User login
Reflectance Confocal Microscopy Videomosaic of Melanoma In Situ
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Optimum antithymocyte globulin exposure after HTC affects survival
Optimum antithymocyte globulin exposure after allogeneic hemopoietic cell transplantation (HTC) is associated with a higher probability of survival as a result of reductions in transplant-related and relapse-related deaths, based on findings from a retrospective multicenter cohort study.
The findings come from a pharmacokinetic-pharmacodynamic analysis of data from 146 patients with acute lymphoid leukemia, acute myeloid leukemia, or myelodysplastic syndrome. All were receiving their first T cell–repleted allogeneic peripheral blood stem cell HCT with antithymocyte globulin (ATG) as part of their nonmyeloablative conditioning regimen. Based on hazard ratios for overall survival, nonrelapse mortality, and relapse-related mortality, the optimum range of ATG exposure was 60-95 arbitrary units per day/mL, Rick Admiraal, MD, of the University Medical Centre Utrecht, Netherlands, and his colleagues reported in the Lancet Haematology (Lancet Haematol. 2017 Apr;4[4]:e183-91).
The estimated 5-year survival was significantly greater with optimum ATG exposure than with below-optimum exposure (69% vs. 32%; hazard ratio, 2.41) or with above-optimum exposure (69% vs. 48%; hazard ratio, 2.11).
Optimum ATG exposure also was associated with a greater likelihood of event-free survival: The hazard ratio was 2.54 for those with below-optimum exposure and 1.83 for those with above-optimum exposure, the researchers said. Further, above-optimum exposure was associated with higher relapse-related mortality (hazard ratio, 2.66). Below-optimum exposure was associated with higher non-relapse mortality (hazard ratio, 4.36) as well as with a higher risk for grade 3-4 acute graft-versus-host disease (hazard ratio, 3.09), but not for chronic graft-versus-host disease (hazard ratio, 2.38).
Optimum target attainment was better with modeled dosing based on absolute lymphocyte counts than with weight-based dosing, the authors said.
The findings underscore the importance of optimum ATG dosing, as “survival after HCT is highly affected by ATG exposure after HCT,” and they suggest that survival chances may be improved with individualized dosing based on lymphocyte counts–a finding that requires assessment in a prospective study, they concluded.
This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no relevant disclosures.
The study by Dr. Admiraal and his associates introduces important concepts regarding ATG dosing, but the suggestion that dosing should be individualized based on lymphocyte count and should target the area under the time-versus-thymoglobulin-concentration curve of 60-95 arbitrary units per day/mL after HCT should not yet become the standard of care.
“As the authors correctly point out, first a prospective study is needed,” Dr. Storek wrote.
However, even if such a study confirms this approach – which the authors previously showed to be of benefit in children – it would apply only to the setting in which it was developed. The problem is that there are numerous HCT settings, each requiring a different dose. Further, there is no universally accepted assay for measuring thymoglobulin concentrations, he noted.
“Following the seminal observations in the paper … much work remains to be done,” he wrote.
Jan Storek, MD, is with the University of Calgary (Alta.) and Alberta Health Services, Calgary. He made his comments in an editorial (Lancet Haematol. 2017 Apr;4[4]:e154-5) published with the study and reported having no disclosures.
The study by Dr. Admiraal and his associates introduces important concepts regarding ATG dosing, but the suggestion that dosing should be individualized based on lymphocyte count and should target the area under the time-versus-thymoglobulin-concentration curve of 60-95 arbitrary units per day/mL after HCT should not yet become the standard of care.
“As the authors correctly point out, first a prospective study is needed,” Dr. Storek wrote.
However, even if such a study confirms this approach – which the authors previously showed to be of benefit in children – it would apply only to the setting in which it was developed. The problem is that there are numerous HCT settings, each requiring a different dose. Further, there is no universally accepted assay for measuring thymoglobulin concentrations, he noted.
“Following the seminal observations in the paper … much work remains to be done,” he wrote.
Jan Storek, MD, is with the University of Calgary (Alta.) and Alberta Health Services, Calgary. He made his comments in an editorial (Lancet Haematol. 2017 Apr;4[4]:e154-5) published with the study and reported having no disclosures.
The study by Dr. Admiraal and his associates introduces important concepts regarding ATG dosing, but the suggestion that dosing should be individualized based on lymphocyte count and should target the area under the time-versus-thymoglobulin-concentration curve of 60-95 arbitrary units per day/mL after HCT should not yet become the standard of care.
“As the authors correctly point out, first a prospective study is needed,” Dr. Storek wrote.
However, even if such a study confirms this approach – which the authors previously showed to be of benefit in children – it would apply only to the setting in which it was developed. The problem is that there are numerous HCT settings, each requiring a different dose. Further, there is no universally accepted assay for measuring thymoglobulin concentrations, he noted.
“Following the seminal observations in the paper … much work remains to be done,” he wrote.
Jan Storek, MD, is with the University of Calgary (Alta.) and Alberta Health Services, Calgary. He made his comments in an editorial (Lancet Haematol. 2017 Apr;4[4]:e154-5) published with the study and reported having no disclosures.
Optimum antithymocyte globulin exposure after allogeneic hemopoietic cell transplantation (HTC) is associated with a higher probability of survival as a result of reductions in transplant-related and relapse-related deaths, based on findings from a retrospective multicenter cohort study.
The findings come from a pharmacokinetic-pharmacodynamic analysis of data from 146 patients with acute lymphoid leukemia, acute myeloid leukemia, or myelodysplastic syndrome. All were receiving their first T cell–repleted allogeneic peripheral blood stem cell HCT with antithymocyte globulin (ATG) as part of their nonmyeloablative conditioning regimen. Based on hazard ratios for overall survival, nonrelapse mortality, and relapse-related mortality, the optimum range of ATG exposure was 60-95 arbitrary units per day/mL, Rick Admiraal, MD, of the University Medical Centre Utrecht, Netherlands, and his colleagues reported in the Lancet Haematology (Lancet Haematol. 2017 Apr;4[4]:e183-91).
The estimated 5-year survival was significantly greater with optimum ATG exposure than with below-optimum exposure (69% vs. 32%; hazard ratio, 2.41) or with above-optimum exposure (69% vs. 48%; hazard ratio, 2.11).
Optimum ATG exposure also was associated with a greater likelihood of event-free survival: The hazard ratio was 2.54 for those with below-optimum exposure and 1.83 for those with above-optimum exposure, the researchers said. Further, above-optimum exposure was associated with higher relapse-related mortality (hazard ratio, 2.66). Below-optimum exposure was associated with higher non-relapse mortality (hazard ratio, 4.36) as well as with a higher risk for grade 3-4 acute graft-versus-host disease (hazard ratio, 3.09), but not for chronic graft-versus-host disease (hazard ratio, 2.38).
Optimum target attainment was better with modeled dosing based on absolute lymphocyte counts than with weight-based dosing, the authors said.
The findings underscore the importance of optimum ATG dosing, as “survival after HCT is highly affected by ATG exposure after HCT,” and they suggest that survival chances may be improved with individualized dosing based on lymphocyte counts–a finding that requires assessment in a prospective study, they concluded.
This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no relevant disclosures.
Optimum antithymocyte globulin exposure after allogeneic hemopoietic cell transplantation (HTC) is associated with a higher probability of survival as a result of reductions in transplant-related and relapse-related deaths, based on findings from a retrospective multicenter cohort study.
The findings come from a pharmacokinetic-pharmacodynamic analysis of data from 146 patients with acute lymphoid leukemia, acute myeloid leukemia, or myelodysplastic syndrome. All were receiving their first T cell–repleted allogeneic peripheral blood stem cell HCT with antithymocyte globulin (ATG) as part of their nonmyeloablative conditioning regimen. Based on hazard ratios for overall survival, nonrelapse mortality, and relapse-related mortality, the optimum range of ATG exposure was 60-95 arbitrary units per day/mL, Rick Admiraal, MD, of the University Medical Centre Utrecht, Netherlands, and his colleagues reported in the Lancet Haematology (Lancet Haematol. 2017 Apr;4[4]:e183-91).
The estimated 5-year survival was significantly greater with optimum ATG exposure than with below-optimum exposure (69% vs. 32%; hazard ratio, 2.41) or with above-optimum exposure (69% vs. 48%; hazard ratio, 2.11).
Optimum ATG exposure also was associated with a greater likelihood of event-free survival: The hazard ratio was 2.54 for those with below-optimum exposure and 1.83 for those with above-optimum exposure, the researchers said. Further, above-optimum exposure was associated with higher relapse-related mortality (hazard ratio, 2.66). Below-optimum exposure was associated with higher non-relapse mortality (hazard ratio, 4.36) as well as with a higher risk for grade 3-4 acute graft-versus-host disease (hazard ratio, 3.09), but not for chronic graft-versus-host disease (hazard ratio, 2.38).
Optimum target attainment was better with modeled dosing based on absolute lymphocyte counts than with weight-based dosing, the authors said.
The findings underscore the importance of optimum ATG dosing, as “survival after HCT is highly affected by ATG exposure after HCT,” and they suggest that survival chances may be improved with individualized dosing based on lymphocyte counts–a finding that requires assessment in a prospective study, they concluded.
This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no relevant disclosures.
FROM THE LANCET HAEMATOLOGY
Key clinical point:
Major finding: The estimated 5-year survival with optimum ATG exposure was 69% vs. 32% and 48% with below- and above-optimum exposure (hazard ratios, 2.41 and 2.11, respectively).
Data source: A retrospective cohort study of 146 patients receiving their first T-cell repleted allogeneic peripheral blood stem cell HCT.
Disclosures: This study was funded by the Dutch Organization for Scientific Research and the Queen Wilhelmina Fund for Cancer Research. Dr. Admiraal reported having no disclosures.
Extended maraviroc helps prevent graft-versus-host disease
ORLANDO – The use of the CCR5 antagonist maraviroc for 90 days is safe and effective for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation, according to findings from a phase II study.
An earlier study showed that CCR5 blockade using maraviroc for 33 days was associated with a low incidence of acute GVHD, as well as with absence of early liver and gut GVHD – although delayed severe cases of visceral GVHD still occurred.
The current study was performed because the prior findings raised concerns that brief blockade was insufficient for preventing GVHD over a longer period of time. The new findings show that an extended course may indeed provide additional benefits, Ran Reshef, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In 37 high-risk patients who received allogeneic stem cell transplantation from unrelated donors using fludarabine/busulfan (Flu/Bu2) conditioning followed by peripheral blood stem cells, maraviroc was given at a dose of 300 mg twice daily, in addition to standard tacrolimus and methotrexate.
The 180-day rates of grade 2-4 and grade 3-4 acute GVHD (the primary endpoint of the study) in these patients were 27% and 5%, respectively. These rates were very similar to the 24% and 6% rates seen in the first study at 6 months after 30 days of maraviroc treatment, said Dr. Reshef of Columbia University Medical Center, New York.
The earlier results were “driven not so much by a reduction in the rates of skin GVHD, but by low rates of visceral GVHD of the gut and the liver – with a striking absence of gut and liver GVHD in the first 100 days,” he said.
Dr. Reshef also noted that the current study had a less favorable donor mix, as no matched related donors were included because of the earlier study’s very low rates of GVHD – with or without maraviroc – in those with related donors, who composed a third of donors.
Long-term follow-up of results from the earlier study, with comparison of a large contemporary control cohort, showed that “there is in fact an impact ... on grade 2-4 and grade 3-4 [GVHD], although the number of events is small, and the study was not powered enough to reach statistical significance,” Dr. Reshef said. The rates of chronic GVHD did not differ between the study subjects and contemporary controls, he noted.
At 100 days in the current study, there were no cases of liver GVHD, two cases of mild upper-GI GVHD, and one case of severe gut GVHD. At 1 year, the disease relapse rate was “fairly reasonable” at 30%, nonrelapse mortality was 12% with only one case of death from GVHD, and the incidence of chronic GVHD was 8%, which was significantly lower than in the prior study, he said.
The low rate of chronic GVHD led to a GVHD/relapse-free survival (GRFS) rate of 49%.
“To put this in context, the [Center for International Blood & Marrow Transplant Research] data for reduced-intensity transplants ... have shown 25% for acute myeloid leukemia and 12% for myelodysplastic syndrome,” he said. “So, we feel that these are by far improved numbers, compared with this benchmark.”
To determine which patients develop GVHD despite chemotaxis blockade and why, Dr. Reshef and his colleagues developed a pharmacodynamic assay to assess the activity of maraviroc in fresh blood samples. They found that those with insufficient CCR5 blockade on day 0 were those with higher incidence of severe acute GVHD, nonrelapse mortality, GRFS, and overall survival.
The investigators performed pharmacokinetic analysis using combined data from both trials to improve understanding of why some patients have insufficient CCR5 blockade. This showed significant variability in day 0 trough of maraviroc among patients (median of 65 ng/mL, range 12-316 ng/mL); levels above the median were associated with a significantly lower incidence of acute grade 2-4 GVHD and a trend toward improved GRFS.
These studies of maraviroc, which was originally developed for the treatment of HIV infection, were done to test the belief that blocking lymphocyte migration might prevent GVHD without interfering with graft-versus-tumor activity. Based on the earlier findings, Dr. Reshef and his colleagues hypothesized that treatment up to day 90 would decrease the rate to less than 30%, from a historical rate of 52%.
Patients in the study were high risk by virtue of age (median, 64 years), HLA matching (matched unrelated, 84%; mismatched unrelated, 16%), and comorbidities (comorbidity index greater than 2 in 49%). Underlying diseases were acute leukemia (78%), myelodysplastic syndrome (16%), and myeloproliferative neoplasm and cutaneous T-cell lymphomas (3% each).
At a median follow-up of 21 months, the 3-month course of maraviroc was well tolerated. Eight patients did not complete treatment because of disease relapse (five patients), skin reaction (one patient), early infection-related death (one patient), or poor tolerance of oral drugs (one patient). Neutrophil, platelet, and T-cell engraftment were similar to historical controls, and rates of infections were also similar, Dr Reshef noted.
“To conclude, an extended course of maraviroc up to day 90 is feasible and safe in the majority of patients,” he said. “This study confirms the effect of CCR5 blockade on visceral GVHD. I’m still awaiting a randomized study to confirm that further.
“A long course of maraviroc does not necessarily affect the rates of acute GVHD, but may help reduce chronic GVHD and improve GRFS,” Dr. Reshef said. “We should look further into the pharmacodynamic and pharmacokinetic variables.”
Dr. Reshef reported receiving research funding from Pfizer.
ORLANDO – The use of the CCR5 antagonist maraviroc for 90 days is safe and effective for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation, according to findings from a phase II study.
An earlier study showed that CCR5 blockade using maraviroc for 33 days was associated with a low incidence of acute GVHD, as well as with absence of early liver and gut GVHD – although delayed severe cases of visceral GVHD still occurred.
The current study was performed because the prior findings raised concerns that brief blockade was insufficient for preventing GVHD over a longer period of time. The new findings show that an extended course may indeed provide additional benefits, Ran Reshef, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In 37 high-risk patients who received allogeneic stem cell transplantation from unrelated donors using fludarabine/busulfan (Flu/Bu2) conditioning followed by peripheral blood stem cells, maraviroc was given at a dose of 300 mg twice daily, in addition to standard tacrolimus and methotrexate.
The 180-day rates of grade 2-4 and grade 3-4 acute GVHD (the primary endpoint of the study) in these patients were 27% and 5%, respectively. These rates were very similar to the 24% and 6% rates seen in the first study at 6 months after 30 days of maraviroc treatment, said Dr. Reshef of Columbia University Medical Center, New York.
The earlier results were “driven not so much by a reduction in the rates of skin GVHD, but by low rates of visceral GVHD of the gut and the liver – with a striking absence of gut and liver GVHD in the first 100 days,” he said.
Dr. Reshef also noted that the current study had a less favorable donor mix, as no matched related donors were included because of the earlier study’s very low rates of GVHD – with or without maraviroc – in those with related donors, who composed a third of donors.
Long-term follow-up of results from the earlier study, with comparison of a large contemporary control cohort, showed that “there is in fact an impact ... on grade 2-4 and grade 3-4 [GVHD], although the number of events is small, and the study was not powered enough to reach statistical significance,” Dr. Reshef said. The rates of chronic GVHD did not differ between the study subjects and contemporary controls, he noted.
At 100 days in the current study, there were no cases of liver GVHD, two cases of mild upper-GI GVHD, and one case of severe gut GVHD. At 1 year, the disease relapse rate was “fairly reasonable” at 30%, nonrelapse mortality was 12% with only one case of death from GVHD, and the incidence of chronic GVHD was 8%, which was significantly lower than in the prior study, he said.
The low rate of chronic GVHD led to a GVHD/relapse-free survival (GRFS) rate of 49%.
“To put this in context, the [Center for International Blood & Marrow Transplant Research] data for reduced-intensity transplants ... have shown 25% for acute myeloid leukemia and 12% for myelodysplastic syndrome,” he said. “So, we feel that these are by far improved numbers, compared with this benchmark.”
To determine which patients develop GVHD despite chemotaxis blockade and why, Dr. Reshef and his colleagues developed a pharmacodynamic assay to assess the activity of maraviroc in fresh blood samples. They found that those with insufficient CCR5 blockade on day 0 were those with higher incidence of severe acute GVHD, nonrelapse mortality, GRFS, and overall survival.
The investigators performed pharmacokinetic analysis using combined data from both trials to improve understanding of why some patients have insufficient CCR5 blockade. This showed significant variability in day 0 trough of maraviroc among patients (median of 65 ng/mL, range 12-316 ng/mL); levels above the median were associated with a significantly lower incidence of acute grade 2-4 GVHD and a trend toward improved GRFS.
These studies of maraviroc, which was originally developed for the treatment of HIV infection, were done to test the belief that blocking lymphocyte migration might prevent GVHD without interfering with graft-versus-tumor activity. Based on the earlier findings, Dr. Reshef and his colleagues hypothesized that treatment up to day 90 would decrease the rate to less than 30%, from a historical rate of 52%.
Patients in the study were high risk by virtue of age (median, 64 years), HLA matching (matched unrelated, 84%; mismatched unrelated, 16%), and comorbidities (comorbidity index greater than 2 in 49%). Underlying diseases were acute leukemia (78%), myelodysplastic syndrome (16%), and myeloproliferative neoplasm and cutaneous T-cell lymphomas (3% each).
At a median follow-up of 21 months, the 3-month course of maraviroc was well tolerated. Eight patients did not complete treatment because of disease relapse (five patients), skin reaction (one patient), early infection-related death (one patient), or poor tolerance of oral drugs (one patient). Neutrophil, platelet, and T-cell engraftment were similar to historical controls, and rates of infections were also similar, Dr Reshef noted.
“To conclude, an extended course of maraviroc up to day 90 is feasible and safe in the majority of patients,” he said. “This study confirms the effect of CCR5 blockade on visceral GVHD. I’m still awaiting a randomized study to confirm that further.
“A long course of maraviroc does not necessarily affect the rates of acute GVHD, but may help reduce chronic GVHD and improve GRFS,” Dr. Reshef said. “We should look further into the pharmacodynamic and pharmacokinetic variables.”
Dr. Reshef reported receiving research funding from Pfizer.
ORLANDO – The use of the CCR5 antagonist maraviroc for 90 days is safe and effective for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic stem cell transplantation, according to findings from a phase II study.
An earlier study showed that CCR5 blockade using maraviroc for 33 days was associated with a low incidence of acute GVHD, as well as with absence of early liver and gut GVHD – although delayed severe cases of visceral GVHD still occurred.
The current study was performed because the prior findings raised concerns that brief blockade was insufficient for preventing GVHD over a longer period of time. The new findings show that an extended course may indeed provide additional benefits, Ran Reshef, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In 37 high-risk patients who received allogeneic stem cell transplantation from unrelated donors using fludarabine/busulfan (Flu/Bu2) conditioning followed by peripheral blood stem cells, maraviroc was given at a dose of 300 mg twice daily, in addition to standard tacrolimus and methotrexate.
The 180-day rates of grade 2-4 and grade 3-4 acute GVHD (the primary endpoint of the study) in these patients were 27% and 5%, respectively. These rates were very similar to the 24% and 6% rates seen in the first study at 6 months after 30 days of maraviroc treatment, said Dr. Reshef of Columbia University Medical Center, New York.
The earlier results were “driven not so much by a reduction in the rates of skin GVHD, but by low rates of visceral GVHD of the gut and the liver – with a striking absence of gut and liver GVHD in the first 100 days,” he said.
Dr. Reshef also noted that the current study had a less favorable donor mix, as no matched related donors were included because of the earlier study’s very low rates of GVHD – with or without maraviroc – in those with related donors, who composed a third of donors.
Long-term follow-up of results from the earlier study, with comparison of a large contemporary control cohort, showed that “there is in fact an impact ... on grade 2-4 and grade 3-4 [GVHD], although the number of events is small, and the study was not powered enough to reach statistical significance,” Dr. Reshef said. The rates of chronic GVHD did not differ between the study subjects and contemporary controls, he noted.
At 100 days in the current study, there were no cases of liver GVHD, two cases of mild upper-GI GVHD, and one case of severe gut GVHD. At 1 year, the disease relapse rate was “fairly reasonable” at 30%, nonrelapse mortality was 12% with only one case of death from GVHD, and the incidence of chronic GVHD was 8%, which was significantly lower than in the prior study, he said.
The low rate of chronic GVHD led to a GVHD/relapse-free survival (GRFS) rate of 49%.
“To put this in context, the [Center for International Blood & Marrow Transplant Research] data for reduced-intensity transplants ... have shown 25% for acute myeloid leukemia and 12% for myelodysplastic syndrome,” he said. “So, we feel that these are by far improved numbers, compared with this benchmark.”
To determine which patients develop GVHD despite chemotaxis blockade and why, Dr. Reshef and his colleagues developed a pharmacodynamic assay to assess the activity of maraviroc in fresh blood samples. They found that those with insufficient CCR5 blockade on day 0 were those with higher incidence of severe acute GVHD, nonrelapse mortality, GRFS, and overall survival.
The investigators performed pharmacokinetic analysis using combined data from both trials to improve understanding of why some patients have insufficient CCR5 blockade. This showed significant variability in day 0 trough of maraviroc among patients (median of 65 ng/mL, range 12-316 ng/mL); levels above the median were associated with a significantly lower incidence of acute grade 2-4 GVHD and a trend toward improved GRFS.
These studies of maraviroc, which was originally developed for the treatment of HIV infection, were done to test the belief that blocking lymphocyte migration might prevent GVHD without interfering with graft-versus-tumor activity. Based on the earlier findings, Dr. Reshef and his colleagues hypothesized that treatment up to day 90 would decrease the rate to less than 30%, from a historical rate of 52%.
Patients in the study were high risk by virtue of age (median, 64 years), HLA matching (matched unrelated, 84%; mismatched unrelated, 16%), and comorbidities (comorbidity index greater than 2 in 49%). Underlying diseases were acute leukemia (78%), myelodysplastic syndrome (16%), and myeloproliferative neoplasm and cutaneous T-cell lymphomas (3% each).
At a median follow-up of 21 months, the 3-month course of maraviroc was well tolerated. Eight patients did not complete treatment because of disease relapse (five patients), skin reaction (one patient), early infection-related death (one patient), or poor tolerance of oral drugs (one patient). Neutrophil, platelet, and T-cell engraftment were similar to historical controls, and rates of infections were also similar, Dr Reshef noted.
“To conclude, an extended course of maraviroc up to day 90 is feasible and safe in the majority of patients,” he said. “This study confirms the effect of CCR5 blockade on visceral GVHD. I’m still awaiting a randomized study to confirm that further.
“A long course of maraviroc does not necessarily affect the rates of acute GVHD, but may help reduce chronic GVHD and improve GRFS,” Dr. Reshef said. “We should look further into the pharmacodynamic and pharmacokinetic variables.”
Dr. Reshef reported receiving research funding from Pfizer.
AT THE 2017 BMT TANDEM MEETINGS
Key clinical point:
Major finding: The 180-day rates of grade 2-4 and grade 3-4 acute GVHD were 27% and 5%, respectively.
Data source: A phase II study of 37 patients.
Disclosures: Dr. Reshef reported receiving research funding from Pfizer.
Can public reporting improve pediatric heart surgery?
Public reporting of cardiac surgery outcomes has been a disruptive force in cardiology, and especially daunting in pediatric cardiac surgery because of low case volumes and rare mortality. To ensure that public reporting achieves its original goals – providing transparency to the patient care process, holding providers accountable, informing decision making for health care consumers, reducing costs, encouraging more efficient use of health system resources, and improving patient care and outcomes – further study that includes use of appropriate risk adjustment is needed, according to commentaries in the April issue of the Journal of Thoracic and Cardiovascular Surgery.
The journal asked two groups to provide perspective on a study Adam D. DeVore, MD, of Duke University in Durham, N.C., and his coauthors published last year (J Am Coll Cardiol. 2016 Mar 1;67:963-72). The study analyzed Medicare claims data from 2006 to 2012 for 37,829 hospitalizations for heart attack, 100,189 for heart failure (HF), and 79,076 for pneumonia. Dr. DeVore and his colleagues found readmission rates for the three conditions did not significantly improve after public reporting protocols were implemented in 2009. However, the study did show a significant decrease in ED visits and observation stays for those with HF: from 2.3% to –0.8% for the former (P = .007); and from 15% to 4% for the latter (P = .04).
• The metrics must be accurate, reliably discern hospital quality, and account for high-risk cases without penalizing hospitals. “In pediatric cardiac surgery, this can be particularly challenging, owing to the very wide heterogeneity of disease and variability in case mix and volumes across centers,” Dr. Gaynor and his coauthors wrote. While methodology for case mix and patient characteristics have improved in recent years, further improvement is needed.
• Metrics must be clearly reported and easy for stakeholders to interpret. “This is critical if the data are to be used to steer patients toward higher-performing centers and/or to provide incentives for hospitals with lower performance to make improvements,” the researchers said.
• Regional reporting or a methodology that indicates where a hospital ranks within larger categories deserve further investigation as tools to help families choose a high-performing center, “ideally based on geography and on the particular type and complexity of disease,” Dr. Gaynor and his coauthors stated (J Thorac Cardiovasc Surg. 2017 Apr;153:904-7).
• Indirect standardization, a statistical methodology used to calculate risk-adjusted performance, could help consumers to interpret hospital performance more easily. This methodology might help classify a hospital with a low-complexity population as a high performer. “Developing better methods to convey this information to consumers is vital,” according to the researchers.
The perspective acknowledged several reports of an unintended consequence of public reporting: surgeons and centers avoiding higher-risk cases to skew their performance scores higher, thus restricting access to care. However, in a separate perspective on Dr. DeVore’s study, James S. Tweddell, MD, of Cincinnati Children’s Hospital Medical Center, and his coauthors, questioned the quality of the evidence on which Dr. Gaynor and his colleagues based their conclusion of risk aversion and limited access to care: a newspaper report from the United Kingdom.
Dr. Tweddell and his coauthors noted, “The predominance of data suggest an overall beneficial impact of public reporting.” They cited a trial that showed a decrease in heart attack–related deaths after public reporting had been implemented (JAMA. 2009 Dec 2;302:2330-7); a 2012 Agency for Healthcare Research and Quality systemic review (Evidence Report No. 208) that showed that research on harm is limited, and most studies do not confirm potential harm; and a meta-analysis that found a 15% reduction in adverse events associated with public reporting (BMC Health Serv Res. 2016;16:296).
“Appropriate risk adjustment is critical to achieve effective and fair transparency, but there is little objective data of harm associated with public reporting,” Dr. Tweddell and his coauthors concluded. While examination of public reporting must continue, they said, “these efforts are likely to result in minor course changes and the effort to inform and educate our patients and their families must continue.”
Ds. Gaynor, Dr. Tweddell, and their coauthors reported having no financial disclosures.
Public reporting of cardiac surgery outcomes has been a disruptive force in cardiology, and especially daunting in pediatric cardiac surgery because of low case volumes and rare mortality. To ensure that public reporting achieves its original goals – providing transparency to the patient care process, holding providers accountable, informing decision making for health care consumers, reducing costs, encouraging more efficient use of health system resources, and improving patient care and outcomes – further study that includes use of appropriate risk adjustment is needed, according to commentaries in the April issue of the Journal of Thoracic and Cardiovascular Surgery.
The journal asked two groups to provide perspective on a study Adam D. DeVore, MD, of Duke University in Durham, N.C., and his coauthors published last year (J Am Coll Cardiol. 2016 Mar 1;67:963-72). The study analyzed Medicare claims data from 2006 to 2012 for 37,829 hospitalizations for heart attack, 100,189 for heart failure (HF), and 79,076 for pneumonia. Dr. DeVore and his colleagues found readmission rates for the three conditions did not significantly improve after public reporting protocols were implemented in 2009. However, the study did show a significant decrease in ED visits and observation stays for those with HF: from 2.3% to –0.8% for the former (P = .007); and from 15% to 4% for the latter (P = .04).
• The metrics must be accurate, reliably discern hospital quality, and account for high-risk cases without penalizing hospitals. “In pediatric cardiac surgery, this can be particularly challenging, owing to the very wide heterogeneity of disease and variability in case mix and volumes across centers,” Dr. Gaynor and his coauthors wrote. While methodology for case mix and patient characteristics have improved in recent years, further improvement is needed.
• Metrics must be clearly reported and easy for stakeholders to interpret. “This is critical if the data are to be used to steer patients toward higher-performing centers and/or to provide incentives for hospitals with lower performance to make improvements,” the researchers said.
• Regional reporting or a methodology that indicates where a hospital ranks within larger categories deserve further investigation as tools to help families choose a high-performing center, “ideally based on geography and on the particular type and complexity of disease,” Dr. Gaynor and his coauthors stated (J Thorac Cardiovasc Surg. 2017 Apr;153:904-7).
• Indirect standardization, a statistical methodology used to calculate risk-adjusted performance, could help consumers to interpret hospital performance more easily. This methodology might help classify a hospital with a low-complexity population as a high performer. “Developing better methods to convey this information to consumers is vital,” according to the researchers.
The perspective acknowledged several reports of an unintended consequence of public reporting: surgeons and centers avoiding higher-risk cases to skew their performance scores higher, thus restricting access to care. However, in a separate perspective on Dr. DeVore’s study, James S. Tweddell, MD, of Cincinnati Children’s Hospital Medical Center, and his coauthors, questioned the quality of the evidence on which Dr. Gaynor and his colleagues based their conclusion of risk aversion and limited access to care: a newspaper report from the United Kingdom.
Dr. Tweddell and his coauthors noted, “The predominance of data suggest an overall beneficial impact of public reporting.” They cited a trial that showed a decrease in heart attack–related deaths after public reporting had been implemented (JAMA. 2009 Dec 2;302:2330-7); a 2012 Agency for Healthcare Research and Quality systemic review (Evidence Report No. 208) that showed that research on harm is limited, and most studies do not confirm potential harm; and a meta-analysis that found a 15% reduction in adverse events associated with public reporting (BMC Health Serv Res. 2016;16:296).
“Appropriate risk adjustment is critical to achieve effective and fair transparency, but there is little objective data of harm associated with public reporting,” Dr. Tweddell and his coauthors concluded. While examination of public reporting must continue, they said, “these efforts are likely to result in minor course changes and the effort to inform and educate our patients and their families must continue.”
Ds. Gaynor, Dr. Tweddell, and their coauthors reported having no financial disclosures.
Public reporting of cardiac surgery outcomes has been a disruptive force in cardiology, and especially daunting in pediatric cardiac surgery because of low case volumes and rare mortality. To ensure that public reporting achieves its original goals – providing transparency to the patient care process, holding providers accountable, informing decision making for health care consumers, reducing costs, encouraging more efficient use of health system resources, and improving patient care and outcomes – further study that includes use of appropriate risk adjustment is needed, according to commentaries in the April issue of the Journal of Thoracic and Cardiovascular Surgery.
The journal asked two groups to provide perspective on a study Adam D. DeVore, MD, of Duke University in Durham, N.C., and his coauthors published last year (J Am Coll Cardiol. 2016 Mar 1;67:963-72). The study analyzed Medicare claims data from 2006 to 2012 for 37,829 hospitalizations for heart attack, 100,189 for heart failure (HF), and 79,076 for pneumonia. Dr. DeVore and his colleagues found readmission rates for the three conditions did not significantly improve after public reporting protocols were implemented in 2009. However, the study did show a significant decrease in ED visits and observation stays for those with HF: from 2.3% to –0.8% for the former (P = .007); and from 15% to 4% for the latter (P = .04).
• The metrics must be accurate, reliably discern hospital quality, and account for high-risk cases without penalizing hospitals. “In pediatric cardiac surgery, this can be particularly challenging, owing to the very wide heterogeneity of disease and variability in case mix and volumes across centers,” Dr. Gaynor and his coauthors wrote. While methodology for case mix and patient characteristics have improved in recent years, further improvement is needed.
• Metrics must be clearly reported and easy for stakeholders to interpret. “This is critical if the data are to be used to steer patients toward higher-performing centers and/or to provide incentives for hospitals with lower performance to make improvements,” the researchers said.
• Regional reporting or a methodology that indicates where a hospital ranks within larger categories deserve further investigation as tools to help families choose a high-performing center, “ideally based on geography and on the particular type and complexity of disease,” Dr. Gaynor and his coauthors stated (J Thorac Cardiovasc Surg. 2017 Apr;153:904-7).
• Indirect standardization, a statistical methodology used to calculate risk-adjusted performance, could help consumers to interpret hospital performance more easily. This methodology might help classify a hospital with a low-complexity population as a high performer. “Developing better methods to convey this information to consumers is vital,” according to the researchers.
The perspective acknowledged several reports of an unintended consequence of public reporting: surgeons and centers avoiding higher-risk cases to skew their performance scores higher, thus restricting access to care. However, in a separate perspective on Dr. DeVore’s study, James S. Tweddell, MD, of Cincinnati Children’s Hospital Medical Center, and his coauthors, questioned the quality of the evidence on which Dr. Gaynor and his colleagues based their conclusion of risk aversion and limited access to care: a newspaper report from the United Kingdom.
Dr. Tweddell and his coauthors noted, “The predominance of data suggest an overall beneficial impact of public reporting.” They cited a trial that showed a decrease in heart attack–related deaths after public reporting had been implemented (JAMA. 2009 Dec 2;302:2330-7); a 2012 Agency for Healthcare Research and Quality systemic review (Evidence Report No. 208) that showed that research on harm is limited, and most studies do not confirm potential harm; and a meta-analysis that found a 15% reduction in adverse events associated with public reporting (BMC Health Serv Res. 2016;16:296).
“Appropriate risk adjustment is critical to achieve effective and fair transparency, but there is little objective data of harm associated with public reporting,” Dr. Tweddell and his coauthors concluded. While examination of public reporting must continue, they said, “these efforts are likely to result in minor course changes and the effort to inform and educate our patients and their families must continue.”
Ds. Gaynor, Dr. Tweddell, and their coauthors reported having no financial disclosures.
FROM THE JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
Key clinical point: Public reporting of outcomes in cardiac surgery in children requires further investigation but has also been associated with improved outcomes.
Major finding: Emergency department visits for patients with heart failure declined from 2.3% before public reporting to –0.8% after implementation, and observation stays declined from 15.1% to 4.1%.
Data source: Analysis of Medicare claims data from 2006 to 2012 for 271,094 patients discharged after hospitalization for heart attack, heart failure or pneumonia.
Disclosures: Dr. Gaynor and Dr. Tweddell had no financial relationships to disclose.
CDC: Some Shigella strains show reduced ciprofloxacin susceptibility
The Centers for Disease Control and Prevention has identified an increase in Shigella isolates with reduced susceptibility to ciprofloxacin, and has released an official health advisory outlining new recommendations for clinical diagnosis, management, and reporting, as well as for laboratories and public health officials.
The Shigella isolates of concern in the United States have minimum inhibitory concentration (MIC) values of 0.12-1 mcg/mL for ciprofloxacin, which is within the range considered susceptible. These strains, however, “often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics,” such as ciprofloxacin, according to the CDC advisory.
It is possible that strains with MIC in the 0.12-1 mcg/mL range may have worse clinical outcome or increased risk of transmission, so the CDC made the following recommendations to clinicians:
• Order a stool culture to obtain isolates for antimicrobial susceptibility testing in suspected cases.
• Order antimicrobial susceptibility testing when ordering a stool culture for Shigella.
• Avoid routine prescribing of antibiotic therapy for Shigella infection, instead reserving antibiotics for patients with a clinical indication or when advised by public health officials in an outbreak setting.
• Tailor antibiotic choice (when antibiotics are indicated) to susceptibility results as soon as possible – with special attention given to the MIC for fluoroquinolone antibiotics.
• Obtain follow-up stool cultures in shigellosis patients who have continued or worsening symptoms despite antibiotic therapy.
• Consult local or state health departments for guidance regarding when patients may return to child care, school, or work.
• Counsel patients with active diarrhea on how they can prevent spreading the infection to others, regardless of whether antibiotic treatment is prescribed.
Additionally, the CDC noted that shigellosis is a nationally notifiable condition; all cases should be reported to the local health department. If a patient with shigellosis and a ciprofloxacin MIC of 0.12-1 mcg/mL is identified, this information should be included in the report to facilitate further testing of the isolate.
The CDC reported that it is working with state and local public health departments and clinical partners to determine if outcomes are indeed worse for patients treated with ciprofloxacin for Shigella strains harboring a quinolone resistance gene, and it will continue to monitor trends in susceptibility of Shigella isolates and to perform genetic testing on select strains to confirm the presence and type of resistance genes.
The Centers for Disease Control and Prevention has identified an increase in Shigella isolates with reduced susceptibility to ciprofloxacin, and has released an official health advisory outlining new recommendations for clinical diagnosis, management, and reporting, as well as for laboratories and public health officials.
The Shigella isolates of concern in the United States have minimum inhibitory concentration (MIC) values of 0.12-1 mcg/mL for ciprofloxacin, which is within the range considered susceptible. These strains, however, “often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics,” such as ciprofloxacin, according to the CDC advisory.
It is possible that strains with MIC in the 0.12-1 mcg/mL range may have worse clinical outcome or increased risk of transmission, so the CDC made the following recommendations to clinicians:
• Order a stool culture to obtain isolates for antimicrobial susceptibility testing in suspected cases.
• Order antimicrobial susceptibility testing when ordering a stool culture for Shigella.
• Avoid routine prescribing of antibiotic therapy for Shigella infection, instead reserving antibiotics for patients with a clinical indication or when advised by public health officials in an outbreak setting.
• Tailor antibiotic choice (when antibiotics are indicated) to susceptibility results as soon as possible – with special attention given to the MIC for fluoroquinolone antibiotics.
• Obtain follow-up stool cultures in shigellosis patients who have continued or worsening symptoms despite antibiotic therapy.
• Consult local or state health departments for guidance regarding when patients may return to child care, school, or work.
• Counsel patients with active diarrhea on how they can prevent spreading the infection to others, regardless of whether antibiotic treatment is prescribed.
Additionally, the CDC noted that shigellosis is a nationally notifiable condition; all cases should be reported to the local health department. If a patient with shigellosis and a ciprofloxacin MIC of 0.12-1 mcg/mL is identified, this information should be included in the report to facilitate further testing of the isolate.
The CDC reported that it is working with state and local public health departments and clinical partners to determine if outcomes are indeed worse for patients treated with ciprofloxacin for Shigella strains harboring a quinolone resistance gene, and it will continue to monitor trends in susceptibility of Shigella isolates and to perform genetic testing on select strains to confirm the presence and type of resistance genes.
The Centers for Disease Control and Prevention has identified an increase in Shigella isolates with reduced susceptibility to ciprofloxacin, and has released an official health advisory outlining new recommendations for clinical diagnosis, management, and reporting, as well as for laboratories and public health officials.
The Shigella isolates of concern in the United States have minimum inhibitory concentration (MIC) values of 0.12-1 mcg/mL for ciprofloxacin, which is within the range considered susceptible. These strains, however, “often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics,” such as ciprofloxacin, according to the CDC advisory.
It is possible that strains with MIC in the 0.12-1 mcg/mL range may have worse clinical outcome or increased risk of transmission, so the CDC made the following recommendations to clinicians:
• Order a stool culture to obtain isolates for antimicrobial susceptibility testing in suspected cases.
• Order antimicrobial susceptibility testing when ordering a stool culture for Shigella.
• Avoid routine prescribing of antibiotic therapy for Shigella infection, instead reserving antibiotics for patients with a clinical indication or when advised by public health officials in an outbreak setting.
• Tailor antibiotic choice (when antibiotics are indicated) to susceptibility results as soon as possible – with special attention given to the MIC for fluoroquinolone antibiotics.
• Obtain follow-up stool cultures in shigellosis patients who have continued or worsening symptoms despite antibiotic therapy.
• Consult local or state health departments for guidance regarding when patients may return to child care, school, or work.
• Counsel patients with active diarrhea on how they can prevent spreading the infection to others, regardless of whether antibiotic treatment is prescribed.
Additionally, the CDC noted that shigellosis is a nationally notifiable condition; all cases should be reported to the local health department. If a patient with shigellosis and a ciprofloxacin MIC of 0.12-1 mcg/mL is identified, this information should be included in the report to facilitate further testing of the isolate.
The CDC reported that it is working with state and local public health departments and clinical partners to determine if outcomes are indeed worse for patients treated with ciprofloxacin for Shigella strains harboring a quinolone resistance gene, and it will continue to monitor trends in susceptibility of Shigella isolates and to perform genetic testing on select strains to confirm the presence and type of resistance genes.
Survey insights: Unwrapping the compensation package
When approached for advice regarding the evaluation of job offers after completion of training, specific day-to-day duties (for example, shift length, teaching time, ICU coverage, and so on), and the overall gestalt of the interview experience, I find that location, lifestyle, and pay are the most consistent and common themes.
People often assume that pay is relatively straightforward, since it can be summarized in a number in the offer, whereas the other factors are harder to evaluate. However, it turns out pay is more complex. As a result, the last several State of Hospital Medicine reports have sought to evaluate compensation packages more thoroughly.
In 2016, the survey started including pay increases by years of experience, as well as CME dollars allotted per year per hospitalist. The goal was to gain deeper insight into the entire financial package, which is tied to a particular hospitalist job.
When looking at the 2014 and 2016 SHM survey results, there are several interesting findings. Base pay makes up the majority of earnings for all types of hospitalists (those seeing adults only, children only, and a mix of adults and children). In academic hospitalist groups, more of the total package of compensation comes from base pay, compared with nonacademic groups, where production and performance pay play a bigger role.
Of interest, despite the increased national attention on quality of care, productivity-based pay increased again (10.5%-14.7%), while performance-based pay (usually tied to quality and safety metrics) decreased (6.6%-5.7%) among groups serving adults. Consistent with prior trends for adults-only hospitalists, the Southern region of the country had the highest percentage of pay derived from productivity (18.8%), as well as of overall compensation in the 2016 report.
For hospitalists serving both adults and children, there was a smaller increase in pay derived from production (12.4%-13.2%), while pay derived from performance dropped more dramatically (8.9%-3.9%).
For hospitalists serving only children, the opposite occurred: Pay derived from production fell from 10.7% to 2.8%. While it is not yet clear why compensation, overall, is moving into closer alignment with productivity, rather than performance on quality and safety metrics, one hypothesis is that work relative value units used for calculating productivity are easier to tie to an individual hospitalist than are quality and safety outcomes.
Employee benefits, as previously defined, increased among hospitalists caring for adults only and those caring for adults and children, with a mean increase in both groups of $5,000. The most generous benefits were typically seen at university-based academic medical centers. Amongst adult-only hospitalists, academic groups offer benefits worth $8,000-$9,000 more per year than in nonacademic groups. Lower benefits were common among practices in the Eastern region and in groups with four or fewer full-time hospitalists. The 2016 survey data on CME dollars revealed a median of $3,000-$4,000 per year, with higher amounts provided in nonacademic groups.
Paid time off (PTO) from work is an ongoing topic of interest on venues such as HMX forum, and, in the surveys, PTO remained fairly consistent among groups caring for adults only and those caring for adults and children, with only 30%-40% of groups offering PTO. The number of PTO hours offered vary substantially, however, ranging from a mean of 126 hours up to 216.4 hours annually. Future analysis of PTO will benefit from a deeper understanding of how many hours equate to a shift (the practical definition of a “day off” for most hospitalists).
Finally, the 2016 survey asked about automatic pay increases based strictly on overall experience or length of employment with the group. Roughly one-fifth to one-third of groups provided some sort of salary increase based on experience in 2015. This practice was more common in the Southern region and in nonteaching hospitals. These data raise the complex topic of seniority among hospitalists and how to define it: years since completing training, years with a particular hospital or group, academic rank, leadership roles, other? Further, if seniority is not recognized in pay, how commonly are groups recognizing it in other ways, such as in preferences related to time on certain services, shift type, or vacation requests?
The expanded survey on hospitalist pay, in addition to the biannual comparison of prior data, will likely continue to add value in assessing and exploring the entire package of compensation. Additional topics of interest moving forward might include better understanding of parental leave, sick time, and the comparison between compensation packages for physician hospitalists and those for inpatient Nurse Practitioners and Physician Assistants. Stay tuned for the next report.
Dr. Anoff is associate professor of clinical practice, division of hospital medicine, department of medicine, University of Colorado at Denver, Aurora.
References
1. (2014). The State of Hospital Medicine Report. Philadelphia: Society of Hospital Medicine. Retrieved from www.hospitalmedicine.org/Survey2014.
2. (2016). The State of Hospital Medicine Report. Philadelphia: Society of Hospital Medicine. Retrieved from www.hospitalmedicine.org/Survey2016.
When approached for advice regarding the evaluation of job offers after completion of training, specific day-to-day duties (for example, shift length, teaching time, ICU coverage, and so on), and the overall gestalt of the interview experience, I find that location, lifestyle, and pay are the most consistent and common themes.
People often assume that pay is relatively straightforward, since it can be summarized in a number in the offer, whereas the other factors are harder to evaluate. However, it turns out pay is more complex. As a result, the last several State of Hospital Medicine reports have sought to evaluate compensation packages more thoroughly.
In 2016, the survey started including pay increases by years of experience, as well as CME dollars allotted per year per hospitalist. The goal was to gain deeper insight into the entire financial package, which is tied to a particular hospitalist job.
When looking at the 2014 and 2016 SHM survey results, there are several interesting findings. Base pay makes up the majority of earnings for all types of hospitalists (those seeing adults only, children only, and a mix of adults and children). In academic hospitalist groups, more of the total package of compensation comes from base pay, compared with nonacademic groups, where production and performance pay play a bigger role.
Of interest, despite the increased national attention on quality of care, productivity-based pay increased again (10.5%-14.7%), while performance-based pay (usually tied to quality and safety metrics) decreased (6.6%-5.7%) among groups serving adults. Consistent with prior trends for adults-only hospitalists, the Southern region of the country had the highest percentage of pay derived from productivity (18.8%), as well as of overall compensation in the 2016 report.
For hospitalists serving both adults and children, there was a smaller increase in pay derived from production (12.4%-13.2%), while pay derived from performance dropped more dramatically (8.9%-3.9%).
For hospitalists serving only children, the opposite occurred: Pay derived from production fell from 10.7% to 2.8%. While it is not yet clear why compensation, overall, is moving into closer alignment with productivity, rather than performance on quality and safety metrics, one hypothesis is that work relative value units used for calculating productivity are easier to tie to an individual hospitalist than are quality and safety outcomes.
Employee benefits, as previously defined, increased among hospitalists caring for adults only and those caring for adults and children, with a mean increase in both groups of $5,000. The most generous benefits were typically seen at university-based academic medical centers. Amongst adult-only hospitalists, academic groups offer benefits worth $8,000-$9,000 more per year than in nonacademic groups. Lower benefits were common among practices in the Eastern region and in groups with four or fewer full-time hospitalists. The 2016 survey data on CME dollars revealed a median of $3,000-$4,000 per year, with higher amounts provided in nonacademic groups.
Paid time off (PTO) from work is an ongoing topic of interest on venues such as HMX forum, and, in the surveys, PTO remained fairly consistent among groups caring for adults only and those caring for adults and children, with only 30%-40% of groups offering PTO. The number of PTO hours offered vary substantially, however, ranging from a mean of 126 hours up to 216.4 hours annually. Future analysis of PTO will benefit from a deeper understanding of how many hours equate to a shift (the practical definition of a “day off” for most hospitalists).
Finally, the 2016 survey asked about automatic pay increases based strictly on overall experience or length of employment with the group. Roughly one-fifth to one-third of groups provided some sort of salary increase based on experience in 2015. This practice was more common in the Southern region and in nonteaching hospitals. These data raise the complex topic of seniority among hospitalists and how to define it: years since completing training, years with a particular hospital or group, academic rank, leadership roles, other? Further, if seniority is not recognized in pay, how commonly are groups recognizing it in other ways, such as in preferences related to time on certain services, shift type, or vacation requests?
The expanded survey on hospitalist pay, in addition to the biannual comparison of prior data, will likely continue to add value in assessing and exploring the entire package of compensation. Additional topics of interest moving forward might include better understanding of parental leave, sick time, and the comparison between compensation packages for physician hospitalists and those for inpatient Nurse Practitioners and Physician Assistants. Stay tuned for the next report.
Dr. Anoff is associate professor of clinical practice, division of hospital medicine, department of medicine, University of Colorado at Denver, Aurora.
References
1. (2014). The State of Hospital Medicine Report. Philadelphia: Society of Hospital Medicine. Retrieved from www.hospitalmedicine.org/Survey2014.
2. (2016). The State of Hospital Medicine Report. Philadelphia: Society of Hospital Medicine. Retrieved from www.hospitalmedicine.org/Survey2016.
When approached for advice regarding the evaluation of job offers after completion of training, specific day-to-day duties (for example, shift length, teaching time, ICU coverage, and so on), and the overall gestalt of the interview experience, I find that location, lifestyle, and pay are the most consistent and common themes.
People often assume that pay is relatively straightforward, since it can be summarized in a number in the offer, whereas the other factors are harder to evaluate. However, it turns out pay is more complex. As a result, the last several State of Hospital Medicine reports have sought to evaluate compensation packages more thoroughly.
In 2016, the survey started including pay increases by years of experience, as well as CME dollars allotted per year per hospitalist. The goal was to gain deeper insight into the entire financial package, which is tied to a particular hospitalist job.
When looking at the 2014 and 2016 SHM survey results, there are several interesting findings. Base pay makes up the majority of earnings for all types of hospitalists (those seeing adults only, children only, and a mix of adults and children). In academic hospitalist groups, more of the total package of compensation comes from base pay, compared with nonacademic groups, where production and performance pay play a bigger role.
Of interest, despite the increased national attention on quality of care, productivity-based pay increased again (10.5%-14.7%), while performance-based pay (usually tied to quality and safety metrics) decreased (6.6%-5.7%) among groups serving adults. Consistent with prior trends for adults-only hospitalists, the Southern region of the country had the highest percentage of pay derived from productivity (18.8%), as well as of overall compensation in the 2016 report.
For hospitalists serving both adults and children, there was a smaller increase in pay derived from production (12.4%-13.2%), while pay derived from performance dropped more dramatically (8.9%-3.9%).
For hospitalists serving only children, the opposite occurred: Pay derived from production fell from 10.7% to 2.8%. While it is not yet clear why compensation, overall, is moving into closer alignment with productivity, rather than performance on quality and safety metrics, one hypothesis is that work relative value units used for calculating productivity are easier to tie to an individual hospitalist than are quality and safety outcomes.
Employee benefits, as previously defined, increased among hospitalists caring for adults only and those caring for adults and children, with a mean increase in both groups of $5,000. The most generous benefits were typically seen at university-based academic medical centers. Amongst adult-only hospitalists, academic groups offer benefits worth $8,000-$9,000 more per year than in nonacademic groups. Lower benefits were common among practices in the Eastern region and in groups with four or fewer full-time hospitalists. The 2016 survey data on CME dollars revealed a median of $3,000-$4,000 per year, with higher amounts provided in nonacademic groups.
Paid time off (PTO) from work is an ongoing topic of interest on venues such as HMX forum, and, in the surveys, PTO remained fairly consistent among groups caring for adults only and those caring for adults and children, with only 30%-40% of groups offering PTO. The number of PTO hours offered vary substantially, however, ranging from a mean of 126 hours up to 216.4 hours annually. Future analysis of PTO will benefit from a deeper understanding of how many hours equate to a shift (the practical definition of a “day off” for most hospitalists).
Finally, the 2016 survey asked about automatic pay increases based strictly on overall experience or length of employment with the group. Roughly one-fifth to one-third of groups provided some sort of salary increase based on experience in 2015. This practice was more common in the Southern region and in nonteaching hospitals. These data raise the complex topic of seniority among hospitalists and how to define it: years since completing training, years with a particular hospital or group, academic rank, leadership roles, other? Further, if seniority is not recognized in pay, how commonly are groups recognizing it in other ways, such as in preferences related to time on certain services, shift type, or vacation requests?
The expanded survey on hospitalist pay, in addition to the biannual comparison of prior data, will likely continue to add value in assessing and exploring the entire package of compensation. Additional topics of interest moving forward might include better understanding of parental leave, sick time, and the comparison between compensation packages for physician hospitalists and those for inpatient Nurse Practitioners and Physician Assistants. Stay tuned for the next report.
Dr. Anoff is associate professor of clinical practice, division of hospital medicine, department of medicine, University of Colorado at Denver, Aurora.
References
1. (2014). The State of Hospital Medicine Report. Philadelphia: Society of Hospital Medicine. Retrieved from www.hospitalmedicine.org/Survey2014.
2. (2016). The State of Hospital Medicine Report. Philadelphia: Society of Hospital Medicine. Retrieved from www.hospitalmedicine.org/Survey2016.
States consider abortion ‘reversal’ bills
Legislation requiring doctors to tell their patients that a medication abortion can be reversed is cropping up across the country.
Already in 2017, Colorado, Georgia, Indiana, Idaho, and North Carolina have introduced versions of the so-called abortion reversal legislation. In March, Utah became the latest state to pass a law addressing discontinuation of a medication abortion. Arkansas, South Dakota, and Arizona have similar laws on the books, but a court challenge ultimately led Arizona to amend its law, significantly toning down the language on reversal.
Utah’s law meanwhile, requires that physicians explain “the options and consequences of aborting a medication-induced abortion” and inform women that mifepristone alone is not always effective in ending a pregnancy. Women who have not yet taken the second drug and who are questioning their decision are encouraged to immediately consult their physician, according to the statute.
Calling the Utah measure an “abortion reversal law” is an inaccurate overreach, said state Sen. Curt Bramble, a Utah Republican who cosponsored the bill. A previous version included language about the potential of progesterone in reversing a medication abortion, but that section was removed after conferring with local physician groups, Sen. Bramble said.
“The purpose of this bill is to provide the most accurate information for a woman contemplating terminating a pregnancy,” Sen. Bramble said in an interview. “I want to make certain that women, if they decide to take the life of that unborn child, that they’re doing so in light of all the available information. If they take mifepristone, and they have second thoughts, that they’re aware that [the pregnancy may still be viable]. What this bill does is hopefully provide them that information before they make the decision to take the drug.”
“Generally, when a physician’s going to be providing an abortion, the physician wants to be very sure that the woman is certain about her decision and wants to address any areas of uncertainty and resolve those before moving forward,” Dr. Grossman said in an interview. “[Utah’s law] kind of implies that if you’re not sure, you can still go forward, and you may still have another chance at continuing the pregnancy. It sends a mixed message to women.”
“Last year, we thought this kind of counseling requirement wasn’t going to be a trend,” Ms. Nash said in an interview. “Yet, there’s been much more energy around these bills this year. Typically, around abortion legislation, you see similar language pop up in various states. In this case, the bills don’t mimic each other at all. I think it’s because some of the bills are trying to account for the fact there is very little scientific evidence to support this idea, so they’re trying different approaches to craft language that could withstand a legal challenge.”
“Anyone who has ever had a surgery or taken a powerful drug knows that it’s common practice to be told all the possible implications and side effects,” Ms. Hamrick said in an interview. “Women should be given all the facts about the drugs sold to them. It’s commonsense, common practice in other settings, and we should trust women with the science.”
She points to AbortionPillReversal.com, a website that assists women in locating physicians trained in the reversal process. San Diego–based family physician George Delgado, MD, who operates the website, said he has a forthcoming research study that will detail 300 successful reversals of mifepristone and that will also show that the success rate using best protocols is between 60% and 70%. The upcoming study builds on a case series he published in 2012 showing that four out of six women who took mifepristone carried their pregnancies to term after receiving 200 mg of intramuscular progesterone (Ann Pharmacother. 2012 Dec;46[12]:e36).
But the American Congress of Obstetricians and Gynecologists states that claims of medication abortion reversal are not supported by the body of scientific evidence, and the approach is not recommended in ACOG’s clinical guidance on medication abortion. In their fact sheet on the issue, they specifically rebut Dr. Delgado’s evidence, noting that it describes only “a handful of experiences” involving varying regimens of injected progesterone, and that it was not a controlled study.
Further, a 2015 study led by Dr. Grossman found that evidence is insufficient to determine whether treatment with progesterone after mifepristone results in a higher proportion of continuing pregnancies, compared with expectant management (Contraception. 2015 Sep;92[3]:206-11).
“As our paper lays out, there’s really no medical evidence that any kind of treatment given to women after taking mifepristone increases the likelihood that pregnancy will continue,” Dr. Grossman said. “It’s very concerning that these laws are being passed based on nonexistent evidence. It essentially forces doctors to tell patients about an unproven therapy and pushes them toward participating in an unmonitored research study.”
Any law that requires a physician to make false statements to patients creates a barrier between the doctor and the patient, said Sarah Prager, MD, director of the family planning division and family planning fellowship at the University of Washington, Seattle.
“These laws get in the way of a strong doctor-patient relationship and harm doctors’ ability to use their medical judgment and practice evidence-based medicine,” Dr. Prager said in an interview. “It could be difficult for patients to trust their doctors if we are legally required to give them information that has no basis in medical evidence.”
[email protected]
On Twitter @legal_med
Legislation requiring doctors to tell their patients that a medication abortion can be reversed is cropping up across the country.
Already in 2017, Colorado, Georgia, Indiana, Idaho, and North Carolina have introduced versions of the so-called abortion reversal legislation. In March, Utah became the latest state to pass a law addressing discontinuation of a medication abortion. Arkansas, South Dakota, and Arizona have similar laws on the books, but a court challenge ultimately led Arizona to amend its law, significantly toning down the language on reversal.
Utah’s law meanwhile, requires that physicians explain “the options and consequences of aborting a medication-induced abortion” and inform women that mifepristone alone is not always effective in ending a pregnancy. Women who have not yet taken the second drug and who are questioning their decision are encouraged to immediately consult their physician, according to the statute.
Calling the Utah measure an “abortion reversal law” is an inaccurate overreach, said state Sen. Curt Bramble, a Utah Republican who cosponsored the bill. A previous version included language about the potential of progesterone in reversing a medication abortion, but that section was removed after conferring with local physician groups, Sen. Bramble said.
“The purpose of this bill is to provide the most accurate information for a woman contemplating terminating a pregnancy,” Sen. Bramble said in an interview. “I want to make certain that women, if they decide to take the life of that unborn child, that they’re doing so in light of all the available information. If they take mifepristone, and they have second thoughts, that they’re aware that [the pregnancy may still be viable]. What this bill does is hopefully provide them that information before they make the decision to take the drug.”
“Generally, when a physician’s going to be providing an abortion, the physician wants to be very sure that the woman is certain about her decision and wants to address any areas of uncertainty and resolve those before moving forward,” Dr. Grossman said in an interview. “[Utah’s law] kind of implies that if you’re not sure, you can still go forward, and you may still have another chance at continuing the pregnancy. It sends a mixed message to women.”
“Last year, we thought this kind of counseling requirement wasn’t going to be a trend,” Ms. Nash said in an interview. “Yet, there’s been much more energy around these bills this year. Typically, around abortion legislation, you see similar language pop up in various states. In this case, the bills don’t mimic each other at all. I think it’s because some of the bills are trying to account for the fact there is very little scientific evidence to support this idea, so they’re trying different approaches to craft language that could withstand a legal challenge.”
“Anyone who has ever had a surgery or taken a powerful drug knows that it’s common practice to be told all the possible implications and side effects,” Ms. Hamrick said in an interview. “Women should be given all the facts about the drugs sold to them. It’s commonsense, common practice in other settings, and we should trust women with the science.”
She points to AbortionPillReversal.com, a website that assists women in locating physicians trained in the reversal process. San Diego–based family physician George Delgado, MD, who operates the website, said he has a forthcoming research study that will detail 300 successful reversals of mifepristone and that will also show that the success rate using best protocols is between 60% and 70%. The upcoming study builds on a case series he published in 2012 showing that four out of six women who took mifepristone carried their pregnancies to term after receiving 200 mg of intramuscular progesterone (Ann Pharmacother. 2012 Dec;46[12]:e36).
But the American Congress of Obstetricians and Gynecologists states that claims of medication abortion reversal are not supported by the body of scientific evidence, and the approach is not recommended in ACOG’s clinical guidance on medication abortion. In their fact sheet on the issue, they specifically rebut Dr. Delgado’s evidence, noting that it describes only “a handful of experiences” involving varying regimens of injected progesterone, and that it was not a controlled study.
Further, a 2015 study led by Dr. Grossman found that evidence is insufficient to determine whether treatment with progesterone after mifepristone results in a higher proportion of continuing pregnancies, compared with expectant management (Contraception. 2015 Sep;92[3]:206-11).
“As our paper lays out, there’s really no medical evidence that any kind of treatment given to women after taking mifepristone increases the likelihood that pregnancy will continue,” Dr. Grossman said. “It’s very concerning that these laws are being passed based on nonexistent evidence. It essentially forces doctors to tell patients about an unproven therapy and pushes them toward participating in an unmonitored research study.”
Any law that requires a physician to make false statements to patients creates a barrier between the doctor and the patient, said Sarah Prager, MD, director of the family planning division and family planning fellowship at the University of Washington, Seattle.
“These laws get in the way of a strong doctor-patient relationship and harm doctors’ ability to use their medical judgment and practice evidence-based medicine,” Dr. Prager said in an interview. “It could be difficult for patients to trust their doctors if we are legally required to give them information that has no basis in medical evidence.”
[email protected]
On Twitter @legal_med
Legislation requiring doctors to tell their patients that a medication abortion can be reversed is cropping up across the country.
Already in 2017, Colorado, Georgia, Indiana, Idaho, and North Carolina have introduced versions of the so-called abortion reversal legislation. In March, Utah became the latest state to pass a law addressing discontinuation of a medication abortion. Arkansas, South Dakota, and Arizona have similar laws on the books, but a court challenge ultimately led Arizona to amend its law, significantly toning down the language on reversal.
Utah’s law meanwhile, requires that physicians explain “the options and consequences of aborting a medication-induced abortion” and inform women that mifepristone alone is not always effective in ending a pregnancy. Women who have not yet taken the second drug and who are questioning their decision are encouraged to immediately consult their physician, according to the statute.
Calling the Utah measure an “abortion reversal law” is an inaccurate overreach, said state Sen. Curt Bramble, a Utah Republican who cosponsored the bill. A previous version included language about the potential of progesterone in reversing a medication abortion, but that section was removed after conferring with local physician groups, Sen. Bramble said.
“The purpose of this bill is to provide the most accurate information for a woman contemplating terminating a pregnancy,” Sen. Bramble said in an interview. “I want to make certain that women, if they decide to take the life of that unborn child, that they’re doing so in light of all the available information. If they take mifepristone, and they have second thoughts, that they’re aware that [the pregnancy may still be viable]. What this bill does is hopefully provide them that information before they make the decision to take the drug.”
“Generally, when a physician’s going to be providing an abortion, the physician wants to be very sure that the woman is certain about her decision and wants to address any areas of uncertainty and resolve those before moving forward,” Dr. Grossman said in an interview. “[Utah’s law] kind of implies that if you’re not sure, you can still go forward, and you may still have another chance at continuing the pregnancy. It sends a mixed message to women.”
“Last year, we thought this kind of counseling requirement wasn’t going to be a trend,” Ms. Nash said in an interview. “Yet, there’s been much more energy around these bills this year. Typically, around abortion legislation, you see similar language pop up in various states. In this case, the bills don’t mimic each other at all. I think it’s because some of the bills are trying to account for the fact there is very little scientific evidence to support this idea, so they’re trying different approaches to craft language that could withstand a legal challenge.”
“Anyone who has ever had a surgery or taken a powerful drug knows that it’s common practice to be told all the possible implications and side effects,” Ms. Hamrick said in an interview. “Women should be given all the facts about the drugs sold to them. It’s commonsense, common practice in other settings, and we should trust women with the science.”
She points to AbortionPillReversal.com, a website that assists women in locating physicians trained in the reversal process. San Diego–based family physician George Delgado, MD, who operates the website, said he has a forthcoming research study that will detail 300 successful reversals of mifepristone and that will also show that the success rate using best protocols is between 60% and 70%. The upcoming study builds on a case series he published in 2012 showing that four out of six women who took mifepristone carried their pregnancies to term after receiving 200 mg of intramuscular progesterone (Ann Pharmacother. 2012 Dec;46[12]:e36).
But the American Congress of Obstetricians and Gynecologists states that claims of medication abortion reversal are not supported by the body of scientific evidence, and the approach is not recommended in ACOG’s clinical guidance on medication abortion. In their fact sheet on the issue, they specifically rebut Dr. Delgado’s evidence, noting that it describes only “a handful of experiences” involving varying regimens of injected progesterone, and that it was not a controlled study.
Further, a 2015 study led by Dr. Grossman found that evidence is insufficient to determine whether treatment with progesterone after mifepristone results in a higher proportion of continuing pregnancies, compared with expectant management (Contraception. 2015 Sep;92[3]:206-11).
“As our paper lays out, there’s really no medical evidence that any kind of treatment given to women after taking mifepristone increases the likelihood that pregnancy will continue,” Dr. Grossman said. “It’s very concerning that these laws are being passed based on nonexistent evidence. It essentially forces doctors to tell patients about an unproven therapy and pushes them toward participating in an unmonitored research study.”
Any law that requires a physician to make false statements to patients creates a barrier between the doctor and the patient, said Sarah Prager, MD, director of the family planning division and family planning fellowship at the University of Washington, Seattle.
“These laws get in the way of a strong doctor-patient relationship and harm doctors’ ability to use their medical judgment and practice evidence-based medicine,” Dr. Prager said in an interview. “It could be difficult for patients to trust their doctors if we are legally required to give them information that has no basis in medical evidence.”
[email protected]
On Twitter @legal_med
Suspected Clozapine-Induced Cardiomyopathy and Heart Failure With Reduced Ejection Fraction
Clozapine is an atypical antipsychotic that is usually reserved for use in patients with treatment-resistant schizophrenia or schizoaffective disorder with suicidalit
Clozapine-induced cardiomyopathy is a diagnosis of exclusion that requires the absence of other etiologies of cardiac dysfunction (ie, coronary artery disease, hypertension, valvular disease, congenital heart disease, etc). Diagnosing a clozapine-related cardiomyopathy may be a long and laborious task. Patients with cardiomyopathy may present with many nonspecific signs and symptoms, such as fatigue, dyspnea, edema, and/or nausea and vomiting, which are present in other diseases; therefore, multiple encounters and lab tests may be needed until a cardiac source is implicated. The exact mechanism is unknown; however, Chow and colleagues believe that clozapine is a direct toxin of the myocardium.5-7
Case Presentation
A 30-year-old woman with a history of asthma, hypothyroidism (euthyroid with supplementation), posttraumatic stress disorder, and schizoaffective disorder was started on clozapine due to major depression and increased suicidal ideation despite previous treatment with several other antipsychotic agents. Clozapine was gradually titrated to a dose of 150 mg twice a day during an inpatient psychiatric admission. Prior to starting clozapine, this patient had been admitted to the psychiatry unit 11 times within the prior 2 years. After initiating and titrating clozapine over 4 months, her psychiatric symptoms markedly improved.
More than 4 years after the initiation of clozapine and after various treatments for multiple symptoms (Sidebar), the patient was diagnosed with heart failure (HF) with a reduced ejection fraction (EF) of 10% to 15%. She was referred to the cardiology HF clinic. Her dose of clozapine 150 mg at bedtime was discontinued after a discussion with psychiatry. She had a negative workup for other HF etiologies and was started on HF medications that included carvedilol, losartan, and spironolactone. After discontinuation of clozapine, her psychiatric symptoms worsened, and she was admitted to the psychiatry unit twice within a year. Two months after clozapine was discontinued, a repeat echocardiogram (ECHO) was obtained and was essentially unchanged. A chest X-ray (CXR) obtained 4 months after clozapine discontinuation demonstrated a normalized cardio-mediastinal silhouette. A third ECHO was ordered during her second psychiatric admission, which was 11 months after clozapine discontinuation; this revealed an improved left ventricular EF (LVEF) of 30% to 35% and resolution of left ventricular (LV) dilation. 
This patient’s clinical course led to an extensive chart review that investigated whether there may have been earlier signs and symptoms of HF or cardiomyopathy. It was discovered that the initial HF signs and symptoms were likely present for about 1 year before the diagnosis was made and after having been on clozapine for about 40 months (Patient’s ECHO before and after clozapine discontinuation, click here for additional ECHO perspectives ).
Discussion
In retrospect, this patient likely had HF for many months prior to the official diagnosis; however, given this patient’s young age, prior history of asthma, respiratory disorders, underlying severe psychiatric disease, and confounding symptoms, it is easy to understand why the diagnosis was initially overlooked and delayed.
This patient did not have significant lower extremity edema, but she reported nausea, vomiting, and weight loss. Typical patients with HF exhibit edema and weight gain unless they experience cardiac cachexia. It is not clear whether this patient had a coexisting gastrointestinal (GI) disorder or whether the GI symptoms were secondary to cardiac cachexia. Additionally, weight gain and metabolic syndrome have been documented with clozapine therapy.
It is interesting that a repeat ECHO within 2 months of clozapine discontinuation did not show an improvement, whereas a CXR at 4 months showed a normal cardiac silhouette, and an ECHO at 11 months showed an improvement in EF and normalization of LV size while on appropriate HF medications. It would have been interesting if an ECHO had been completed at 4 months to correspond with the time when the CXR normalized.
There does not seem to be a high level of awareness regarding this potentially fatal diagnosis of cardiomyopathy related to the use of clozapine. A recent review of clozapine-induced cardiomyopathy by Alawami and colleagues revealed characteristics, including median age of diagnosis of 33.5 years, a mean daily dose of 360 mg (range 125-700 mg/d), average time of therapy until the development of symptoms 14.4 months (range between 3 weeks and 4 years), and the presence of ventricular dilation in 39%.8 The most common symptoms on clinical presentation were shortness of breath (60%), palpitations (36%), cough (16%), fatigue (16%), and chest pain (8%).8
It is interesting that edema was not present in the patients studied in their review; this difference from the usual presentation of severe HF may lower clinical suspicion and makes diagnosing this type of cardiomyopathy more difficult. Alawami also noted that patients with an LVEF < 25% at the time of diagnosis tended to have a poorer prognosis with the highest risk of mortality and limited recovery. Fortunately, in this case, the patient’s LVEF improved significantly, and it will be interesting to continue to monitor the patient for further improvement.
As a result of this case, the authors have performed a chart review on all patients prescribed clozapine at VA Loma Linda Healthcare System. Additionally, this case supports the implementation of better cardiomyopathy monitoring of all clozapine patients. It may be recommended to obtain a baseline CXR in all patients starting clozapine, conduct monthly cardiomyopathy symptom screening that coincides with ANC monitoring, and perform an ECHO immediately on any clinical suspicion of cardiomyopathy.
Conclusion
Better awareness and regular screening for signs and symptoms of HF may help prevent a delay in diagnosing a rare but serious and potentially fatal condition associated with clozapine. Chest X-rays demonstrating cardiomegaly can be helpful when the early diagnosis of HF is suspected and may be the first diagnostic imaging test to normalize after clozapine discontinuation.
Since clozapine is a REMS medication and all patients are scheduled for regular ANC follow-up, it would seem prudent that patients also should be screened for signs and symptoms of HF, including the new onset or worsening of baseline shortness of breath, palpitations, cough, fatigue, chest pain, edema, gastroparesis, and perhaps extreme weight loss. Once a physician suspects HF, an ECHO should be obtained immediately.
In addition to the clozapine boxed warning for cardiomyopathy, it would be helpful if the clozapine patient counseling information section had a specific warning that advises patients to contact their clinician if they develop the signs and symptoms of HF.
1. Clozaril [package insert]. Rosemont, PA: HLS Therapeutics (USA), Inc; 2015.
2. Youssef DL, Narayanan P, Gill N. Incidence and risk factors for clozapine-induced myocarditis and cardiomyopathy at a regional mental health service in Australia. Austalas Psychiatry. 2016;24(2):176-180.
3. La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Eng J Med. 2001;345(3):224-225.
4. Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet. 1999;354(9193):1841-1845.
5. Chow V, Yeoh T, Ng AC, et al. Asymptomatic left ventricular dysfunction with long-term clozapine treatment for schizophrenia: a multicenter cross-sectional cohort study. Open Heart 2014;1(1):e000030.
6. Scelsa SN, Simpson DM, McQuistion HL, Fineman A, Ault K, Reichler B. Clozapine-induced myotoxicity in patients with chronic psychotic disorders. Neurology. 1996;47(6):1518-1523.
7. Reznik I, Volchek L, Mester R, et al. Myotoxicity and neurotoxicity during clozapine treatment. Clin Neuropharmacol. 2000;23(5):276-280.
8. Alawami A, Wasywich C, Cicovic A, Kenedi C. A systematic review of clozapine induced cardiomyopathy. Int J Cardiol. 2014;176(2):315-320.
Clozapine is an atypical antipsychotic that is usually reserved for use in patients with treatment-resistant schizophrenia or schizoaffective disorder with suicidalit
Clozapine-induced cardiomyopathy is a diagnosis of exclusion that requires the absence of other etiologies of cardiac dysfunction (ie, coronary artery disease, hypertension, valvular disease, congenital heart disease, etc). Diagnosing a clozapine-related cardiomyopathy may be a long and laborious task. Patients with cardiomyopathy may present with many nonspecific signs and symptoms, such as fatigue, dyspnea, edema, and/or nausea and vomiting, which are present in other diseases; therefore, multiple encounters and lab tests may be needed until a cardiac source is implicated. The exact mechanism is unknown; however, Chow and colleagues believe that clozapine is a direct toxin of the myocardium.5-7
Case Presentation
A 30-year-old woman with a history of asthma, hypothyroidism (euthyroid with supplementation), posttraumatic stress disorder, and schizoaffective disorder was started on clozapine due to major depression and increased suicidal ideation despite previous treatment with several other antipsychotic agents. Clozapine was gradually titrated to a dose of 150 mg twice a day during an inpatient psychiatric admission. Prior to starting clozapine, this patient had been admitted to the psychiatry unit 11 times within the prior 2 years. After initiating and titrating clozapine over 4 months, her psychiatric symptoms markedly improved.
More than 4 years after the initiation of clozapine and after various treatments for multiple symptoms (Sidebar), the patient was diagnosed with heart failure (HF) with a reduced ejection fraction (EF) of 10% to 15%. She was referred to the cardiology HF clinic. Her dose of clozapine 150 mg at bedtime was discontinued after a discussion with psychiatry. She had a negative workup for other HF etiologies and was started on HF medications that included carvedilol, losartan, and spironolactone. After discontinuation of clozapine, her psychiatric symptoms worsened, and she was admitted to the psychiatry unit twice within a year. Two months after clozapine was discontinued, a repeat echocardiogram (ECHO) was obtained and was essentially unchanged. A chest X-ray (CXR) obtained 4 months after clozapine discontinuation demonstrated a normalized cardio-mediastinal silhouette. A third ECHO was ordered during her second psychiatric admission, which was 11 months after clozapine discontinuation; this revealed an improved left ventricular EF (LVEF) of 30% to 35% and resolution of left ventricular (LV) dilation.
This patient’s clinical course led to an extensive chart review that investigated whether there may have been earlier signs and symptoms of HF or cardiomyopathy. It was discovered that the initial HF signs and symptoms were likely present for about 1 year before the diagnosis was made and after having been on clozapine for about 40 months (Patient’s ECHO before and after clozapine discontinuation, click here for additional ECHO perspectives ).
Discussion
In retrospect, this patient likely had HF for many months prior to the official diagnosis; however, given this patient’s young age, prior history of asthma, respiratory disorders, underlying severe psychiatric disease, and confounding symptoms, it is easy to understand why the diagnosis was initially overlooked and delayed.
This patient did not have significant lower extremity edema, but she reported nausea, vomiting, and weight loss. Typical patients with HF exhibit edema and weight gain unless they experience cardiac cachexia. It is not clear whether this patient had a coexisting gastrointestinal (GI) disorder or whether the GI symptoms were secondary to cardiac cachexia. Additionally, weight gain and metabolic syndrome have been documented with clozapine therapy.
It is interesting that a repeat ECHO within 2 months of clozapine discontinuation did not show an improvement, whereas a CXR at 4 months showed a normal cardiac silhouette, and an ECHO at 11 months showed an improvement in EF and normalization of LV size while on appropriate HF medications. It would have been interesting if an ECHO had been completed at 4 months to correspond with the time when the CXR normalized.
There does not seem to be a high level of awareness regarding this potentially fatal diagnosis of cardiomyopathy related to the use of clozapine. A recent review of clozapine-induced cardiomyopathy by Alawami and colleagues revealed characteristics, including median age of diagnosis of 33.5 years, a mean daily dose of 360 mg (range 125-700 mg/d), average time of therapy until the development of symptoms 14.4 months (range between 3 weeks and 4 years), and the presence of ventricular dilation in 39%.8 The most common symptoms on clinical presentation were shortness of breath (60%), palpitations (36%), cough (16%), fatigue (16%), and chest pain (8%).8
It is interesting that edema was not present in the patients studied in their review; this difference from the usual presentation of severe HF may lower clinical suspicion and makes diagnosing this type of cardiomyopathy more difficult. Alawami also noted that patients with an LVEF < 25% at the time of diagnosis tended to have a poorer prognosis with the highest risk of mortality and limited recovery. Fortunately, in this case, the patient’s LVEF improved significantly, and it will be interesting to continue to monitor the patient for further improvement.
As a result of this case, the authors have performed a chart review on all patients prescribed clozapine at VA Loma Linda Healthcare System. Additionally, this case supports the implementation of better cardiomyopathy monitoring of all clozapine patients. It may be recommended to obtain a baseline CXR in all patients starting clozapine, conduct monthly cardiomyopathy symptom screening that coincides with ANC monitoring, and perform an ECHO immediately on any clinical suspicion of cardiomyopathy.
Conclusion
Better awareness and regular screening for signs and symptoms of HF may help prevent a delay in diagnosing a rare but serious and potentially fatal condition associated with clozapine. Chest X-rays demonstrating cardiomegaly can be helpful when the early diagnosis of HF is suspected and may be the first diagnostic imaging test to normalize after clozapine discontinuation.
Since clozapine is a REMS medication and all patients are scheduled for regular ANC follow-up, it would seem prudent that patients also should be screened for signs and symptoms of HF, including the new onset or worsening of baseline shortness of breath, palpitations, cough, fatigue, chest pain, edema, gastroparesis, and perhaps extreme weight loss. Once a physician suspects HF, an ECHO should be obtained immediately.
In addition to the clozapine boxed warning for cardiomyopathy, it would be helpful if the clozapine patient counseling information section had a specific warning that advises patients to contact their clinician if they develop the signs and symptoms of HF.
Clozapine is an atypical antipsychotic that is usually reserved for use in patients with treatment-resistant schizophrenia or schizoaffective disorder with suicidalit
Clozapine-induced cardiomyopathy is a diagnosis of exclusion that requires the absence of other etiologies of cardiac dysfunction (ie, coronary artery disease, hypertension, valvular disease, congenital heart disease, etc). Diagnosing a clozapine-related cardiomyopathy may be a long and laborious task. Patients with cardiomyopathy may present with many nonspecific signs and symptoms, such as fatigue, dyspnea, edema, and/or nausea and vomiting, which are present in other diseases; therefore, multiple encounters and lab tests may be needed until a cardiac source is implicated. The exact mechanism is unknown; however, Chow and colleagues believe that clozapine is a direct toxin of the myocardium.5-7
Case Presentation
A 30-year-old woman with a history of asthma, hypothyroidism (euthyroid with supplementation), posttraumatic stress disorder, and schizoaffective disorder was started on clozapine due to major depression and increased suicidal ideation despite previous treatment with several other antipsychotic agents. Clozapine was gradually titrated to a dose of 150 mg twice a day during an inpatient psychiatric admission. Prior to starting clozapine, this patient had been admitted to the psychiatry unit 11 times within the prior 2 years. After initiating and titrating clozapine over 4 months, her psychiatric symptoms markedly improved.
More than 4 years after the initiation of clozapine and after various treatments for multiple symptoms (Sidebar), the patient was diagnosed with heart failure (HF) with a reduced ejection fraction (EF) of 10% to 15%. She was referred to the cardiology HF clinic. Her dose of clozapine 150 mg at bedtime was discontinued after a discussion with psychiatry. She had a negative workup for other HF etiologies and was started on HF medications that included carvedilol, losartan, and spironolactone. After discontinuation of clozapine, her psychiatric symptoms worsened, and she was admitted to the psychiatry unit twice within a year. Two months after clozapine was discontinued, a repeat echocardiogram (ECHO) was obtained and was essentially unchanged. A chest X-ray (CXR) obtained 4 months after clozapine discontinuation demonstrated a normalized cardio-mediastinal silhouette. A third ECHO was ordered during her second psychiatric admission, which was 11 months after clozapine discontinuation; this revealed an improved left ventricular EF (LVEF) of 30% to 35% and resolution of left ventricular (LV) dilation.
This patient’s clinical course led to an extensive chart review that investigated whether there may have been earlier signs and symptoms of HF or cardiomyopathy. It was discovered that the initial HF signs and symptoms were likely present for about 1 year before the diagnosis was made and after having been on clozapine for about 40 months (Patient’s ECHO before and after clozapine discontinuation, click here for additional ECHO perspectives ).
Discussion
In retrospect, this patient likely had HF for many months prior to the official diagnosis; however, given this patient’s young age, prior history of asthma, respiratory disorders, underlying severe psychiatric disease, and confounding symptoms, it is easy to understand why the diagnosis was initially overlooked and delayed.
This patient did not have significant lower extremity edema, but she reported nausea, vomiting, and weight loss. Typical patients with HF exhibit edema and weight gain unless they experience cardiac cachexia. It is not clear whether this patient had a coexisting gastrointestinal (GI) disorder or whether the GI symptoms were secondary to cardiac cachexia. Additionally, weight gain and metabolic syndrome have been documented with clozapine therapy.
It is interesting that a repeat ECHO within 2 months of clozapine discontinuation did not show an improvement, whereas a CXR at 4 months showed a normal cardiac silhouette, and an ECHO at 11 months showed an improvement in EF and normalization of LV size while on appropriate HF medications. It would have been interesting if an ECHO had been completed at 4 months to correspond with the time when the CXR normalized.
There does not seem to be a high level of awareness regarding this potentially fatal diagnosis of cardiomyopathy related to the use of clozapine. A recent review of clozapine-induced cardiomyopathy by Alawami and colleagues revealed characteristics, including median age of diagnosis of 33.5 years, a mean daily dose of 360 mg (range 125-700 mg/d), average time of therapy until the development of symptoms 14.4 months (range between 3 weeks and 4 years), and the presence of ventricular dilation in 39%.8 The most common symptoms on clinical presentation were shortness of breath (60%), palpitations (36%), cough (16%), fatigue (16%), and chest pain (8%).8
It is interesting that edema was not present in the patients studied in their review; this difference from the usual presentation of severe HF may lower clinical suspicion and makes diagnosing this type of cardiomyopathy more difficult. Alawami also noted that patients with an LVEF < 25% at the time of diagnosis tended to have a poorer prognosis with the highest risk of mortality and limited recovery. Fortunately, in this case, the patient’s LVEF improved significantly, and it will be interesting to continue to monitor the patient for further improvement.
As a result of this case, the authors have performed a chart review on all patients prescribed clozapine at VA Loma Linda Healthcare System. Additionally, this case supports the implementation of better cardiomyopathy monitoring of all clozapine patients. It may be recommended to obtain a baseline CXR in all patients starting clozapine, conduct monthly cardiomyopathy symptom screening that coincides with ANC monitoring, and perform an ECHO immediately on any clinical suspicion of cardiomyopathy.
Conclusion
Better awareness and regular screening for signs and symptoms of HF may help prevent a delay in diagnosing a rare but serious and potentially fatal condition associated with clozapine. Chest X-rays demonstrating cardiomegaly can be helpful when the early diagnosis of HF is suspected and may be the first diagnostic imaging test to normalize after clozapine discontinuation.
Since clozapine is a REMS medication and all patients are scheduled for regular ANC follow-up, it would seem prudent that patients also should be screened for signs and symptoms of HF, including the new onset or worsening of baseline shortness of breath, palpitations, cough, fatigue, chest pain, edema, gastroparesis, and perhaps extreme weight loss. Once a physician suspects HF, an ECHO should be obtained immediately.
In addition to the clozapine boxed warning for cardiomyopathy, it would be helpful if the clozapine patient counseling information section had a specific warning that advises patients to contact their clinician if they develop the signs and symptoms of HF.
1. Clozaril [package insert]. Rosemont, PA: HLS Therapeutics (USA), Inc; 2015.
2. Youssef DL, Narayanan P, Gill N. Incidence and risk factors for clozapine-induced myocarditis and cardiomyopathy at a regional mental health service in Australia. Austalas Psychiatry. 2016;24(2):176-180.
3. La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Eng J Med. 2001;345(3):224-225.
4. Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet. 1999;354(9193):1841-1845.
5. Chow V, Yeoh T, Ng AC, et al. Asymptomatic left ventricular dysfunction with long-term clozapine treatment for schizophrenia: a multicenter cross-sectional cohort study. Open Heart 2014;1(1):e000030.
6. Scelsa SN, Simpson DM, McQuistion HL, Fineman A, Ault K, Reichler B. Clozapine-induced myotoxicity in patients with chronic psychotic disorders. Neurology. 1996;47(6):1518-1523.
7. Reznik I, Volchek L, Mester R, et al. Myotoxicity and neurotoxicity during clozapine treatment. Clin Neuropharmacol. 2000;23(5):276-280.
8. Alawami A, Wasywich C, Cicovic A, Kenedi C. A systematic review of clozapine induced cardiomyopathy. Int J Cardiol. 2014;176(2):315-320.
1. Clozaril [package insert]. Rosemont, PA: HLS Therapeutics (USA), Inc; 2015.
2. Youssef DL, Narayanan P, Gill N. Incidence and risk factors for clozapine-induced myocarditis and cardiomyopathy at a regional mental health service in Australia. Austalas Psychiatry. 2016;24(2):176-180.
3. La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Eng J Med. 2001;345(3):224-225.
4. Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet. 1999;354(9193):1841-1845.
5. Chow V, Yeoh T, Ng AC, et al. Asymptomatic left ventricular dysfunction with long-term clozapine treatment for schizophrenia: a multicenter cross-sectional cohort study. Open Heart 2014;1(1):e000030.
6. Scelsa SN, Simpson DM, McQuistion HL, Fineman A, Ault K, Reichler B. Clozapine-induced myotoxicity in patients with chronic psychotic disorders. Neurology. 1996;47(6):1518-1523.
7. Reznik I, Volchek L, Mester R, et al. Myotoxicity and neurotoxicity during clozapine treatment. Clin Neuropharmacol. 2000;23(5):276-280.
8. Alawami A, Wasywich C, Cicovic A, Kenedi C. A systematic review of clozapine induced cardiomyopathy. Int J Cardiol. 2014;176(2):315-320.
Second cancers take greater toll on younger patients
Second cancers take a greater toll on patients under the age of 40, according to research published in JAMA Oncology.
Researchers studied 14 types of cancer occurring in more than 1 million patients.
For nearly all of the cancers studied, 5-year survival rates were much higher if the cancer occurred as a first malignancy rather than a second cancer.
These survival differences were more pronounced in pediatric patients and adolescents and young adults (AYAs) than they were in patients age 40 and older.
Researchers hope these findings will help guide clinicians in providing age-specific recommendations on cancer prevention, screening, treatment, and survivorship, especially among the AYA population.
“Although the increased incidence of second cancers is well known among cancer survivors, less is known about outcomes of these cancers or the influence of age,” said Theresa Keegan, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.
With this in mind, Dr Keegan and her colleagues analyzed data on patients diagnosed with either a single cancer or a first and second malignancy during 1992 through 2008. The researchers used Surveillance, Epidemiology and End Results program data collected from 13 cancer registries.
The team collected data on the 14 most common cancer types that affect AYAs: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), soft tissue sarcoma, and bone sarcoma, as well as female breast, thyroid, testicular, colorectal, central nervous system, cervical, and ovarian cancers.
There were a total of 15,954 pediatric patients (younger than 15 years at diagnosis), 125,750 AYAs (ages 15 to 39), and 878,370 older adult patients (age 40 and older).
Survival rates
For pediatric patients, the 5-year relative survival was 80% for a first cancer and 47% for a second primary malignancy.
For AYAs, the 5-year relative survival was 81% for a first cancer and 60% for a second primary malignancy.
For older adults, the 5-year relative survival was 70% for a first cancer and 61% for a second primary malignancy.
When the researchers looked at 5-year survival by age and individual cancer types, they found striking differences depending on whether it was a first or second malignancy in all but 2 of the 14 cancer types, testicular cancer and melanoma.
“For almost every type of cancer, the AYA population did worse with a secondary cancer,” said study author Melanie Goldfarb, MD, of John Wayne Cancer Institute at Providence Saint John’s Health Center in Santa Monica, California.
“What struck us was that the second cancer caused such an increased risk of death.”
Lymphomas
For pediatric patients with HL, the 5-year relative survival was 95% when patients had HL as a first cancer. There were no data on HL as a second primary malignancy.
For AYAs, the 5-year relative survival was 93% when patients had HL as a first cancer and 72% when they had HL as a second primary malignancy.
For older adults, the 5-year relative survival was 69% when patients had HL as a first cancer and 54% when they had HL as a second primary malignancy.
For pediatric patients with NHL, the 5-year relative survival was 84% when patients had NHL as a first cancer and 63% when they had NHL as a second primary malignancy.
For AYAs, the 5-year relative survival was 64% when patients had NHL as a first cancer and 22% when they had NHL as a second primary malignancy.
For older adults, the 5-year relative survival was 57% when patients had NHL as a first cancer and 54% when they had NHL as a second primary malignancy.
Leukemias
For pediatric patients with ALL, the 5-year relative survival was 87% when patients had ALL as a first cancer and 63% when they had ALL as a second primary malignancy.
For AYAs, the 5-year relative survival was 48% when patients had ALL as a first cancer and 26% when they had ALL as a second primary malignancy.
For older adults, the 5-year relative survival was 17% when patients had ALL as a first cancer and 11% when they had ALL as a second primary malignancy.
For pediatric patients with AML, the 5-year relative survival was 57% when patients had AML as a first cancer and 29% when they had AML as a second primary malignancy.
For AYAs, the 5-year relative survival was 46% when patients had AML as a first cancer and 23% when they had AML as a second primary malignancy.
For older adults, the 5-year relative survival was 12% when patients had AML as a first cancer and 10% when they had AML as a second primary malignancy.
Why younger patients tend to fare worse after a second cancer than older patients is not fully understood or specifically addressed in the current study, the researchers noted.
Now, the team plans to examine how the time between getting a first and second cancer affects survival and whether the type of treatment for the first cancer influences the outcome of a second cancer. 
Second cancers take a greater toll on patients under the age of 40, according to research published in JAMA Oncology.
Researchers studied 14 types of cancer occurring in more than 1 million patients.
For nearly all of the cancers studied, 5-year survival rates were much higher if the cancer occurred as a first malignancy rather than a second cancer.
These survival differences were more pronounced in pediatric patients and adolescents and young adults (AYAs) than they were in patients age 40 and older.
Researchers hope these findings will help guide clinicians in providing age-specific recommendations on cancer prevention, screening, treatment, and survivorship, especially among the AYA population.
“Although the increased incidence of second cancers is well known among cancer survivors, less is known about outcomes of these cancers or the influence of age,” said Theresa Keegan, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.
With this in mind, Dr Keegan and her colleagues analyzed data on patients diagnosed with either a single cancer or a first and second malignancy during 1992 through 2008. The researchers used Surveillance, Epidemiology and End Results program data collected from 13 cancer registries.
The team collected data on the 14 most common cancer types that affect AYAs: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), soft tissue sarcoma, and bone sarcoma, as well as female breast, thyroid, testicular, colorectal, central nervous system, cervical, and ovarian cancers.
There were a total of 15,954 pediatric patients (younger than 15 years at diagnosis), 125,750 AYAs (ages 15 to 39), and 878,370 older adult patients (age 40 and older).
Survival rates
For pediatric patients, the 5-year relative survival was 80% for a first cancer and 47% for a second primary malignancy.
For AYAs, the 5-year relative survival was 81% for a first cancer and 60% for a second primary malignancy.
For older adults, the 5-year relative survival was 70% for a first cancer and 61% for a second primary malignancy.
When the researchers looked at 5-year survival by age and individual cancer types, they found striking differences depending on whether it was a first or second malignancy in all but 2 of the 14 cancer types, testicular cancer and melanoma.
“For almost every type of cancer, the AYA population did worse with a secondary cancer,” said study author Melanie Goldfarb, MD, of John Wayne Cancer Institute at Providence Saint John’s Health Center in Santa Monica, California.
“What struck us was that the second cancer caused such an increased risk of death.”
Lymphomas
For pediatric patients with HL, the 5-year relative survival was 95% when patients had HL as a first cancer. There were no data on HL as a second primary malignancy.
For AYAs, the 5-year relative survival was 93% when patients had HL as a first cancer and 72% when they had HL as a second primary malignancy.
For older adults, the 5-year relative survival was 69% when patients had HL as a first cancer and 54% when they had HL as a second primary malignancy.
For pediatric patients with NHL, the 5-year relative survival was 84% when patients had NHL as a first cancer and 63% when they had NHL as a second primary malignancy.
For AYAs, the 5-year relative survival was 64% when patients had NHL as a first cancer and 22% when they had NHL as a second primary malignancy.
For older adults, the 5-year relative survival was 57% when patients had NHL as a first cancer and 54% when they had NHL as a second primary malignancy.
Leukemias
For pediatric patients with ALL, the 5-year relative survival was 87% when patients had ALL as a first cancer and 63% when they had ALL as a second primary malignancy.
For AYAs, the 5-year relative survival was 48% when patients had ALL as a first cancer and 26% when they had ALL as a second primary malignancy.
For older adults, the 5-year relative survival was 17% when patients had ALL as a first cancer and 11% when they had ALL as a second primary malignancy.
For pediatric patients with AML, the 5-year relative survival was 57% when patients had AML as a first cancer and 29% when they had AML as a second primary malignancy.
For AYAs, the 5-year relative survival was 46% when patients had AML as a first cancer and 23% when they had AML as a second primary malignancy.
For older adults, the 5-year relative survival was 12% when patients had AML as a first cancer and 10% when they had AML as a second primary malignancy.
Why younger patients tend to fare worse after a second cancer than older patients is not fully understood or specifically addressed in the current study, the researchers noted.
Now, the team plans to examine how the time between getting a first and second cancer affects survival and whether the type of treatment for the first cancer influences the outcome of a second cancer.
Second cancers take a greater toll on patients under the age of 40, according to research published in JAMA Oncology.
Researchers studied 14 types of cancer occurring in more than 1 million patients.
For nearly all of the cancers studied, 5-year survival rates were much higher if the cancer occurred as a first malignancy rather than a second cancer.
These survival differences were more pronounced in pediatric patients and adolescents and young adults (AYAs) than they were in patients age 40 and older.
Researchers hope these findings will help guide clinicians in providing age-specific recommendations on cancer prevention, screening, treatment, and survivorship, especially among the AYA population.
“Although the increased incidence of second cancers is well known among cancer survivors, less is known about outcomes of these cancers or the influence of age,” said Theresa Keegan, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.
With this in mind, Dr Keegan and her colleagues analyzed data on patients diagnosed with either a single cancer or a first and second malignancy during 1992 through 2008. The researchers used Surveillance, Epidemiology and End Results program data collected from 13 cancer registries.
The team collected data on the 14 most common cancer types that affect AYAs: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), soft tissue sarcoma, and bone sarcoma, as well as female breast, thyroid, testicular, colorectal, central nervous system, cervical, and ovarian cancers.
There were a total of 15,954 pediatric patients (younger than 15 years at diagnosis), 125,750 AYAs (ages 15 to 39), and 878,370 older adult patients (age 40 and older).
Survival rates
For pediatric patients, the 5-year relative survival was 80% for a first cancer and 47% for a second primary malignancy.
For AYAs, the 5-year relative survival was 81% for a first cancer and 60% for a second primary malignancy.
For older adults, the 5-year relative survival was 70% for a first cancer and 61% for a second primary malignancy.
When the researchers looked at 5-year survival by age and individual cancer types, they found striking differences depending on whether it was a first or second malignancy in all but 2 of the 14 cancer types, testicular cancer and melanoma.
“For almost every type of cancer, the AYA population did worse with a secondary cancer,” said study author Melanie Goldfarb, MD, of John Wayne Cancer Institute at Providence Saint John’s Health Center in Santa Monica, California.
“What struck us was that the second cancer caused such an increased risk of death.”
Lymphomas
For pediatric patients with HL, the 5-year relative survival was 95% when patients had HL as a first cancer. There were no data on HL as a second primary malignancy.
For AYAs, the 5-year relative survival was 93% when patients had HL as a first cancer and 72% when they had HL as a second primary malignancy.
For older adults, the 5-year relative survival was 69% when patients had HL as a first cancer and 54% when they had HL as a second primary malignancy.
For pediatric patients with NHL, the 5-year relative survival was 84% when patients had NHL as a first cancer and 63% when they had NHL as a second primary malignancy.
For AYAs, the 5-year relative survival was 64% when patients had NHL as a first cancer and 22% when they had NHL as a second primary malignancy.
For older adults, the 5-year relative survival was 57% when patients had NHL as a first cancer and 54% when they had NHL as a second primary malignancy.
Leukemias
For pediatric patients with ALL, the 5-year relative survival was 87% when patients had ALL as a first cancer and 63% when they had ALL as a second primary malignancy.
For AYAs, the 5-year relative survival was 48% when patients had ALL as a first cancer and 26% when they had ALL as a second primary malignancy.
For older adults, the 5-year relative survival was 17% when patients had ALL as a first cancer and 11% when they had ALL as a second primary malignancy.
For pediatric patients with AML, the 5-year relative survival was 57% when patients had AML as a first cancer and 29% when they had AML as a second primary malignancy.
For AYAs, the 5-year relative survival was 46% when patients had AML as a first cancer and 23% when they had AML as a second primary malignancy.
For older adults, the 5-year relative survival was 12% when patients had AML as a first cancer and 10% when they had AML as a second primary malignancy.
Why younger patients tend to fare worse after a second cancer than older patients is not fully understood or specifically addressed in the current study, the researchers noted.
Now, the team plans to examine how the time between getting a first and second cancer affects survival and whether the type of treatment for the first cancer influences the outcome of a second cancer.
Cord blood product bests standard UCB transplant
The expanded umbilical cord blood (UCB) product NiCord can provide benefits over standard UCB transplant, according to research published in Biology of Blood and Marrow Transplantation.
NiCord is a stand-alone graft derived from a single UCB unit that has been expanded in culture and enriched with stem and progenitor cells.
The study showed that patients transplanted with NiCord had shorter time to engraftment, a lower risk of infection, and shorter hospital stays than patients who received standard UCB transplants.
On the other hand, there was no significant difference between the transplant groups when it came to grade 2-4 acute graft-versus-host disease (GVHD), relapse, or survival within 100 days of transplant.
“Our results indicate that rapid hematopoietic recovery from Gamida Cell’s NiCord transplantation approach is associated with clinical benefit,” said study author Mitchell Horwitz, MD, of Duke University School of Medicine in Durham, North Carolina.
Dr Horwitz receives research support from Gamida Cell Ltd., makers of NiCord.
Patient characteristics
The researchers compared 18 consecutive NiCord-transplanted patients and 86 consecutive patients who received standard UCB transplants. All of the patients received total body irradiation-based myeloablative conditioning.
In both arms, most patients received a double transplant. In the NiCord arm, 61.1% of patients (n=11) received NiCord along with a second unmanipulated UCB unit. In the standard UCB arm, 95.3% of patients (n=82) received a double UCB transplant.
Patients in the NiCord arm were older than patients in the standard UCB arm, with median ages of 45.5 (range, 42-57) and 37.5 (range, 28-51), respectively.
Most patients in both arms had acute leukemia or myelodysplastic syndromes (about 89%), although roughly 11% had lymphoid malignancies.
There were no significant differences between the arms when it came to patient sex, pre-transplant weight, cytomegalovirus serostatus, and Karnofsky Performance Status.
Results
The median time to neutrophil engraftment was 12.5 days (range, 10-18) in the NiCord arm and 27 days (range, 23-28) in the standard UCB arm (P<0.001).
All of the patients studied had at least 1 infection of any severity. However, patients in the NiCord arm had a significantly lower risk of infection than patients in the standard UCB arm.
In an analysis adjusted for age, disease stage, and grade 2-4 acute GVHD, the risk ratios (RRs) for NiCord versus standard UCB transplant were as follows:
- Total infection—RR=0.72, P=0.03
- Grade 2-3 infection—RR=0.38, P=0.001
- Bacterial infection—RR=0.42, P=0.008
- Grade 2-3 bacterial infection—RR=0.23, P=0.006.
Patients in the NiCord arm spent a mean of 72.4 days out of the hospital in the first 100 days after transplant, compared to 48.6 days for the standard UCB arm (P=0.001).
After the researchers adjusted for age and Karnofsky Performance Status, patients in the NiCord arm had a mean of 20.2 more days out of the hospital than their peers who received standard UCB (P=0.005).
The incidence of grade 2-4 acute GHVD was 55.6% in the NiCord arm and 41.9% in the standard UCB arm (P=0.31). The rate of second transplant was 5.6% and 11.6%, respectively (P=0.68).
The rate of relapse was 0% in the NiCord arm and 7% in the standard UCB arm (P=0.59). And the rate of death was 5.6% and 16.3%, respectively (P=0.46).
The expanded umbilical cord blood (UCB) product NiCord can provide benefits over standard UCB transplant, according to research published in Biology of Blood and Marrow Transplantation.
NiCord is a stand-alone graft derived from a single UCB unit that has been expanded in culture and enriched with stem and progenitor cells.
The study showed that patients transplanted with NiCord had shorter time to engraftment, a lower risk of infection, and shorter hospital stays than patients who received standard UCB transplants.
On the other hand, there was no significant difference between the transplant groups when it came to grade 2-4 acute graft-versus-host disease (GVHD), relapse, or survival within 100 days of transplant.
“Our results indicate that rapid hematopoietic recovery from Gamida Cell’s NiCord transplantation approach is associated with clinical benefit,” said study author Mitchell Horwitz, MD, of Duke University School of Medicine in Durham, North Carolina.
Dr Horwitz receives research support from Gamida Cell Ltd., makers of NiCord.
Patient characteristics
The researchers compared 18 consecutive NiCord-transplanted patients and 86 consecutive patients who received standard UCB transplants. All of the patients received total body irradiation-based myeloablative conditioning.
In both arms, most patients received a double transplant. In the NiCord arm, 61.1% of patients (n=11) received NiCord along with a second unmanipulated UCB unit. In the standard UCB arm, 95.3% of patients (n=82) received a double UCB transplant.
Patients in the NiCord arm were older than patients in the standard UCB arm, with median ages of 45.5 (range, 42-57) and 37.5 (range, 28-51), respectively.
Most patients in both arms had acute leukemia or myelodysplastic syndromes (about 89%), although roughly 11% had lymphoid malignancies.
There were no significant differences between the arms when it came to patient sex, pre-transplant weight, cytomegalovirus serostatus, and Karnofsky Performance Status.
Results
The median time to neutrophil engraftment was 12.5 days (range, 10-18) in the NiCord arm and 27 days (range, 23-28) in the standard UCB arm (P<0.001).
All of the patients studied had at least 1 infection of any severity. However, patients in the NiCord arm had a significantly lower risk of infection than patients in the standard UCB arm.
In an analysis adjusted for age, disease stage, and grade 2-4 acute GVHD, the risk ratios (RRs) for NiCord versus standard UCB transplant were as follows:
- Total infection—RR=0.72, P=0.03
- Grade 2-3 infection—RR=0.38, P=0.001
- Bacterial infection—RR=0.42, P=0.008
- Grade 2-3 bacterial infection—RR=0.23, P=0.006.
Patients in the NiCord arm spent a mean of 72.4 days out of the hospital in the first 100 days after transplant, compared to 48.6 days for the standard UCB arm (P=0.001).
After the researchers adjusted for age and Karnofsky Performance Status, patients in the NiCord arm had a mean of 20.2 more days out of the hospital than their peers who received standard UCB (P=0.005).
The incidence of grade 2-4 acute GHVD was 55.6% in the NiCord arm and 41.9% in the standard UCB arm (P=0.31). The rate of second transplant was 5.6% and 11.6%, respectively (P=0.68).
The rate of relapse was 0% in the NiCord arm and 7% in the standard UCB arm (P=0.59). And the rate of death was 5.6% and 16.3%, respectively (P=0.46).
The expanded umbilical cord blood (UCB) product NiCord can provide benefits over standard UCB transplant, according to research published in Biology of Blood and Marrow Transplantation.
NiCord is a stand-alone graft derived from a single UCB unit that has been expanded in culture and enriched with stem and progenitor cells.
The study showed that patients transplanted with NiCord had shorter time to engraftment, a lower risk of infection, and shorter hospital stays than patients who received standard UCB transplants.
On the other hand, there was no significant difference between the transplant groups when it came to grade 2-4 acute graft-versus-host disease (GVHD), relapse, or survival within 100 days of transplant.
“Our results indicate that rapid hematopoietic recovery from Gamida Cell’s NiCord transplantation approach is associated with clinical benefit,” said study author Mitchell Horwitz, MD, of Duke University School of Medicine in Durham, North Carolina.
Dr Horwitz receives research support from Gamida Cell Ltd., makers of NiCord.
Patient characteristics
The researchers compared 18 consecutive NiCord-transplanted patients and 86 consecutive patients who received standard UCB transplants. All of the patients received total body irradiation-based myeloablative conditioning.
In both arms, most patients received a double transplant. In the NiCord arm, 61.1% of patients (n=11) received NiCord along with a second unmanipulated UCB unit. In the standard UCB arm, 95.3% of patients (n=82) received a double UCB transplant.
Patients in the NiCord arm were older than patients in the standard UCB arm, with median ages of 45.5 (range, 42-57) and 37.5 (range, 28-51), respectively.
Most patients in both arms had acute leukemia or myelodysplastic syndromes (about 89%), although roughly 11% had lymphoid malignancies.
There were no significant differences between the arms when it came to patient sex, pre-transplant weight, cytomegalovirus serostatus, and Karnofsky Performance Status.
Results
The median time to neutrophil engraftment was 12.5 days (range, 10-18) in the NiCord arm and 27 days (range, 23-28) in the standard UCB arm (P<0.001).
All of the patients studied had at least 1 infection of any severity. However, patients in the NiCord arm had a significantly lower risk of infection than patients in the standard UCB arm.
In an analysis adjusted for age, disease stage, and grade 2-4 acute GVHD, the risk ratios (RRs) for NiCord versus standard UCB transplant were as follows:
- Total infection—RR=0.72, P=0.03
- Grade 2-3 infection—RR=0.38, P=0.001
- Bacterial infection—RR=0.42, P=0.008
- Grade 2-3 bacterial infection—RR=0.23, P=0.006.
Patients in the NiCord arm spent a mean of 72.4 days out of the hospital in the first 100 days after transplant, compared to 48.6 days for the standard UCB arm (P=0.001).
After the researchers adjusted for age and Karnofsky Performance Status, patients in the NiCord arm had a mean of 20.2 more days out of the hospital than their peers who received standard UCB (P=0.005).
The incidence of grade 2-4 acute GHVD was 55.6% in the NiCord arm and 41.9% in the standard UCB arm (P=0.31). The rate of second transplant was 5.6% and 11.6%, respectively (P=0.68).
The rate of relapse was 0% in the NiCord arm and 7% in the standard UCB arm (P=0.59). And the rate of death was 5.6% and 16.3%, respectively (P=0.46).