival at 3 years is 60%, and the estimated overall survival is 81%.
Twenty-three percent of CP-CML patients experienced an AOE designated a serious AE, and 28% experienced any AOE. The median time to onset for AOEs was 14.1 months (range, 0.3–44.0).
Four percent of CP-CML patients experienced a venous thromboembolism (VTE) that was considered an serious AE, and 5% experienced any VTE.
The most common all-grade, treatment-emergent AEs occurring in at least 40% of CP-CML patients were abdominal pain (46%), rash (46%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (41%).
Outcomes after dose reductions
On October 10, 2013, Ariad provided dose-reduction recommendations to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:
- CP-CML patients who already achieved an MCyR should have their ponatinib dose reduced to 15 mg/day
- CP-CML patients who had not already achieved an MCyR should have their dose reduced to 30 mg/day
- Advanced-phase patients should have their dose reduced to 30 mg/day.
As of February 2015, with 1.3 years (16 months) of follow-up after these recommendations, 95% of CP-CML patients maintained their response, whether or not they underwent prospective dose reductions.
Of the patients who were in MCyR as of October 10, 2013, and had a prospective dose reduction, 95% (61/64) maintained their response at 1.3 years. Of the patients who were in MMR as of October 10, 2013, and had a prospective dose reduction, 94% (44/47) maintained their response at 1.3 years.
Forty-two patients in MCyR did not undergo prospective dose reductions (the majority of which were already at a reduced dose of 30 mg or 15 mg as of October 10, 2013). Of these patients, 93% (n=39) maintained an MCyR after 1.3 more years of ponatinib treatment.
Twenty-four patients in MMR did not undergo prospective dose reductions, and 96% of these patients (n=22) maintained their response at 1.3 years.
Seven percent (5/71) of patients without prior AOEs who underwent dose reductions had a new AOE during the 1.3-year interval after dose reduction.
Thirteen percent (9/67) of patients without prior AOEs who did not undergo dose reductions had a new AOE in the same time interval.
*Information in the abstract differs from that presented at the meeting.
JAK inhibitor can provide long-term disease control in PV
Image courtesy of AFIP
VIENNA—Updated results from the phase 3 RESPONSE trial suggest the JAK1/2 inhibitor ruxolitinib can provide long-term disease control in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea.
At 18 months of follow-up, 80% of patients had achieved a durable response to ruxolitinib, sustaining hematocrit levels below 45% without the use of phlebotomy and experiencing reductions in spleen size.
In addition, 83% of patients were still receiving ruxolitinib at last follow-up.
“Polycythemia vera can lead to serious complications if inadequately controlled, and these data demonstrate the ability of [ruxolitinib] to provide a durable and comprehensive clinical benefit in this patient population,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis et Université Paris Diderot in France.
Dr Kiladjian presented these results at the 20th Congress of the European Hematology Association (abstract S447). The RESPONSE trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.
The study included 222 patients with PV whose were resistant to or could not tolerate hydroxyurea. They were randomized 1:1 to receive either ruxolitinib (at a starting dose of 10 mg twice daily) or best available therapy (BAT), which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the trial.
The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from week 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.
Patients were deemed eligible for phlebotomy if they had hematocrit that was greater than 45% and had increased 3 or more percentage points from the time they entered the trial or if they had hematocrit greater than 48%.
The researchers performed a second, preplanned analysis at 80 weeks (18 months), evaluating the durability of primary response, hematocrit control, spleen size reduction, complete hematologic remission, and safety. The team also conducted a separate analysis evaluating hematologic parameters.
Results at 32 and 80 weeks
Twenty-one percent of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved the primary endpoint (P<0.0001). All but 1 of the responders in the ruxolitinib arm maintained this response at 80 weeks.
Sixty percent of patients in the ruxolitinib arm and 20% in the BAT arm achieved hematocrit control without phlebotomy through week 32. Patients in the ruxolitinib arm had an 89% probability of maintaining this response for 80 weeks from the time of initial response. Of the 98 patients on ruxolitinib at week 32, 90% did not have a phlebotomy between weeks 32 and 80.
At week 32, 38% of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved a 35% or greater reduction in spleen volume. All of the ruxolitinib-treated patients maintained this response at 80 weeks.
At week 32, 24% of patients in the ruxolitinib arm had a complete hematologic remission, as did 9% of patients in the BAT arm. Patients in the ruxolitinib arm had a 69% probability of maintaining this response for 80 weeks.
A separate analysis of the data at 18 months demonstrated that ruxolitinib treatment also led to sustained control of white blood cell and platelet levels, with the largest reductions occurring in patients who had the most elevated values at baseline.
At week 80, 83% of patients in the ruxolitinib arm remained on treatment (median exposure of 111 weeks), but none of the patients in the BAT arm were still receiving their assigned therapy.
At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued treatment due to adverse events.
“There is currently a significant unmet need for patients with polycythemia vera who are unable to tolerate or control their disease on other treatments,” Dr Kiladjian said. “For these patients, [ruxolitinib] represents a valuable new option, as confirmed by results from the long-term, phase 3 study.”
Image courtesy of AFIP
VIENNA—Updated results from the phase 3 RESPONSE trial suggest the JAK1/2 inhibitor ruxolitinib can provide long-term disease control in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea.
At 18 months of follow-up, 80% of patients had achieved a durable response to ruxolitinib, sustaining hematocrit levels below 45% without the use of phlebotomy and experiencing reductions in spleen size.
In addition, 83% of patients were still receiving ruxolitinib at last follow-up.
“Polycythemia vera can lead to serious complications if inadequately controlled, and these data demonstrate the ability of [ruxolitinib] to provide a durable and comprehensive clinical benefit in this patient population,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis et Université Paris Diderot in France.
Dr Kiladjian presented these results at the 20th Congress of the European Hematology Association (abstract S447). The RESPONSE trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.
The study included 222 patients with PV whose were resistant to or could not tolerate hydroxyurea. They were randomized 1:1 to receive either ruxolitinib (at a starting dose of 10 mg twice daily) or best available therapy (BAT), which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the trial.
The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from week 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.
Patients were deemed eligible for phlebotomy if they had hematocrit that was greater than 45% and had increased 3 or more percentage points from the time they entered the trial or if they had hematocrit greater than 48%.
The researchers performed a second, preplanned analysis at 80 weeks (18 months), evaluating the durability of primary response, hematocrit control, spleen size reduction, complete hematologic remission, and safety. The team also conducted a separate analysis evaluating hematologic parameters.
Results at 32 and 80 weeks
Twenty-one percent of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved the primary endpoint (P<0.0001). All but 1 of the responders in the ruxolitinib arm maintained this response at 80 weeks.
Sixty percent of patients in the ruxolitinib arm and 20% in the BAT arm achieved hematocrit control without phlebotomy through week 32. Patients in the ruxolitinib arm had an 89% probability of maintaining this response for 80 weeks from the time of initial response. Of the 98 patients on ruxolitinib at week 32, 90% did not have a phlebotomy between weeks 32 and 80.
At week 32, 38% of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved a 35% or greater reduction in spleen volume. All of the ruxolitinib-treated patients maintained this response at 80 weeks.
At week 32, 24% of patients in the ruxolitinib arm had a complete hematologic remission, as did 9% of patients in the BAT arm. Patients in the ruxolitinib arm had a 69% probability of maintaining this response for 80 weeks.
A separate analysis of the data at 18 months demonstrated that ruxolitinib treatment also led to sustained control of white blood cell and platelet levels, with the largest reductions occurring in patients who had the most elevated values at baseline.
At week 80, 83% of patients in the ruxolitinib arm remained on treatment (median exposure of 111 weeks), but none of the patients in the BAT arm were still receiving their assigned therapy.
At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued treatment due to adverse events.
“There is currently a significant unmet need for patients with polycythemia vera who are unable to tolerate or control their disease on other treatments,” Dr Kiladjian said. “For these patients, [ruxolitinib] represents a valuable new option, as confirmed by results from the long-term, phase 3 study.”
Image courtesy of AFIP
VIENNA—Updated results from the phase 3 RESPONSE trial suggest the JAK1/2 inhibitor ruxolitinib can provide long-term disease control in patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea.
At 18 months of follow-up, 80% of patients had achieved a durable response to ruxolitinib, sustaining hematocrit levels below 45% without the use of phlebotomy and experiencing reductions in spleen size.
In addition, 83% of patients were still receiving ruxolitinib at last follow-up.
“Polycythemia vera can lead to serious complications if inadequately controlled, and these data demonstrate the ability of [ruxolitinib] to provide a durable and comprehensive clinical benefit in this patient population,” said Jean-Jacques Kiladjian, MD, PhD, of Hôpital Saint-Louis et Université Paris Diderot in France.
Dr Kiladjian presented these results at the 20th Congress of the European Hematology Association (abstract S447). The RESPONSE trial was sponsored by Incyte Corporation and Novartis Pharmaceuticals, the companies developing ruxolitinib.
The study included 222 patients with PV whose were resistant to or could not tolerate hydroxyurea. They were randomized 1:1 to receive either ruxolitinib (at a starting dose of 10 mg twice daily) or best available therapy (BAT), which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the trial.
The study’s primary endpoint was the proportion of patients who achieved hematocrit control and were not eligible for phlebotomy from week 8 through 32 (with no more than 1 instance of phlebotomy eligibility between randomization and week 8) and who saw a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.
Patients were deemed eligible for phlebotomy if they had hematocrit that was greater than 45% and had increased 3 or more percentage points from the time they entered the trial or if they had hematocrit greater than 48%.
The researchers performed a second, preplanned analysis at 80 weeks (18 months), evaluating the durability of primary response, hematocrit control, spleen size reduction, complete hematologic remission, and safety. The team also conducted a separate analysis evaluating hematologic parameters.
Results at 32 and 80 weeks
Twenty-one percent of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved the primary endpoint (P<0.0001). All but 1 of the responders in the ruxolitinib arm maintained this response at 80 weeks.
Sixty percent of patients in the ruxolitinib arm and 20% in the BAT arm achieved hematocrit control without phlebotomy through week 32. Patients in the ruxolitinib arm had an 89% probability of maintaining this response for 80 weeks from the time of initial response. Of the 98 patients on ruxolitinib at week 32, 90% did not have a phlebotomy between weeks 32 and 80.
At week 32, 38% of patients in the ruxolitinib arm and 1% of patients in the BAT arm achieved a 35% or greater reduction in spleen volume. All of the ruxolitinib-treated patients maintained this response at 80 weeks.
At week 32, 24% of patients in the ruxolitinib arm had a complete hematologic remission, as did 9% of patients in the BAT arm. Patients in the ruxolitinib arm had a 69% probability of maintaining this response for 80 weeks.
A separate analysis of the data at 18 months demonstrated that ruxolitinib treatment also led to sustained control of white blood cell and platelet levels, with the largest reductions occurring in patients who had the most elevated values at baseline.
At week 80, 83% of patients in the ruxolitinib arm remained on treatment (median exposure of 111 weeks), but none of the patients in the BAT arm were still receiving their assigned therapy.
At 80 weeks, the most common adverse events in the ruxolitinib arm were headache (22%), diarrhea (20%), pruritus (20%), and fatigue (17%). Grade 3 or 4 anemia and thrombocytopenia occurred in 2% and 6% of patients, respectively. Five percent of patients discontinued treatment due to adverse events.
“There is currently a significant unmet need for patients with polycythemia vera who are unable to tolerate or control their disease on other treatments,” Dr Kiladjian said. “For these patients, [ruxolitinib] represents a valuable new option, as confirmed by results from the long-term, phase 3 study.”
mAb produces responses in AL amyloidosis
VIENNA—A monoclonal antibody (mAb) can produce responses in patients with light chain (AL) amyloidosis and persistent organ dysfunction, according to research presented at the 20th Congress of the European Hematology Association.
In an ongoing phase 1/2 trial, the mAb, known as NEOD001, produced a cardiac response in 57% of evaluable patients and a renal response in 60% of evaluable patients.
Michaela Liedtke, MD, of the Stanford University School of Medicine in California, presented these results as abstract S104*. The research was sponsored by Prothena Therapeutics Ltd., the company developing NEOD001.
Dr Liedtke presented results of an interim analysis as of February 28, 2015. The analysis included 27 patients with AL amyloidosis who had received 1 or more anti-plasma-cell systemic therapies, had a partial response or better, and did not require additional chemotherapy. The patients also had persistent organ dysfunction.
Patients received a dose of NEOD001 every 28 days, in 1 of 7 dosing cohorts (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, 16 mg/kg, and 24 mg/kg). They received a total of 327 infusions, with an average treatment duration of 12 months.
The patients’ median age was 60 (range, 38-80), and they had received a median of 2 prior treatments (range, 1-7). A third of patients each had 1 organ system involved (n=9), 2 organ systems involved (n=9), or 3 or more organ systems involved (n=9).
Safety data
The most frequently reported treatment-emergent adverse events (occurring in more than 10% of subjects) were fatigue (37%), upper respiratory tract infection (26%), cough (19%), dyspnea (19%), headache (15%), anemia (15%), increased blood creatinine (15%), peripheral edema (15%), edema (11%), diarrhea (11%), nausea (11%), and hyponatremia (11%).
There were no reports of hypersensitivity reactions to NEOD001 or drug-related serious adverse events, and no anti-NEOD001 antibodies were detected. There were no dose-limiting toxicities, and none of the patients discontinued treatment due to drug-related adverse events.
All patients remaining in the study were escalated to a dose of 24 mg/kg as of December 2, 2014.
Renal and cardiac responses
In a best-response analysis, 60% (9/15) of renal-evaluable patients demonstrated a renal response to NEOD001, defined as a 30% decrease in proteinuria in the absence of estimated glomerular filtration rate (eGFR) worsening. The other 40% of patients (n=6) had stable disease.
In another best-response analysis, 57% (8/14) of cardiac-evaluable patients had a cardiac response to NEOD001, defined as more than 30% and 300 pg/mL decrease in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). The other 43% of patients (n=6) had stable disease.
Longer treatment with NEOD001 was significantly associated with NT-proBNP decline (P<0.0001).
“[M]onthly infusions of NEOD001 correlate significantly with decreases in both cardiac and renal biomarkers over time,” Dr Liedtke said. “Decreases in cardiac biomarkers predict increased survival, and decreases in renal biomarkers predict delayed time to kidney failure.”
*Information in the abstract differs from that presented at the meeting.
VIENNA—A monoclonal antibody (mAb) can produce responses in patients with light chain (AL) amyloidosis and persistent organ dysfunction, according to research presented at the 20th Congress of the European Hematology Association.
In an ongoing phase 1/2 trial, the mAb, known as NEOD001, produced a cardiac response in 57% of evaluable patients and a renal response in 60% of evaluable patients.
Michaela Liedtke, MD, of the Stanford University School of Medicine in California, presented these results as abstract S104*. The research was sponsored by Prothena Therapeutics Ltd., the company developing NEOD001.
Dr Liedtke presented results of an interim analysis as of February 28, 2015. The analysis included 27 patients with AL amyloidosis who had received 1 or more anti-plasma-cell systemic therapies, had a partial response or better, and did not require additional chemotherapy. The patients also had persistent organ dysfunction.
Patients received a dose of NEOD001 every 28 days, in 1 of 7 dosing cohorts (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, 16 mg/kg, and 24 mg/kg). They received a total of 327 infusions, with an average treatment duration of 12 months.
The patients’ median age was 60 (range, 38-80), and they had received a median of 2 prior treatments (range, 1-7). A third of patients each had 1 organ system involved (n=9), 2 organ systems involved (n=9), or 3 or more organ systems involved (n=9).
Safety data
The most frequently reported treatment-emergent adverse events (occurring in more than 10% of subjects) were fatigue (37%), upper respiratory tract infection (26%), cough (19%), dyspnea (19%), headache (15%), anemia (15%), increased blood creatinine (15%), peripheral edema (15%), edema (11%), diarrhea (11%), nausea (11%), and hyponatremia (11%).
There were no reports of hypersensitivity reactions to NEOD001 or drug-related serious adverse events, and no anti-NEOD001 antibodies were detected. There were no dose-limiting toxicities, and none of the patients discontinued treatment due to drug-related adverse events.
All patients remaining in the study were escalated to a dose of 24 mg/kg as of December 2, 2014.
Renal and cardiac responses
In a best-response analysis, 60% (9/15) of renal-evaluable patients demonstrated a renal response to NEOD001, defined as a 30% decrease in proteinuria in the absence of estimated glomerular filtration rate (eGFR) worsening. The other 40% of patients (n=6) had stable disease.
In another best-response analysis, 57% (8/14) of cardiac-evaluable patients had a cardiac response to NEOD001, defined as more than 30% and 300 pg/mL decrease in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). The other 43% of patients (n=6) had stable disease.
Longer treatment with NEOD001 was significantly associated with NT-proBNP decline (P<0.0001).
“[M]onthly infusions of NEOD001 correlate significantly with decreases in both cardiac and renal biomarkers over time,” Dr Liedtke said. “Decreases in cardiac biomarkers predict increased survival, and decreases in renal biomarkers predict delayed time to kidney failure.”
*Information in the abstract differs from that presented at the meeting.
VIENNA—A monoclonal antibody (mAb) can produce responses in patients with light chain (AL) amyloidosis and persistent organ dysfunction, according to research presented at the 20th Congress of the European Hematology Association.
In an ongoing phase 1/2 trial, the mAb, known as NEOD001, produced a cardiac response in 57% of evaluable patients and a renal response in 60% of evaluable patients.
Michaela Liedtke, MD, of the Stanford University School of Medicine in California, presented these results as abstract S104*. The research was sponsored by Prothena Therapeutics Ltd., the company developing NEOD001.
Dr Liedtke presented results of an interim analysis as of February 28, 2015. The analysis included 27 patients with AL amyloidosis who had received 1 or more anti-plasma-cell systemic therapies, had a partial response or better, and did not require additional chemotherapy. The patients also had persistent organ dysfunction.
Patients received a dose of NEOD001 every 28 days, in 1 of 7 dosing cohorts (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, 16 mg/kg, and 24 mg/kg). They received a total of 327 infusions, with an average treatment duration of 12 months.
The patients’ median age was 60 (range, 38-80), and they had received a median of 2 prior treatments (range, 1-7). A third of patients each had 1 organ system involved (n=9), 2 organ systems involved (n=9), or 3 or more organ systems involved (n=9).
Safety data
The most frequently reported treatment-emergent adverse events (occurring in more than 10% of subjects) were fatigue (37%), upper respiratory tract infection (26%), cough (19%), dyspnea (19%), headache (15%), anemia (15%), increased blood creatinine (15%), peripheral edema (15%), edema (11%), diarrhea (11%), nausea (11%), and hyponatremia (11%).
There were no reports of hypersensitivity reactions to NEOD001 or drug-related serious adverse events, and no anti-NEOD001 antibodies were detected. There were no dose-limiting toxicities, and none of the patients discontinued treatment due to drug-related adverse events.
All patients remaining in the study were escalated to a dose of 24 mg/kg as of December 2, 2014.
Renal and cardiac responses
In a best-response analysis, 60% (9/15) of renal-evaluable patients demonstrated a renal response to NEOD001, defined as a 30% decrease in proteinuria in the absence of estimated glomerular filtration rate (eGFR) worsening. The other 40% of patients (n=6) had stable disease.
In another best-response analysis, 57% (8/14) of cardiac-evaluable patients had a cardiac response to NEOD001, defined as more than 30% and 300 pg/mL decrease in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). The other 43% of patients (n=6) had stable disease.
Longer treatment with NEOD001 was significantly associated with NT-proBNP decline (P<0.0001).
“[M]onthly infusions of NEOD001 correlate significantly with decreases in both cardiac and renal biomarkers over time,” Dr Liedtke said. “Decreases in cardiac biomarkers predict increased survival, and decreases in renal biomarkers predict delayed time to kidney failure.”
*Information in the abstract differs from that presented at the meeting.
Drug may be ‘important treatment option’ for AML
Photo courtesy of ASH
VIENNA—Adding the anticancer quinolone derivative vosaroxin to treatment with cytarabine can improve outcomes for some older patients with relapsed/refractory acute myeloid leukemia (AML), results of the phase 3 VALOR trial suggest.
AML patients age 60 and older with refractory and early relapse disease had improved survival rates when they received vosaroxin and cytarabine, compared to patients who received cytarabine and placebo.
However, for older patients with late-relapse AML, the addition of vosaroxin had no significant impact on survival.
Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented these result at the 20th Congress of the European Hematology Association (abstract P197*). The trial was sponsored by Sunesis Pharmaceuticals, the company developing vosaroxin.
“AML is a disease that primarily affects older patients, and clinical outcomes among these patients is abysmal,” Dr Ravandi noted. “These patients have had few options outside of clinical trial enrollment.”
“Results from the analyses presented today show compelling survival and durable responses, with comparable early mortality, for the vosaroxin and cytarabine treatment arm in the older refractory and early relapse patients. Given these results, I believe vosaroxin represents an important new treatment option.”
VALOR is a randomized, double-blind, phase 3 trial that enrolled 711 adult patients with relapsed or refractory AML. Patients were stratified for age, geographic region, and disease status, then randomized 1:1 to receive vosaroxin and cytarabine or placebo and cytarabine.
Dr Ravandi and his colleagues presented results from the subgroups of patients age 60 years and older (451/711) with late-relapse disease (n=87) and refractory or early relapse disease (combined n=364).
Late-relapse disease
Patients with late-relapse disease had a significantly higher complete response (CR) rate if they received vosaroxin/cytarabine rather than placebo/cytarabine. The rates were 57% and 28%, respectively (P=0.0064).
However, there was no significant difference between the treatment arms with regard to overall survival (OS), leukemia-free survival (LFS), or event-free survival (EFS).
The median OS was 9.2 months in the vosaroxin/cytarabine arm and 9.8 months in the placebo/cytarabine arm (hazard ratio [HR]=1.06, P=0.82). The median OS, censored for transplant, was 9.1 months in both arms (HR=0.92, P=0.78).
The median LFS was 10.3 months in the vosaroxin/cytarabine arm and 8.7 months in the placebo/cytarabine arm (HR=1.16, P=0.77). And the median EFS was 5.5 months and 2.3 months, respectively (HR=0.65, P=0.0852).
Thirty-day all-cause mortality was 11% the vosaroxin/cytarabine arm and 2% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 18% and 14%, respectively.
Refractory/early relapse disease
Patients with refractory AML (n=210) and those with early relapse disease (n=154) had significant improvements in CR and survival when they received vosaroxin and cytarabine. The CR rate was 26% in the vosaroxin/cytarabine arm and 10% in the placebo/cytarabine arm (P=0.0001).
The median OS was 6.5 months in the vosaroxin/cytarabine arm and 3.9 months in the placebo/cytarabine arm (HR=0.69, P=0.0008). The median OS, censored for transplant, was 6.2 months and 3.9 months, respectively (HR=0.71, P=0.0048).
The median LFS was 9.7 months in the vosaroxin/cytarabine arm and 5.5 months in the placebo/cytarabine arm (HR=0.50, P=0.0424). And the median EFS was 1.7 months and 1.3 months, respectively (HR=0.59, P<0.0001).
Rates of all-cause mortality were comparable between the arms. Thirty-day all-cause mortality was 10% in the vosaroxin/cytarabine arm and 11% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 21% and 25%, respectively.
Adverse events
Ninety-four percent of patients in the vosaroxin/cytarabine arm and 86% of those in the placebo/cytarabine arm experienced a grade 3 or higher adverse event (AE). The rate of treatment-related, grade 3 or higher AEs was 74% and 60%, respectively.
The most common grade 3 or higher AEs—occurring in at least 10% of patients in the vosaroxin/cytarabine and placebo/cytarabine arms, respectively—were febrile neutropenia (43% vs 30%), thrombocytopenia (24% vs 25%), anemia (23% vs 24%), neutropenia (19% vs 14%), hypokalemia (15% vs 7%), stomatitis (16% vs 4%), sepsis (12% vs 6%), and pneumonia (11% vs 8%).
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of ASH
VIENNA—Adding the anticancer quinolone derivative vosaroxin to treatment with cytarabine can improve outcomes for some older patients with relapsed/refractory acute myeloid leukemia (AML), results of the phase 3 VALOR trial suggest.
AML patients age 60 and older with refractory and early relapse disease had improved survival rates when they received vosaroxin and cytarabine, compared to patients who received cytarabine and placebo.
However, for older patients with late-relapse AML, the addition of vosaroxin had no significant impact on survival.
Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented these result at the 20th Congress of the European Hematology Association (abstract P197*). The trial was sponsored by Sunesis Pharmaceuticals, the company developing vosaroxin.
“AML is a disease that primarily affects older patients, and clinical outcomes among these patients is abysmal,” Dr Ravandi noted. “These patients have had few options outside of clinical trial enrollment.”
“Results from the analyses presented today show compelling survival and durable responses, with comparable early mortality, for the vosaroxin and cytarabine treatment arm in the older refractory and early relapse patients. Given these results, I believe vosaroxin represents an important new treatment option.”
VALOR is a randomized, double-blind, phase 3 trial that enrolled 711 adult patients with relapsed or refractory AML. Patients were stratified for age, geographic region, and disease status, then randomized 1:1 to receive vosaroxin and cytarabine or placebo and cytarabine.
Dr Ravandi and his colleagues presented results from the subgroups of patients age 60 years and older (451/711) with late-relapse disease (n=87) and refractory or early relapse disease (combined n=364).
Late-relapse disease
Patients with late-relapse disease had a significantly higher complete response (CR) rate if they received vosaroxin/cytarabine rather than placebo/cytarabine. The rates were 57% and 28%, respectively (P=0.0064).
However, there was no significant difference between the treatment arms with regard to overall survival (OS), leukemia-free survival (LFS), or event-free survival (EFS).
The median OS was 9.2 months in the vosaroxin/cytarabine arm and 9.8 months in the placebo/cytarabine arm (hazard ratio [HR]=1.06, P=0.82). The median OS, censored for transplant, was 9.1 months in both arms (HR=0.92, P=0.78).
The median LFS was 10.3 months in the vosaroxin/cytarabine arm and 8.7 months in the placebo/cytarabine arm (HR=1.16, P=0.77). And the median EFS was 5.5 months and 2.3 months, respectively (HR=0.65, P=0.0852).
Thirty-day all-cause mortality was 11% the vosaroxin/cytarabine arm and 2% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 18% and 14%, respectively.
Refractory/early relapse disease
Patients with refractory AML (n=210) and those with early relapse disease (n=154) had significant improvements in CR and survival when they received vosaroxin and cytarabine. The CR rate was 26% in the vosaroxin/cytarabine arm and 10% in the placebo/cytarabine arm (P=0.0001).
The median OS was 6.5 months in the vosaroxin/cytarabine arm and 3.9 months in the placebo/cytarabine arm (HR=0.69, P=0.0008). The median OS, censored for transplant, was 6.2 months and 3.9 months, respectively (HR=0.71, P=0.0048).
The median LFS was 9.7 months in the vosaroxin/cytarabine arm and 5.5 months in the placebo/cytarabine arm (HR=0.50, P=0.0424). And the median EFS was 1.7 months and 1.3 months, respectively (HR=0.59, P<0.0001).
Rates of all-cause mortality were comparable between the arms. Thirty-day all-cause mortality was 10% in the vosaroxin/cytarabine arm and 11% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 21% and 25%, respectively.
Adverse events
Ninety-four percent of patients in the vosaroxin/cytarabine arm and 86% of those in the placebo/cytarabine arm experienced a grade 3 or higher adverse event (AE). The rate of treatment-related, grade 3 or higher AEs was 74% and 60%, respectively.
The most common grade 3 or higher AEs—occurring in at least 10% of patients in the vosaroxin/cytarabine and placebo/cytarabine arms, respectively—were febrile neutropenia (43% vs 30%), thrombocytopenia (24% vs 25%), anemia (23% vs 24%), neutropenia (19% vs 14%), hypokalemia (15% vs 7%), stomatitis (16% vs 4%), sepsis (12% vs 6%), and pneumonia (11% vs 8%).
*Information in the abstract differs from that presented at the meeting.
Photo courtesy of ASH
VIENNA—Adding the anticancer quinolone derivative vosaroxin to treatment with cytarabine can improve outcomes for some older patients with relapsed/refractory acute myeloid leukemia (AML), results of the phase 3 VALOR trial suggest.
AML patients age 60 and older with refractory and early relapse disease had improved survival rates when they received vosaroxin and cytarabine, compared to patients who received cytarabine and placebo.
However, for older patients with late-relapse AML, the addition of vosaroxin had no significant impact on survival.
Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented these result at the 20th Congress of the European Hematology Association (abstract P197*). The trial was sponsored by Sunesis Pharmaceuticals, the company developing vosaroxin.
“AML is a disease that primarily affects older patients, and clinical outcomes among these patients is abysmal,” Dr Ravandi noted. “These patients have had few options outside of clinical trial enrollment.”
“Results from the analyses presented today show compelling survival and durable responses, with comparable early mortality, for the vosaroxin and cytarabine treatment arm in the older refractory and early relapse patients. Given these results, I believe vosaroxin represents an important new treatment option.”
VALOR is a randomized, double-blind, phase 3 trial that enrolled 711 adult patients with relapsed or refractory AML. Patients were stratified for age, geographic region, and disease status, then randomized 1:1 to receive vosaroxin and cytarabine or placebo and cytarabine.
Dr Ravandi and his colleagues presented results from the subgroups of patients age 60 years and older (451/711) with late-relapse disease (n=87) and refractory or early relapse disease (combined n=364).
Late-relapse disease
Patients with late-relapse disease had a significantly higher complete response (CR) rate if they received vosaroxin/cytarabine rather than placebo/cytarabine. The rates were 57% and 28%, respectively (P=0.0064).
However, there was no significant difference between the treatment arms with regard to overall survival (OS), leukemia-free survival (LFS), or event-free survival (EFS).
The median OS was 9.2 months in the vosaroxin/cytarabine arm and 9.8 months in the placebo/cytarabine arm (hazard ratio [HR]=1.06, P=0.82). The median OS, censored for transplant, was 9.1 months in both arms (HR=0.92, P=0.78).
The median LFS was 10.3 months in the vosaroxin/cytarabine arm and 8.7 months in the placebo/cytarabine arm (HR=1.16, P=0.77). And the median EFS was 5.5 months and 2.3 months, respectively (HR=0.65, P=0.0852).
Thirty-day all-cause mortality was 11% the vosaroxin/cytarabine arm and 2% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 18% and 14%, respectively.
Refractory/early relapse disease
Patients with refractory AML (n=210) and those with early relapse disease (n=154) had significant improvements in CR and survival when they received vosaroxin and cytarabine. The CR rate was 26% in the vosaroxin/cytarabine arm and 10% in the placebo/cytarabine arm (P=0.0001).
The median OS was 6.5 months in the vosaroxin/cytarabine arm and 3.9 months in the placebo/cytarabine arm (HR=0.69, P=0.0008). The median OS, censored for transplant, was 6.2 months and 3.9 months, respectively (HR=0.71, P=0.0048).
The median LFS was 9.7 months in the vosaroxin/cytarabine arm and 5.5 months in the placebo/cytarabine arm (HR=0.50, P=0.0424). And the median EFS was 1.7 months and 1.3 months, respectively (HR=0.59, P<0.0001).
Rates of all-cause mortality were comparable between the arms. Thirty-day all-cause mortality was 10% in the vosaroxin/cytarabine arm and 11% in the placebo/cytarabine arm. Sixty-day all-cause mortality was 21% and 25%, respectively.
Adverse events
Ninety-four percent of patients in the vosaroxin/cytarabine arm and 86% of those in the placebo/cytarabine arm experienced a grade 3 or higher adverse event (AE). The rate of treatment-related, grade 3 or higher AEs was 74% and 60%, respectively.
The most common grade 3 or higher AEs—occurring in at least 10% of patients in the vosaroxin/cytarabine and placebo/cytarabine arms, respectively—were febrile neutropenia (43% vs 30%), thrombocytopenia (24% vs 25%), anemia (23% vs 24%), neutropenia (19% vs 14%), hypokalemia (15% vs 7%), stomatitis (16% vs 4%), sepsis (12% vs 6%), and pneumonia (11% vs 8%).
*Information in the abstract differs from that presented at the meeting.